Immunohistochemiocal subtyping using CK20 and CK5 can identify urothelial carcinomas of the upper urinary tract with a poor prognosis - Sikic, Danijel; Keck, Bastian; Wach, Sven; Taubert, Helge; Wullich, Bernd; Goebell, Peter; Kahlmeyer, Andreas; Olbert, Peter; Isfort, Philipp; Nimphius, Wilhelm; Hartmann, Arndt; Giedl, Josef (PLoS ONE, 2017)
Genome-wide analyses revealed basal and luminal subtypes of urothelial carcinomas of the bladder. It is unknown if this subtyping can also be applied to upper tract urothelial carcinomas.Tumor samples from 222 patients with upper tract urothelial carcinomas who were treated with radical nephroureterectomy were analyzed for the expression of seven basal/luminal immunohistochemical markers (CK5, EGFR, CD44, CK20, p63, GATA3, FOXA1).Hierarchical clustering revealed a basal-like subtype (enrichment of CK5, EGFR and CD44) in 23.9% and a luminal-like subtype (enrichment of CK20, GATA3, p63 and FOXA1) in 13.1% of the patients. In 60.8%, little to no markers were expressed, whereas markers of both subtypes were expressed in 2.2%. By using CK5 and CK20 as surrogate markers for the basal and luminal subtypes, we defined four subtypes of upper tract urothelial carcinomas: (i) exclusively CK20 positive and CK5 negative (CK20+/CK5-), (ii) exclusively CK5 positive and CK20 negative (CK20-/ CK5+), (iii) both markers positive (CK20+/CK5+) and (iv) both markers negative (CK20-/CK5-). A receiver-operator analysis provided the optimal cut-off values for this discrimination. An immunoreactive score >1 for CK5 and >6 for CK20 were defined as positive. In multivariate Cox's regression analysis, the CK20+/CK5- subtype was an independent negative prognostic marker with a 3.83-fold increased risk of cancer-specific death (p = 0.02) compared to the other three subtypes.Immunohistochemical subgrouping of upper tract urothelial carcinomas by analyzing CK5 and CK20 expression can be performed in a routine setting and can identify tumors with a significantly worse cancer-specific survival prognosis.
EVALuna2:6876

Immunoscore feasibility study in routine postsurgical pathologic review for early-stage colon cancer (CC) cases risk-assessment - Belaloui, K.; Malifarge, E.; Bohm, J.; Bossard, C.; Dienstmann, R.; Garcia, S.; Geppert, Carol-Immanuel; Gogenur, I.; Hartmann, Arndt; Hatzibougias, D.; Landolfi, S.; Mishaeli, M.; et al. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-02-21

Immunoscore predicts significant differences in time to recurrence in stage I colon cancer patients - Galon, J.; Hermitte, F.; Mlecnik, B.; Marliot, F.; Bifulco, C.; Lugli, A.; Nagtegaal, I.; Hartmann, Arndt; Van Den Eynde, M.; Roehrl, M.; Ohashi, P.; Zavadova, E.; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2020-01-07

Immunotherapy in Genitourinary Cancers: Role of Surgical Pathologist for Detection of Immunooncologic Predictive Factors - Bahlinger, Veronika; Hartmann, Arndt; Eckstein, Markus (Advances in Anatomic Pathology, 2023)
Genitourinary malignancies include a broad spectrum of distinct tumor entities occurring in the kidney, the urinary tract, the prostate, the adrenal glands, the penis, and testicles. Each tumor entity presents with unique biological characteristics, especially in terms of immunobiology. The immune landscape of genitourinary malignancies differs between immunoreactive tumors like urothelial carcinoma or carcinomas of the kidney, for which several immunotherapeutic treatment options have been approved in the past years. In contrast, prostate cancer presents with low immunogenicity and previous trials exploring immune checkpoint inhibitors and other immunotherapeutic agents did not proof substantial survival benefits. In this review, we are presenting a streamlined overview on the role of surgical pathologists within the contemporary practice of immune oncology. It includes current indications for pathologic programmed death-ligand 1 (PD-L1) assessment and important pathologic considerations on PD-L1 testing harmonization including interassay and algorithm variabilities. In addition, we will discuss emerging biomarkers beyond PD-L1 and their potential to predict immunotherapy responses including tumor mutational burden, microsatellite instability, gene expression signatures, and histologic factors.
CRIS-Team Scopus Importer:2023-04-21
Keywords: genitourinary tumors; immunotherapy; microsatellite instability; PD-1; PD-L1; tumor mutational burden

Immunotherapy in urothelial carcinoma from a pathologist's perspective - Erlmeier, Franziska; Steffens, Sandra; Hartmann, Arndt (Aktuelle Urologie, 2017)
Immunotherapy with programmed cell death protein-1 (PD-1) antibodies (pembrolizumab and nivolumab) has been approved in Europe for the first-line treatment of several tumour entities, e. g. malignant melanoma. Following the resounding therapeutic success of these antibodies in different types of tumours, their potential in urological tumours has been investigated in several studies. The approval of the PD-1 antibody nivolumab for the treatment of metastasised renal cell carcinoma has set a new milestone in urooncology. This success continued with the approval of the programmed cell death ligand 1 (PD-L1) atezolizumab for advanced urothelial carcinoma in 2016. In addition, several ongoing clinical trials of other checkpoint inhibitors have also shown promising efficacy in advanced urothelial carcinoma. The decision to treat a patient with immunotherapy is based, among other things, on the immunohistochemical staining and evaluation by a pathologist. However, due to the lack of standardised evaluation protocols and detection systems, it is difficult to compare different studies and evaluate the efficacy of the respective antibodies.
EVALuna2:6866

IMP3 and p16 expression in squamous cell carcinoma of the head and neck: A comparative immunohistochemical analysis - Riener, Marc-Oliver; Hoegel, Josef; Iro, Heinrich; Hartmann, Arndt; Agaimy, Abbas (Oncology Letters, 2017)
Expression of p16 has been established as a good surrogate marker for high-risk human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) patients, and it has been associated with an improved prognosis, irrespective of the actual HPV status. Conversely, the human insulin-like growth factor II mRNA binding protein 3 (IMP3) has been related to aggressiveness in several types of tumors. The aim of the present study was to investigate and compare p16 and IMP3 as markers of favorable and unfavorable behavior, respectively, in head and neck SCC (HNSCC), with particular reference to the HPV status. Both markers were analyzed by immunohistochemical analysis of 156 HNSCC samples originating from the oropharynx (n=81), oral cavity (n=44), larynx (n=15), hypopharynx (n=10) and nasopharynx (n=6). The HPV status was examined in a randomly selected representative subcohort (n=38) using polymerase chain reaction. Of the 156 HNSCC samples, 81 (51.9%) and 54 (34.6%) were positive for IMP3 and p16, respectively. IMP3 expression (P=0.022), p16 expression (P<0.001) and the combination of these markers (P<0.001) were significantly associated with tumor site. In particular, 69/81 (85%) OPSCC samples were positive for either one or both markers compared with 36/75 (48%) SCC samples from other sites. p16 expression was significantly associated with HPV infection (P=0.017) and a trend towards a negative association between IMP3 expression and HPV infection was observed (P=0.053). The results of the present study suggested that IMP3 and p16 are more frequently expressed in OPSCC compared with other HNSCCs. The prognostic impact of IMP3 on OPSCC remains to be investigated in a larger series with an extended follow-up period.
EVALuna2:6894

Impact of age and gender on tumor related prognosis in gastrointestinal stromal tumors (GIST) - Kramer, Klaus; Knippschild, Uwe; Mayer, Benjamin; Boegelspacher, Kira; Spatz, Hanno; Henne-Bruns, Doris; Agaimy, Abbas; Schwab, Matthias; Schmieder, Michael (BMC Cancer, 2015)
Risk classification and prediction of prognosis in GIST is still a matter of debate. Data on the impact of age and gender as potential confounding factors are limited. Therefore we comprehensively investigated age and gender as independent risk factors for GIST.Two independent patient cohorts (cohort I, n = 87 [<50 years]; cohort II, n = 125 [>=50 years]) were extracted from the multicentre Ulmer GIST registry including a total of 659 GIST patients retrospectively collected in 18 collaborative German oncological centers. Based on demographic and clinicopathological parameters and a median follow-up time of 4.3 years (range 0.56; 21.33) disease-specific-survival (DSS), disease-free-survival (DFS) and overall survival (OS) were calculated.GIST patients older than fifty years showed significantly worse DSS compared to younger patients (p = 0.021; HR = 0.307, 95% CI [0.113; 0.834]). DSS was significantly more favorable in younger female GIST patients compared with elderly females (p = 0.008). Female gender resulted again in better prognosis in younger patients (p = 0.033).Patient age (<50 years) and female gender were significantly associated with a more favourable prognosis in GIST. Extended studies are warranted to confirm our clinical results and to elucidate underlying pathophysiological mechanisms.
EVALuna2:6716

Impact of fibroblast growth factor receptor 1 (FGFR1) amplification on the prognosis of breast cancer patients - Erber, Ramona; Rübner, Matthias; Davenport, Simon; Hauke, Sven; Beckmann, Matthias; Hartmann, Arndt; Häberle, Lothar; Gaß, Paul; Press, Michael F.; Fasching, Peter (Breast Cancer Research and Treatment, 2020)
Purpose: Various aberrations in the fibroblast growth factor receptor genes FGFR1, FGFR2, and FGFR3 are found in different cancers, including breast cancer (BC). This study analyzed the impact of FGFR amplification on the BC prognosis. Methods: The study included 894 BC patients. The amplification rates of FGFR1, FGFR2, and FGFR3 were evaluated on tissue microarrays using fluorescence in situ hybridization (FISH). Associations between these parameters and prognosis were analyzed using multivariate Cox regression analyses. Results: FGFR1 FISH was assessable in 503 samples, FGFR2 FISH in 447, and FGFR3 FISH in 562. The FGFR1 amplification rate was 6.6% (n = 33). Increased FGFR2 copy numbers were seen in 0.9% (n = 4); only one patient had FGFR3 amplification (0.2%). Most patients with FGFR1 amplification had luminal B-like tumors (69.7%, n = 23); only 32.6% (n = 153) of patients without FGFR1 amplification had luminal B-like BC. Other patient and tumor characteristics appeared similar between these two groups. Observed outcome differences between BC patients with and without FGFR1 amplification did not achieve statistical significance; however, there was a trend toward poorer distant metastasis-free survival in BC patients with FGFR1 amplification (HR = 2.08; 95% CI 0.98 to 4.39, P = 0.05). Conclusion: FGFR1 amplification occurs most frequently in patients with luminal B-like BC. The study showed a nonsignificant correlation with the prognosis, probably due to the small sample size. Further research is therefore needed to address the role of FGFR1 amplifications in early BC patients. FGFR2 and FGFR3 amplifications are rare in patients with primary BC.
CRIS-Team Scopus Importer:2020-09-04
Keywords: Amplification; Breast cancer; FGFR1; FGFR2; FGFR3; FISH; Prognosis

Impact of postoperative radiotherapy and HER2/new overexpression in salivary duct carcinoma : A monocentric clinicopathologic analysis - Haderlein, Marlen; Scherl, Claudia; Semrau, Sabine; Lettmaier, Sebastian; Hecht, Markus; Erber, Ramona; Iro, Heinrich; Agaimy, Abbas; Fietkau, Rainer (Strahlentherapie und Onkologie, 2017)
Retrospective Investigation of the prognostic relevance of clinicopathologic parameters in patients with salivary duct carcinoma (SDC).An experienced pathologist reviewed 67 patients with de novo SDC or SDC ex pleomorphic adenoma. Paraffin-embedded tumor samples were examined by immunohistochemistry for expression of HER2/neu, androgen (AR), progesterone (PR), estrogen (ER), epidermal growth factor (EGFR) and programmed death ligand 1 (PD-L1-R) receptor. In 45 patients who had cM0 and follow-up data available, survival rates were calculated (Kaplan-Meier method) and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox-regression analysis).Overexpression of HER2/neu, AR, ER, PR, EGFR, PD-L1-R was found in 25.4%, 84%, 0%, 0%, 17.9%, 16.4% of patients. Overall (OS), disease-free (DFS), distant-metastases-free survival (DMFS) and locoregional control (LRC) were 92.3/72.4/56.9%, 78.2/58.1/58.1%, 85.4/65.2/65.2% and 89.7/81.9/81.9% after 1/3/5 years (medial follow-up 26 months). In univariate analysis a positive resection margin (p = 0.008) and no postoperative radiotherapy (p = 0.001) predict an increased locoregional recurrence rate. In multivariate analysis only postoperative radiotherapy is statistically significant (p = 0.004). Presence of lymph node metastases, a lymph node density >4 and HER2/neu overexpression predict decreased DFS and DMFS. In multivariate HER2/neu overexpression was the only significant predictor for reduced DFS (p = 0.04) and DMFS (p = 0.02).Postoperative radiotherapy is the only significant predictor for LRC. HER2/neu receptor expression is an independent prognostic factor for decreased DFS and DMFS in patients with SDC. In addition to radio(chemo)therapy, intensified first-line treatment regimens should also be evaluated in the future.
EVALuna2:6895

Impact of spatially heterogeneous trop‐2 expression on prognosis in oral squamous cell carcinoma - Erber, Ramona; Spoerl, Steffen; Mamilos, Andreas; Krupar, Rosemarie; Hartmann, Arndt; Rübner, Matthias; Taxis, Juergen; Wittenberg, Mareike; Reichert, Torsten E.; Spanier, Gerrit; Spörl, Silvia (International Journal of Molecular Sciences, 2022)
Oral cancer often presents with aggressive behavior and a high risk of recurrence and metastasis. For oral squamous cell carcinoma (OSCC), which is the most frequent histological subtype, therapy strategies include surgery, radiation therapy, chemotherapy, immune checkpoint inhibitors, and EGFR inhibitors. Recently, a Trop‐2 antibody‐drug conjugate (ADC) has been approved in the United States of America for the treatment of advanced triple‐negative breast cancer. However, this ADC has also been tested in other solid tumors including head & neck squamous cell carcinoma. The prognostic impact of Trop‐2 has already been reported for several cancers. We studied the prognostic influence of Trop‐2 protein expression on OSCC patients’ survival. The cohort comprised n = 229 OSCC patients with available archived tumor tissue and corresponding non‐neoplastic oral mucosa tissue. Using immunohistochemistry, we investigated Trop‐2 expression in both the central and peripheral regions of each tumor and in corresponding non‐neoplastic oral mucosa. In patients suffering from OSCC with combined high central and low peripheral Trop‐2 expression, five‐year overall survival (OS) was 41.2%, whereas 55.6% of OSCC patients who presented lower central and/or higher peripheral tumoral Trop‐2 expression were alive after five years (p = 0.075). In multivariate Cox regression, the expression pattern of high central tumoral and lower peripheral Trop‐2 expression was significantly correlated with impaired OS (HR = 1.802, 95%‐CI: 1.134–2.864; p = 0.013) and recurrence‐free survival (RFS) (HR = 1.633, 95%‐CI: 1.042–2.560; p = 0.033), respectively, when adjusting for co‐variables. Hence, Trop‐2 may serve as an independent prognostic biomarker in OSCC. In subsequent studies, the pathophysiological meaning of downregulated Trop‐2 expression in the OSCC periphery has to be analyzed.
CRIS-Team Scopus Importer:2022-01-21
Keywords: Antibody‐drug conjugates; Biomarker; Head and neck cancer; Immunohistochemistry; Oral squamous cell carcinoma; Prognosis; TACSTD2; Trop‐2; Tumor associated calcium signal transducer 2

Impact of the Corona Pandemic on Cervical Cancer Screening Assessment - Stübs, Frederik; Behrens, Annika; Seibold, Anja; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Koch, Martin C.; Mehlhorn, Grit; Beckmann, Matthias; Theuser, Anna Katharin; Schulmeyer, Carla; et al. (In Vivo, 2024)
BACKGROUND/AIM: The global impact of the COVID-19 pandemic resulted in disruptions to healthcare systems throughout the world. The numbers of cytology examinations, human papillomavirus (HPV) tests, and women referred for colposcopy decreased in many countries. There have been no reports on cervical cancer screening in Germany. This study aimed to describe changes in the numbers of colposcopies, cytology examinations, HPV tests, and histological results during the pandemic compared to the pre-pandemic years in order to evaluate the impact of the COVID-19 pandemic on cervical cancer screening. PATIENTS AND METHODS: The numbers of colposcopies, cytology examinations, HPV tests, and histologic results were analyzed retrospectively for the period January 2018 to December 2022. The 2 years period before the pandemic (2018 and 2019) were compared with the 3 years period of the pandemic (2020-2022). RESULTS: In total, 6,518 colposcopies were performed in 5,579 women. The numbers of colposcopies, cytology examinations, and high-risk HPV (hrHPV) tests increased during the pandemic years. The number of biopsies per year taken was stable (range=450-554). The relative numbers of cervical intraepithelial neoplasia (CIN) III/HSIL findings were stable, while the numbers of cervical cancers identified increased slightly from 15 (6.6%) in 2018 to 22 (7.4%) in 2022. CONCLUSION: Increases in numbers of women examined and colposcopies were observed in the years 2021 and 2022 during the pandemic, in comparison to the preceding years. These also led to increases in the figures for cytology, hrHPV, histology, and operations. The onset of the pandemic occurred in the same year as a newly organized screening program started in Germany. The increases might therefore be due to the newly organized screening system.
CRIS-Team Scopus Importer:2024-03-15
Keywords: cervical cancer; cervical cancer screening; cervical dysplasia; COVID-19 pandemic; High-grade squamous intraepithelial lesion (HSIL)

Impaired T-bet-pSTAT1? and perforin-mediated immune responses in the tumoral region of lung adenocarcinoma - Andreev, Katerina; Trufa, Denis; Siegemund, Raphaela; Rieker, Ralf; Hartmann, Arndt; Schmidt, Joachim; Sirbu, Horia; Finotto, Susetta (British Journal of Cancer, 2015)
In spite of modern therapies for non-small-cell lung cancer (NSCLC), prognosis for many patients is still poor and survival rates are low. Immunotherapy is the possibility to improve the lung immune response surrounding the tumour. However, this approach requires detailed understanding of the local immune-responses of NSCLC patients.We analysed samples from three different regions within the lungs of NSCLC patients, whereas we distinguished between patients suffering from adenocarcinoma and squamous cell carcinoma. Expression of type 1 T helper (Th1)/type 1 cytotoxic (Tc1) factors was assessed by quantitative real-time PCR, western blot analyses or immunohistochemistry. Cytotoxic cell activity of CD8(+) T cells was determined via co-culture with autologous tumour cells and apoptosis assay.We found decreased levels of the transcription factor T-box expressed in T cells (T-bet or Tbx21) and of the downstream activated IFN-?-dependent pSTAT1? isoform in the lung tumour areas of patients with NSCLC as compared with tumour-free control regions. In these patients, reduced T-bet and pSTAT1? levels were found associated with increased immunosuppressive markers like cytotoxic T lymphocyte-associated protein 4, programmed cell death 1 and with a suppression of the Th1 cell cytokine production and Tc1 cell activity.These findings confirm a central role of T-bet in targeted immunotherapy for patients with NSCLC.
EVALuna2:6728

Impairment of α-tubulin and F-actin interactions of GJB3 induces aneuploidy in urothelial cells and promotes bladder cancer cell invasion - Liu, Junnan; Wang, Xue; Jiang, Wencheng; Azoitei, Anca; Eiseler, Tim; Eckstein, Markus; Hartmann, Arndt; Stilgenbauer, Stephan; Elati, Mohamed; Hohwieler, Meike; Kleger, Alexander; John, Axel; et al. (Cellular & Molecular Biology Letters, 2024)
Background: We have previously identified an unsuspected role for GJB3 showing that the deficiency of this connexin protein induces aneuploidy in human and murine cells and accelerates cell transformation as well as tumor formation in xenograft models. The molecular mechanisms by which loss of GJB3 leads to aneuploidy and cancer initiation and progression remain unsolved. Methods: GJB3 expression levels were determined by RT-qPCR and Western blot. The consequences of GJB3 knockdown on genome instability were assessed by metaphase chromosome counting, multinucleation of cells, by micronuclei formation and by the determination of spindle orientation. Interactions of GJB3 with α-tubulin and F-actin was analyzed by immunoprecipitation and immunocytochemistry. Consequences of GJB3 deficiency on microtubule and actin dynamics were measured by live cell imaging and fluorescence recovery after photobleaching experiments, respectively. Immunohistochemistry was used to determine GJB3 levels on human and murine bladder cancer tissue sections. Bladder cancer in mice was chemically induced by BBN-treatment. Results: We find that GJB3 is highly expressed in the ureter and bladder epithelium, but it is downregulated in invasive bladder cancer cell lines and during tumor progression in both human and mouse bladder cancer. Downregulation of GJB3 expression leads to aneuploidy and genomic instability in karyotypically stable urothelial cells and experimental modulation of GJB3 levels alters the migration and invasive capacity of bladder cancer cell lines. Importantly, GJB3 interacts both with α-tubulin and F-actin. The impairment of these interactions alters the dynamics of these cytoskeletal components and leads to defective spindle orientation. Conclusion: We conclude that deregulated microtubule and actin dynamics have an impact on proper chromosome separation and tumor cell invasion and migration. Consequently, these observations indicate a possible role for GJB3 in the onset and spreading of bladder cancer and demonstrate a molecular link between enhanced aneuploidy and invasive capacity cancer cells during tumor cell dissemination. Graphical Abstract: (Figure presented.)
CRIS-Team Scopus Importer:2024-07-12
Keywords: Chromosomal imbalance; Invadopodia; Metastasis; MIBC; Spindle orientation

Implementation of double immune checkpoint blockade increases response rate to induction chemotherapy in head and neck cancer - Semrau, Sabine; Gostian, Antoniu Oreste; Traxdorf, Maximilian; Eckstein, Markus; Rutzner, Sandra; von der Grün, Jens; Illmer, Thomas; Hautmann, Matthias; Klautke, Gunther; Laban, Simon; Brunner, Thomas; Tamaskovics, Bálint; et al. (Cancers, 2021)
To determine whether a single dose of double immune checkpoint blockade (induction chemoimmunotherapy (ICIT)) adds benefit to induction single-cycle platinum doublet (induction chemotherapy (IC)) in locally advanced head and neck squamous cell carcinoma (HNSCC), patients treated with cisplatin 30 mg/m2 d1-3 and docetaxel 75 mg/m2 d1 combined with durvalumab 1500 mg fixed dose d5 and tremelimumab 75 mg fixed dose d5 (ICIT) within the CheckRad-CD8 trial were compared with a retrospective cohort receiving the same chemotherapy (IC) without immunotherapy. The endpoint of this analysis was the complete response rate (CR). A total of 53 patients were treated with ICIT and 104 patients with IC only. CR rates were 60.3% for ICIT and 40.3% for IC (p = 0.018). In the total population (n = 157), the most important predictor to achieve a CR was treatment type (OR: 2.21 for ICIT vs. IC; p = 0.038, multivariate analysis). The most diverse effects in CR rates between ICIT and IC were observed in younger (age ≤ 60) patients with HPV-positive OPSCCs (82% vs. 33%, p = 0.176), while there was no difference in older patients without HPV-positive OPSCCs (53% vs. 48%). The analysis provides initial evidence that ICIT could result in higher CR rates than IC. Young patients with HPV-positive OPSCCs may have the greatest benefit from additional immune checkpoint inhibitors.
CRIS-Team Scopus Importer:2021-04-30
Keywords: Combined modality therapy; Double immune checkpoint inhibition; Head and neck neoplasms; HPV-positive OPSCC; Immunotherapy; Induction therapy; Organ preservation

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia - Ries, Jutta; Agaimy, Abbas; Wehrhan, Falk; Baran, Christoph; Bolze, Stella; Danzer, Eva; Frey, Silke; Jantsch, Jonathan; Möst, Tobias; Büttner-Herold, Maike; Wickenhauser, Claudia; Kesting, Marco Rainer; et al. (Biomedicines, 2021)
Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation. Material and Methods: PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined. Results: Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (PE = 0.001; PS = 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP (p = 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP (p = 0.007), but not in its subepithelial layers (p = 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years. Conclusion: Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions.
CRIS-Team WoS Importer:2021-03-19

Improved Bladder Tumor RNA Isolation from Archived Tissues Using Methylene Blue for Normalization, Multiplex RNA Hybridization, Sequencing and Subtyping - Köhler, Stefanie; Brandl, Lisa; Strissel, Pamela; Glossner, Laura; Ekici, Arif Bülent; Angeloni, Miriam; Ferrazzi, Fulvia; Bahlinger, Veronika; Hartmann, Arndt; Beckmann, Matthias; Eckstein, Markus; Strick, Reiner (International Journal of Molecular Sciences, 2022)
Methylene blue (MB) is a dye used for histology with clinical importance and intercalates into nucleic acids. After MB staining of formalin fixed paraffin embedded (FFPE) muscle invasive bladder cancer (MIBC) and normal urothelium, specific regions could be microdissected. It is not known if MB influences RNA used for gene expression studies. Therefore, we analyzed MIBC using five different RNA isolation methods comparing patient matched FFPE and fresh frozen (FF) tissues pre-stained with or without MB. We demonstrate a positive impact of MB on RNA integrity with FF tissues using real time PCR with no interference of its chemical properties. FFPE tissues showed no improvement of RNA integrity, which we propose is due to formalin induced nucleotide crosslinks. Using direct multiplex RNA hybridization the best genes for normalization of MIBC and control tissues were identified from 34 reference genes. In addition, 5SrRNA and 5.8SrRNA were distinctive reference genes detecting <200 bp fragments important for mRNA analyses. Using these normalized RNAs from MB stained MIBC and applying multiplex RNA hybridization and mRNA sequencing, a minimal gene expression panel precisely identified luminal and basal MIBC tumor subtypes, important for diagnosis, prognosis and chemotherapy response.
CRIS-Team WoS Importer:2022-09-30

Improved HER2 Tumor Segmentation with Subtype Balancing Using Deep Generative Networks - Öttl, Mathias; Steenpaß, Jana; Rübner, Matthias; Geppert, Carol-Immanuel; Qiu, Jingna; Wilm, Frauke; Hartmann, Arndt; Beckmann, Matthias; Fasching, Peter; Maier, Andreas; Erber, Ramona; Breininger, Katharina (Proceedings - International Symposium on Biomedical Imaging, 2023)
Tumor segmentation in histopathology images is often complicated by its composition of different histological subtypes and class imbalance. Oversampling subtypes with low prevalence features is not a satisfactory solution since it eventually leads to overfitting. We propose to create synthetic images with semantically-conditioned deep generative networks and to combine subtype-balanced synthetic images with the original dataset to achieve better segmentation performance. We show the suitability of Generative Adversarial Networks (GANs) and especially diffusion models to create realistic images based on subtype-conditioning for the use case of HER2-stained histopathology. Additionally, we show the capability of diffusion models to conditionally inpaint HER2 tumor areas with modified subtypes. Combining the original dataset with the same amount of diffusion-generated images increased the tumor Dice score from 0.833 to 0.854 and almost halved the variance between the HER2 subtype recalls. These results create the basis for more reliable automatic HER2 analysis with lower performance variance between individual HER2 subtypes.
CRIS-Team Scopus Importer:2023-10-06
Keywords: Diffusion Models; Generative Models; HER2; Histopathology; Segmentation; Subtypes

Improving detection of carcinoma in situ in bladder cancer: urinary cytology vs the Xpert® BC Monitor - Haas, Maximilian; Kriegmair, Maximilian C.; Breyer, Johannes; Sikic, Danijel; Wezel, Felix; Roghmann, Florian; Brehmer, Mirco; Wirtz, Ralph M.; Jarczyk, Jonas; Erben, Philipp; Bahlinger, Veronika; Goldschmidt, Franziska; et al. (Bju International, 2024)
Objective: To investigate and compare the performance of urinary cytology and the Xpert BC Monitor test in the detection of bladder cancer in various clinically significant patient cohorts, including patients with carcinoma in situ (CIS), in a prospective multicentre setting, aiming to identify potential applications in clinical practice. Patients and Methods: A total of 756 patients scheduled for transurethral resection of bladder tumour (TURBT) were prospectively screened between July 2018 and December 2020 at six German University Centres. Central urinary cytology and Xpert BC Monitor tests were performed prior to TURBT. The diagnostic performance of urinary cytology and the Xpert BC Monitor was evaluated according to sensitivity (SN), specificity (SC), negative predictive value (NPV) and positive predictive value (PPV). Statistical comparison of urinary cytology and the Xpert BC Monitor was conducted using the McNemar test. Results: Of 756 screened patients, 733 (568 male [78%]; median [interquartile range] age 72 [62–79] years) were included. Bladder cancer was present in 482 patients (65.8%) with 258 (53.5%) high-grade tumours. Overall SN, SC, NPV and PPV were 39%, 93%, 44% and 92% for urinary cytology, and 75%, 69%, 59% and 82% for the Xpert BC Monitor. In patients with CIS (concomitant or solitary), SN, SC, NPV and PPV were 59%, 93%, 87% and 50% for urinary cytology, and 90%, 69%, 95% and 50% for the Xpert BC Monitor. The Xpert BC Monitor missed four tumours (NPV = 98%) in patients with solitary CIS, while potentially avoiding 63.3% of TURBTs in inconclusive or negative cystoscopy and a negative Xpert result. Conclusion: Positive urinary cytology may indicate bladder cancer and should be taken seriously. The Xpert BC Monitor may represent a useful diagnostic tool for correctly identifying patients with solitary CIS and unsuspicious or inconclusive cystoscopy.
CRIS-Team Scopus Importer:2024-05-17
Keywords: bladder cancer; carcinoma in situ; cytology; NMIBC; urine marker; Xpert

Inactivating Mutations of RB1 and TP53 Correlate With Sarcomatous Histomorphology and Metastasis/Recurrence in Gastrointestinal Stromal Tumors - Merten, Larissa; Agaimy, Abbas; Moskalev, Evgeny; Giedl, Josef; Kayser, Claudia; Geddert, Helene; Schaefer, Inga-Marie; Cameron, Silke; Werner, Martin; Stroebel, Philip; Hartmann, Arndt; Haller, Florian (American Journal of Clinical Pathology, 2016)
Loss-of-function mutations in TP53 and CDKN2A have been found at varying frequencies in gastrointestinal stromal tumors (GISTs), while no mutations of RB1 have been reported to date. The aim of the current study was to determine the mutation frequency of TP53, RB1, and CDKN2A in GISTs.A cohort of 83 primary untreated GISTs was analyzed for mutations in TP53, RB1, and CDKN2A by massive parallel sequencing. Tumors with mutations in TP53 and RB1 were analyzed by fluorescence in situ hybridization for the corresponding gene loci.Two GISTs harbored inactivating mutations in RB1, and two other GISTs displayed inactivating mutations in TP53 All four tumors were KIT mutant high-risk tumors with highly cellular sarcomatous histomorphology and variable combinations of plump spindle cells to epithelioid highly atypical cells and high mitotic activity. Three of these patients developed recurrent or metastatic disease, while the fourth patient showed tumor rupture intraoperatively. The combined overall frequency of TP53 and RB1 mutations was 13% considering high-risk or malignant GISTs.TP53 and RB1 mutations seem to be restricted to high-risk/malignant GISTs and occur at an equal although relatively low frequency.
EVALuna2:6897

Incidental finding of a giant asymptomatic right atrial tumor - Strecker, Thomas; Agaimy, Abbas; Zelzer, Peter; Weyand, Michael; Wachter, David Lukas (International Journal of Clinical and Experimental Pathology, 2014)
Primary cardiac tumors are very rare, atrial myxoma being the most common benign tumor of the heart. They may present with a great variety of incidental asymptomatic masses to severe life-threatening cardiovascular complications necessitating emergency surgery. Here we report the diagnostic evaluation and successful surgical resection of such a giant cardiac tumor which was found on a routine medical check-up in a 62-year-old patient. Histology confirmed diagnosis of unusually huge myxoma. This article demonstrates it's necessary to include cardiac tumors in the differential diagnosis of subtle and non-specific cardiothoracic symptoms.
EVALuna2:6611

Incidental papillary fibroelastoma of the tricuspid valve - Strecker, Thomas; Scheuermann, Sabine; Nooh, Ehab; Weyand, Michael; Agaimy, Abbas (Journal of Cardiothoracic Surgery, 2014)
Primary cardiac tumors are very rare, papillary fibroelastoma (PFE) being the second most common benign tumor of the heart in previous series. However, as a consequence of increased imaging examinations, incidental PFE may represent the most common cardiac tumor. Their clinical presentation varies from incidental asymptomatic masses to severe life-threatening cardiovascular complications necessitating emergency surgery. Here we report the diagnostic evaluation and successful surgical resection of such a cardiac tumor in a 67-year-old woman. Histology confirmed diagnosis of a papillary fibroelastoma. This report demonstrates it's necessary to include cardiac tumors in the differential diagnosis of subtle and non-specific cardiothoracic symptoms.
EVALuna2:6684

Increased angiogenesis and FGFR protein expression indicate a favourable prognosis in bladder cancer - Bertz, Simone; Abee, Christine; Schwarz-Furlan, Stephan; Alfer, Joachim; Hofstaedter, Ferdinand; Stoehr, Robert; Hartmann, Arndt; Gaumann, Andreas K. A. (Virchows Archiv, 2014)
Compared to other members of the fibroblast growth factor receptor (FGFR) family, only few studies investigate FGFR3 in tumour angiogenesis. We investigated the connection between angiogenesis and FGF/FGFR expression including FGFR3 mutation status in urothelial carcinomas. Immunohistochemistry was performed in invasive and non-invasive urothelial cancers of 61 patients. Protein expression of CD31, factor VIII (FVIII), FGF-1/2, FGFR1, FGFR3 and FGFR4 and FGFR3 mutation status were evaluated. Morphometric assessment of angiogenesis including microvessel count (MVC) and vascular surface area (VSA) was analysed. Correlation and survival analyses (overall survival (OS) and disease-free survival (DFS)) with univariate and multivariate analyses were performed. CD31 values (MVC and VSA) significantly correlated with OS and DFS. OS and DFS were significantly better in patients with FGFR3 overexpression. Multivariate analysis revealed FGFR3 protein expression and tumour grading (WHO classification 2004) as independent prognostic factors of OS and VSA of CD31 and FGFR3 protein expression of DFS. FGFR3 mutation status was correlated with VSA measured by FVIII. FGFR3 may be able to induce a pro-angiogenic phenotype in urothelial carcinomas and significantly influence prognosis. Consequently, FGFR3 is a potential therapeutic target also from the angiogenesis perspective.
EVALuna2:6661

Increased expression of c-Jun in nonalcoholic fatty liver disease - Dorn, Christoph; Engelmann, Julia C.; Saugspier, Michael; Koch, Andreas; Hartmann, Arndt; Mueller, Martina; Spang, Rainer; Bosserhoff, Anja; Hellerbrand, Claus (Laboratory Investigation, 2014)
Overnutrition is the major cause of nonalcoholic fatty liver disease (NAFLD) and its advanced form nonalcoholic steatohepatitis (NASH). We aimed to develop and characterize a murine model, which resembles both the pathology and nutritional situation, of NASH patients in Western societies. Mice were fed with a NASH-inducing diet (ND) containing sucrose, cholesterol and fats rich in saturated fatty acids in a composition, which mimics Western food. After 12 weeks, ND-fed mice revealed obesity and impaired glucose tolerance. In the liver, ND-feeding led to marked steatosis, hepatocellular damage, inflammation and beginning fibrosis. Transcriptome-wide gene expression analysis and search for over-represented transcription factor target sites among the differentially expressed genes identified activator protein-1 (AP-1) as the most likely factor to cause the transcriptional changes in ND livers. Combining differentially expressed gene and protein-protein interaction network analysis identified c-Jun as hub in the largest connected deregulated sub-network in ND livers. Accordingly, ND livers revealed c-Jun-phosphorylation and nuclear translocation. Moreover, hepatic c-Jun expression was enhanced in ND-fed mice. Combined tissue microarray technology and immunohistochemical analysis confirmed enhanced hepatic c-Jun levels in NAFLD patients, which correlated with inflammation, and notably, with the degree of hepatic steatosis. In summary, our new mouse model shows important pathological changes also found in human NASH and indicates c-Jun/AP-1 activation as critical regulator of hepatic alterations. Abundance of c-Jun in NAFLD likely facilitates development and progression of NASH.
EVALuna2:6603

Increased expression of OLFM4 and lysozyme during necrotizing enterocolitis in neonates: an observational research study - Diez, Sonja; Renner, Marcus; Bahlinger, Veronika; Hartmann, Arndt; Besendörfer, Manuel; Müller, Hanna (BMC Pediatrics, 2022)
Background: In neonatal patients with necrotizing enterocolitis (NEC) the inflammatory response is mediated by a plurality of different proteins. The proteins olfactomedin 4 (OLFM4) and lysozyme (LYZ) are part of the intestinal mucosal defense and especially OLFM4 has rarely been evaluated in neonatal gastrointestinal diseases. The aim of this study was to analyze whether expression levels of both proteins of innate immunity, OLFM4 and lysozyme, were increased during NEC in neonates. Methods: Intestinal tissues of patients with NEC were examined with immunohistochemical staining of formalin-fixed and paraffin-embedded sections of resected tissue using antibodies against OLFM4 and lysozyme. Staining-positive tissues were semi-quantitatively scored from 0 (no staining), 1 (weak staining), 2 (moderate staining) to 3 (highly intense staining) by two individual investigators. Intestinal tissue of infants with volvulus was used as a control as other intestinal tissue without major inflammation was not available. Results: Both applied antibodies against OLFM4 showed different staining patterns with higher staining intensity of the antibody OLFM4 (D1E4M). OLFM4 (median score of the antibody OLFM4 (D1E4M): 3.0) and lysozyme (median score: 3.0) are highly expressed in intestinal and immune cells during NEC. Expression of OLFM4 and lysozyme in the control samples with volvulus was observable but significantly lower (median score of the antibody OLFM4 (D1E4M): 1.25; median score of the antibody against LYZ: 2.0; p = 0.033 and p = 0.037, respectively). Conclusions: Both proteins, OLFM4 and lysozyme, may play a role in the pathogenesis of NEC in neonatal patients, but the exact mechanisms of OLFM4 and lysozyme function and their role in immunological responses have not yet been resolved in detail. These observations add new insights as basis for further large-scale population research.
CRIS-Team Scopus Importer:2022-04-22
Keywords: Inflammation; Lysozyme; Necrotizing enterocolitis; Neonatal gastrointestinal diseases; OLFM4

Increased expression of the immunosuppressive interleukin-35 in patients with non-small cell lung cancer - Heim, Lisanne; Kachler, Katerina; Siegmund, Raphaela; Trufa, Denis; Mittler, Susanne; Geppert, Carol-Immanuel; Friedrich, Juliane; Rieker, Ralf; Sirbu, Horia; Finotto, Susetta (British Journal of Cancer, 2019)
Background: The immunosuppressive role of the cytokine IL-35 in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, we analysed the localisation and regulation of IL-35 in the lung of patients with non-small cell lung cancer (NSCLC) to further elucidate the immune-escape of cancer cells in perioperative course of disease. Methods: Interleukin 35 (IL-35) was measured by ELISA in postoperative serum from 7 patients with NSCLC as well as 8 samples from healthy controls. Immunohistochemistry, FACS analysis, real-time PCR, as well as western blot from samples of the control (CTR), peri-tumoural (PT) and the tumoural (TU) region of the lung derived from patients with NSCLC and 10 controls were performed. Results: Here we found elevated levels of IL-35 in the TU region as well as postoperative serum from patients with lung adenocarcinoma. Consistently, we found an increased expression of IL-35 + Foxp-3 + cells, which associated with ARG1 mRNA expression and decreased TNFA in the TU region of the lung of patients with NSCLC as compared to their CTR region. Furthermore, in the CTR region of the lung of patients with NSCLC, CD68 + macrophages were induced and correlated with IL-35 + cells. Finally, IL-35 positively correlated with TTF-1 + PD-L1 + cells in the TU region of NSCLC patients. Conclusions: Induced IL-35 + Foxp3 + cell numbers in the TU region of the lung of patients with NSCLC associated with ARG1 mRNA expression and with TTF-1 + PD-L1 + cells. In the tumour-free CTR area, IL-35 correlated with CD68 + macrophages. Thus inhibitors to IL-35 would probably succeed in combination with antibodies against immune checkpoints like PD-L1 and PD-1 currently used against NSCLC because they would inhibit immunosuppressive macrophages and T regulatory cells while promoting T cell-mediated anti-tumoural immune responses in the microenvironment as well as the TU region of NSCLC patients.
CRIS-Team Scopus Importer:2019-05-10

Increased expression of the Th17-IL-6R/pSTAT3/BATF/Ror?T-axis in the tumoural region of adenocarcinoma as compared to squamous cell carcinoma of the lung - Balabko, Liubov; Andreev, Katerina; Burmann, Nadine; Schubert, Melanie; Mathews, Martina; Trufa, Denis; Reppert, Sarah; Rau, Tilmann; Schicht, Martin; Sirbu, Horia; Hartmann, Arndt; Finotto, Susetta (Scientific Reports, 2014)
Here we describe increased expression of IL6R in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to squamous cell lung carcinoma. Moreover, here we found increased IL6R in the tumour free part of the lung. By using a murine model of lung adenocarcinoma, we discovered that few lung tumour cells expressed IL-6R and CD4+CD25+Foxp-3+ T regulatory cells down-regulated IL-6R in the tumour bearing lungs. Downstream of IL-6R, the Th17 lineage-specification factors: Signal transducer and activator of transcription 3 (STAT3), Basic leucine zipper transcription factor, BATF and a protein encoded by the RORC in human (RAR-related orphan receptor C) (ROR?T), were also found induced in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to those carrying squamous cell carcinoma. Moreover, pSTAT3 protein was found phosphorylated and auto-phosphorylated in the tumoural region of patients with adeno cell carcinoma of the lung as compared to the tumoural region of patients with squamous cell carcinoma of the lung. Intranasal application of anti-IL-6R antibodies in a murine model of lung adenocarcinoma, induced T regulatory cell markers such as Foxp3, Ctla4, Icos, Il10, Il21, Folr4 and Lag3 and inhibited Rorc in lung adenocarcinoma.
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Increased IgG4-positive plasma cells in nodular-sclerosing Hodgkin lymphoma: a diagnostic pitfall - Nowak, Verena; Agaimy, Abbas; Kristiansen, Glen; Gütgemann, Ines (Histopathology, 2019)
Aims: Despite increasing interest in the recently established immunoglobulin 4-related disease (IgG4-RD), its pathogenesis and aetiology remain largely unclear. Characteristic histopathological features are one of the key elements of diagnosis, including ‘storiform’ fibrosis, obliterative phlebitis, increased lymphoplasmacytic infiltration and increased levels of IgG4 in serum and tissue. Histopathological features of IgG4-RD are striking but not specific, and can pose a pitfall for surgical pathologists. This paper aims to determine the actual amount of IgG4+ plasma cells in nodular-sclerosing Hodgkin lymphoma (NSHL) and its potential to be misdiagnosed in routine clinical practice. Methods and results: IgG4+ plasma cells per high-power field (HPF) and the ratio of IgG4+ versus IgG+ plasma cells (IgG4/IgG ratio) in lymph node biopsies of 24 patients with nodular-sclerosing Hodgkin lymphoma (NSHL) were determined using immunohistochemistry and consensus scoring criteria as used for IgG4-RD. Ten lymph node biopsies with reactive follicular hyperplasia were assessed for comparison. Higher numbers of IgG4+ plasma cells (P < 0.001) were observed in NSHL versus follicular hyperplasia (mean 34 versus 8 per HPF) with a mean IgG4/IgG ratio of 0.38 versus 0.18. Five cases (21%) fulfilled the consensus criteria of IgG4-RD, with >50 IgG4+ plasma cells per HPF and an IgG4/IgG ratio of >0.4. The mean count of IgG4+ plasma cells per HPF in NSHL varied greatly (3–88) with increased numbers of IgG4+ plasma cells seen near areas of fibrosclerosis. Conclusions: Significantly higher levels of IgG4+ plasma cells are common in NSHL, emphasising the need to exclude Reed–Sternberg cells by morphology and immunohistochemistry in biopsies where IgG4-RD is suspected.
CRIS-Team Scopus Importer:2019-12-10
Keywords: Hodgkin lymphoma; IgG4-related disease; IgG4/IgG ratio; nodular-sclerosing Hodgkin lymphoma

Increased Proliferation as Independent Predictor of Disease Recurrence in Initial Stage pTa Urothelial Bladder Cancer - Breyer, Johannes; Shalekenov, Sanzhar; Aziz, Atiqullah; van Rhijn, Bas W. G.; Bruendl, Johannes; Lausenmeyer, Eva; Schaefer, Julius; Denzinger, Stefan; Giedl, Christian; Burger, Maximilian; Hartmann, Arndt; Evert, Matthias; et al. (Bladder Cancer, 2017)
OBJECTIVES: To investigate the predictive impact of the proliferation biomarker Ki-67 on the clinical course of patients with initial stage pTa urothelial carcinoma of the bladder (UCB). METHODS: We retrospectively analyzed all patients treated by transurethral resection of bladder tumors (TUR-B) for UCB between 1992-2004 in a single-center. Disease recurrence (≥pTa UCB) and absent tumor in histopathology, assessed by TUR-B with a non-malignant result for endoscopic suspect bladder lesion displayed endpoints. Immunohistochemical (IHC) analysis of formalin-fixed and paraffin-embedded tissue blocks was performed with an immunostainer using a primary antibody for Ki-67. Semiquantitative evaluation of Ki-67 was performed by three reviewers. Increased proliferation was defined with a cut-off value of ≥50%. Uni- and multivariable binary regression analyses were applied to address prediction of disease recurrence. RESULTS: 215 patients (84% male, median age 69 years at first diagnosis) were evaluable and included to the study. 89 patients stayed disease-free (41%), 126 patients showed recurrence (59%). Recurrence rates of patients with Ki-67 expression <10%, 10-24%, 25-49% and ≥50% were 14.8% vs. 30.8% vs. 63.9% and 80.7%, respectively (p < 0.001). In Kaplan-Meier analysis patients with increased proliferation ≥50% showed a statistically significant worse 10-year recurrence-free survival (19% vs. 57%, p < 0.001). Multivariable regression analysis revealed instillation treatment (p = 0.001) and high proliferation of Ki-67 (p < 0.001) to be independent predictors of recurrence in stage pTa UCB. CONCLUSIONS: High proliferation with Ki-67 expression ≥50% was strongly associated with worse recurrence-free survival in patients with initial stage pTa UCB. Stage pTa UCB patients with increased Ki-67 expression should undergo a strictly follow-up regime comparable to stage pT1 bladder carcinoma, while at least patients with Ki-67 expression <10% might be feasible for more liberate follow-up regime after evaluation of our data in randomized, prospective and multicenter studies.
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Increasing Biomarker Guidance in the Treatment of Urothelial Carcinoma: Systematic Review of International Clinical Trials - Bolenz, Christian; Kunath, Frank; Zengerling, Friedemann; Wezel, Felix; Schmidt, Stefanie; Hartmann, Arndt; Eckstein, Markus (Urologia Internationalis, 2023)
Purpose: Precision oncology requires biomarker testing from tumor tissue for clinical decision-making and selection of targeted therapies. We systematically evaluated the role of tissue biomarker testing within interventional clinical trials for locally advanced and metastatic urothelial carcinoma (UC). Methods: A systematic search within the publicly available ClinicalTrials.gov database was performed for the period 1995 to January 2020. We searched for all interventional studies on systemic treatments for advanced UC. Two investigators independently screened the records and extracted the data for statistical analyses. Results: We included 356 studies out of 827 initial records in the final analysis. The overall number of interventional trials in UC patients significantly increased during the past 25 years. Forty-three studies (12.1%) required specific biomarker testing as a prerequisite for inclusion. Of the remaining 313 trials, explorative biomarkers of interest were studied in 83 studies (23.3%). In trials with obligate biomarker testing as a precondition for study inclusion, only 3 studies (7%) required an actual fresh pretreatment biopsy, while the majority of studies did not state any tissue requirements (55.8%) or accepted archival tissue samples (37.3%). Among studies without biomarker prerequisites, freshly obtained tissue samples were required in 16.3% of studies evaluating immune checkpoint inhibition and 5.7% evaluating targeted therapy. The collection of archival tissue was allowed in 67.4% and 20% of studies evaluating immune checkpoint inhibitors and targeted therapies, respectively. Conclusion: There has been an increase in the number of studies using biomarker-guided interventions for the treatment of advanced UC over the past 25 years. Studies investigating druggable targets in actual UC biopsies immediately before treatment are still rare. Standardized criteria for tissue-based biomarker testing may further accelerate personalized treatment of patients with advanced UC.
CRIS-Team WoS Importer:2023-02-03

Individual dynamics of uterine natural killer cells in natural and stimulated cycles monitored using a new endometrial dating method - Alfer, Joachim; Fattahi, Amir; Bleisinger, Nathalie; Antoniadis, Sophia; Krieg, Jurgen; Dittrich, Ralf; Beckmann, Matthias; Hartmann, Arndt; Popovici, Roxana M.; Tremellen, Kelton (American Journal of Reproductive Immunology, 2022)
Problem It is important to evaluate the dynamics of uterine natural killer (uNK) cells in hormone replacement therapy (HRT) cycles, given their potential role in implantation and the common usage of HRT cycles with in vitro fertilization (IVF). Method of study A total of 132 subfertile patients were evaluated during the secretory phase of either natural ovulation (OV) or HRT cycles, with two biopsies taken on approximately days 5 and 10 after ovulation/progesterone administration in a single menstrual cycle. Immunohistochemical Personal Endometrial Maturation Analysis (PEMA) was used to better quantify secretory-phase endometrial development, in combination with subsequent evaluation of uNK cell density. Results uNK cell density increased rapidly from the early to mid-secretory phase, with mean uNK densities of 113 and 117 per mm(2) in first biopsies and 315 and 387 per mm(2) in second biopsies for OV and HRT cycles, respectively. After reassessment of endometrial development with PEMA, the first and second biopsies in HRT and OV cycles were histologically dated to developmental ranges between days 15-20 (first biopsy) and days 19-25 (second biopsy). Conclusion Subfertile women showed variable endometrial development in PEMA assessment, with uNK cell density correlating with the dating results. Overall, comparable levels of uNK cell density were observed in OV and HRT cycles. Importantly, uNK cell density depends on the histological maturation stage, with similar low coefficients of determination. This observation suggests that aberrant uNK cell results more likely reflect displaced endometrial maturation, rather than an intrinsic anomaly in uNK cell trafficking.
CRIS-Team WoS Importer:2022-09-30

Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer - Hecht, Markus; Eckstein, Markus; Rutzner, Sandra; von der Grün, Jens; Illmer, Thomas; Klautke, Gunther; Laban, Simon; Hautmann, Matthias Günther; Brunner, Thomas B.; Tamaskovics, Bálint; Hinke, Axel; Zhou, Jianguo; et al. (Journal for ImmunoTherapy of Cancer, 2022)
Purpose The first aim of the trial is to study feasibility of combined programmed death protein ligand 1/cytotoxic T-lymphocyte-associated protein 4 inhibition concomitant to radiotherapy. In addition, efficacy of the entire treatment scheme consisting of induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy (RIT) after intratumoral CD8 +immune cell-based patient selection will be analyzed. Methods Patients with stage III-IVB head and neck squamous cell carcinoma were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30 mg/m² days 1-3, docetaxel 75 mg/m² day 1, durvalumab 1500 mg fix dose day 5 and tremelimumab 75 mg fix dose day 5. Patients with increased intratumoral CD8 +immune cell density or pathological complete response (pCR) in the rebiopsy entered RIT up to a total dose of 70 Gy. Patients received further three cycles of durvalumab/tremelimumab followed by eight cycles of durvalumab mono (every 4 weeks). The intended treatment for patients not meeting these criteria was standard radiochemotherapy outside the trial. Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80%. Results Between September 2018 and May 2020, 80 patients were enrolled (one excluded). Out of these, 23 patients had human papilloma virus (HPV)-positive oropharyngeal cancer. Median follow-up was 17.2 months. After induction chemoimmunotherapy 41 patients had pCR and 31 had increased intratumoral CD8 +immune cells. Of 60 patients entering RIT (primary endpoint cohort), 10 experienced imiting toxic (mainly hepatitis) and four discontinued for other reasons, resulting in a feasibility rate of 82%. The RIT cohort (n=60) had a progression-free survival (PFS) rate at one and 2 years of 78% and 72%, respectively, and an overall survival rate at one and 2 years of 90% and 84%, respectively. Patients with HPV-positive oropharyngeal cancers had greater benefit from RIT with a 2-year PFS rate of 94% compared with 64% for HPV-negative oropharyngeal cancers and other locations. In the entire study cohort (n=79) the 2-year PFS rate was 68% (91% for HPV-positive oropharynx vs 59% for others). Toxicity grade 3-4 mainly consisted of dysphagia (53%), leukopenia (52%) and infections (32%). Conclusions The trial met the primary endpoint feasibility of RIT. Induction chemo-immunotherapy followed by chemotherapy-free RIT after intratumoral CD8 +immune cell-based patient selection has promising PFS. Trial registration number The trial was registered with ClinicalTrials.gov (identifier: NCT03426657). The trial was conducted as investigator-sponsored trial (IST).
CRIS-Team Scopus Importer:2022-02-11
Keywords: radioimmunotherapy

Induction of pulmonary HLA-G expression by SARS-CoV-2 infection - Seliger, Barbara; Jasinski-Bergner, Simon; Massa, Chiara; Mueller, Anja; Biehl, Katharina; Yang, Bo; Bachmann, Michael; Jonigk, Danny; Eichhorn, Philip; Hartmann, Arndt; Wickenhauser, Claudia; Bauer, Marcus (Cellular and Molecular Life Sciences, 2022)
The non-classical human leukocyte antigen (HLA)-G exerts immune-suppressive properties modulating both NK and T cell responses. While it is physiologically expressed at the maternal-fetal interface and in immune-privileged organs, HLA-G expression is found in tumors and in virus-infected cells. So far, there exists little information about the role of HLA-G and its interplay with immune cells in biopsies, surgical specimen or autopsy tissues of lung, kidney and/or heart muscle from SARS-CoV-2-infected patients compared to control tissues. Heterogeneous, but higher HLA-G protein expression levels were detected in lung alveolar epithelial cells of SARS-CoV-2-infected patients compared to lung epithelial cells from influenza-infected patients, but not in other organs or lung epithelia from non-viral-infected patients, which was not accompanied by high levels of SARS-CoV-2 nucleocapsid antigen and spike protein, but inversely correlated to the HLA-G-specific miRNA expression. High HLA-G expression levels not only in SARS-CoV-2-, but also in influenza-infected lung tissues were associated with a high frequency of tissue-infiltrating immune cells, but low numbers of CD8(+) cells and an altered expression of hyperactivation and exhaustion markers in the lung epithelia combined with changes in the spatial distribution of macrophages and T cells. Thus, our data provide evidence for an involvement of HLA-G and HLA-G-specific miRNAs in immune escape and as suitable therapeutic targets for the treatment of SARS-CoV-2 infections.
CRIS-Team WoS Importer:2022-11-18

Inflamed benign tumors of the parotid gland: Diagnostic pitfalls from a potentially misleading entity - Mantsopoulos, Konstantinos; Psychogios, Georgios; Agaimy, Abbas; Künzel, Julian; Zenk, Johannes; Iro, Heinrich; Bohr, Christopher (Head and Neck-Journal For the Sciences and Specialties of the Head and Neck, 2015)
The purpose of this study was to evaluate our experience in the diagnostic approach to inflamed benign tumors of the parotid gland at a single tertiary center.A retrospective evaluation was carried out for all patients with signs of inflammation in the parotid gland on the ground of a benign parotid tumor, as confirmed by permanent histology.Sixteen patients were detected for our study. Histopathologic examination confirmed cystadenolymphoma in 11 cases (with metaplastic changes in 2 cases), 2 pleomorphic adenomas, 2 monomorphic adenomas, and 1 oncocytic cystadenoma. Diverse clinical signs (inflammation signs, facial palsy), ultrasound and MRI findings (poorly defined lesion margins), and the presence of squamous metaplastic changes on cytology often raised the suspicion of parotid malignancy or abscess.In most cases, a high suspicion index combined with close monitoring of the patient may allow prompt and successful diagnosis and therapy. © 2014 Wiley Periodicals, Inc. Head Neck 37: 23-29, 2015.
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Inflammatory biomarkers and bladder cancer prognosis: a systematic review - Masson-Lecomte, Alexandra; Rava, Marta; Real, Francisco X.; Hartmann, Arndt; Allory, Yves; Malats, Nuria (European Urology, 2014)
Host immune response has an impact on tumour development and progression. There is interest in the use of inflammatory biomarkers (InfBMs) in cancer care. Although several studies assessing the potential prognostic value of InfBMs in cancer have been published in the past decades, they have had no impact on the management of patients with urothelial bladder carcinoma (UBC).To review and summarise the scientific literature on the prognostic value of tumour, serum, urine, and germline DNA InfBMs on UBC.A systematic review of the literature was performed searching the Medline and Embase databases for original articles published between January 1975 and November 2013. The main inclusion criterion was the provision of a survival analysis (Kaplan-Meier and/or Cox) according to the Reporting Recommendations for Tumor Marker Prognostic Studies guidelines for the assessment of prognostic markers. We focused on markers assessed at least twice in the literature. Findings are reported following Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines.Overall, 34 publications, mostly retrospective, fulfilled the main inclusion criterion. Main limitations of these studies were missing relevant information about design or analysis and heterogeneous methodology used. Inflammatory cells, costimulatory molecules in tumour cells, and serum cytokines showed prognostic significance, mainly in univariable analyses. High C-reactive protein values were consistently reported as an independent prognostic factor for mortality in invasive UBC.There is a dearth of studies on InfBMs in UBC compared with other tumour types. Evidence suggests that InfBMs may have an impact on the management of patients with UBC. Currently, methodological drawbacks of the studies limit the translational potential of results.In this review, we analysed studies evaluating the impact of inflammatory response on bladder cancer progression. Despite methodological limitations, some inflammatory biomarkers should be further analysed because they hold promise to improve patient care.
EVALuna2:6672

Inflammatory leiomyosarcoma shows frequent co-expression of smooth and skeletal muscle markers supporting a primitive myogenic phenotype: a report of 9 cases with a proposal for reclassification as low-grade inflammatory myogenic tumor - Michal, Michael; Rubin, Brian P.; Kazakov, Dmitry V.; Michalová, Květoslava; Šteiner, Petr; Grossmann, Petr; Hájková, Veronika; Martínek, Petr; Švajdler, Marian; Agaimy, Abbas; Hadravský, Ladislav; Kalmykova, Antonina V.; et al. (Virchows Archiv, 2020)
Inflammatory leiomyosarcoma (ILMS) is a very rare soft tissue tumor that usually follows an indolent clinical course, but long-term follow-up studies are lacking. Recent publications primarily focused on its genetic profile characterized by a near haploid genome. One study also showed these tumors to have upregulation of genes known to be crucial for skeletal muscle differentiation. Nevertheless, immunohistochemical expression of skeletal muscle markers, as well as markers that would help to distinguish ILMS from a long list of relevant differential diagnostic entities, has not been extensively studied. Nine cases of ILMS were collected and stained by a broad IHC panel which, besides others, contained MyoD1, myogenin, and PAX-7. A subset of cases was also analyzed by 2 different NGS assays and by MDM2 fluorescence in situ hybridization. Five male and 4 female patients ranged in age from 25 to 54 years (mean, 36 years). The tumors showed a predilection for intramuscular sites of the lower limbs (n = 4) and back (n = 2), whereas the remaining 3 cases affected an unspecified skeletal muscle, lung, and omentum. Follow-up with an average length of 10.6 years (range 0.5–22) was available for 8 patients. The omental tumor spread locally within the abdominal cavity, but the patient has been free of disease 7 years after treatment. None of the 5 patients with somatic soft tissue tumors (and follow-up longer than 1.5 years) had either recurrence or metastasis. Immunohistochemical studies revealed a substantial expression of skeletal muscle markers in almost all cases. This phenotype coupled with a highly characteristic genotype and significantly more indolent clinical behavior as compared with conventional leiomyosarcoma of deep soft tissue offers a strong rationale to change the current nomenclature. Based on the clinicopathological features and gene expression profile, we propose the name low-grade inflammatory myogenic tumor.
CRIS-Team Scopus Importer:2020-03-06
Keywords: Histiocyte-rich rhabdomyoblastic tumor; Inflammatory leiomyosarcoma; Low-grade inflammatory myogenic tumor; MyoD1; Rhabdomyosarcoma; Smooth muscle tumors

Influence of Family History of Breast or Ovarian Cancer on Pathological Complete Response and Long-Term Prognosis in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy - Wunderle, Marius; Häberle, Lothar; Hein, Alexander; Jud, Sebastian; Lux, Michael P.; Hack, Carolin; Emons, Julius; Heindl, Felix; Nabieva, Naiba; Löhberg, Christian; Schulz-Wendtland, Rüdiger; Hartmann, Arndt; et al. (Breast Care, 2020)
Purpose: In breast cancer, a pathological complete response (pCR) has been described as generally resulting in a favorable prognosis. However, there are subgroups, such as patients with a mutation in BRCA1 or BRCA2,in which the effect of pCR on the prognosis is suspected to be weaker. Patients with a family history of breast and/or ovarian cancer may therefore react differently in relation to pCR and prognosis, and this is investigated in this study. Patients and Methods: Breast cancer patients were identified from a clinical breast cancer registry. The study subjects had been treated with neoadjuvant chemotherapy from 2001 to 2018 and their pathological and clinical information as well as medical family history were available. They were considered to have a positive family history if they had at least 1 first-degree relative with breast and/or ovarian cancer. Multivariate logistic regression analyses were performed to study the association between family history, pCR (ypT0; ypN0), and disease-free survival (DFS). Results: Of 1,480 patients, 228 (15.4%) had a positive family history. The pCR rates were 24.9% in all patients, and 24.4% and 27.6% in those without/with a family history, respectively. Family history was not associated with a higher pCR rate (adjusted odds ratio [OR] 1.23; 95% confidence interval [CI] 0.85-1.76; p = 0.27) or a different disease-free survival (DFS; adjusted hazard ratio [HR] 1.15; 95% CI 0.88-1.52; p = 0.30). pCR did not affect the prognosis differently in relation to family history. Conclusions: In this retrospective analysis, family history was not associated with pCR and DFS. pCR improved survival, independently of family history.
CRIS-Team Scopus Importer:2020-07-24
Keywords: Breast cancer; Family history; Neoadjuvant chemotherapy; Ovarian cancer; Pathological complete response; Prognosis

Influence of labor on direct and indirect determinants of placental 11beta-hydroxysteroid dehydrogenase activity - Hübner, Hanna; Heussner, Kirsten; Rübner, Matthias; Schmid, Matthias; Nadal, Jennifer; Wölfle, Joachim; Hartner, Andrea; Menendez-Castro, Carlos; Rauh, Manfred; Beckmann, Matthias; Kehl, Sven; Fahlbusch, Fabian (Archives of Gynecology and Obstetrics, 2020)
Purpose: Labor is a complex process involving multiple para-, auto- and endocrine cascades. The interaction of cortisol, corticotropin-releasing hormone (CRH) and progesterone is essential. The action of cortisol on the human feto-placental unit is regulated by 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2/HSD11B2) that converts cortisol into inactive cortisone. The majority of studies on the assessment of placental 11β-HSD2 function determined indirect activity parameters. It remains elusive if indirect measurements correlate with enzymatic function and if these parameters are affected by potential confounders (e.g., mode of delivery). Thus, we compared determinants of indirect 11β-HSD2 tissue activity with its direct enzymatic turnover rate in placental samples from spontaneous births and cesarean (C)-sections. Methods: Using LC–MS/MS, we determined CRH, cortisol, cortisone, progesterone and 17-hydroxy(OH)-progesterone in human term placentas (spontaneous birth vs. C-section, n = 5 each) and measured the enzymatic glucocorticoid conversion rates in placental microsomes. Expression of HSD11B1, 2 and CRH was determined via qRT-PCR in the same samples. Results: Cortisol–cortisone ratio correlated with direct microsomal enzymatic turnover. While this observation seemed independent of sampling site, a strong influence of mode of delivery on tissue steroids was observed. The mRNA expression of HSD11B2 correlated with indirect and direct cortisol turnover rates in C-section placentas only. In contrast to C-sections, CRH, cortisol and cortisone levels were significantly increased in placental samples following spontaneous birth. Conclusion: Labor involves a series of complex hormonal processes including activation of placental CRH and glucocorticoid metabolism. This has to be taken into account when selecting human cohorts for comparative analysis of placental steroids.
CRIS-Team Scopus Importer:2020-09-11
Keywords: 11beta-hydroxysteroid dehydrogenase; CRH; LC–MS/MS; Mode of delivery; Placenta

Influence of low FODMAP and gluten-free diets on disease activity and intestinal microbiota in patients with non-celiac gluten sensitivity - Dieterich, Walburga; Schuppan, Detlef; Schink, Monic; Schwappacher, Raphaela; Wirtz, Stefan; Agaimy, Abbas; Neurath, Markus; Zopf, Yurdagül (Clinical Nutrition, 2019)
Background & aims: Non-celiac gluten sensitivity (NCGS) is characterized by intestinal and extra intestinal symptoms triggered by ingestion of gluten. However, non-gluten triggers have recently been implicated, and a FODMAP (fermentable oligo-, di-, monosaccharides and polyols)-reduced diet can partially improve symptoms in NCGS. Our aim was to analyze the effect of a low FODMAP versus a gluten-free diet (GFD) on clinical symptoms, psychological well-being, intestinal inflammation and integrity, and stool microbiota.
CRIS-Team WoS Importer:2019-05-21

Influence of p16 status on indication and outcome of salvage neck dissection in oropharyngeal cancer - Müller, Sarina Katrin; Mantsopoulos, Konstantinos; Semrau, Sabine; Agaimy, Abbas; Eckstein, Markus; Traxdorf, Maximilian; Gostian, Antoniu Oreste; Goncalves, Miguel; Sievert, Matti; Haderlein, Marlen; Grundtner, Philipp; Hecht, Markus; et al. (Acta Oto-Laryngologica, 2020)
Background: Human papillomavirus (HPV)+ and HPV– oropharyngeal squamous cell carcinomas (OPSCC) are separate tumor entities. Aims/Objectives: The aim of this study was to examine if the p16 status influences the need and outcome of a salvage neck dissection (SND) after primary radiochemotherapy (pRCT). Material and methods: Retrospective study of 164 patients (n = 108 p16–, n = 56 p16+) who underwent pRCT for OPSCC between 2009 and 2016. HPV status was defined via p16 immunohistochemical staining. Clinical nodal status was assessed using ultrasound and computed tomography of the neck with contrast. Results: Of the 56 p16+ patients, 17 (30.4%) patients were given an indication for a SND after pRCT with 4 (23.5%) patients showing persistent malignant nodes. Of the 108 p16– patients, 24 (22.2%) patients underwent a SND with 8 (33.3%) patients showing persistent malignant nodes. There was no significant association of the p16 status and neither the indication for SND (p(Chi2(two-sided)-Test) = 0.25, ϕ = 0.34) nor the occurrence of positive nodes (p(Chi2(two-sided)-Test) = 0.74, ϕ = 0.50). The probability for persistence of the ypN + nodal status independent of HPV-status was 29.2%(12/41). Conclusions and significance: There was neither a significant association between the p16 status and the indication for a SND nor for persistent malignant nodal disease after pRCT.
CRIS-Team Scopus Importer:2020-11-06
Keywords: de-escalation; HPV; Oropharyngeal cancer; p16; radiochemotherapy

Influence of the Family Anamnesis of Breast or Ovarian Cancer on the pathological Complete Remission and the Prognosis in Patients with Breast Cancer after neoadjuvant Chemotherapy - Gaß, Paul; Haberle, L.; Hein, Alexander; Jud, Sebastian; Lux, M. P.; Hack, Caroline; Emons, J.; Heindl, Felix; Nabieva, Naiba; Löhberg, Christian; Schulz-Wendtland, Rüdiger; Hartmann, Arndt; et al. (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Inhibition of integrin αvβ6 sparks T-cell antitumor response and enhances immune checkpoint blockade therapy in colorectal cancer - Busenhart, Philipp; Montalban-Arques, Ana; Katkeviciute, Egle; Morsy, Yasser; Van Passen, Chiara; Hering, Larissa; Atrott, Kirstin; Lang, Silvia; Garzon, Jesus Francisco Glaus; Naschberger, Elisabeth; Hartmann, Arndt; Rogler, Gerhard; et al. (Journal for ImmunoTherapy of Cancer, 2022)
Background Integrin αvβ6 is a heterodimeric cell surface protein whose cellular expression is determined by the availability of the integrin β6 subunit (ITGB6). It is expressed at very low levels in most organs during tissue homeostasis but shows highly upregulated expression during the process of tumorigenesis in many cancers of epithelial origin. Notably, enhanced expression of integrin αvβ6 is associated with aggressive disease and poor prognosis in numerous carcinoma entities. Integrin αvβ6 is one of the major physiological activators of transforming growth factor-β (TGF-β), which has been shown to inhibit the antitumor T-cell response and cause resistance to immunotherapy in mouse models of colorectal and mammary cancer. In this study, we investigated the effect of ITGB6 expression and antibody-mediated integrin αvβ6 inhibition on the tumor immune response in colorectal cancer. Methods Using orthotopic and heterotopic tumor cell injection, we assessed the effect of ITGB6 on tumor growth and tumor immune response in wild type mice, mice with defective TGF-β signaling, and mice treated with anti-integrin αvβ6 antibodies. To examine the effect of ITGB6 in human colorectal cancer, we analyzed RNAseq data from the colon adenocarcinoma dataset of The Cancer Genome Atlas (TCGA-COAD). Results We demonstrate that expression of ITGB6 is an immune evasion strategy in colorectal cancer, causing inhibition of the antitumor immune response and resistance to immune checkpoint blockade therapy by activating latent TGF-β. Antibody-mediated inhibition of integrin αvβ6 sparked a potent cytotoxic T-cell response and overcame resistance to programmed cell death protein 1 (PD-1) blockade therapy in ITGB6 expressing tumors, provoking a drastic increase in anti-PD-1 treatment efficacy. Further, we show that the majority of tumors in patients with colorectal cancer express sufficient ITGB6 to provoke inhibition of the cytotoxic T-cell response, indicating that most patients could benefit from integrin αvβ6 blockade therapy. Conclusions These findings propose inhibition of integrin αvβ6 as a promising new therapy for colorectal cancer, which blocks tumor-promoting TGF-β activation, prevents tumor exclusion of cytotoxic T-cells and enhances the efficacy of immune checkpoint blockade therapy.
CRIS-Team Scopus Importer:2022-02-25
Keywords: CD8-positive T-lymphocytes; cytotoxicity; drug evaluation; immunologic; immunotherapy; preclinical; tumor microenvironment

Initial clinical results with a fusion prototype for mammography and three-dimensional ultrasound with a standard mammography system and a standard ultrasound probe - Emons, Julius; Wunderle, Marius; Hartmann, Arndt; Radicke, Marcus; Rauh, Claudia; Uder, Michael; Gaß, Paul; Fasching, Peter; Langemann, Hanna; Beckmann, Matthias; Schulz-Wendtland, Rüdiger; Jud, Sebastian (Acta Radiologica, 2018)
BACKGROUND: Combinations *Equal contributors. of different imaging techniques in fusion devices appear to be associated with improvements in diagnostic assessment. PURPOSE: The aim of this study was to test the feasibility of using an automated standard three-dimensional (3D) ultrasound (US) device fused with standard mammography for the first time in breast cancer patients. MATERIAL AND METHODS: Digital mammograms and 3D automated US images were obtained in 23 patients with highly suspicious breast lesions. A recently developed fusion machine consisting of an ABVS 3D US transducer from an Acuson S2000 machine and a conventional Mammomat Inspiration device (both Siemens Healthcare GmbH, Erlangen, Germany) were used for the purpose. The feasibility of the examinations, imaging coverage, and patients' experience of the procedure were examined. RESULTS: In 15 out of 19 patients, the region of interest (ROI) with the tumor marked in the mammogram was visible on US. The examination was experienced positively by the patients, with no unexpected pain or injury. The examination was time-saving and well tolerated. CONCLUSION: In conclusion, we have shown initial clinical feasibility of an US/radiography fusion prototype with good localization and evaluation of the ROIs. The combined examination was well tolerated. The simultaneous evaluation with mammography and US imaging may be able to improve detection and reduce examiner-related variability.
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In Reply: Colonic-Type Adenocarcinoma of the Tongue and Oral Cavity (CATOC) - Agaimy, Abbas (Head and Neck Pathology, 2018)
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In-situ analysis of mast cells and dendritic cells in coronary atherosclerosis in chronic kidney disease (CKD) - Wachter, David; Neureiter, D.; Campean, Valentina; Hilgers, Karl Friedrich; Buettner-Herold, M.; Daniel, Christoph; Benz, Kerstin; Amann, Kerstin Ute (Histology and Histopathology, 2018)
AIMS: Mast cells (MC) and dendritic cells (DC) have immune modulatory function and can influence T-cell activity. Both cell types have been found in atherosclerotic plaques and are thought to play an important role for plaque stability. Compared to matched segments of the non-renal population, patients with chronic kidney disease (CKD) show a more pronounced and more aggressive course of atherosclerosis with higher plaque calcification and significantly higher complications rates. It was the aim of this study to analyze the number and localization of MCs and DCs, macrophages, T- and B-cells as well as the expression of markers of inflammation such as CRP and NFκB in calcified and non-calcified atherosclerotic plaques of patients with CKD and control patients. METHODS: Fifty coronary atherosclerotic plaques from patients with endstage CKD (CKD, n=25) and control (n=25) patients were categorized according to the Stary classification and investigated using immunohistochemistry (markers for MC, DC, T, B, macrophage and NFκB). Expression was analyzed separately for the complete plaque area as well as for the different plaque subregions and correlations were analyzed. RESULTS: We found only very few DCs and MCs per lesion area with slightly increased numbers in calcified plaques. MCs per plaque area were significantly more frequent in CKD than in control patients and this was independent of plaque calcification. MCs were most frequently found in the shoulder and basis of the plaque. DCs per plaque area were significantly less in calcified plaques of CKD compared to control patients. In control, but not in CKD patients, DCs were significantly more frequent in calcified than in non-calcified plaques. Within the plaques DCs were similarly distributed between all 4 subregions. CONCLUSIONS: Coronary atherosclerotic plaques of CKD patients showed a significantly higher number of MCs whereas DCs were less frequent compared to control patients particularly if plaques were calcified. These findings might indicate a potential proinflammatory role of MCs, but not of DCs in atherosclerotic lesions of CKD patients, adding another characteristic of advanced atherosclerosis in these patients.
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In stage pT1 non-muscle-invasive bladder cancer (NMIBC), high KRT20 and low KRT5 mRNA expression identify the luminal subtype and predict recurrence and survival - Breyer, Johannes; Wirtz, Ralph M.; Otto, Wolfgang; Erben, Philipp; Kriegmair, Maximilian C.; Stoehr, Robert; Eckstein, Markus; Eidt, Sebastian; Denzinger, Stefan; Burger, Maximilian; Hartmann, Arndt (Virchows Archiv, 2017)
Differential expression of cytokeratins (CK) is a characteristic feature of chemoresistant luminal (KRT20) and chemosensitive intrinsic aggressive basal (KRT5) subtypes in muscle-invasive bladder cancer (MIBC). We investigated mRNA expression of KRT5 and KRT20 and its predictive value in stage pT1 bladder cancer. In retrospective analysis of clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder, a single-step RT-qPCR was used to measure mRNA expression. Furthermore, immunohistochemical (IHC) staining of CK20, panCK, and MIB1 was performed. Valid measurements were obtained from 231 samples out of a series of 284 patients. Spearman correlation revealed significant associations between mRNA and protein expression of KRT20/CK20 (? 0.6096, p < 0.0001) and MKI67/MIB1 (? 0.5467, p < 0.0001). A positive correlation was found between MKI67 and KRT20 expression (? 0.3492, p < 0.0001), while MKI67 and KRT5 were negatively correlated (? -0.1693, p = 0.01). High KRT20 expression (>=40.26) was significantly associated with worse recurrence free survival (RFS) (p = 0.001), progression-free survival (PFS) (p = 0.0003), and cancer specific survival (CSS) (p = 0.0414). The combination of high KRT20 expression and low KRT5 expression (<36.83) was associated with unfavorable RFS (p = 0.0038) and PFS (p = 0.0003) and proved to be the only independent predictor for RFS (p = 0.0055) and PFS (p = 0.0023) in multivariate analysis. KRT20 mRNA determination was superior to CK20 protein estimation with regard to RFS and PFS prediction. KRT20 and KRT5 mRNA quantification can predict recurrence and progression of stage pT1 NMIBC reflecting basal and luminal subtypes of MIBC and is superior to CK20 protein expression determined by IHC.
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Insufficient Angiogenesis: Cause of Abnormally Thin Endometrium in Subfertile Patients? - Alfer, Joachim; Happel, Lars; Dittrich, Ralf; Beckmann, Matthias; Hartmann, Arndt; Gaumann, Andreas; Buck, Volker U.; Classen-Linke, Irmgard (Geburtshilfe und Frauenheilkunde, 2017)
This study investigated subfertile patients with abnormally thin endometrium after infertility treatment. As they had adequate serum concentrations of hormones, an endometrial factor for subfertility was suspected.To elucidate the cause of subfertility, endometrial biopsies were taken in each patient in the late proliferative and mid-secretory phases of one menstrual cycle. Endometrial biopsies from women with normal menstrual cycles and confirmed fertility who were undergoing hysterectomy for benign uterine disease were used as positive controls. The tissue samples were investigated for steroid hormone receptor expression and for the proliferation marker Ki-67. Immunohistochemistry was performed with antibodies against the marker molecules for endometrial receptivity - ? 3 integrin, VEGF, LIF, and CD56 (large granular lymphocytes, LGLs).The steroid hormone receptors for estrogen (E2) and progesterone (P) were expressed normally (at the first biopsy) and were down-regulated (at the second biopsy) within the cycle. Strikingly, all of the marker molecules investigated showed negative or weak and inadequate expression in the mid-secretory phase. Numbers of LGLs remained as low as in the proliferative phase. In contrast, fertile patients were found to express these marker molecules distinctly in the mid-secretory phase.It may be hypothesized that a severe deficiency of these angiogenesis-related marker molecules leads to defective development of the endometrium, which remains thin. Deficient angiogenetic development may thus provide an explanation for the endometrial factor that causes infertility. Further investigations will need to focus on identifying the regulating factors that act between steroid receptor activation and the expression of these marker molecules.
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Integrated Analysis of PTEN and p4EBP1 Protein Expression as Predictors for pCR in HER2-Positive Breast Cancer - Loibl, Sibylle; Darb-Esfahani, Silvia; Huober, Jens; Klimowicz, Alexander; Furlanetto, Jenny; Lederer, Bianca; Hartmann, Arndt; Eidtmann, Holger; Pfitzner, Berit; Fasching, Peter; Tiemann, Katharina; Jackisch, Christian; et al. (Clinical Cancer Research, 2016)
The PI3K/AKT pathway and phosphatase and tensin homolog (PTEN) aberrations are common in breast cancer. We investigated the correlation between phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), PTEN, p4EBP1 (phosphorylated E4 binding protein 1), and pathologic complete response (pCR) in patients receiving neoadjuvant therapy.We retrospectively evaluated PIK3CA, PTEN, and p4EBP1 protein expression in centrally HER2-positive patients (n = 181) who received epirubicin cyclophosphamide/trastuzumab followed by docetaxel/trastuzumab alone or concomitant/followed by capecitabine within the GeparQuattro study. PTEN was assessed using the automated quantitative immunofluorescence analysis and was analyzed as a dichotomic variable. p4EBP1 was assessed by immunohistochemistry and used as a continuous and dichotomic variable.p4EBP1 was available from 137, PTEN from 108, and PIK3CA genotype from 83 patients. Overall, the pCR rate in PTEN-low tumors was 27.6%, and in PTEN-high tumors, it was 57.1% (P = 0.010). pCR rates were not statistically different between PIK3CA wild-type and mutant (35% vs. 22%) or p4EBP1 IRS <= 4 and IRS > 4 (39% vs. 33%). pCR rate was 57.1% (8/14) in PTEN-high/PIK3CA wild-type and decreased to 15.4% in PTEN-low/PIK3CA-mutant tumors (P = 0.023). In multivariable analysis adjusted for baseline parameters, PTEN independently predicted pCR in the following cohorts: overall [OR, 7.54; 95% confidence interval (CI), 2.03-28.06; P = 0.003], PIK3CA wild-type (OR, 23.81; 95% CI, 1.75-324.05; P = 0.017), p4EBP1 IRS > 4 (OR, 11.53; 95% CI, 1.84-72.24; P = 0.009), and hormone receptor-positive (OR, 40.91; 95% CI, 2.93-570.44; P = 0.006). p4EBP1 was independently predictive for pCR in PIK3CA wild-type tumors (OR, 0.14; 95% CI, 0.03-0.78; P = 0.025).The study showed the potential role of PIK3CA genotype, PTEN, and p4EBP in predicting pCR after anthracycline-taxane-based chemotherapy and anti-HER2 treatment. Clin Cancer Res; 22(11); 2675-83. ©2016 AACR.
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Integrating Genomics and Clinical Data for Statistical Analysis by Using GEnome MINIng (GEMINI) and Fast Healthcare Interoperability Resources (FHIR): System Design and Implementation - Gründner, Julian; Wolf, Nicolas; Tögel, Lars; Haller, Florian; Prokosch, Hans-Ulrich; Christoph, Jan (Journal of Medical Internet Research, 2020)
Background: The introduction of next-generation sequencing (NGS) into molecular cancer diagnostics has led to an increase in the data available for the identification and evaluation of driver mutations and for defining personalized cancer treatment regimens. The meaningful combination of omics data, ie, pathogenic gene variants and alterations with other patient data, to understand the full picture of malignancy has been challenging.
CRIS-Team WoS Importer:2020-12-11

Integration of spatial pd-l1 expression with the tumor immune microenvironment outperforms standard pd-l1 scoring in outcome prediction of urothelial cancer patients - Weyerer, Veronika; Strissel, Pamela; Strick, Reiner; Sikic, Danijel; Geppert, Carol-Immanuel; Bertz, Simone; Lange, Fabienne; Taubert, Helge; Wach, Sven; Breyer, Johannes; Bolenz, Christian; Erben, Philipp; et al. (Cancers, 2021)
Background: Immune therapy has gained significant importance in managing urothelial cancer. The value of PD-L1 remains a matter of controversy, thus requiring an in-depth analysis of its biological and clinical relevance. Methods: A total of 193 tumors of muscle-invasive bladder cancer patients (MIBC) were assessed with four PD-L1 assays. PD-L1 scoring results were correlated with data from a comprehensive digital-spatial immune-profiling panel using descriptive statistics, hierarchical clustering and uni-/multivariable survival analyses. Results: PD-L1 scoring algorithms are heterogeneous (agreements from 63.1% to 87.7%), and stems from different constellations of immune and tumor cells (IC/TC). While Ventana IC5% algorithm identifies tumors with high inflammation and favorable baseline prognosis, CPS10 and the TCarea25%/ICarea25% algorithm identify tumors with TC and IC expression. Spatially organized immune phenotypes, which correlate either with high PD-L1 IC expression and favorable prognosis or constitutive PD-L1 TC expression and poor baseline prognosis, cannot be resolved properly by PD-L1 algorithms. PD-L1 negative tumors with relevant immune infiltration can be detected by sTILs scoring on HE slides and digital CD8+ scoring. Conclusions: Contemporary PD-L1 scoring algorithms are not sufficient to resolve spatially distributed MIBC immune phenotypes and their clinical implications. A more comprehensive view of immune phenotypes along with the integration of spatial PD-L1 expression on IC and TC is necessary in order to stratify patients for ICI.
CRIS-Team Scopus Importer:2021-05-21
Keywords: Bladder cancer; Immune phenotypes; PD-1; PD-L1; TILs; Urothelial cancer

Interictal magnetoencephalography used in magnetic resonance imaging-negative patients with epilepsy - Wu, Xueqing; Rampp, Stefan; Buchfelder, Michael; Kuwert, Torsten; Blümcke, Ingmar; Zhou, D.; Stefan, Herrmann; Dörfler, Arnd (Acta Neurologica Scandinavica, 2013)
Purpose: This study aims to investigate the contributions of magnetoencephalography (MEG) in magnetic resonance imaging (MRI)-negative patients. Methods: A total of 18 MRI-negative patients diagnosed with refractory epilepsy, subjected to MEG investigation, and subsequently underwent surgery were selected for retrospective analysis. A 1.5-tesla Magnetom Sonata with an eight-channel head array coil was used. MEG data were obtained using a 74/248-channel system. Results: A total of 16 patients (16/18) had positive MEG results, comprising 12 patients with monofocal localizations, five with multifocal localizations, and one with unremarkable results in MEG. In addition, 12 patients had indicative single photon-emission computed tomography (SPECT), five had indicative fluorodeoxyglucose positron emission tomography (FDG-PET), and all the patients had intracranial electroencephalography (EEG) (14 with subdural electrodes and four with electrocorticography). The intracranial EEG recordings of nine patients were guided by MEG informative results. Among these 18 patients, 10 exhibited good postoperative outcomes (Engel I and II), four of which were completely seizure-free. All these ten patients had clear monofocal localization in MEG, including nine with accordant indicative metabolic changes in either SPECT or FDG-PET, or both. None of the five patients with multifocal localizations achieved good postoperative outcomes. Conclusion: For cases with negative MRI findings, epilepsy surgery may be an alternative option for pharmaco-resistant patients if epileptogenic focus localizations by MEG are present in multimodal evaluation. © 2012 John Wiley & Sons A/S.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Magnetic resonance imaging; Magnetoencephalography; Non-lesional epilepsy; Outcome

Interleukin-10-regulated tumour tolerance in non-small cell lung cancer - Vahl, Julius Malte; Friedrich, Juliane; Mittler, Susanne; Trump, Sonja; Heim, Lisanne; Kachler, Katerina; Balabko, Liubov; Fuhrich, Nicole; Geppert, Carol-Immanuel; Trufa, Denis; Sopel, Nina; Rieker, Ralf; et al. (British Journal of Cancer, 2017)
Lung cancer is the most life-threatening cancer type worldwide. Treatment options include surgery, radio- and chemotherapy, as well as the use of immunomodulatory antibodies. Interleukin (IL)-10 is an immunosuppressive cytokine involved in tumour immune escape.Immunohistochemistry (IHC) on human lung surgery tissue as well as human tumour cell line cultures, FACS analysis, real-time PCR and experimental lung cancer.Here we discovered a positive correlation between IL-10 and IL-10 receptor (IL-10R) expression in the lung with tumour diameter in patients with lung cancer (non-small cell lung cancer), the most life-threatening cancer type worldwide. IL-10 and IL-10R were found induced in cells surrounding the lung tumour cells, and IL-10R was mainly expressed on the surface of Foxp-3(+) T-regulatory lymphocytes infiltrating the tumour of these patients where its expression inversely correlated with programmed cell death 1. These findings were confirmed in translational studies. In a human lung adenocarcinoma cell line, IL-10R was found induced under metabolic restrictions present during tumour growth, whereby IL-10 inhibited PDL1 and tumour cell apoptosis.These new findings suggest that IL-10 counteracts IFN-? effects on PD1/PDL1 pathway, resulting in possible resistance of the tumour to anti-PD1/PDL1 immunotherapy.British Journal of Cancer advance online publication 10 October 2017 doi:10.1038/bjc.2017.336 www.bjcancer.com.
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International Opinions on Grading of Urothelial Carcinoma: A Survey Among European Association of Urology and International Society of Urological Pathology Members - Beijert, Irene J.; Cheng, Liang; Liedberg, Fredrik; Plass, Karin; Williamson, Sean R.; Gontero, Paolo; Ribal, Maria J.; Babjuk, Marko; Black, Peter C.; Kamat, Ashish M.; Algaba, Ferran; Berman, David M.; et al. (European Urology Open Science, 2023)
Background: Grade of non–muscle-invasive bladder cancer (NMIBC) is an important prognostic factor for progression. Currently, two World Health Organization (WHO) classification systems (WHO1973, categories: grade 1–3, and WHO2004 categories: papillary urothelial neoplasm of low malignant potential [PUNLMP], low-grade [LG], high-grade [HG] carcinoma) are used. Objective: To ask the European Association of Urology (EAU) and International Society of Urological Pathology (ISUP) members regarding their current practice and preferences of grading systems. Design, setting, and participants: A web-based, anonymous questionnaire with ten questions on grading of NMIBC was created. The members of EAU and ISUP were invited to complete an online survey by the end of 2021. Thirteen experts had previously answered the same questions. Outcome measurements and statistical analysis: The submitted answers from 214 ISUP members, 191 EAU members, and 13 experts were analyzed. Results and limitations: Currently, 53% use only the WHO2004 system and 40% use both systems. According to most respondents, PUNLMP is a rare diagnosis with management similar to Ta-LG carcinoma. The majority (72%) would consider reverting back to WHO1973 if grading criteria were more detailed. Separate reporting of WHO1973-G3 within WHO2004-HG would influence clinical decisions for Ta and/or T1 tumors according the majority (55%). Most respondents preferred a two-tier (41%) or a three-tier (41%) grading system. The current WHO2004 grading system is supported by a minority (20%), whereas nearly half (48%) supported a hybrid three- or four-tier grading system composed of both WHO1973 and WHO2004. The survey results of the experts were comparable with ISUP and EAU respondents. Conclusions: Both the WHO1973 and the WHO2004 grading system are still widely used. Even though opinions on the future of bladder cancer grading were strongly divided, there was limited support for WHO1973 and WHO2004 in their current formats, while the hybrid (three-tier) grading system with LG, HG-G2, and HG-G3 as categories could be considered the most promising alternative. Patient summary: Grading of non–muscle-invasive bladder cancer (NMIBC) is a matter of ongoing debate and lacks international consensus. We surveyed urologists and pathologists of European Association of Urology and International Society of Urological Pathology on their preferences regarding NMIBC grading to generate a multidisciplinary dialogue. Both the “old” World Health Organization (WHO) 1973 and the “new” WHO2004 grading schemes are still used widely. However, continuation of both the WHO1973 and the WHO2004 system showed limited support, while a hybrid grading system composed of both the WHO1973 and the WHO2004 classification system may be considered a promising alternative.
CRIS-Team Scopus Importer:2023-05-19
Keywords: Bladder; Cancer; European Association of Urology; Grading; International Society of Urological Pathology; Survey; WHO1973; WHO2004

International Society of Urological Pathology Expert Opinion on Grading of Urothelial Carcinoma - van der Kwast, Theodorus H.; Liedberg, Fredrik; Black, Peter C.; Kamat, Ashish; van Rhijn, Bas W. G.; Algaba, Ferran; Berman, David M.; Hartmann, Arndt; Lopez-Beltran, Antonio; Samaratunga, Hemamali; Varma, Murali; Cheng, Liang (European Urology Focus, 2021)
Context: Grading is the mainstay for treatment decisions for patients with non–muscle-invasive bladder cancer (NMIBC). Objective: To determine the requirements for an optimal grading system for NMIBC via expert opinion. Evidence acquisition: A multidisciplinary working group established by the International Society of Urological Pathology reviewed available clinical, histopathological, and molecular evidence for an optimal grading system for bladder cancer. Evidence synthesis: Bladder cancer grading is a continuum and five different grading systems based on historical grounds could be envisaged. Splitting of the World Health Organization (WHO) 2004 low-grade class for NMIBC lacks diagnostic reproducibility and molecular-genetic support, while showing little difference in progression rate. Subdividing the clinically heterogeneous WHO 2004 high-grade class for NMIBC into intermediate and high risk categories using the WHO 1973 grading is supported by both clinical and molecular-genetic findings. Grading criteria for the WHO 1973 scheme were detailed on the basis of literature findings and expert opinion. Conclusions: Splitting of the WHO 2004 high-grade category into WHO 1973 grade 2 and 3 subsets is recommended. Provision of more detailed histological criteria for the WHO 1973 grading might facilitate the general acceptance of a hybrid four-tiered grading system or—as a preferred option—a more reproducible three-tiered system distinguishing low-, intermediate (high)-, and high-grade NMIBC. Patient summary: Improvement of the current systems for grading bladder cancer may result in better informed treatment decisions for patients with bladder cancer. A three-tiered grading system for non–muscle invasive bladder cancer derived by splitting the heterogeneous World Health Organization (WHO) 2004 high-grade category into WHO 1973 grade 2 and 3 subsets is recommended, as this may result in more informed treatment decisions.
CRIS-Team Scopus Importer:2021-04-02
Keywords: Bladder cancer; Expert opinion; Grading system; Non-muscle invasive bladder cancer; Pathology; WHO 1973; WHO 2004

International Society of Urological Pathology (ISUP) Consensus Conference on Current Issues in Bladder Cancer. Working Group 1: Comparison of Bladder Cancer Grading System Performance. - Downes, Michelle R.; Hartmann, Arndt; Shen, Steven; Tsuzuki, Toyonori; van Rhijn, Bas W. G.; Bubendorf, Lukas; van der Kwast, Theodorus H.; Cheng, Liang (American Journal of Surgical Pathology, 2024)
Grade is a key prognostic factor in determining progression in nonmuscle invasive papillary urothelial carcinomas. The 2 most common grading methods in use worldwide are the World Health Organization (WHO) 2004 and 1973 schemes. The International Society of Urological Pathology (ISUP) organized the 2022 consensus conference in Basel, Switzerland on current issues in bladder cancer and tasked working group 1 to make recommendations for future iterations of bladder cancer grading. For this purpose, the ISUP developed in collaboration with the European Association of Urology a 10-question survey for their memberships to understand the current use of grading schemes by pathologists and urologists and to ascertain the areas of potential improvements. An additional survey was circulated to the ISUP membership for their opinion on interobserver variability in grading, reporting of urine cytology, and challenges encountered in grade assignment. Comprehensive literature reviews were performed on bladder cancer grading prognosis and interobserver variability along with The Paris System for urine cytology. There are notable differences in practice patterns between North American and European pathologists in terms of used grading scheme and diagnosis of papillary urothelial neoplasm of low malignant potential. Areas of common ground include difficulty in grade assignment, a desire to improve grading criteria, and a move towards subclassifying high-grade urothelial carcinomas. The surveys and in-person voting demonstrated a strong preference to refine current grading into a 3-tier scheme with the division of WHO 2004 high grade into clinically relevant categories. More variable opinions were voiced regarding the use of papillary urothelial carcinoma with low malignant potential.
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International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study - Pages, Franck; Mlecnik, Bernhard; Marliot, Florence; Bindea, Gabriela; Ou, Fang-Shu; Bifulco, Carlo; Lugli, Alessandro; Zlobec, Inti; Rau, Tilman T.; Berger, Martin D.; Nagtegaal, Iris D.; Vink-Borger, Elisa; et al. (Lancet, 2018)
BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system. INTERPRETATION: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer. FUNDING: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.
EVALuna2:34256

Interobserver reproducibility of a hybrid three-tier grading system of papillary nonmuscle invasive urothelial carcinoma: an international Uropathology study - Downes, Michelle R.; Lajkosz, Katherine; Algaba, Ferran; Allory, Yves; Amin, Mahul B.; Cheng, Liang; Desai, Sangeeta; Eckstein, Markus; Hartmann, Arndt; Lopez-Beltran, Antonio; Mannweiler, Sebastian; van Montfoort, Maurits L.; et al. (Histopathology, 2025)
Aims: A hybrid-three tier system with low grade (LG), high grade- G2 (HG-G2), high grade- G3 (HG-G3) has been proposed in recognition of, and to help address, the clinical heterogeneity within high grade WHO 2004/2022. We assessed interobserver reproducibility amongst international uropathologists using this three-tier approach. Methods and Results: Papillary Ta nonmuscle invasive bladder cancer (NMIBC) specimens (n = 30) were selected and graded by two uropathologists and assessed using WHO 2004/2022 and WHO 1973 and categorized as LG (n = 15), HG-G2 (n = 8), HG-G3 (n = 7), and photographed at 10× and 20× magnification. Images were circulated via Survey Monkey to invited uropathologists who determined: (1) that image was LG or HG, and (2) if HG, assigned to G2 or G3. Model-based kappa measure of association was used to assess interrater agreement. Eighteen uropathologists:(eight North American, eight European, two other) assessed 60 images with 1076 gradings for analysis. The kappa value amongst Europeans versus North Americans was 0.663 versus 0.647 for 10× images and 0.682 versus 0.623 for 20× images. At 10×, agreement for LG, HG-G2, and HG-G3 was 74.6%, 63.6%, and 92.0%, and at 20× was 64.3%, 63.9%, and 95.2% respectively. Conclusion: Three-tier grading of papillary Ta NMIBC had substantial interobserver agreement amongst international uropathologists. The recognition of the HG-G3 case reached the highest concordance. North American uropathologists had comparable kappa scores (substantial agreement) to Europeans, despite being unaccustomed to separating HG cases into G2 and G3, demonstrating three-tier grading could be “quickly” adopted by genitourinary experts if endorsed and required by the relevant bodies in their jurisdiction of practice.
CRIS-Team Scopus Importer:2025-04-01
Keywords: bladder cancer; hybrid grading; interobserver variation; nonmuscle invasive; papillary

Interplay between the prostaglandin transporter OATP2A1 and prostaglandin E2-mediated cellular effects - Bujok, Krystyna; Gläser, Hartmut; Schuh, Wolfgang; Rau, Tilman; Schmidt, Ingrid; Fromm, Martin; Mandery, Kathrin (Cellular Signalling, 2015)
Prostaglandins such as prostaglandin E2 (PGE2) play a pivotal role in physiological and pathophysiological pathways in gastric mucosa. Little is known about the interrelation of the prostaglandin E (EP) receptors with the prostaglandin transporter OATP2A1 in the gastric mucosa and gastric carcinoma. Therefore, we first investigated the expression of OATP2A1 and EP4 in normal and carcinoma gastric mucosa. Different PGE2-mediated cellular pathways and mechanisms were investigated using human embryonic kidney cells (HEK293) and the human gastric carcinoma cell line AGS stably transfected with OATP2A1. Colocalization and expression of OATP2A1 and EP4 were detected in mucosa of normal gastric tissue and of gastric carcinomas. OATP2A1 reduced the PGE2-mediated cAMP production in HEK293 and AGS cells overexpressing EP4 and OATP2A1. The expression of OATP2A1 in AGS cells resulted in a reduction of [(3)H]-thymidine incorporation which was in line with a higher accumulation of AGS-OATP2A1 cells in S-phase of the cell cycle compared to control cells. In contrast, the expression of OATP2A1 in HEK293 cells had no influence on the distribution in the S-phase compared to control cells. OATP2A1 also diminished the PGE2-mediated expression of interleukin-8 mRNA (IL-8) and hypoxia-inducible-factor 1? (HIF1?) protein in AGS-OATP2A1 cells. The expression of OATP2A1 increased the sensitivity of AGS cells against irinotecan which led to reduced cell viability. Taken together, these data show that OATP2A1 influences PGE2-mediated cellular pathways. Therefore, OATP2A1 needs to be considered as a key determinant for the understanding of the physiology and pathophysiology of prostaglandins in healthy and tumorous gastric mucosa.
EVALuna2:6643

Intestinal Barrier Healing Is Superior to Endoscopic and Histologic Remission for Predicting Major Adverse Outcomes in Inflammatory Bowel Disease: The Prospective ERIca Trial - Rath, Timo; Atreya, Raja; Bodenschatz, Julia; Uter, Wolfgang; Geppert, Carol-Immanuel; Vitali, Francesco; Fischer, Sarah; Waldner, Maximilian; Colombel, Jean Frédéric; Hartmann, Arndt; Neurath, Markus (Gastroenterology, 2023)
Background & Aims: Endoscopic and histologic remission have emerged as key therapeutic goals in the management of inflammatory bowel diseases (IBD) that are associated with favorable long-term disease outcomes. Here, we prospectively compared the predictive value of barrier healing with endoscopic and histologic remission for predicting long-term disease behavior in a large cohort of patients with IBD in clinical remission. Methods: At baseline, patients with IBD in clinical remission underwent ileocolonoscopy with assessment of intestinal barrier function by confocal endomicroscopy. Endoscopic and histologic disease activity, as well as barrier healing, was prospectively assessed along established scores. During subsequent follow-up, patients were closely monitored for clinical disease activity and the occurrence of major adverse outcomes (MAOs): disease flares, IBD-related hospitalization or surgery, and initiation or dose escalation of systemic steroids, immunosuppressants, small molecules, or biological therapy. Results: The final analysis included 181 patients, 100 with Crohn's disease [CD] and 81 with ulcerative colitis (UC). During a mean follow-up of 35 (CD) and 25 (UC) months, 73% of patients with CD and 69% of patients with UC experienced at least 1 MAO. The probability of MAO-free survival was significantly higher in patients with IBD with endoscopic remission compared with endoscopically active disease. In addition, histologic remission predicted MAO-free survival in patients with UC but not CD. Barrier healing on endomicroscopy was superior to endoscopic and histologic remission for predicting MAO-free survival in both UC and CD. Conclusions: Barrier healing is associated with decreased risk of disease progression in patients with clinically remittent IBD, with superior predictive performance compared with endoscopic and histologic remission. Analysis of barrier function might be considered as a future treatment target in clinical trials. ClinicalTrials.gov number, NCT05157750.
CRIS-Team Scopus Importer:2023-01-27
Keywords: Confocal Laser Endomicroscopy; Endoscopy; Histology; Inflammatory Bowel Diseases; Intestinal Barrier

Intra-abdominal ALK-positive anaplastic large cell lymphoma in a patient with neurofibromatosis type 1 - Agaimy, Abbas; Semrau, Sabine; Heinz, Marco (Histopathology, 2016)
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Intra-abdominal EWSR1/FUS-CREM-rearranged malignant epithelioid neoplasms: two cases of an emerging aggressive entity with emphasis on misleading immunophenotype - Agaimy, Abbas; Stöhr, Robert; Otto, Mike; Braesen, Jan Hinrich; Pfarr, Nicole; Konukiewitz, Bjoern; Kasajima, Atsuko; Hartmann, Arndt; Kloeppel, Guenter (Virchows Archiv, 2021)
CREB family (CREB1, ATF1, and CREM) gene fusions are defining markers in diverse mesenchymal neoplasms (clear cell sarcoma, angiomatoid fibrous histiocytoma, and others). However, neoplasms harboring EWSR1-CREM/FUS-CREM fusions are rare and poorly characterized. We describe two cases (55-year-old male with 7.5 cm renal mass and 32-year-old female with 5.5 cm mesenteric mass) illustrating their misleading immunophenotypes. Histologically, both showed eosinophilic and focally clear epithelioid cells arranged into sheets, nests, and trabeculae. Immunohistochemistry showed ALK, EMA, and AE1/AE3 immunoreactivity suggesting ALK-rearranged renal cell carcinoma (Case 1) and coexpression of keratin, EMA, synaptophysin, and chromogranin-A, suggesting neuroendocrine neoplasm (Case 2). Targeted RNA sequencing revealed EWSR1-CREM (Case 1) and FUS-CREM (Case 2) fusions. These cases add to the spectrum of CREM fusion-positive intra-abdominal epithelioid neoplasms. Their unusual immunophenotype and unexpected sites represent major pitfalls, underline a wide differential diagnosis, and emphasize the value of molecular testing in correctly diagnosing them.
CRIS-Team Scopus Importer:2021-07-16
Keywords: ALK; CREB; CREM; EWSR1; FUS; Mesentery; Neuroendocrine; Paraganglioma; Primary renal sarcoma; RCC

Intracranial hemorrhage in COVID-19 patients during extracorporeal membrane oxygenation for acute respiratory failure: a nationwide register study report - von Stillfried, Saskia; Bülow, Roman David; Röhrig, Rainer; Meybohm, Patrick; Boor, Peter; Böcker, Jana; Schmidt, Jens; Tholen, Pauline; Majeed, Raphael; Wienströer, Jan; Weis, Joachim; Bremer, Juliane; et al. (Critical Care, 2022)
Background: In severe cases, SARS-CoV-2 infection leads to acute respiratory distress syndrome (ARDS), often treated by extracorporeal membrane oxygenation (ECMO). During ECMO therapy, anticoagulation is crucial to prevent device-associated thrombosis and device failure, however, it is associated with bleeding complications. In COVID-19, additional pathologies, such as endotheliitis, may further increase the risk of bleeding complications. To assess the frequency of bleeding events, we analyzed data from the German COVID-19 autopsy registry (DeRegCOVID). Methods: The electronic registry uses a web-based electronic case report form. In November 2021, the registry included N = 1129 confirmed COVID-19 autopsy cases, with data on 63 ECMO autopsy cases and 1066 non-ECMO autopsy cases, contributed from 29 German sites. Findings: The registry data showed that ECMO was used in younger male patients and bleeding events occurred much more frequently in ECMO cases compared to non-ECMO cases (56% and 9%, respectively). Similarly, intracranial bleeding (ICB) was documented in 21% of ECMO cases and 3% of non-ECMO cases and was classified as the immediate or underlying cause of death in 78% of ECMO cases and 37% of non-ECMO cases. In ECMO cases, the three most common immediate causes of death were multi-organ failure, ARDS and ICB, and in non-ECMO cases ARDS, multi-organ failure and pulmonary bacterial ± fungal superinfection, ordered by descending frequency. Interpretation: Our study suggests the potential value of autopsies and a joint interdisciplinary multicenter (national) approach in addressing fatal complications in COVID-19.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Autopsy; Bleeding events; COVID-19; ECMO; Intracranial bleeding; Registry

Intraductal carcinoma of the prostate is an aggressive form of invasive carcinoma and should be graded - Samaratunga, Hemamali; Delahunt, Brett; Egevad, Lars; Srigley, John R.; Billis, Athanase; Bostwick, David G.; Camparo, Philippe; Cheng, Liang; Clouston, David; Denham, James; Furusato, Bungo; Hartmann, Arndt; et al. (Pathology, 2019)
Infiltration of the prostatic ducts by prostatic adenocarcinoma occurs relatively frequently, being most commonly associated with high grade disease. It is now recognised that intraductal carcinoma of the prostate (IDCP) has an associated poor prognosis and this is reflected in its histological, molecular and immunohistochemical features. The current recommendation of the World Health Organization is that IDCP not be taken into consideration when grading prostate adenocarcinoma. It is apparent that Gleason did not differentiate between IDCP and stromal invasive carcinoma when developing and validating his grading system, and recent studies suggest that the incorporation of IDCP grading into the overall grading of the specimen provides additional prognostic information.
CRIS-Team Scopus Importer:2019-12-27
Keywords: intraductal carcinoma of prostate; ISUP grade; prognosis; Prostate adenocarcinoma

Intraductal carcinoma of the prostate is an aggressive form of invasive carcinoma and should be graded - Samaratunga, Hemamali; Delahunt, Brett; Egevad, Lars; Srigley, John R.; Billis, Athanase; Bostwick, David G.; Camparo, Philippe; Cheng, Liang; Clouston, David; Denham, James; Furusato, Bungo; Hartmann, Arndt; et al. (Pathology, 2020)
Infiltration of the prostatic ducts by prostatic adenocarcinoma occurs relatively frequently, being most commonly associated with high grade disease. It is now recognised that intraductal carcinoma of the prostate (IDCP) has an associated poor prognosis and this is reflected in its histological, molecular and immunohistochemical features. The current recommendation of the World Health Organization is that IDCP not be taken into consideration when grading prostate adenocarcinoma. It is apparent that Gleason did not differentiate between IDCP and stromal invasive carcinoma when developing and validating his grading system, and recent studies suggest that the incorporation of IDCP grading into the overall grading of the specimen provides additional prognostic information.
EVALuna2:212459

Intraductal Papillary Mucinous Neoplasms of Minor Salivary Glands With AKT1 p.Glu17Lys Mutation - Agaimy, Abbas; Müller, Susanna; Bumm, Klaus; Iro, Heinrich; Moskalev, Evgeny; Hartmann, Arndt; Stoehr, Robert; Haller, Florian (American Journal of Surgical Pathology, 2018)
The spectrum of low-grade intraductal papillary proliferations of the salivary glands is heterogenous, and reproducible morphologic diagnostic criteria have not yet been established. Recognized types are sialadenoma papilliferum, inverted ductal papilloma, and intraductal papilloma, but some lesions have been possibly included in the morphologic spectrum of cystadenoma or low-grade intraductal carcinomas. We herein present detailed morphologic, immunophenotypic, and genotypic features of 3 minor salivary gland neoplasms affecting 2 men (aged 65 and 71 y) and 1 woman (aged 78 y). They ranged in size from 1 to 2.5 cm. All tumors showed atypical papillary intraductal growth that presented either as uninodular/unicystic lesions (intraductal papilloma-like; n=2) or as a discontinuous growth along the ductal system in a manner similar to pancreatic intraductal papillary mucinous neoplasm (n=1). Variable cytologic and architectural atypia was observed, ranging from bland intraductal papilloma-like features, to areas mimicking atypical ductal hyperplasia and low-grade ductal carcinoma in situ of the breast. Amplicon-based massive parallel sequencing revealed an identical AKT1 p.Glu17Lys mutation in all 3 cases, but absence of concurring mutations in other genes of the RAS or PI3K pathway. This small series represents the first genetic study on salivary intraductal papillary neoplasms. Our cases showed significant variation in the degree of cytologic and architectural atypia, which overlaps with intraductal papillomas at the one end and with low-grade intraductal carcinoma at the other end of the spectrum, suggesting a disease continuum. As the full biological and morphologic characteristics of these ductal papillary lesions remain to be defined, the noncommitted term "intraductal papillary neoplasms" might be more appropriate. Our novel genetic findings mirror similar activating mutations of AKT1 and other PI3K pathway members in intraductal papillary lesions of the breast and anogenital glands.
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Intraparotid classical and nodular lymphocyte-predominant Hodgkin lymphoma: pattern analysis with emphasis on associated lymphadenoma-like proliferations - Agaimy, Abbas; Wild, Vanessa; Maerkl, Bruno; Wachter, David; Hartmann, Arndt; Rosenwald, Andreas; Ihrler, Stephan (American Journal of Surgical Pathology, 2015)
Most of the lymphoproliferative diseases involving the salivary glands represent indolent non-Hodgkin B-cell lymphoma (marginal zone lymphoma) related to chronic autoimmune sialadenitis (Sjögren disease). Other types of non-Hodgkin lymphomas involve the salivary glands less frequently. On rare occasions, classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) present initially as a primary salivary gland mass. We analyzed a series of CHL (n=3) and NLPHL (n=6) presenting initially as parotid gland tumors concerning their pattern (parenchymal vs. intraparotid lymph node) and the presence of salivary inclusions and epithelial proliferations within the lymphoma infiltrate. The pattern of infiltration was determined on hematoxylin and eosin-stained slides assisted by immunostaining for pancytokeratin to highlight lobular salivary gland parenchyma. Patients included 6 male and 3 female individuals with a mean age of 62 years (range, 36 to 88 y). Lymphoma was localized within intraparotid lymph nodes in 8 cases and was limited to salivary parenchyma in 1 case. Parenchymal involvement in nodal-based cases was scored as absent (3) or minimal (5). Salivary inclusions (acini and ductules) within affected lymph nodes were noted in 6 cases (4/5 NLPHLs and 2/3 CHLs). In 3/6 NLPHL cases, salivary inclusions showed variable proliferative changes ranging from prominent lymphoepithelial lesions to cystic and oncocytic (Warthin-like) epithelial changes. Scanty small lymphoepithelial lesions were seen in 1 of the 3 CHL cases. One NLPHL in the intraparotid lymph node was accompanied by prominent lymphoepithelial sialadenitis in the absence of clinical signs of Sjögren disease. This study highlights that a majority of parotid gland Hodgkin lymphomas arise within intraparotid lymph nodes. Frequent entrapment and proliferation of salivary ducts and acini within the lymphoma infiltrate might mimic a variety of benign lymphoepithelial mass-forming lesions (nonsebaceous lymphadenoma, Warthin tumor, and autoimmune sialadenitis). Pancytokeratin stain is helpful for reliable assessment of the background architecture.
EVALuna2:6714

Introducing a novel highly prognostic grading scheme based on tumour budding and cell nest size for squamous cell carcinoma of the uterine cervix - Jesinghaus, Moritz; Strehl, Johanna; Boxberg, Melanie; Bruehl, Frido; Wenzel, Adrian; Konukiewitz, Bjoern; Schlitter, Anna M.; Steiger, Katja; Warth, Arne; Schnelzer, Andreas; Kiechle, Marion; Beckmann, Matthias; et al. (Journal of Pathology: Clinical Research, 2018)
A novel histopathological grading system based on tumour budding and cell nest size has recently been shown to outperform conventional (WHO-based) grading algorithms in several tumour entities such as lung, oral, and oesophageal squamous cell carcinoma (SCC) in terms of prognostic patient stratification. Here, we tested the prognostic value of this innovative grading approach in two completely independent cohorts of SCC of the uterine cervix. To improve morphology-based grading, we investigated tumour budding activity and cell nest size as well as several other histomorphological factors (e.g., keratinization, nuclear size, mitotic activity) in a test cohort (n = 125) and an independent validation cohort (n = 122) of cervical SCC. All parameters were correlated with clinicopathological factors and patient outcome. Small cell nest size and high tumour budding activity were strongly associated with a dismal patient prognosis (p < 0.001 for overall survival [OS], disease-specific survival, and disease-free survival; test cohort) in both cohorts of cervical SCC. A novel grading algorithm combining these two parameters proved to be a highly effective, stage-independent prognosticator in both cohorts (OS: p < 0.001, test cohort; p = 0.001, validation cohort). In the test cohort, multivariate statistical analysis of the novel grade revealed that the hazard ratio (HR) for OS was 2.3 for G2 and 5.1 for G3 tumours compared to G1 neoplasms (p = 0.010). In the validation cohort, HR for OS was 3.0 for G2 and 7.2 for G3 tumours (p = 0.012). In conclusion, our novel grading algorithm incorporating cell nest size and tumour budding allows strongly prognostic histopathological grading of cervical SCC superior to WHO-based grading. Therefore, our data can be regarded as a cross-organ validation of previous results demonstrated for oesophageal, lung, and oral SCC. We suggest this grading algorithm as an additional morphology-based parameter for the routine diagnostic assessment of this tumour entity.
EVALuna2:35627

Invagination as Manifestation of a Perivascular Epithelioid Cell Neoplasm (PEComa) of the Colon - Neuhaus, Lukas; Probst, Andreas; Messmann, Helmut; Siebert, Lena; Vlasenko, Dmytro; Agaimy, Abbas; Ting, Saskia (American Journal of Gastroenterology, 2018)
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In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease - Atreya, Raja; Neumann, Helmut; Neufert, Clemens; Waldner, Maximilian; Billmeier, Ulrike; Zopf, Yurdagül; Willma, Marcus; App, Christine; Münster, Tino; Kessler, Hermann; Maas, Stefanie; Gebhardt, Bernd; et al. (Nature Medicine, 2014)
As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn's disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohn's disease led to detection of intestinal mTNF(+) immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF(+) cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF(+) cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn's disease and autoimmune or inflammatory disorders.
EVALuna2:1838

In vivo monitoring of the anti-angiogenic therapeutic effect of the pan-deacetylase inhibitor panobinostat by small animal PET in a mouse model of gastrointestinal cancers - Maschauer, Simone; Gahr, Susanne; Gandesiri, Muktheshwar; Tripal, Philipp; Schneider-Stock, Regine; Kuwert, Torsten; Ocker, Matthias; Prante, Olaf (Nuclear Medicine and Biology, 2016)
Deacetylase inhibitors have recently been established as a novel therapeutic approach to solid and hematologic cancers and have also been demonstrated to possess anti-angiogenic properties. Although these compounds show a good efficacy in vitro and in vivo, no data on monitoring and predicting treatment response are currently available. We therefore investigated the effect of the pan-deacetylase inhibitor panobinostat (LBH589) on gastrointestinal cancer models and the suitability of 2-[(18)F]FGlc-RGD as a specific agent for imaging integrin ?v?3 expression during tumor angiogenesis using small animal positron emission tomography (PET).The effect of panobinostat on cell viability in vitro was assessed with a label-free impedance based real-time analysis. Nude mice bearing HT29 and HepG2 tumors were treated with daily i.p. injections of 10mg/kg panobinostat for 4weeks. During this time, tumor size was determined with a calliper and mice were repeatedly subjected to PET imaging. Tumor tissues were analyzed immunohistochemically with a focus on proliferation and endothelial cell markers (Ki-67, Meca-32) and by Western blot applying specific markers of apoptosis.In vitro, panobinostat inhibited the proliferation of HepG2 and HT29 cells. Contrary to the situation in HepG2 tumors in vivo, where panobinostat treatment is known to reduce proliferation and vascularization resulting in a decreased tumor growth, HT29 tumors did not show any effect on these parameters. We demonstrated by Western blotting, that panobinostat induced apoptosis in HT29 tumors in vivo. Longitudinal PET imaging studies in HepG2 tumor-bearing mice using 2-[(18)F]FGlc-RGD demonstrated that the standard uptake value (SUVmax) in HepG2 tumors was significantly decreased by 39% at day 7 after treatment. The comparative PET study using HT29 tumor-bearing animals did not reveal any response of the tumors to panobinostat treatment.Small-animal PET imaging using 2-[(18)F]FGlc-RGD was successfully applied to the non-invasive monitoring of the HepG2-tumor response to panobinostat in nude mice early after begin of treatment. Thus, PET imaging of angiogenesis using 2-[(18)F]FGlc-RGD could be a valuable tool to monitor panobinostat therapy in further preclinical studies.When successfully translated to the clinical surrounding, PET imaging of angiogenesis could therefore facilitate therapy planning and monitoring of therapy success with panobinostat in hepatocellular carcinoma.
EVALuna2:6737

Iota-carrageenan neutralizes SARS-CoV-2 and inhibits viral replication in vitro - Morokutti-Kurz, Martina; Fröba, Maria; Graf, Philipp; Große, Maximilian; Grassauer, Andreas; Auth, Jürgen; Schubert, Ulrich; Prieschl-Grassauer, Eva (PLoS ONE, 2021)
In the absence of a vaccine and other effective prophylactic or therapeutic countermeasures the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) remains a significant public health threat. Attachment and entry of coronaviruses including SARS-CoV-2 is mainly mediated by the spike glycoprotein. Here, we show that iota-carrageenan can inhibit the cell entry of the SARS-CoV-2 spike pseudotyped lentivirus in a dose dependent manner. SARS-CoV-2 spike pseudotyped lentivirus particles were efficiently neutralized with an IC50 value of 2.6 μg/ml iota-carrageenan. Experiments with patient isolated wild type SARS-CoV-2 virus showed an inhibition of replication in a similar range. In vitro data on iota-carrageenan against various Rhino- and endemic Coronaviruses showed similar IC50 values and translated readily into clinical effectiveness when a nasal spray containing iota-carrageenan demonstrated a reduction of severity and duration of symptoms of common cold caused by various respiratory viruses. Accordingly, our in vitro data on SARS-CoV-2 spike pseudotyped lentivirus and replication competent SARS-CoV-2 suggest that administration of iota-carrageenan may be an effective and safe prophylaxis or treatment for SARS-CoV-2 infections.
CRIS-Team Scopus Importer:2021-03-05

Ischaemia-related cell damage in extracorporeal preserved tissue - new findings with a novel perfusion model - Taeger, Christian; Müller-Seubert, Wibke; Horch, Raymund E.; Präbst, Konstantin; Münch, Frank; Geppert, Carol-Immanuel; Birkholz, Torsten; Dragu, Adrian (Journal of Cellular and Molecular Medicine, 2014)
Tissue undergoing free transfer in transplant or reconstructive surgery always is at high risk of ischaemia-related cell damage. This study aims at assessing different procedures using an extracorporeal perfusion and oxygenation system to investigate the expression of hypoxia inducible factor (HIF)-1-? as marker for hypoxia and of the pro-apoptotic protein Caspase-3 in skeletal muscle to elucidate potential improvements in tissue conservation. Twenty-four porcine rectus abdominis muscles were assigned to five different groups and examined after they had been extracorporeally preserved for 60 min. time. Group I was left untreated (control), group II was perfused with a cardioplegic solution, group III was flushed with 10 ml of a cardioplegic solution and then left untreated. Group IV and V were perfused and oxygenated with either an isotone crystalloid solution or a cardioplegic solution. Among others, immunohistochemistry (Caspase-3 and HIF-1-?) of muscle samples was performed. Furthermore, oxygen partial pressure in the perfusate at the arterial and venous branch was measured. Expression of Caspase-3 after 60 min. was reduced in all groups compared to the control group. Furthermore, all groups (except group III) expressed less HIF-1-? than the control group. Oxygenation leads to higher oxygen levels at the venous branch compared to groups without oxygenation. Using an extracorporeal perfusion and oxygenation system cell damage could be reduced as indicated by stabilized expressions of Caspase-3 and HIF-1-? for 60 min. of tissue preservation. Complete depletion of oxygen at the venous branch can be prevented by oxygenation of the perfusate with ambient air.
EVALuna2:6573

Is extracapsular dissection for pleomorphic adenoma rather a euphemism for enucleation that jeopardises the intactness of the capsule? - Mantsopoulos, Konstantinos; Iro, A. K.; Sievert, Matti; Müller, Sarina Katrin; Agaimy, Abbas; Schapher, Mirco; Koch, Matthias; Iro, Heinrich (British Journal of Oral and Maxillofacial Surgery, 2021)
The aim of this study was to compare several surgical modalities with respect to the incidence of positive margins and focal capsular exposure of pleomorphic adenoma of the parotid gland. The clinical records and histopathological findings of all patients who underwent parotidectomy for pleomorphic adenoma between 2006 and 2020 were retrospectively evaluated (n = 845). The lesion was removed by extracapsular dissection in 577 cases (68%) and facial nerve dissection in 268 (32%). Our analysis did not reveal a statistically significant difference between the examined modalities regarding positive margins (p=0.648) or capsular exposure (p=0.112). Recurrences were detected in 7/845 cases (0.82%) with a mean (range) follow-up time of 82.3 (6-183) months. The choice of surgical method does not seem to have a significant effect on the incidence of positive margins, or on the capsular exposure of a pleomorphic adenoma.
CRIS-Team Scopus Importer:2021-07-30
Keywords: capsule; complete parotidectomy; extracapsular dissection; partial superficial parotidectomy; pleomorphic adenoma; superficial parotidectomy

Isolation of Human Endothelial Cells from Normal Colon and Colorectal Carcinoma - An Improved Protocol - Naschberger, Elisabeth; Regensburger, Daniela; Tenkerian, Clara; Langheinrich, Melanie; Engel, Felix; Geppert, Carol-Immanuel; Hartmann, Arndt; Grützmann, Robert; Schellerer, Vera; Stürzl, Michael (Journal of Visualized Experiments, 2018)
Primary cells isolated from human carcinomas are valuable tools to identify pathogenic mechanisms contributing to disease development and progression. In particular, endothelial cells (EC) constituting the inner surface of vessels, directly participate in oxygen delivery, nutrient supply, and removal of waste products to and from tumors, and are thereby prominently involved in the constitution of the tumor microenvironment (TME). Tumor endothelial cells (TECs) can be used as cellular biosensors of the intratumoral microenvironment established by communication between tumor and stromal cells. TECs also serve as targets of therapy. Accordingly, in culture these cells allow studies on mechanisms of response or resistance to anti-angiogenic treatment. Recently, it was found that TECs isolated from human colorectal carcinoma (CRC) exhibit memory-like effects based on the specific TME they were derived from. Moreover, these TECs actively contribute to the establishment of a specific TME by the secretion of different factors. For example, TECs in a prognostically favorable Th1-TME secrete the anti-angiogenic tumor-suppressive factor secreted protein, acidic and rich in cysteine-like 1 (SPARCL1). SPARCL1 regulates vessel homeostasis and inhibits tumor cell proliferation and migration. Hence, cultures of pure, viable TECs isolated from human solid tumors are a valuable tool for functional studies on the role of the vascular system in tumorigenesis. Here, a new up-to-date protocol for the isolation of primary EC from the normal colon as well as CRC is described. The technique is based on mechanical and enzymatic tissue digestion, immunolabeling, and fluorescence activated cell sorting (FACS)-sorting of triple-positive cells (CD31, VE-cadherin, CD105). With this protocol, viable TEC or normal endothelial cell (NEC) cultures could be isolated from colon tissues with a success rate of 62.12% when subjected to FACS-sorting (41 pure EC cultures from 66 tissue samples). Accordingly, this protocol provides a robust approach to isolate human EC cultures from normal colon and CRC.
EVALuna2:34267

Jejunitis and brown bowel syndrome with multifocal carcinogenesis of the small bowel - Raithel, Martin; Rau, Tilman; Hagel, Alexander; Albrecht, Heinz; De Rossi, Thomas; Kirchner, Thomas; Hahn, Eckhart Georg (World Journal of Gastroenterology, 2015)
This is the first report describing a case where prolonged, severe malabsorption from brown bowel syndrome progressed to multifocally spread small bowel adenocarcinoma. This case involves a female patient who was initially diagnosed with chronic jejunitis associated with primary diffuse lymphangiectasia at the age of 26 years. The course of the disease was clinically, endoscopically, and histologically followed for 21 years until her death at the age 47 due to multifocal, metastasizing adenocarcinoma of the small bowel. Multiple lipofuscin deposits (so-called brown bowel syndrome) and severe jejunitis were observed microscopically, and sections of the small bowel showed dense lymphoplasmacytic infiltration of the lamina propria as well as blocked lymphatic vessels. After several decades, multifocal nests of adenocarcinoma cells and extensive, flat, neoplastic mucosal proliferations were found only in the small bowel, along with a loss of the mismatch repair protein MLH1 as a long-term consequence of chronic jejunitis with malabsorption. No evidence was found for hereditary nonpolyposis colon carcinoma syndrome. This article demonstrates for the first time multifocal carcinogenesis in the small bowel in a malabsorption syndrome in an enteritis-dysplasia-carcinoma sequence.
EVALuna2:1973

Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment - Fasching, Peter A.; Heusinger, Katharina; Haeberle, Lothar; Niklos, Melitta; Hein, Alexander; Bayer, Christian M.; Rauh, Claudia; Schulz-Wendtland, Rüdiger; Bani, Mayada; Schrauder, Michael; Kahmann, Laura; Lux, Michael P.; et al. (BMC Cancer, 2011)
Background: The pathological complete response (pCR) after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer.Methods: Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible.Results: Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1) and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9). The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells.Conclusions: Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further. © 2011 Fasching et al; licensee BioMed Central Ltd.
CRIS-Team Scopus Importer:2021-07-19

KRAS codon 12 mutations characterize a subset of de novo proliferating “metaplastic” Warthin tumors - Agaimy, Abbas; Mantsopoulos, Konstantinos; Iro, Heinrich; Stöhr, Robert (Virchows Archiv, 2023)
Warthin tumor (WT; synonym: cystadenolymphoma) represents one of the most frequent salivary gland tumors with a frequency equaling or even outnumbering that of pleomorphic adenomas in some series. Histologically, the tumor displays tall columnar oncocytic cells, arranged into two cell-thick layers lining variably cystic glands within an organoid lymphoid stroma. Tumors with exuberant squamous metaplasia in response to FNA-induced or other types of tissue injury/infarction have been referred to as “metaplastic WTs.” However, the same terminology was used for tumors with variable mucinous cell and solid or stratified epidermoid proliferations (occasionally mimicking mucoepidermoid carcinoma), although the “metaplasia concept” has never been proven for the latter. We herein investigated 22 WTs showing prominent mucoepidermoid-like or solid oncocytoma-like proliferations without prior FNA or histological evidence of infarction/ trauma using the TruSight Tumor 15 gene panel and KRAS pyrosequencing. As a control, we tested 11 conventional WTs. No statistically significant differences were observed between the two subcohorts regarding patient’s age and tumor size. Six of 22 (27%) proliferating/ metaplastic WTs revealed oncogenic KRAS mutations clustering at codon 12 (exon 2), while all conventional tumors lacked these mutations. Our findings are in line with a neoplastic nature of the epidermoid/ mucoepidermoid proliferations in non-injured “metaplastic” Warthin tumors. We propose the descriptive term “de novo proliferating Warthin tumor” for this variant to distinguish it from infarcted/inflamed genuine metaplastic Warthin tumor.
CRIS-Team Scopus Importer:2023-02-17
Keywords: Cystadenolymphoma; KRAS mutations; Metaplastic Warthin tumor; Mucoepidermoid carcinoma; Salivary glands; Warthin tumor

KRAS, EGFR, PDGFR-?, KIT and COX-2 status in carcinoma showing thymus-like elements (CASTLE) - Veits, Lothar; Schupfner, Rupert; Hufnagel, Petra; Penzel, Roland; Freitag, Jens; Stroebel, Philipp; Kern, Michael A.; Schroeder, Soeren; Neuhold, Nikolaus; Schmid, Kurt W.; Schirmacher, Peter; Hartmann, Arndt; et al. (Diagnostic Pathology, 2014)
CASTLE (Carcinoma showing thymus-like elements) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid.We retrospectively investigated 6 cases of this very rare neoplasm in order to investigate the mutational status of KRAS, EGFR, PDGFR-? and KIT, as well as the immunohistochemical expression pattern of CD117, EGFR and COX-2, and possibly find new therapeutic targets.Diagnosis was confirmed by a moderate to strong expression of CD5, CD117 and CK5/6, whereas thyroglobulin, calcitonin and TTF-1 were negative in all cases. Tumors were also positive for COX-2 and in nearly all cases for EGFR. In four cases single nucleotide polymorphisms (SNPs) could be detected in exon 12 of the PDGFR-? gene (rs1873778), in three cases SNPs were found in exon 20 of the EGFR gene (rs1050171). No mutations were found in the KIT and KRAS gene.All tumors showed a COX-2 expression as well as an EGFR expression except for one case and a wild-type KRAS status. No activating mutations in the EGFR, KIT and PDGFR-? gene could be detected. Our data may indicate a potential for targeted therapies, but if these therapeutic strategies are of benefit in CASTLE remains to be determined.The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1658499296115016.
EVALuna2:6606

Krt20, krt5, esr1 and erbb2 expression can predict pathologic outcome in patients undergoing neoadjuvant chemotherapy and radical cystectomy for muscle-invasive bladder cancer - Jütte, Hendrik; Reike, Moritz; Wirtz, Ralph M.; Kriegmair, Maximilian; Erben, Philipp; Tully, Karl; Weyerer, Veronika; Eckstein, Markus; Hartmann, Arndt; Eidt, Sebastian; Wezel, Felix; Bolenz, Christian; et al. (Journal of Personalized Medicine, 2021)
Patients with muscle-invasive bladder cancer (MIBC) that underwent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) show improved overall survival, especially those with pathological complete response (pCR). The response to NAC according to molecular subtypes has been discussed. Molecular targets such as estrogen receptor (ESR1) and human epidermal growth factor receptor 2 (ERBB2) play an important role in breast cancer management and have also been associated with urothelial bladder cancer. Hence, the association of Keratin 20 (KRT20) Keratin 5 (KRT5), ESR1, and ERBB2 mRNA expression in MIBC at transurethral resection (TUR-BT) with pCR after NAC was analyzed retrospectively. Formalin-fixed paraffin-embedded tumour tissue samples from TUR-BT of 54 patients (42 males, 12 females, median age of 64) with MIBC were analyzed for KRT20, KRT5, ESR1, and ERBB2 mRNA expression. After NAC, RC was performed, and the specimens were evaluated for pCR. Statistical analyses comprised nonparametric and chi2 testing, partition models, and Spearman correlation analyses. After NAC, 22 out of 54 patients (40.7%) had pCR. Tumours with an elevated expression of markers associated with luminal differentiation (KRT20, ERBB2, ESR1) were associated with a higher chance of pCR (55% vs. 15.8%, p = 0.009). Elevated ERBB2 expression was positively correlated with luminal expression features such as KRT20, and negatively with basal characteristics such as KRT5. Patients with MIBC showing a high expression of ERBB2, ESR1, or KRT20 have a significantly higher chance of pCR following NAC. These findings might improve patient selection for NAC in MIBC.
CRIS-Team Scopus Importer:2021-06-25
Keywords: Bladder cancer; Chemotherapy; Muscle invasive; Risk stratification; Subtype

Langerhans Cell Histiocytosis Associated with Renal Cell Carcinoma Is a Neoplastic Process: Clinicopathologic and Molecular Study of 7 Cases - Agaimy, Abbas; Bonert, Michael; Naqvi, Asghar; Wang, Chunjie; Trpkov, Kiril; Dettmar, Peer; Wintzer, Hanns Olof; Stöhr, Robert; Hes, Ondřej; Williamson, Sean R.; Gibson, Ian W.; Hartmann, Arndt (American Journal of Surgical Pathology, 2020)
Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder composed of Langerhans cells admixed with reactive mononuclear and granulocytic cells, associated with prominent eosinophils. LCH is considered a neoplasm, driven in most cases by oncogenic RAS/RAF/MEK/ERK pathway mutations. The disease predominantly affects children. Urinary system involvement has rarely been reported in a multisystem disease setting. We describe 7 patients who presented with LCH occurring within (6 cases) or after (1 case) a resected clear cell (n=6) or clear cell papillary (n=1) renal cell carcinoma (RCC), identified prospectively in our routine and consultation files (2012 to 2019). The patients included 5 women and 2 men, with a median age of 54 years (range, 39 to 73 y), none with a history of LCH or LCH manifestations before the time of RCC diagnosis. The median size of the RCC was 3.5 cm (range, 1.8 to 8.3 cm). Treatment included partial (5 cases), or radical (2 cases) nephrectomy. All RCCs on gross examination showed at least focal cystic changes and were low grade (World Health Organization [WHO]/International Society of Urologic Pathologists [ISUP] grade 1 to 2). The LCH foci were detected as incidental histological finding within the resected RCC in all six cases and they were limited to few high-power fields (<2 mm2) in 5 of 6 cases, but in the sixth case, they occupied almost the entire clear cell papillary RCC (2 cm nodule). No LCH manifestations were detected in the normal kidney or in perinephric fat. The seventh patient developed LCH within inguinal deep soft tissue followed by systemic manifestations 6 years after clear cell RCC. Langerhans cell immunophenotype was supported by the reactivity for S-100, CD1a, and langerin and by the negative pankeratin. Successful pyrosequencing of microdissected LCH DNA revealed the V600E BRAF mutation in all 6 cases of LCH within RCC. To our knowledge, only 3 similar cases were published since 1980; the only case tested for BRAF mutation showed wild-type BRAF. This is the first study analyzing the morphologic and genetic features of a cohort of LCH associated with RCC. In our experience, these cases may be underrecognized in practice, or may erroneously be diagnosed as RCC dedifferentiation or high-grade sarcomatoid transformation. Finally, the detection of BRAF mutation further confirms that LCH in this setting is indeed a neoplasm, rather than a reactive lesion.
CRIS-Team Scopus Importer:2020-12-04
Keywords: BRAF V600E; concurrent; kidney; Langerhans cell histiocytosis; RCC; renal cell carcinoma

Langerhans Cell Histiocytosis Occurring in a Renal Cell Carcinoma is a Neoplastic Process: Clinicopathologic and Molecular Study of Five Cases - Agaimy, Abbas; Bonert, Michael; Naqvi, Asghar; Wang, Chunjie; Hes, Ondrej; Trpkov, Kiril; Gibson, Ian; Hartmann, Arndt (LABORATORY INVESTIGATION, 2020)
CRIS-Team WoS Importer:2020-03-24

Large nested variant of urothelial carcinoma: a clinicopathological study of 36 cases - Comperat, Eva; Mckenney, Jesse K.; Hartmann, Arndt; Hes, Ondrej; Bertz, Simone; Varinot, Justine; Brimo, Fadi (Histopathology, 2017)
AIMS: The large nested variant of urothelial carcinoma (LNUC) has been added to the World Health Organization (WHO) 2016 classification. Scant data exist, and little is known about its clinical behaviour. MATERIAL AND RESULTS: Cases fulfilling the morphological criteria of LNUC were collected. Pure and mixed cases (i.e. with other patterns of invasive UC) were studied. Immunohistochemical staining with cytokeratin (CK)7, p63, GATA-3, CK20, p53 and Ki-67 was performed. Included were 26 cystectomies (RC) and 10 resections (TURB) belonging to 36 patients with an average age of 66.7 years. Fourteen (39%) were pure LNUCs, and 22 (61%) displayed mixed features. Seventy per cent of the TURBs had pT2 tumours, while 58% of RCs had extravesical disease (≥pT3 and/or ≥pN1), with the rate of advanced disease being higher in mixed (69%) in comparison to pure cases (40%). Similarly, 38% of mixed cases had nodal metastases in comparison to 20% of pure cases. Overall, eight patients (24%) died of disease at a mean interval time of 21.7 months and seven patients (21%) showed recurrence or metastases. Disease progression was significantly higher in mixed cases (55 and 31% in mixed and pure cases, respectively). Positive staining was: CK7 = 87.5%, CK20 = 72%, GATA-3 = 91%, P63 = 100%, p53 = 56% and Ki-67 = mean of 16%. CONCLUSION: Despite the bland cytological appearance and deceptive pattern of invasion of the LNUC, our study validates its fully malignant potential with metastatic spread and tumour-related deaths. Distinguishing mixed from pure LNUCs seems to be of value. LNUCs show comparable immunophenotype to both conventional urothelial carcinoma and the nested variant of urothelial carcinoma.
EVALuna2:34252

Large nested variant of urothelial carcinoma: a prime example of a FGFR3-mutated, luminal tumour - Weyerer, Veronika; Eckstein, Markus; Comperat, E.; Juette, H.; Allory, Y.; Stoehr, R.; Wullich, Bernd; Roupret, M.; Hartmann, Arndt; Bertz, Simone (VIRCHOWS ARCHIV, 2019)
CRIS-Team WoS Importer:2019-09-27

Leukocytosis and Neutrophilia as independent prognostic Biomarkers for clinical Outcome in the randomized Phase III CAO/ARO/AIO-04 Rectal Cancer Study - Diefenhardt, M.; Hofheinz, R-D; Martin, D.; Beissbarth, T.; Arnold, D.; Hartmann, Arndt; Von Der Grun, J.; Grützmann, Robert; Liersch, T.; Stroebel, P.; Grabenbauer, G. G.; Rieger, M.; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO-04 randomized phase 3 rectal cancer trial - Diefenhardt, Markus; Hofheinz, Ralf Dieter; Martin, Daniel; Beißbarth, Tim; Arnold, Dirk; Hartmann, Arndt; von der Grün, Jens; Grützmann, Robert; Liersch, Torsten; Ströbel, Philipp; Grabenbauer, Gerhard G.; Rieger, Michael; et al. (International Journal of Cancer, 2019)
Peripheral blood leukocytosis and neutrophilia reflect cancer inflammation and have been proposed as prognostic immunological biomarkers in various malignancies. However, previous studies were limited by their retrospective nature and small patient numbers. Baseline peripheral blood leukocytes, neutrophils, hemoglobin, platelets, lactate dehydrogenase and carcinoembryonic antigen (CEA) were correlated with clinicopathologic characteristics, and clinical outcome in 1236 patients with rectal cancer treated with 5-FU-based preoperative chemoradiotherapy (CRT) alone or with oxaliplatin followed by surgery and adjuvant chemotherapy within the CAO/ARO/AIO-04 randomized phase 3 trial. Multivariable analyses were performed using Cox regression models. After a median follow-up of 50 months, baseline leukocytosis remained an independent adverse prognostic factor for disease-free survival (DFS; HR 1.457; 95% CI 1.163–1.825; p = 0.001), distant metastasis (HR 1.696; 95% CI 1.266–2.273; p < 0.001) and overall survival (OS; HR 1.716; 95% CI 1.264–2.329; p = 0.001) in multivariable analysis. Similar significant findings were observed for neutrophilia and high CEA levels. Conversely, treatment-induced leukopenia correlated with favorable DFS (p = 0.037), distant metastasis (p = 0.028) and OS (p = 0.012). Intriguingly, addition of oxaliplatin to 5-FU CRT resulted in a significant DFS improvement only in patients with neutrophilia and leukocytosis (p = 0.028 and p = 0.002). Our findings have important clinical implications and provide high-level evidence on the adverse prognostic role of leukocytes and neutrophils, and the impact of chemotherapy in the context of these biomarkers. These data could help guide patient stratification and should be further validated within prospective studies.
CRIS-Team Scopus Importer:2019-05-07
Keywords: clinical radiotherapeutic studies; clinical trials; colorectal cancer; molecular markers of metastasis and progression; radiochemotherapy

Life-threatening Autoimmune Cardiomyopathy Reproducibly Induced in a Patient by Checkpoint Inhibitor Therapy - Tajmir-Riahi, Azadeh; Bergmann, Tanja; Schmid, Michael; Agaimy, Abbas; Schuler, Gerold; Heinzerling, Lucie (Journal of Immunotherapy, 2018)
Checkpoint inhibitors induce a plethora of immune-related adverse events (irAEs) including autoimmune colitis, hepatitis, endocrinopathies, and rarer side effects like neuritis. Here, a case of autoimmune cardiomyopathy (grade 3 CTCAE) and myocarditis under combination therapy with nivolumab plus ipilimumab in a 72-year-old melanoma patient is reported. Treatment induced a partial response for 14 months. However, after 10 infusions the patient developed dyspnea, edema of the legs, ascites and a weight gain of 10 kg because of a decompensated heart insufficiency with a reduced ejection fraction from formerly 48%-50% to 15%. Ischemia and viral infections were ruled out. Histopathology showed hypertrophic myocarditis with interstitial lymphocytes. Prednisolone improved the patient's condition within 3 days, leading to a 25% and 30% ejection fraction after 2 and 8 weeks, respectively, and clinical symptoms subsided completely. Importantly, reinduction of anti-PD1 therapy resulted in a flare of myocarditis. Awareness for potentially life-threatening irAE of checkpoint inhibitors like autoimmune cardiomyopathy and myocarditis is crucial to rapidly initiate adequate treatment.
EVALuna2:34413

Lipomatous basal cell adenoma (Basal cell lipoadenoma) – Report of the first two cases - Petersson, Fredrik; Agaimy, Abbas (Annals of Diagnostic Pathology, 2020)
We present, to the best of our knowledge, the first two cases (60 year old female and 71 year old male) of basal cell adenoma with significant adipocytic components and suggest the term “lipomatous basal cell adenoma” for these lesions. Both tumors presented as slow growing nodules in the parotid gland. The two cases represent different points on a histopathological spectrum with one case being extremely well differentiated with distinct spiradenoma-like histological features; distinct bilayering, duct formation with secretory material and very low proliferative activity and the other case displaying more primitive cytological features composed of a predominant uniform, (p63-positive; CK 7-negative) basaloid, abluminal cell type, high proliferative activity and only scattered true ducts composed of (CK7-positive, p63-negative) luminal cells.
CRIS-Team Scopus Importer:2019-12-31
Keywords: Basal cell adenoma; Lipoma; Lipomatous; Metaplasia; Salivary gland

Lipomatous Hypertrophy of the Atrial Septum in a Patient Undergoing Coronary Artery Bypass Surgery - Strecker, Thomas; Weyand, Michael; Agaimy, Abbas (Case Reports in Pathology, 2016)
Background. Lipomatous hypertrophy of the atrial septum (LHAS) is a rare entity characterized by mass-forming deposition of fatty tissue within the atrial septum. To date, <300 cases have been reported; many of them were autopsy findings. The clinical presentation of LHAS varies from incidental asymptomatic mass (most frequent form) to severe life-threatening cardiovascular complications necessitating emergency cardiac surgery. Case Presentation. Here, we present the successful surgical resection of such a massive LHAS which was found incidentally on preoperative investigation of a 71-year-old patient with progressive coronary heart disease. Histology confirmed the diagnosis of lipomatous hypertrophy of the atrial septum. Conclusions. The described case report illustrates an unusual example of LHAS in a patient undergoing a planned coronary artery bypass surgery. In this case, surgical intervention was justified to avoid later outflow obstructions.
EVALuna2:6927

Lipomatous Solitary Fibrous Tumors Harbor Rare NAB2-STAT6 Fusion Variants and Show Up-Regulation of the Gene PPARG, Encoding for a Regulator of Adipocyte Differentiation - Haller, Florian; Schlieben, Lea D.; Ferrazzi, Fulvia; Michal, Michael; Stöhr, Robert; Moskalev, Evgeny; Bieg, Matthias; Bovée, Judith V.M.G.; Ströbel, Philip; Ishaque, Naveed; Grützmann, Robert; Meidenbauer, Norbert; et al. (American Journal of Pathology, 2021)
Solitary fibrous tumors (SFTs) harbor activating NAB2-STAT6 gene fusions. Different variants of the NAB2-STAT6 gene fusion have been associated with distinct clinicopathologic features. Lipomatous SFTs are a morphologic variant of SFTs, characterized by a fat-forming tumor component. Our aim was to evaluate NAB2-STAT6 fusion variants and to further study the molecular genetic features in a cohort of lipomatous SFTs. A hybrid-capture–based next-generation sequencing panel was employed to detect NAB2-STAT6 gene fusions at the RNA level. In addition, the RNA expression levels of 507 genes were evaluated using this panel, and were compared with a control cohort of nonlipomatous SFTs. Notably, 5 of 11 (45%) of lipomatous SFTs in the current series harbored the uncommon NAB2 exon 4–STAT6 exon 4 gene fusion variant, which is observed in only 0.9% to 1.4% of nonlipomatous SFTs. Furthermore, lipomatous SFTs displayed significant differences in gene expression compared with their nonlipomatous counterparts, including up-regulation of the gene peroxisome proliferator activated receptor-γ (PPARG). Peroxisome proliferator activated receptor-γ is a nuclear receptor regulating adipocyte differentiation, providing a possible explanation for the fat-forming component in lipomatous SFTs. In summary, the current study provides a possible molecular genetic basis for the distinct morphologic features of lipomatous SFTs.
CRIS-Team Scopus Importer:2021-06-04

Liver-intestine-cadherin is a sensitive marker of intestinal differentiation during barrett's carcinogenesis - Mokrowiecka, Anna; Zonnur, Sarah; Veits, Lothar; Musial, Jacek; Kordek, Radzislaw; Lochowski, Mariusz; Kozak, Jozef; Malecka-Panas, Ewa; Vieth, Michael; Hartmann, Arndt (Digestive Diseases and Sciences, 2013)
Background: Histopathologic differentiation between the stages of Barrett's carcinogenesis is often challenging. Liver-intestine (LI)-cadherin, an intestine-specific marker, is involved in intestinal metaplasia development in gastric and colon cancers and could be of value in diagnosis and differentiation. Aims: To examine the expression of LI-cadherin in the sequence of Barrett's carcinogenesis and to evaluate its association with clinicopathological data. Methods: LI-cadherin expression was immunohistologically investigated, by use of anti-CDH17 antibody, in gastric mucosa (GM) biopsies taken from the cardia (n = 9), in Barrett's esophagus (BE) without intraepithelial neoplasia (without IEN) (n = 9) and BE with low-grade IEN (n = 11), and in esophageal adenocarcinoma (ADC) (n = 13). Results: The immunoreactivity score was highest in adenocarcinoma (mean IRS = 4.0), and dropped gradually from BE with IEN and BE without IEN (mean IRS = 2.0) to cardia mucosa (IRS = 0). Similarly, the intensity of staining and the percentage of positive cells increased during the sequential stages of BE carcinogenesis. Comparative analysis showed that LI-cadherin expression was significantly different between cardiac epithelium and ADC. Also, percentage of positive cells in GM was significantly different from that in BE with IEN. LI-cadherin IRS was lower for tumors with poor differentiation than for moderately differentiated tumors, but the difference was not statistically significant. Conclusions: LI-cadherin is a sensitive marker of intestinal metaplasia and can be helpful for early histologic diagnosis of Barrett's esophagus; it is, however, not significantly different between BE with and without IEN, and cannot be used to distinguish between these. © 2012 The Author(s).
CRIS-Team Scopus Importer:2025-03-05
Keywords: Barrett's esophagus; Esophageal adenocarcinoma; Intestinal metaplasia; Intraepithelial neoplasia; LI-cadherin

Locoregional metastatic behavior in a complex mosaic of primary malignant tumors of the parotid gland - Varga, Regina; Iro, Ann Kristin; Thimsen, Vivian; Sievert, Matti; Agaimy, Abbas; Balk, Matthias; Rupp, Robin; Grundtner, Philipp; Koch, Michael; Iro, Heinrich; Mantsopoulos, Konstantinos (American Journal of Otolaryngology, 2023)
Background: The aim of the study was to investigate primary locoregional metastatic behavior in a large sample of various malignant tumors of the parotid gland with varying grades following surgical treatment consisting of complete parotidectomy and neck dissection. Methods: The records of all patients treated for primary malignant tumors of the parotid gland by means of complete parotidectomy and neck dissection between 2007 and 2022 were studied retrospectively. Results: 196 patients formed our study sample (98 females, 98 males). The mean age was 65.7 years (22–101 years). 92 cases presented with low-grade subtypes, 19 with intermediate-grade, and 85 with high-grade carcinomas. The locoregional lymphatic network had been invaded in a total of 66/196 cases (33.6 %). The intraparotid lymph nodes were positive in 54/196 cases (27.5 %) and the cervical lymph nodes in 41/196 cases (20.9 %). In 12 out of the 66 cases with a pN+ status, the neck had been invaded without involvement of the intraparotideal lymph nodes (18.2 %). Male patients tended to suffer from more aggressive carcinomas, and high-grade subtypes presented significantly more frequently as locally advanced tumors. Higher grading was significantly associated with the involvement of the parotid (p < 0.001) and cervical (p < 0.001) lymph nodes. Intermediate and low-grade cases presented similar behavior concerning tumorous invasion of the lymphatic network of the parotid gland (p = 0.522) and the neck (p = 0.467). Conclusion: The locoregional metastatic potential of parotid malignant tumors depends upon a variety of histopathologic factors, which have to be considered in the decision-making process concerning the management of locoregional lymph nodes.
CRIS-Team Scopus Importer:2023-07-21
Keywords: High-grade; Low-grade; Malignant tumor; Neck dissection; Parotid gland; Parotidectomy

Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene-specific DNA methylation patterns - Bure, Irina; Geer, Sandra; Knopf, Jasmin; Roas, Maike; Henze, Sabine; Stroebel, Philipp; Agaimy, Abbas; Wiemann, Stefan; Hoheisel, Joerg D.; Hartmann, Arndt; Haller, Florian; Moskalev, Evgeny (Genes Chromosomes & Cancer, 2018)
Aberrant alterations of DNA methylation are common events in oncogenesis. The origin of cancer-associated epigenetic defects is of interest for mechanistic understanding of malignant transformation and-in the long run-therapeutic modulation of DNA methylation in a locus-specific manner. Given the ability of certain long noncoding RNAs to operate as an interface between DNA and the epigenetic modification machinery which can interact with DNA methyltransferases, we hypothesized-considering HOTAIR as an example-that this transcript may contribute to gene specificity of DNA methylation. Using gastrointestinal stromal tumors (GISTs, n = 67) as a model, we confirmed upregulation of HOTAIR in tumors with high risk of recurrence and showed high abundance of the transcript in GIST cell lines. HOTAIR knockdown in GIST-T1 cells triggered transcriptional response of genes involved in the organization and disassembly of the extracellular matrix and, notably, induced global locus-specific alterations of DNA methylation patterns. Hypomethylation was induced at a total of 507 CpG sites, whereas 382 CpG dinucleotides underwent gain of methylation upon HOTAIR depletion. Importantly, orchestrated gain or loss of methylation at multiple individual CpG sites was shown for cancer-related DPP4, RASSF1, ALDH1A3, and other targets. Collectively, our data indicate that HOTAIR enables target specificity of DNA methylation in GIST and is capable of dual (hypo- and hypermethylation) regulation by a yet to be defined mechanism. The results further suggest the feasibility of manipulating DNA methylation in a targeted manner and are of interest in the context of epigenetic cancer therapy.
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Long-term Combination Therapy with Anti-TNF plus Vedolizumab Induces and Maintains Remission in Therapy-refractory Ulcerative Colitis - Fischer, Sören; Rath, Timo; Geppert, Carol-Immanuel; Manger, Bernhard; Schett, Georg; Neurath, Markus; Atreya, Raja (American Journal of Gastroenterology, 2017)
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Long-term control with chemoradiation of initially metastatic mixed adenoneuroendocrine carcinoma of the rectum: A case report - Semrau, S.; Agaimy, Abbas; Pavel, Marianne Ellen; Lubgan, Dorota; Schmidt, Daniela; Golcher, H.; Grützmann, Robert; Fietkau, Rainer; Cavallaro, Alexander Josef (Journal of Medical Case Reports, 2019)
Background: Mixed adenoneuroendocrine carcinomas are highly malignant tumors with both adenocarcinomatous and neuroendocrine components. They can originate in any organ but are more common in the rectum. Due to their rarity, current treatment recommendations for mixed adenoneuroendocrine carcinoma are based on limited data and follow general guidelines for the management of adenocarcinomas and neuroendocrine neoplasms. Uncertainty regarding the efficacy of the available local and systemic treatment strategies is a compounding issue. Even those patients with locally limited disease have a relatively short life expectancy. In this report, we describe a case of deep rectal mixed adenoneuroendocrine carcinoma with long survival after chemoradiation. Case presentation: A 48-year-old Caucasian woman was diagnosed with a grade 3 rectal adenocarcinoma combined with a poorly differentiated large cell neuroendocrine carcinoma component and synchronous metastases (cT3cN1cM1) in both lobes of the liver in 2012. She received concomitant chemoradiotherapy followed by four additional cycles of cisplatin plus irinotecan. Initial treatment induced complete remission of the rectal tumor and liver metastases. Consequently, it was not necessary to surgically resect the primary tumor or any of the metastases. Three months after the end of treatment, one metastasis in the first segment of the liver showed regrowth, and stereotactic body radiotherapy of the metastasis and chemotherapy resulted in a clinical complete response. The patient has been recurrence-free for more than 5 years. Conclusions: Extended long-term control of a poorly differentiated metastatic (stage IV) mixed adenoneuroendocrine carcinoma is rare. The multimodal first- and second-line regimens of radiotherapy and chemotherapy described in this case report represent a new therapeutic approach. Encouraged by the results in this case, we compiled a review of the literature on mixed adenoneuroendocrine carcinoma.
CRIS-Team Scopus Importer:2019-05-14
Keywords: Chemoradiation; MANEC; Rectum; SBRT

Long-term durability of Starr-Edwards disk mitral valve prosthesis over 46 years - Strecker, Thomas; Agaimy, Abbas; Roesch, Johannes; Jasinski, Dominik (Journal of Cardiac Surgery, 2020)
CRIS-Team Scopus Importer:2020-05-08
Keywords: cardiac surgery; computed tomography; echocardiography; long-term durability; mechanical mitral valve prosthesis

Long-term endothelial dysfunction in irradiated vessels: an immunohistochemical analysis - Preidl, Raimund; Möbius, Patrick; Weber, Manuel; Amann, Kerstin Ute; Neukam, Friedrich Wilhelm; Kesting, Marco Rainer; Geppert, Carol-Immanuel; Wehrhan, Falk (Strahlentherapie und Onkologie, 2019)
BACKGROUND: Microvascular free flap reconstruction has become a standard technique in head and neck reconstructive surgery. Pre-operative radiotherapy is associated with a higher incidence of free flap malperfusion and the need for operative revision. Irradiated vessels present characteristic histomorphological and structural changes. Alterations in endothelial cells of irradiated arteries remain incompletely investigated especially with regard to long-term changes in endothelial dysfunction supporting an intraluminal pro-thrombotic and pro-inflammatory milieu. METHODS: Endothelial expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E‑ and P‑selectin, endothelial NO-synthase (eNOS), thrombomodulin and plasminogen activator inhibitor-1 (PAI-1) in irradiated and non-irradiated arteries was analysed using immunohistochemistry and Remmele scale grading. The average radiation dose was 58.7 ± 7.0 Gy; the time interval between end of radiation and tissue sampling was 106.0 ± 86.8 months. RESULTS: Endothelial expression of ICAM-1, VCAM-1, E‑ and P‑selectin as well as PAI-1 was significantly increased in previously irradiated arteries compared with non-irradiated controls, whereas thrombomodulin and eNOS expression did not show any differences. However, when comparing non-irradiated free flap arteries with irradiated arteries from the head and neck area in respective individuals, eNOS expression was significantly lower in irradiated vessels whereas ICAM-1, VCAM-1, E‑/p-Selectin and PAI-1 showed significantly higher expression levels. CONCLUSION: There is ongoing endothelial dysfunction in terms of increased expression of pro-thrombotic and pro-inflammatory markers in irradiated arteries even years after radiotherapy. Treating this endothelial dysfunction might reduce the complication rates associated with microvascular free flap reconstructions in irradiated patients.
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Long-term endothelial dysfunction in irradiated vessels: an immunohistochemical analysis Langzeit-Endothelfunktionsstörung in bestrahlten Gefäßen: immunhistochemische Analyse - Preidl, Raimund; Möbius, Patrick; Weber, Manuel; Amann, Kerstin Ute; Neukam, Friedrich Wilhelm; Kesting, Marco Rainer; Geppert, Carol-Immanuel; Wehrhan, Falk (Strahlentherapie und Onkologie, 2019)
Background: Microvascular free flap reconstruction has become a standard technique in head and neck reconstructive surgery. Pre-operative radiotherapy is associated with a higher incidence of free flap malperfusion and the need for operative revision. Irradiated vessels present characteristic histomorphological and structural changes. Alterations in endothelial cells of irradiated arteries remain incompletely investigated especially with regard to long-term changes in endothelial dysfunction supporting an intraluminal pro-thrombotic and pro-inflammatory milieu. Methods: Endothelial expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E‑ and P‑selectin, endothelial NO-synthase (eNOS), thrombomodulin and plasminogen activator inhibitor-1 (PAI-1) in irradiated and non-irradiated arteries was analysed using immunohistochemistry and Remmele scale grading. The average radiation dose was 58.7 ± 7.0 Gy; the time interval between end of radiation and tissue sampling was 106.0 ± 86.8 months. Results: Endothelial expression of ICAM-1, VCAM-1, E‑ and P‑selectin as well as PAI-1 was significantly increased in previously irradiated arteries compared with non-irradiated controls, whereas thrombomodulin and eNOS expression did not show any differences. However, when comparing non-irradiated free flap arteries with irradiated arteries from the head and neck area in respective individuals, eNOS expression was significantly lower in irradiated vessels whereas ICAM-1, VCAM-1, E‑/p-Selectin and PAI-1 showed significantly higher expression levels. Conclusion: There is ongoing endothelial dysfunction in terms of increased expression of pro-thrombotic and pro-inflammatory markers in irradiated arteries even years after radiotherapy. Treating this endothelial dysfunction might reduce the complication rates associated with microvascular free flap reconstructions in irradiated patients.
CRIS-Team Scopus Importer:2019-05-03
Keywords: Endothelial dysfunction; Free tissue flaps; Radiation dosage; Radiotherapy; Reconstructive surgery

Long-Term Endurance Exercise in Humans Stimulates Cell Fusion of Myoblasts along with Fusogenic Endogenous Retroviral Genes In Vivo - Frese, Sebastian; Rübner, Matthias; Suhr, Frank; Konou, Thierry M.; Tappe, Kim A.; Toigo, Marco; Jung, Hans H.; Henke, Christine; Steigleder, Ruth; Strissel, Pamela; Hübner, Hanna; Beckmann, Matthias; et al. (PLoS ONE, 2015)
Myogenesis is defined as growth, differentiation and repair of muscles where cell fusion of myoblasts to multinucleated myofibers is one major characteristic. Other cell fusion events in humans are found with bone resorbing osteoclasts and placental syncytiotrophoblasts. No unifying gene regulation for natural cell fusions has been found. We analyzed skeletal muscle biopsies of competitive cyclists for muscle-specific attributes and expression of human endogenous retrovirus (ERV) envelope genes due to their involvement in cell fusion of osteoclasts and syncytiotrophoblasts. Comparing muscle biopsies from post- with the pre-competitive seasons a significant 2.25-fold increase of myonuclei/mm fiber, a 2.38-fold decrease of fiber area/nucleus and a 3.1-fold decrease of satellite cells (SCs) occurred. We propose that during the pre-competitive season SC proliferation occurred following with increased cell fusion during the competitive season. Expression of twenty-two envelope genes of muscle biopsies demonstrated a significant increase of putative muscle-cell fusogenic genes Syncytin-1 and Syncytin-3, but also for the non-fusogenic erv3. Immunohistochemistry analyses showed that Syncytin-1 mainly localized to the sarcolemma of myofibers positive for myosin heavy-chain isotypes. Cellular receptors SLC1A4 and SLC1A5 of Syncytin-1 showed significant decrease of expression in post-competitive muscles compared with the pre-competitive season, but only SLC1A4 protein expression localized throughout the myofiber. Erv3 protein was strongly expressed throughout the myofiber, whereas envK1-7 localized to SC nuclei and myonuclei. Syncytin-1 transcription factors, PPAR? and RXR?, showed no protein expression in the myofiber, whereas the pCREB-Ser133 activator of Syncytin-1 was enriched to SC nuclei and myonuclei. Syncytin-1, Syncytin-3, SLC1A4 and PAX7 gene regulations along with MyoD1 and myogenin were verified during proliferating or actively-fusing human primary myoblast cell cultures, resembling muscle biopsies of cyclists. Myoblast treatment with anti-Synycytin-1 abrogated cell fusion in vitro. Our findings support functional roles for ERV envelope proteins, especially Syncytin-1, contributing to cell fusion of myotubes.
EVALuna2:17549

Long-Term Experience of Chemoradiotherapy Combined with Deep Regional Hyperthermia for Organ Preservation in High-Risk Bladder Cancer (Ta, Tis, T1, T2) - Merten, Ricarda; Ott, Oliver; Haderlein, Marlen; Bertz, Simone; Hartmann, Arndt; Wullich, Bernd; Keck, Bastian; Kühn, Reinhard; Rödel, Claus Michael; Weiss, Christian; Gall, Christine; Uter, Wolfgang; et al. (Oncologist, 2019)
Background: The aim of this study was to evaluate the efficacy and safety of chemoradiotherapy (RCT) combined with regional deep hyperthermia (RHT) of high-risk bladder cancer after transurethral resection of bladder tumor (TUR-BT). Materials and methods: Between 1982 and 2016, 369 patients with pTa, pTis, pT1, and pT2 cN0–1 cM0 bladder cancer were treated with a multimodal treatment after TUR-BT. All patients received radiotherapy (RT) of the bladder and regional lymph nodes. RCT was administered to 215 patients, RCT + RHT was administered to 79 patients, and RT was used in 75 patients. Treatment response was evaluated 4–6 weeks after treatment with TUR-BT. Results: Complete response (CR) overall was 83% (290/351), and in treatment groups was RT 68% (45/66), RCT 86% (178/208), and RCT + RHT 87% (67/77). CR was significantly improved by concurrent RCT compared with RT (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.05–5.12; p =.037), less influenced by hyperthermia (OR, 2.56; 95% CI, 0.88–8.00; p =.092). Overall survival (OS) after RCT was superior to RT (hazard ratio [HR], 0.7; 95% CI, 0.50–0.99; p =.045). Five-year OS from unadjusted Kaplan-Meier estimates was RCT 64% versus RT 45%. Additional RHT increased 5-year OS to 87% (HR, 0.32; 95% CI, 0.18–0.58; p =.0001). RCT + RHT compared with RCT showed a significantly better bladder-preservation rate (HR, 0.13; 95% CI, 0.03–0.56; p =.006). Median follow-up was 71 months. The median number of RHT sessions was five. Conclusion: The multimodal treatment consisted of a maximal TUR-BT followed by RT; concomitant platinum-based chemotherapy combined with RHT in patients with high-grade bladder cancer improves local control, bladder-preservation rate, and OS. It offers a promising alternative to surgical therapies like radical cystectomy. Implications for Practice: Radical cystectomy with appropriate lymph node dissection has long represented the standard of care for muscle-invasive bladder cancer in medically fit patients, despite many centers reporting excellent long-term results for bladder preserving strategies. This retrospective analysis compares different therapeutic modalities in bladder-preservation therapy. The results of this study show that multimodal treatment consisting of maximal transurethral resection of bladder tumor followed by radiotherapy, concomitant platinum-based chemotherapy combined with regional deep hyperthermia in patients with Ta, Tis, T1–2 bladder carcinomas improves local control, bladder-preservation rate, and survival. More importantly, these findings offer a promising alternative to surgical therapies like radical cystectomy. The authors hope that, in the future, closer collaboration between urologists and radiotherapists will further improve treatments and therapies for the benefit of patients.
CRIS-Team Scopus Importer:2019-08-13
Keywords: Bladder cancer; Bladder preservation; Chemoradiotherapy; Hyperthermia; Radiotherapy

Long‐term follow‐up of patients receiving neoadjuvant treatment modalties for soft tissue sarcomas of the extremities - Rauch, Miriam; Agaimy, Abbas; Semrau, Sabine; Willner, Alexander; Ott, Oliver; Fietkau, Rainer; Hohenberger, Werner; Croner, Roland S.; Grützmann, Robert; Fechner, Katja; Vassos, Nikolaos (Cancers, 2021)
Background: Neoadjuvant treatment modalities in soft tissue sarcoma (STS) of the extremities have become more popular in recent years, but because of the rarity and heterogeneity of STS, there are yet few studies on the long‐term impact of neoadjuvant treatment modalities, especially in terms of neoadjuvant radiochemotherapy. Methods: The study enrolled 136 patients with primary STS of the extremities who underwent surgery with curative intent or neoadjuvant therapy, followed by surgery in a 15‐year period. Neoadjuvant treatment consisted of radiotherapy (RT) with 60 Gy and in most cases simultaneous chemotherapy (CTx) with ifosfamide (1.5 g/m2/d, d1–5, q28) and doxorubicine (50 mg/m2/d, d3, q28). We investigated the clinical, (post)‐operative and histopathological data and the oncological follow‐up as well. The median follow‐up period was 82 months (range 6–202). Results: A total of 136 patients (M:F = 73:63) with a mean age of 62 years (range; 21–93) was observed. Seventy‐four patients (54.4%) received neoadjuvant therapy (NT), 62 patients (45.6%) received primary surgery (PS). When receiving NT, patients with high‐risk STS had a lower risk to develop distant metastasis (p = 0.025). Age, histological type, tumor size and surgical margins (R0 vs. R1) had no influence on any survival rates. There was an association between NT and the occurrence of postoperative complications (p = 0.001). The 5‐year local recurrence free survival (LRFS), metastasis free survival (MFS), disease free survival (DFS) and overall survival (OS) rate of the whole cohort was 89.9%, 77.0%, 70.6% and 72.6%; whereas the 5‐year LRFS, MFS, DFS and OS rate was 90.5%, 67.2%, 64.1% and 62.8% for the NT group and 89.5%, 88.3%. 78.4% and 83.8% for the PS group. Conclusion: Multimodal treatment strategies in patients with STS of extremities lead to excellent oncological outcomes. Patients with high‐risk STS had a significantly better MFS when receiving NT than patients with low‐risk STS. NT was associated with a higher probability of postoperative but well‐manageable complications.
CRIS-Team Scopus Importer:2021-10-29
Keywords: Extremity; Neoadjuvant therapy; Radiation; Radiochemotherapy; Soft tissue sarcoma

Long term follow up of through-the-scope balloon dilation as compared to strictureplasty and bowel resection of intestinal strictures in crohn's disease - Krauss, Ekaterina; Agaimy, Abbas; Gottfried, Angelina; Maiss, Juergen; Weidinger, Thomas; Albrecht, Heinz; Hartmann, Arndt; Hohenberger, Werner; Neurath, Markus; Kessler, Hermann; Mudter, Jonas (International Journal of Clinical and Experimental Pathology, 2014)
Ileo-colonic strictures are common complication of Crohn's disease (CD), and may result in repeated endoscopic or surgical therapy with a risk of further complications, such as perforation or short bowel syndrome. Strictures develop as a consequence of tissue remodelling and fibrosis due to chronic inflammation. This study compares the outcome of CD patients undergoing primarily endoscopic treatment with those undergoing surgery at an university hospital.In this study we retrospectively included 88 CD patients with intestinal strictures (37 males, 51 females, mean age 40 years, range 19-65 years) of both our medical and our surgical department, who underwent either surgical or endoscopic therapy between January 2002 and January 2006 with prospective, controlled follow-up, extended till January 2010 (mean follow-up period: 5 years; range 4-8 years). The primary end-point was operation- and symptom-free time. Patients were primarily divided into four groups: only surgical therapy, only endoscopic therapy, endoscopy with subsequent surgery, and initial surgical therapy followed by endoscopic dilations.53% of all patients remained surgery-free with mean follow-up of 49 months; a single endoscopic dilation was sufficient enough in 9 patients to achieve a surgery-free time of 51 months, other patients required up to 5 dilations. The average interval between first and second dilation was 6.5 months, between second and third 10.5 months. In the group of patients with only endoscopic therapy, surgery- and symptom-free time was shorter, as compared to the group of only surgical therapy. We found that stenoses in the surgical group with an average length of 6.5 cm were as expected longer, as compared to the endoscopic group (3 cm, ranging from 2-4 cm). The surgery-free time was 49 months (42-71 months, P = 0.723) with a symptom-free time of 12 months (4.5-46 months, P = 0.921). In the group of only surgically treated patients, 68.4% of the patients had only one stenosis, 18.4% had 2-3 stenoses and 13.2% more than 3 stenoses. In all patients the surgery- and symptoms- free time was 69 months (57-83 months, P = 0.850 and 0.908). The other two groups showed similar results. We found no significant effect of characteristic of stenosis (length, inflammation, the number of stenoses), injection of prednisolone, disease activity at the time of dilation and medication at the time of dilation on the long-term outcome. Importantly, the success of symptom free time correlated with the diameter of the balloon.Endoscopic dilation should be considered as a first-line therapy for short, accessible, fibrotic strictures. Careful patient selection and proper diagnostic imaging pre-procedure are essential requirements for safe and successful treatment. The balloon diameter seems to correlate positively with the long term outcome of dilation. However, at ever shorter intervals between endoscopic interventions, surgery should be discussed as an option for further treatment.
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Long-term outcomes of cyclosporin induction and ustekinumab maintenance combination therapy in patients with steroid-refractory acute severe ulcerative colitis - Vitali, Francesco; Rath, Timo; Klenske, Entcho; Vögele, Anna-Lena; Ganzleben, Ingo; Zundler, Sebastian; Strobel, Deike; Geppert, Carol-Immanuel; Hartmann, Arndt; Neurath, Markus; Atreya, Raja (Therapeutic Advances in Gastroenterology, 2024)
Background: Effective management of patients with acute severe ulcerative colitis (ASUC) is a major challenge and there remains a paucity of available maintenance treatment options after efficacious cyclosporin induction therapy. Objectives: We investigated the long-term effectiveness and safety of cyclosporin and ustekinumab combination therapy in patients with steroid refractory ASUC. Design: Monocentric, prospective study. Methods: We included patients with steroid refractory ASUC with multiple failed prior advanced therapies, who were treated with cyclosporin and ustekinumab combination therapy. Results: Among the 11 included patients, 10 had prior failure to infliximab and 8 failed at least three previous biological therapies. The mean baseline Mayo and Lichtiger scores were 10.9 (9–12) and 13.3 (11–14), respectively. Ustekinumab was initiated 3.2 weeks (1–8) after initiation of cyclosporin treatment and combination therapy was continued for a mean of 11.5 (4–20) weeks. Clinical response was achieved in six patients at week 16 and clinical steroid-free clinical remission in five patients at week 48. Endoscopic remission was achieved in five patients at week 16 and together with histological remission in five patients at week 52. Intestinal ultrasound demonstrated mean bowel wall thickening in the sigmoid colon of 5.5 mm at baseline and 3.5 mm at week 52, respectively. Two patients had to undergo colectomy (mean 4.5 months, range 3–6) and three stopped ustekinumab therapy due to ineffectiveness. Overall, combination therapy was well tolerated. Conclusion: Combination of cyclosporin and ustekinumab therapy allowed nearly half of ASUC patients to reach clinical and endoscopic remission after 52 weeks, warranting further studies. Trial registration: Not applicable.
CRIS-Team Scopus Importer:2024-01-19
Keywords: cyclosporin; proctocolectomy; severe ulcerative colitis; sonography; ustekinumab

Loss of AQP3 protein expression is associated with worse progression-free and cancer-specific survival in patients with muscle-invasive bladder cancer - Rubenwolf, Peter; Thomas, Christian; Denzinger, Stefan; Hartmann, Arndt; Burger, Maximilian; Georgopoulos, Nikolaos T.; Otto, Wolfgang (World Journal of Urology, 2015)
Urothelial carcinoma has recently been shown to express several aquaporins (AQP), with AQP3 being of particular interest as its expression is reduced or lost in tumours of higher grade and stage. Loss of AQP3 expression was associated with worse progression-free survival (PFS) in patients with pT1 bladder cancer. The objective of this study was to investigate the prognostic value of AQP3 expression in patients with muscle-invasive bladder carcinoma (MIBC).Retrospective single-centre analysis of the oncological outcome of patients following radical cystectomy (Cx) due to MIBC. Immunohistochemistry was used to assess AQP3 protein expression in 100 Cx specimens. Expression levels of AQP3 were related to clinicopathological variables. The impact of biomarker expression on progression-free, cancer-specific and overall survival was determined by multivariate Cox regression analysis (MVA).High expression of AQP3 by the tumour was associated with a statistically significantly improved PFS (75 vs. 19 %, p = 0.043) and CSS (75 vs. 18 %, p = 0.030) and, alongside lymph node involvement, was an independent predictor of PFS (HR 2.871, CI 1.066-7.733, p = 0.037), CSS (HR 3.325, CI 1.204-8.774, p = 0.019) and OS (HR 2.001, CI 1.014-3.947) in MVA.Although the results of the study would be strengthened by a larger, more appropriately powered, prospective, multi-institutional study, our findings strongly suggest that AQP3 expression status may represent an independent predictor of PFS and CSS in MIBC and may help select patients in need for (neo-)adjuvant chemotherapy.
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Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer - Lorsy, Eva; Topuz, Aylin Sophie; Geisler, Cordelia; Stahl, Sarah; Garczyk, Stefan; Von Stillfried, Saskia; Hoss, Mareike; Gluz, Oleg; Hartmann, Arndt; Knuechel, Ruth; Dahl, Edgar (PLoS ONE, 2016)
Dickkopf 3 (DKK3) has been associated with tumor suppression of various tumor entities including breast cancer. However, the functional impact of DKK3 on the tumorigenesis of distinct molecular breast cancer subtypes has not been considered so far. Therefore, we initiated a study analyzing the subtype-specific DKK3 expression pattern as well as its prognostic and functional impact with respect to breast cancer subtypes. Based on three independent tissue cohorts including one in silico dataset (n = 30, n = 463 and n = 791) we observed a clear down-regulation of DKK3 expression in breast cancer samples compared to healthy breast tissue controls on mRNA and protein level. Interestingly, most abundant reduction of DKK3 expression was detected in the highly aggressive basal breast cancer subtype. Analyzing a large in silico dataset comprising 3,554 cases showed that low DKK3 mRNA expression was significantly associated with reduced recurrence free survival (RFS) of luminal and basal-like breast cancer cases. Functionally, DKK3 re-expression in human breast cancer cell lines led to suppression of cell growth possibly mediated by up-regulation of apoptosis in basal-like but not in luminal-like breast cancer cell lines. Moreover, ectopic DKK3 expression in mesenchymal basal breast cancer cells resulted in partial restoration of epithelial cell morphology which was molecularly supported by higher expression of epithelial markers like E-Cadherin and down-regulation of mesenchymal markers such as Snail 1. Hence, we provide evidence that down-regulation of DKK3 especially promotes tumorigenesis of the aggressive basal breast cancer subtype. Further studies decoding the underlying molecular mechanisms of DKK3-mediated effects may help to identify novel targeted therapies for this clinically highly relevant breast cancer subtype.
EVALuna2:6919

Loss of enhancer of zeste homologue 2 (EZH2) at tumor invasion front is correlated with higher aggressiveness in colorectal cancer cells - Böhm, Julian; Muenzner, Julienne Kathrin; Caliskan, Aylin; Ndreshkjana, Benardina; Erlenbach-Wünsch, Katharina; Merkel, Susanne; Croner, Roland; Rau, Tilman; Geppert, Carol-Immanuel; Hartmann, Arndt; Roehe, Adriana Vial; Schneider-Stock, Regine (Journal of Cancer Research and Clinical Oncology, 2019)
Purpose: Enhancer of zeste homolog 2 (EZH2) is associated with epigenetic gene silencing and aggressiveness in many tumor types. However, the prognostic impact of high EZH2 expression is controversially discussed for colorectal cancer. For this reason, we immunohistochemically analyzed EZH2 expression in 105 specimens from colon cancer patients separately for tumor center and invasion front. Methods: All sections from tissue microarrays were evaluated manually and digitally using Definiens Tissue Studio software (TSS). To mirror-image the EZH2 status at the tumor invasion front, we treated HCT116 colon cancer cells with the EZH2 inhibitor 3-Deazaneplanocin A (DZNep) and studied the growth of in ovo xenografts in the chorioallantoic membrane (CAM) assay. Results: We showed a significant decrease in EZH2 expression and the repressive H3K27me3 code at the tumor invasion front as supported by the TSS-constructed heatmaps. Loss of EZH2 at tumor invasion front, but not in tumor center was correlated with unfavorable prognosis and more advanced tumor stages. The observed cell cycle arrest in vitro and in vivo was associated with higher tumor aggressiveness. Xenografts formed by DZNep-treated HCT116 cells showed loosely packed tumor masses, infiltrative growth into the CAM, and high vessel density. Conclusion: The differences in EZH2 expression between tumor center and invasion front as well as different scoring and cutoff values can most likely explain controversial literature data concerning the prognostic value of EZH2. Epigenetic therapies using EZH2 inhibitors have to be carefully evaluated for each specific tumor type, since alterations in cell differentiation might lead to unfavorable results.
CRIS-Team Scopus Importer:2019-07-23
Keywords: CAM assay; Colorectal cancer; EZH2; EZH2 inhibition; Tumor invasion front; Worse prognosis

Loss of expression of the SWI/SNF complex is a frequent event in undifferentiated/dedifferentiated urothelial carcinoma of the urinary tract - Agaimy, Abbas; Bertz, Simone; Cheng, Liang; Hes, Ondrej; Junker, Kerstin; Keck, Bastian; Lopez-Beltran, Antonio; Stoeckle, Michael; Wullich, Bernd; Hartmann, Arndt (Virchows Archiv, 2016)
Loss of the SWI/SNF chromatin remodeling complex has been recently implicated in the pathogenesis of dedifferentiated carcinomas from different organs, but its possible role in undifferentiated urothelial carcinoma (UC) has not been studied to date. In this study, we analyzed by immunohistochemistry 14 undifferentiated UCs (11 from bladder and 3 from renal pelvis) with a nondescript anaplastic or rhabdoid morphology, using commercially available antibodies against the SWI/SNF components SMARCB1 (INI1), SMARCA2, SMARCA4, SMARCC1, SMARCC2, and ARID1A. Patients were eight females and six males aged 40 to 84 years (median, 65). All tumors were muscle-invasive (9 were T3-4). A conventional UC component was seen in eight cases and varied from in situ to papillary. The undifferentiated component comprised 60-100 % of the tumors. Histologically, most tumors showed diffuse dyscohesive or pseudoalveolar growth of variably sized cells with frequent rhabdoid features. Transition from conventional to undifferentiated UC was abrupt, except in one case. The undifferentiated component almost always expressed pan-cytokeratin AE1/AE3 (13/14) and variably vimentin (8/14) and GATA3 (9/14). Complete loss of at least one SWI/SNF subunit limited to the undifferentiated component was detected in 10/14 cases (71 %). SMARCA2 was most frequently lost (six) followed by ARID1A (four), SMARCB1/INI1 (two), SMARCA4 (one), and SMARCC1 (one). This is the first study exploring SWI/SNF expression in undifferentiated UC of the urinary tract. Our results are in line with recent studies reporting involvement of the SWI/SNF complex in the dedifferentiation process of a variety of epithelial neoplasms in different organs, including the urinary tract, and association with aggressive clinical course.
EVALuna2:6799

Loss of EZH2 at tumor invasive front is correlated with higher aggressiveness - Böhm, Julian; Muenzner, Julienne K.; Caliskan, Aylin; Ndreshkjana, Benardina; Erlenbach-Wunsch, Katharina; Merkel, Susanne; Croner, Roland S.; Rau, Tilman T.; Geppert, Carol-Immanuel; Hartmann, Arndt; Vial-Roehe, Adriana; Schneider-Stock, Regine (2018)
EVALuna2:205467

Loss of Fumarate Hydratase and Aberrant Protein Succination Detected With S-(2-Succino)-Cysteine Staining to Identify Patients With Multiple Cutaneous and Uterine Leiomyomatosis and Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome - Llamas-Velasco, Mar; Requena, Luis; Adam, Julie; Frizzell, Norma; Hartmann, Arndt; Mentzel, Thomas (American Journal of Dermatopathology, 2016)
Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is an autosomal dominant disorder caused by heterozygotic germline mutations in fumarate hydratase (FH) with incomplete penetrance, and clinically challenging to diagnose. Immunohistochemical stainings may favor an earlier diagnosis.The authors have tested 31 smooth muscle neoplasms. Ten of the 13 lesions from patients with HLRCC syndrome showed negative FH staining. Most sporadic piloleiomyomas presented strongly positive FH staining although 5 cases were negative. Sensitivity of FH staining in our series is 83.3% but specificity is 75%. Anti-S-(2-succino)-cysteine (2SC) showed the opposite intensity staining pattern and showed great correlation with anti-FH (rho spearman = -0.797). Anti-2SC staining increased the diagnostic accuracy in 19% of the cases.The main limitation of this study is the lack additional clinical data to further classify the cases as the case inclusion was histopathological.Negative FH staining could indicate a high risk of HLRCC but it could also suggest the presence of a syndrome in up to 25% of sporadic cases. Thus, when there is a doubtful case, anti-2SC may be added to exclude the syndrome if a negative staining is found.
EVALuna2:6917

Loss of MTUS1/ATIP expression is associated with adverse outcome in advanced bladder carcinomas: data from a retrospective study - Rogler, Anja; Hoja, Sabine; Giedl, Josef; Ekici, Arif Bülent; Wach, Sven; Taubert, Helge; Goebell, Peter; Wullich, Bernd; Stoeckle, Michael; Lehmann, Jan; Petsch, Sabrina; Hartmann, Arndt; et al. (BMC Cancer, 2014)
Seventy percent of all bladder tumours tend to recur and need intensive surveillance, and a subset of tumours progress to muscle-invasive and metastatic disease. However, it is still difficult to find the adequate treatment for every individual patient as it is a very heterogeneous disease and reliable biomarkers are still missing. In our study we searched for new target genes in the critical chromosomal region 8p and investigated the potential tumour suppressor gene candidate MTUS1/ATIP in bladder cancer.MTUS1 was identified to be the most promising deleted target gene at 8p in aCGH analysis with 19 papillary bladder tumours. A correlation with bladder cancer was further validated using immunohistochemistry of 85 papillary and 236 advanced bladder tumours and in functional experiments. Kaplan-Meier analysis and multivariate Cox-regression addressed overall survival (OS) and disease-specific survival (DSS) as a function of MTUS1/ATIP expression. Bivariate correlations investigated associations between MTUS1/ATIP expression, patient characteristics and histopathology. MTUS1 expression was analysed in cell lines and overexpressed in RT112, where impact on viability, proliferation and migration was measured.MTUS1 protein expression was lost in almost 50% of all papillary and advanced bladder cancers. Survival, however, was only influenced in advanced carcinomas, where loss of MTUS1 was associated with adverse OS and DSS. In this cohort, there was also a significant correlation of MTUS1 expression and histological subtype: positive expression was detected in all micropapillary tumours and aberrant nuclear staining was detected in a subset of plasmocytoid urothelial carcinomas. MTUS1 was expressed in all investigated bladder cell lines and overexpression in RT112 led to significantly decreased viability.MTUS1 is a tumour suppressor gene in cultured bladder cancer cells and in advanced bladder tumours. It might represent one new target gene at chromosome 8p and can be used as an independent prognostic factor for advanced bladder cancer patients. The limitation of the study is the retrospective data analysis. Thus, findings should be validated with a prospective advanced bladder tumour cohort.
EVALuna2:6624

Loss of ORP3 induces aneuploidy and promotes bladder cancer cell invasion through deregulated microtubule and actin dynamics - Wang, Xue; Liu, Junnan; Azoitei, Anca; Eiseler, Tim; Meessen, Sabine; Jiang, Wencheng; Zheng, Xi; Makori, Arika W.; Eckstein, Markus; Hartmann, Arndt; Stilgenbauer, Stephan; Elati, Mohamed; et al. (Cellular and Molecular Life Sciences, 2023)
We have recently shown that loss of ORP3 leads to aneuploidy induction and promotes tumor formation. However, the specific mechanisms by which ORP3 contributes to ploidy-control and cancer initiation and progression is still unknown. Here, we report that ORP3 is highly expressed in ureter and bladder epithelium while its expression is downregulated in invasive bladder cancer cell lines and during tumor progression, both in human and in mouse bladder cancer. Moreover, we observed an increase in the incidence of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced invasive bladder carcinoma in the tissue-specific Orp3 knockout mice. Experimental data demonstrate that ORP3 protein interacts with γ-tubulin at the centrosomes and with components of actin cytoskeleton. Altering the expression of ORP3 induces aneuploidy and genomic instability in telomerase-immortalized urothelial cells with a stable karyotype and influences the migration and invasive capacity of bladder cancer cell lines. These findings demonstrate a crucial role of ORP3 in ploidy-control and indicate that ORP3 is a bona fide tumor suppressor protein. Of note, the presented data indicate that ORP3 affects both cell invasion and migration as well as genome stability through interactions with cytoskeletal components, providing a molecular link between aneuploidy and cell invasion and migration, two crucial characteristics of metastatic cells.
CRIS-Team Scopus Importer:2023-09-29
Keywords: Chromosomal imbalance; Invadopodia; Metastasis; OSBPL3; Spindle orientation; Urothelial carcinoma

Low cytoplasmic and nuclear KPNA2 expression in radiotherapy-treated head and neck squamous cell cancer is associated with an adverse outcome - Erben, Pia; Brunner, Kathrin; Hecht, Markus; Haderlein, Marlen; Buettner-Herold, Maike; Agaimy, Abbas; Fietkau, Rainer; Hartmann, Arndt; Distel, Luitpold (International Journal of Clinical and Experimental Pathology, 2015)
KPNA2 has effects on carcinogenesis, cell differentiation and transcriptional regulation. KPNA2 has been linked to DNA damage repair by its role to import the DNA double strand break repair complex MRN into the nucleus. The aim of our study was to evaluate the prognostic value of KPNA2 expression in both cytoplasmic and nuclear location in patients with HNSCC treated with radio(chemo)therapy.225 patients with HNSCC treated with neoadjuvant, definitive or adjuvant radio(chemo)therapy were included. Immunohistochemical staining was performed on tissue micro arrays to evaluate nuclear and cytoplasmic KPNA2 expression.The median fraction of tumor cells with nuclear KPNA2 expression was 15%. 47% of tumor samples showed positive cytoplasmic staining. Patients with low nuclear as well as negative cytoplasmic expression tended to have an unfavorable prognosis. There was no correlation between nuclear and cytoplasmic KPNA2 expression. Low nuclear combined with negative cytoplasmic KPNA2 had a clearly unfavorable prognostic effect in local failure-free survival (P=0.014), metastasis-free survival (P=0.001) and no evidence of disease (P=0.008). A combination of low nuclear/negative cytoplasmic with high nuclear/high cytoplasmic KPNA2 expression was prognostically unfavorable with regard to tumor specific survival (P=0.021) and to a lower extent to overall survival (P=0.18). In multivariate analysis low nuclear/negative cytoplasmic versus any high KPNA2 (P=0.008) and T-category (P=0.002) proved as independent prognostic variables.The combination of nuclear and cytoplasmic KPNA2 expression is a potential excellent prognostic parameter in HNSCC treated with radio(chemo)therapy.
EVALuna2:6796

Low frequency of HNPCC-associated microsatellite instability and aberrant MMR protein expression in early-onset bladder cancer - Giedl, Josef; Schneckenpointner, Roland; Filbeck, Thomas; Ruemmele, Petra; Hofstaedter, Ferdinand; Burger, Maximilian; Hartmann, Arndt; Stoehr, Robert (American Journal of Clinical Pathology, 2014)
Recently, it was shown that patients with Lynch syndrome due to an MSH2 mutation are at increased risk for the development of bladder cancer. To further this discussion, we screened the largest investigated cohort of patients with early-onset bladder cancer for microsatellite instability (MSI) and mismatch repair (MMR) deficiency to determine a possible role of Lynch syndrome in young patients with bladder cancer.A total of 109 cases of bladder tumors from young patients (aged <45 years) were examined for MSI (Bethesda consensus panel). Expression of MMR proteins (hMLH1, hMSH2, and hMSH6) was evaluated by immunohistochemistry using a tissue microarray. Results were compared with a series of unselected consecutive bladder tumors (n = 95).Regarding the frequency of MSI high (1% vs 0%) or abnormal expression of MMR proteins (2% vs 6.5%), no significant difference between the early-onset and unselected patient group was found.In young patients with bladder tumors, MSI and defects in MMR protein expression were not more frequent than in a series of consecutive bladder tumors. Most bladder tumors in young patients are not to be attributed to Lynch syndrome.
EVALuna2:6663

Low-grade Endometrioid Stromal Sarcoma of the Paratestis: A Novel Report With Molecular Confirmation of JAZF1/SUZ12 Translocation - Agaimy, Abbas; Moskalev, Evgeny; Weisser, Wera; Bach, Thorsten; Haller, Florian; Hartmann, Arndt (American Journal of Surgical Pathology, 2018)
Tumors with Müllerian-like serous or mucinous phenotypes originating in the testis and its adnexa are rare neoplasms that have been increasingly recognized in recent years. Cystadenomas with or without ovarian-type stroma, borderline tumors, and adenocarcinomas are the main documented types. Although a handful cases of putative endometrioid adenocarcinomas have been reported, to our knowledge no case of endometrial stromal-type neoplasm has ever been reported in the literature. A 59-year-old man presented with a 2 cm left intrascrotal mass that was found on sonographic examination to arise from the epididymal tail with prominent vascularization. He was otherwise healthy without significant clinical history, endocrinopathy, or external hormone therapy. His testicular tumor markers (beta-HCG, AFP) were normal. Histologic examination of the resection showed a multinodular tumor closely associated with the epididymis and composed of monotonous rounded to ovoid cells with scanty cytoplasm and prominent spiral-like arterioles and capillaries. Mitotic activity was high. No other tumor component was seen. Immunohistochemistry revealed strong and diffuse expression of vimentin, CD10, estrogen receptor, and progesterone receptor. Molecular examination (performed on paraffin-embedded tumor tissue using a 517 gene fusion next-generation sequencing assay) showed a JAZF1/SUZ12 translocation, which was then confirmed by fluorescence in situ hybridization (FISH). These findings are consistent with a low-grade endometrioid stromal sarcoma originating in the paratestis. This report represents a novel addition to the growing spectrum of Müllerian-analog testicular adnexal neoplasms.
EVALuna2:34099

Low-grade (polymorphous) adenocarcinoma of the middle ear mimicking a jugulotympanic paraganglioma - Mantsopoulos, Konstantinos; Fietkau, Rainer; Hornung, Joachim; Agaimy, Abbas; Iro, Heinrich; Taha, Lava (HNO, 2021)
A 64-year-old female patient presented with otalgia and hearing loss in the right ear. On otoscopy, the right tympanic membrane was highly vascularized and bulged into the anteroinferior quadrant. High-resolution computed tomography revealed an osteolytic lesion with occupation of the hypotympanum extending into the petrous apex and right parapharyngeal space as well as infiltration of the wall of the right internal carotid artery. MRI strengthened the suspicion of a jugulotympanic paraganglioma. The biopsy material obtained through exploratory tympanotomy was assessed as a low-grade polymorphic adenocarcinoma. The tumor was treated with definitive chemoradiotherapy. Posttherapeutic imaging after 4 months did not show any evidence of tumor progression.
CRIS-Team WoS Importer:2021-06-18

Low-grade (polymorphous) adenocarcinoma of the middle ear mimicking a jugulotympanic paraganglioma. German version - Mantsopoulos, Konstantinos; Fietkau, Rainer; Hornung, Joachim; Agaimy, Abbas; Iro, Heinrich; Taha, Lava (HNO, 2021)
A 64-year-old female patient presented with otalgia and hearing loss in the right ear. On otoscopy, the right tympanic membrane was highly vascularized and bulged into the anteroinferior quadrant. High-resolution computed tomography revealed an osteolytic lesion with occupation of the hypotympanum extending into the petrous apex and right parapharyngeal space as well as infiltration of the wall of the right internal carotid artery. MRI strengthened the suspicion of a jugulotympanic paraganglioma. The biopsy material obtained through exploratory tympanotomy was assessed as a low-grade polymorphic adenocarcinoma. The tumor was treated with definitive chemoradiotherapy. Posttherapeutic imaging after 4 months did not show any evidence of tumor progression.
CRIS-Team WoS Importer:2021-05-07

Lung cancer presenting with central nervous system metastasis: Clinicopathological and molecular analysis of 171 cases - Demleitner, Madeleine; Erlenbach-Wünsch, Katharina; Coras, Roland; Erber, Ramona; Polifka, Iris; Eyüpoglu, Ilker Yasin; Fuchs, Florian; Hartmann, Arndt; Agaimy, Abbas (Annals of Diagnostic Pathology, 2023)
A subset of lung carcinoma presents initially with brain metastasis. Precise subtyping is mandatory for optimized treatment of these advanced aggressive carcinomas. We herein analyzed surgical biopsies from 171 Patients (99 males and 72 females aged 48–96; mean, 72), who presented with brain metastasis of lung cancer. In addition to conventional subtyping, we applied an extended immunohistochemistry (IHC) panel and performed several molecular tests looking for potential therapeutic targets other than EGFR mutations. Non-small cell carcinoma (NSCLC) comprised 157 (91.8 %) of cases: 109 (63.7 %) adenocarcinomas, 27 (15.8 %) squamous cell (SCC), 18 (10.5 %) large cell undifferentiated, 1 (0.6 %) adenosquamous and 2 (1.2 %) unclassified carcinomas. Of the adenocarcinomas, 81.7 % were TTF1+. Notably, 45 % of those TTF1-negative cases expressed HepPar1. SMARCA4 and SMARCA2 loss was observed in 13/171 (7.6 %) and 32/163 (19.6 %) cases, respectively; mainly TTF1- (40.0 %) and HepPar1+ (38.1 %) adenocarcinomas were affected by SMARCA2/4 loss. Loss of at least one mismatch repair (MMR) protein was observed in 3/156 (1.9 %) cases (2 adenocarcinomas and 1 large cell neuroendocrine carcinoma/LCNEC). Limited available data on mutation testing showed a frequency of EGFR mutations of 4.3% and of KRAS mutations of 57%. HER2 expression (2+/3+) was found in 45/166 (27.1 %) of cases with amplification verified by CISH in 18/38 (47.4 % of immunopositive cases and 10.5 % of the whole cohort); all but one were adenocarcinomas. Other genetic abnormalities detected included EML4::ALK rearrangements in 3 (1.8 %; 2 TTF1+ adenocarcinomas and 1 LCNEC) and RET rearrangements in one SCNEC. Variable subsets of tumors revealed amplifications of several potentially therapeutically targetable genes including MYC (30.0 %), MET (10.1 %), HER2 (10 %), FGFR1 (9.6 %), FGFR3 (4.6 %), and FGFR2 (3.4 %). This study highlights a highly heterogeneous molecular background in lung cancer presenting with CNS metastases. These findings highlight the need for individualized tumor testing strategies looking for potential therapeutic targets for this aggressive disease.
CRIS-Team Scopus Importer:2023-01-27
Keywords: ALK; Central nervous system metastasis; Immune therapy; Microsatellite instability; NSCLC; SMARCA4

Lymph node metastases detection in Whole Slide Images using prototypical patterns and transformer-guided multiple instance learning - Heinlein, Lukas; Benz, Michaela; Kuritcyn, Petr; Bruns, Volker; Hartmann, Arndt; Geppert, Carol-Immanuel; Keil, Felix; Evert, Katja; Wittenberg, Thomas (Current Directions in Biomedical Engineering, 2023)
Background: The examination of lymph nodes (LNs) regarding metastases is vital for the staging of cancer patients, which is necessary for diagnosis and adequate treatment selection. Advancements in digital pathology, utilizing Whole-Slide Images (WSIs) and convolutional neural networks (CNNs), pose new opportunities to automate this procedure, thus reducing pathologists' workload while simultaneously increasing the accuracy in metastases detection. Objective: To address the task of LN-metastases detection, the use of weakly supervised transformers are applied for the analysis of WSIs. Methods Materials: As WSIs are too large to be processed as a whole, they are divided into non-overlapping patches, which are converted to feature vectors using a CNN network, pre-trained on HE-stained colon cancer resections. A subset of these patches serves as input for a transformer to predict if a LN contains a metastasis. Hence, selecting a representative subset is an important part of the pipeline. Hereby, a prototype based clustering is employed and different sampling strategies are tested. Finally, the chosen feature vectors are fed into a transformer-based multiple instance learning (MIL) architecture, classifying the LNs into healthy/negative (that is, containing no metastases), or metastatic/positive (that is, containing metastases). The proposed model is trained only on the Camelyon16 training data (LNs from breast cancer patients), and evaluated on the Camelyon16 test set. Results: The trained model achieves accuracies of up to 92.3% on the test data (from breast LNs). While the model struggles with smaller metastases, high specificities of up to 96.9% can be accomplished. Additionally, the model is evaluated on LNs from a different primary tumor (colon), where accuracies between 62.3% and 95.9% could be obtained. Conclusion: The investigated transformer-model performs very good on LN data from the public LN breast data, but the domain transfer to LNs from the colon needs more research.
CRIS-Team Scopus Importer:2023-10-20
Keywords: breast cancer; colon cancer; Lymph node metastases; prototypical patterns; transformer; whole slide image

Lymph node ratio is of limited value for the decision-making process in the treatment of patients with laryngeal cancer - Kuenzel, Julian; Mantsopoulos, Konstantinos; Psychogios, Georgios; Agaimy, Abbas; Grundtner, Philipp; Koch, Michael; Iro, Heinrich (European Archives of Oto-Rhino-Laryngology, 2015)
The lymph node ratio (LNR) combines two types of information–about the extent of neck dissection and about the extent of the pathological examination of the specimen–and thus represents an interesting variable for risk assessment in patients with head and neck cancer. This retrospective study with data from January 1, 1980, to December 31, 2010, evaluates the utility of the LNR as a potential prognostic predictor in patients with laryngeal squamous cell carcinoma (LSCC). A total of 202 consecutive patients with regionally metastasized LSCC who underwent primary surgery with or without adjuvant treatment were included. The mean follow-up period was 4.4 years. The LNR was calculated as the ratio of positive nodes to the total number of nodes removed during neck dissection. Multivariate analysis was carried out. Peak values as averaged clusters of individual LNRs were registered at three points (LNR 0.05, 0.07, and 0.09). LNR 0.09 was a significant prognostic parameter in the Cox regression model (P = 0.007). Patients with an LNR > 0.09 had a hazard ratio of 2.065 for a disease-specific survival event in comparison with LNR < 0.09. The most accurate LNR for LSCC is expected to be located in the range of 0.08-0.1. The LNR seems to be of limited value for the decision-making process in the treatment of patients with LSCC, in comparison with other locations. Prospective trials will be required in order to allow evidence-based recommendations for treatment decisions based on the LNR.
EVALuna2:6680

Machine Learning Accurately Predicts Muscle Invasion of Bladder Cancer Based on Three miRNAs - Eckhart, Lea; Rau, Sabrina; Eckstein, Markus; Stahl, Phillip R.; Ayoubian, Hiresh; Heinzelbecker, Julia; Zohari, Farzaneh; Hartmann, Arndt; Stöckle, Michael; Lenhof, Hans Peter; Junker, Kerstin (Journal of Cellular and Molecular Medicine, 2025)
The aim of this study was to validate the diagnostic potential of four previously identified miRNAs in two independent cohorts and to develop accurate classification models to predict invasiveness of bladder cancer. Furthermore, molecular subtypes were investigated. The miRNAs were isolated from pTa low-grade (lg) (n = 113), pT1 high-grade (hg) (n = 133) and muscle-invasive bladder cancer (MIBC) (n = 136) tumour tissue samples (FFPE) after either transurethral resection of a bladder tumour (TURB) or cystectomy (CYS). In both cohorts, the expression of miR-138-5p and miR-200a-3p was significantly lower, and the expression of miR-146b-5p and miR-155-5p was significantly higher in MIBC compared to pTa lg. A k-nearest neighbours (KNN) classifier trained to distinguish pTa lg from MIBC based on three miRNAs achieved an accuracy of 0.94. The accuracy remained at 0.91 when the classifier was applied exclusively to the TURB samples. To guarantee reliable predictions, a conformal prediction approach was applied to the KNN model, which eliminated all misclassifications on the test cohort. pT1 hg samples were classified as MIBC in 32% of cases using the KNN model. miR-146b-5p, miR-155-5p and miR-200a-3p expressions are significantly associated with particular molecular subtypes. In conclusion, we confirmed that the four miRNAs significantly distinguish MIBC from NMIBC. A classification model based on three miRNAs was able to accurately classify the phenotype of invasive tumors. This could potentially support the histopathological diagnosis in bladder cancer and therefore, the clinical decision between performing a radical cystectomy and pursuing bladder-conserving strategies, especially in pT1 hg tumors.
CRIS-Team Scopus Importer:2025-03-07
Keywords: machine learning algorithms; microRNA; molecular subtypes; muscle-invasive bladder cancer; pT1 high-grade tumours

Machine Learning-assisted immunophenotyping of peripheral blood identifies innate immune cells as best predictor of response to induction chemo-immunotherapy in head and neck squamous cell carcinoma – knowledge obtained from the CheckRad-CD8 trial - Hecht, Markus; Frey, Benjamin; Gaipl, Udo; Tianyu, Xie; Eckstein, Markus; Donaubauer, Anna-Jasmina; Klautke, Gunther; Illmer, Thomas; Fleischmann, Maximilian; Laban, Simon; Hautmann, Matthias G.; Tamaskovics, Bálint; et al. (Neoplasia, 2024)
Purpose: Individual prediction of treatment response is crucial for personalized treatment in multimodal approaches against head-and-neck squamous cell carcinoma (HNSCC). So far, no reliable predictive parameters for treatment schemes containing immunotherapy have been identified. This study aims to predict treatment response to induction chemo-immunotherapy based on the peripheral blood immune status in patients with locally advanced HNSCC. Methods: The peripheral blood immune phenotype was assessed in whole blood samples in patients treated in the phase II CheckRad-CD8 trial as part of the pre-planned translational research program. Blood samples were analyzed by multicolor flow cytometry before (T1) and after (T2) induction chemo-immunotherapy with cisplatin/docetaxel/durvalumab/tremelimumab. Machine Learning techniques were used to predict pathological complete response (pCR) after induction therapy. Results: The tested classifier methods (LDA, SVM, LR, RF, DT, and XGBoost) allowed a distinct prediction of pCR. Highest accuracy was achieved with a low number of features represented as principal components. Immune parameters obtained from the absolute difference (lT2-T1l) allowed the best prediction of pCR. In general, less than 30 parameters and at most 10 principal components were needed for highly accurate predictions. Across several datasets, cells of the innate immune system such as polymorphonuclear cells, monocytes, and plasmacytoid dendritic cells are most prominent. Conclusions: Our analyses imply that alterations of the innate immune cell distribution in the peripheral blood following induction chemo-immuno-therapy is highly predictive for pCR in HNSCC.
CRIS-Team Scopus Importer:2024-01-26
Keywords: Chemotherapy; HNSCC; Immune phenotyping; Immunotherapy; Induction therapy

Machine Learning-Supported Diagnosis of Small Blue Round Cell Sarcomas Using Targeted RNA Sequencing. - Schlieben, Lea D.; Carta, Maria Giulia; Moskalev, Evgeny; Stöhr, Robert; Metzler, Markus; Besendörfer, Manuel; Meidenbauer, Norbert; Semrau, Sabine; Janka, Rolf Matthias; Grützmann, Robert; Wiemann, Stefan; Hartmann, Arndt; et al. (Journal of Molecular Diagnostics, 2024)
Small blue round cell sarcomas (SBRCSs) are a heterogeneous group of tumors with overlapping morphologic features but markedly varying prognosis. They are characterized by distinct chromosomal alterations, particularly rearrangements leading to gene fusions, whose detection currently represents the most reliable diagnostic marker. Ewing sarcomas are the most common SBRCSs, defined by gene fusions involving EWSR1 and transcription factors of the ETS family, and the most frequent non-EWSR1-rearranged SBRCSs harbor a CIC rearrangement. Unfortunately, currently the identification of CIC::DUX4 translocation events, the most common CIC rearrangement, is challenging. Here, we present a machine-learning approach to support SBRCS diagnosis that relies on gene expression profiles measured via targeted sequencing. The analyses on a curated cohort of 69 soft-tissue tumors showed markedly distinct expression patterns for SBRCS subgroups. A random forest classifier trained on Ewing sarcoma and CIC-rearranged cases predicted probabilities of being CIC-rearranged >0.9 for CIC-rearranged-like sarcomas and <0.6 for other SBRCSs. Testing on a retrospective cohort of 1335 routine diagnostic cases identified 15 candidate CIC-rearranged tumors with a probability >0.75, all of which were supported by expert histopathologic reassessment. Furthermore, the multigene random forest classifier appeared advantageous over using high ETV4 expression alone, previously proposed as a surrogate to identify CIC rearrangement. Taken together, the expression-based classifier can offer valuable support for SBRCS pathologic diagnosis.
EVALuna2:565265

Macrophage polarization differs between apical granulomas, radicular cysts, and dentigerous cysts - Weber, Manuel; Schlittenbauer, Tilo; Möbius, Patrick; Büttner-Herold, Maike; Ries, Jutta; Preidl, Raimund; Geppert, Carol-Immanuel; Neukam, Friedrich Wilhelm; Wehrhan, Falk (Clinical Oral Investigations, 2017)
Apical periodontitis can appear clinically as apical granulomas or radicular cysts. There is evidence that immunologic factors are involved in the pathogenesis of both pathologies. In contrast to radicular cysts, the dentigerous cysts have a developmental origin. Macrophage polarization (M1 vs M2) is a main regulator of tissue homeostasis and differentiation. There are no studies comparing macrophage polarization in apical granulomas, radicular cysts, and dentigerous cysts.Forty-one apical granulomas, 23 radicular cysts, and 23 dentigerous cysts were analyzed in this study. A tissue microarray (TMA) of the 87 consecutive specimens was created, and CD68-, CD11c-, CD163-, and MRC1-positive macrophages were detected by immunohistochemical methods. TMAs were digitized, and the expression of macrophage markers was quantitatively assessed.Radicular cysts are characterized by M1 polarization of macrophages while apical granulomas show a significantly higher degree of M2 polarization. Dentigerous cysts have a significantly lower M1 polarization than both analyzed periapical lesions (apical granulomas and radicular cysts) and accordingly, a significantly higher M2 polarization than radicular cysts. Macrophage cell density in dentigerous cysts is significantly lower than in the periapical lesions.The development of apical periodontitis towards apical granulomas or radicular cysts might be directed by macrophage polarization. Radicular cyst formation is associated with an increased M1 polarization of infiltrating macrophages. In contrast to radicular cysts, dentigerous cysts are characterized by a low macrophage infiltration and a high degree of M2 polarization, possibly reflecting their developmental rather than inflammatory origin.As M1 polarization of macrophages is triggered by bacterial antigens, these results underline the need for sufficient bacterial clearance during endodontic treatment to prevent a possible M1 macrophage-derived stimulus for radicular cyst formation.
EVALuna2:6886

Macrophages and dendritic cells as actors in the immune reaction of classical hodgkin lymphoma - Tudor, Christiane; Bruns, Heiko; Daniel, Christoph; Distel, Luitpold; Hartmann, Arndt; Gerbitz, Armin; Büttner, Maike (PLoS ONE, 2014)
The inflammatory infiltrate plays a pivotal role in classical Hodgkin lymphoma (cHL). Here, we focussed on the role of macrophages (M?) and dendritic cells (DC).M? and DC infiltration was investigated in 106 cHL specimens using immunohistochemistry and cytokine expression was analyzed in a subset by real-time PCR. Human peripheral blood-derived monocytes, DC, M? stimulated with GM-CSF (M?GM-CSF, pro-inflammatory M?-1-model) or M-CSF (M?M-CSF, immunomodulatory M?-2-model) were incubated with cHL cell line (L1236, HDLM2) supernatants (SN). DC maturation or M? polarization were investigated by flow cytometry. Furthermore, the impact of DC or M? on cHL cell proliferation was analyzed by BrdU/CFSE assay.In cHL tissues mature myeloid (m)DC and M? predominated. High numbers of CD83+ mDC and low numbers of CD163+ M? were associated with improved disease specific survival. In numerous cHL specimens increased levels of both pro- and anti-inflammatory cytokines and of IL13 and GM-CSF were observed compared to reactive lymphadenopathies. Maturation of DC and induction and maintenance of an immunomodulatory M? phenotype were promoted by SN derived from cHL cell lines. TNF? neutralization in SN resulted in a significant inhibition of mDC maturation. DC and pro-inflammatory M? inhibited the proliferation of cHL cells.Adopting an immunomodulatory phenotype is a potential mechanism for how M? promote immune evasion in cHL. Mature DC, in contrast, might participate in antitumoral immunit
EVALuna2:6630

MAGE-A expression in oral and laryngeal leukoplakia predicts malignant transformation - Baran, Christoph; Agaimy, Abbas; Wehrhan, Falk; Weber, Manuel; Hille, Verena; Brunner, Kathrin; Wickenhauser, Claudia; Siebolts, Udo; Nkenke, Emeka; Kesting, Marco Rainer; Ries, Jutta (Modern Pathology, 2019)
Leukoplakia is a potential precursor of oral as well as laryngeal squamous cell carcinoma. Risk assessment of malignant transformation based on the grade of dysplasia of leukoplakia often does not lead to reliable results. However, oral squamous cell carcinoma, laryngeal squamous cell carcinoma, and leukoplakia express single or multiple members of the melanoma-associated antigens A (MAGE-A) family, while MAGE-A are absent in healthy mucosal tissue. The present study aimed at determining if there is an association between the expression of MAGE-A in leukoplakia and malignant transformation to oral or laryngeal squamous cell carcinoma. Paraffin-embedded tissues of 205 oral and laryngeal leukoplakia, 90 corresponding tumors, and 40 healthy oral mucosal samples were included in the study. The grade of dysplasia of the leukoplakia samples was determined histopathologically. The leukoplakia samples were divided into lesions that transformed to oral and laryngeal squamous cell carcinoma (n = 91) and lesions that did not (n = 114) during a 5 years follow-up. The expression of MAGE-A3/6 and MAGE-A4 was analyzed by real-time RT-PCR. The expression of MAGE-A 1–4, 6, and 12 was determined by immunohistochemistry. A total of 59.3% of the transforming leukoplakia expressed at least one of the examined antigens as opposed to an expression rate of 3.5% of all non-transforming leukoplakia. There was no MAGE-A expression in healthy oral mucosa. The risk of malignant transformation was statistically significantly associated with MAGE-A expression in immunohistochemistry (p < 0.001) and real-time RT-PCR (MAGE-A3/6, p = 0.001; MAGE-A4, p = 0.002) analyses. There was no significant association between MAGE-A expression and the grade of dysplasia (“low-grade”, D0/D1; “high-grade”, D2/D3) in immunohistochemistry (p = 0.412) and real-time RT-PCR (MAGE-A3/6, p = 0.667; MAGE-A4, p = 0.756). It seems that the analysis of the MAGE-A expression profile may support the identification of leukoplakia at risk for malignant transformation. Therefore, efforts should be made to establish this analysis as a routine procedure in addition to conventional histopathology.
CRIS-Team Scopus Importer:2019-08-06

Magnetoencephalography for epileptic focus localization in a series of 1000 cases - Rampp, Stefan; Stefan, Hermann; Wu, Xueqing; Kaltenhäuser, Martin; Maess, Burkhard; Schmitt, Friedhelm C.; Wolters, Carsten H.; Hamer, Hajo; Kasper, Burkhard; Schwab, Stefan; Dörfler, Arnd; Blümcke, Ingmar; et al. (Brain, 2019)
The aim of epilepsy surgery in patients with focal, pharmacoresistant epilepsies is to remove the complete epileptogenic zone to achieve long-term seizure freedom. In addition to a spectrum of diagnostic methods, magnetoencephalography focus localization is used for planning of epilepsy surgery. We present results from a retrospective observational cohort study of 1000 patients, evaluated using magnetoencephalography at the University Hospital Erlangen over the time span of 28 years. One thousand consecutive cases were included in the study, evaluated at the University Hospital Erlangen between 1990 and 2018. All patients underwent magnetoencephalography as part of clinical workup for epilepsy surgery. Of these, 405 underwent epilepsy surgery after magnetoencephalography, with postsurgical follow-ups of up to 20 years. Sensitivity for interictal epileptic activity was evaluated, in addition to concordance of localization with the consensus of presurgical workup on a lobar level. We evaluate magnetoencephalography characteristics of patients who underwent epilepsy surgery versus patients who did not proceed to surgery. In operated patients, resection of magnetoencephalography localizations were related to postsurgical seizure outcomes, including long-term results after several years. In comparison, association of lesionectomy with seizure outcomes was analysed. Measures of diagnostic accuracy were calculated for magnetoencephalography resection and lesionectomy. Sensitivity for interictal epileptic activity was 72% with significant differences between temporal and extra-temporal lobe epilepsy. Magnetoencephalography was concordant with the presurgical consensus in 51% and showed additional or more focal involvement in an additional 32%. Patients who proceeded to surgery showed a significantly higher percentage of monofocal magnetoencephalography results. Complete magnetoencephalography resection was associated with significantly higher chances to achieve seizure freedom in the short and long-term. Diagnostic accuracy was significant in temporal and extra-temporal lobe cases, but was significantly higher in extra-temporal lobe epilepsy (diagnostic odds ratios of 4.4 and 41.6). Odds ratios were also higher in non-lesional versus lesional cases (42.0 versus 6.2). The results show that magnetoencephalography provides non-redundant information, which significantly contributes to patient selection, focus localization and ultimately long-term seizure freedom after epilepsy surgery. Specifically in extra-temporal lobe epilepsy and non-lesional cases, magnetoencephalography provides excellent accuracy.
CRIS-Team Scopus Importer:2019-10-08
Keywords: epilepsy; epilepsy surgery; long-term outcome; magnetic source imaging; magnetoencephalography

Magnification endoscopy with optical chromoendoscopy for in vivo assessment of histological inflammation in patients with inflammatory bowel disease - Klenske, E.; Atreya, Raja; Hartmann, Arndt; Fischer, Sören; Hirschmann, Simon; Zundler, Sebastian; Iacucci, M.; Neurath, Markus; Rath, Timo (JOURNAL OF CROHNS & COLITIS, 2019)
CRIS-Team WoS Importer:2019-03-20

Magnification endoscopy with optical chromoendoscopy shows strong correlation with histologic inflammation in patients with inflammatory bowel disease - Klenske, Entcho; Atreya, Raja; Hartmann, Arndt; Fischer, Sören; Hirschmann, Simon; Zundler, Sebastian; Iaccuci, Marietta; Neurath, Markus; Rath, Timo (Endoscopy International Open, 2019)
Background and study aims Apart from mucosal healing as an established treatment goal in inflammatory bowel diseases (IBD), recent evidence suggests that histologic healing may become another key prognostic parameter in IBD patients. We aimed to evaluate whether magnification endoscopy with optical chromoendoscopy can accurately assess histologic inflammation in IBD patients.
CRIS-Team WoS Importer:2019-09-13

MALDI Mass Spectrometry Imaging—Prognostic Pathways and Metabolites for Renal Cell Carcinomas - Erlmeier, Franziska; Sun, Na; Shen, Jian; Feuchtinger, Annette; Buck, Achim; Prade, Verena M.; Kunzke, Thomas; Schraml, Peter; Moch, Holger; Autenrieth, Michael; Weichert, Wilko; Hartmann, Arndt; et al. (Cancers, 2022)
High mass resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) is a suitable method for biomarker detection for several tumor entities. Renal cell carcinoma (RCC) is the seventh most common cancer type and accounts for more than 80% of all renal tumors. Prognostic biomarkers for RCC are still missing. Therefore, we analyzed a large, multicenter cohort including the three most common RCC subtypes (clear cell RCC (ccRCC), papillary RCC (pRCC) and chromophobe RCC (chRCC)) by MALDI for prognostic biomarker detection. MALDI-Fourier-transform ion cyclotron resonance (FT-ICR)-MSI analysis was performed for renal carcinoma tissue sections from 782 patients. SPACiAL pipeline was integrated for automated co-registration of histological and molecular features. Kaplan–Meier analyses with overall survival as endpoint were executed to determine the metabolic features associated with clinical outcome. We detected several pathways and metabolites with prognostic power for RCC in general and also for different RCC subtypes.
CRIS-Team Scopus Importer:2022-04-15
Keywords: chromophobe renal cell carcinoma; clear-cell renal cell carcinoma; mass spectrometry imaging; metabolomics; papillary renal cell carcinoma

Malignancies associated with GIST: a retrospective study with molecular analysis of KIT and PDGFRA - Mayr, Patrick; Märkl, Bruno; Agaimy, Abbas; Kriening, Bernadette; Dintner, Sebastian; Schenkirsch, Gerhard; Schneider-Stock, Regine (Langenbecks Archives of Surgery, 2019)
Purpose: Gastrointestinal stromal tumors (GISTs) are the most common soft tissue tumors of the GI tract. Studies have been published reporting additional neoplasms in GIST patients. This study aimed to evaluate possible associations of mutation type, morphology, and clinical aspects of GISTs. Methods: All cases of GIST were identified from our pathology files. Coding exons of KIT and PDGFRA in GISTs with additional malignancies were sequenced. Results: A total of 70 of 188 (37%) retrieved patients with confirmed diagnosis of GIST showed at least one additional malignant neoplasm. Fifty of these GISTs were located in the stomach (71%), 8 in the small intestine (11%), 5 in the colon/rectum (7%), and 7 cases (6.2%) were of undetermined sites of origin. The distribution of identified mutations was similar to that described in GISTs without secondary malignancies. A total of 37 of 57 cases (65%) showed mutations in the KIT gene exon 11, 3 (5%) cases in exon 9, and 1 (2%) case in exon 13. Nine tumors (16%) had mutations of the PDGFRA gene. KIT and PDGFRA wild-type status were found in seven cases (12%). Most of the secondary neoplasms were located within the GI tract (34%), in the urogenital system (24%), or the breast/female genital tract (20%). Conclusion: This study confirms the high rate of additional malignant tumors in GIST patients. GIST features in these cases are very similar to those with sole GIST.
CRIS-Team Scopus Importer:2019-08-13
Keywords: Additional/secondary malignancy; Gastrointestinal stromal tumor; GIST; KIT; Mutation; PDGFRA

Malignant ascites occurs most often in patients with high-grade serous papillary ovarian cancer at initial diagnosis: a retrospective analysis of 191 women treated at Bayreuth Hospital, 2006-2015 - Krugmann, Jens; Schwarz, Corinna Lang; Melcher, Balint; Sterlacci, William; Ozalinskaite, Agne; Lermann, Johannes; Agaimy, Abbas; Vieth, Michael (Archives of Gynecology and Obstetrics, 2019)
BackgroundMalignant ascites often develops in patients with ovarian cancer, but there is a lack of more detailed characterization of the different histological subtypes.MethodsAscites specimens from patients with ovarian cancer who were treated at Bayreuth Hospital from 2006 to 2015, with follow-up until December 2016, were reevaluated retrospectively.ResultsA total of 191 women (mean age 64years, range 48-79) were included, of whom 180 (94.2%) had carcinoma, three (1.6%) had malignant mixed mullerian tumors (MMMTs), four (2.1%) had sex cord-stromal tumors (SCSTs), three (1.6%) had germ cell tumors (GCTs), and one (0.5%) had a sarcoma. The carcinoma group comprised 134 (70.1%) patients with high-grade serous papillary ovarian cancer, 17 (8.9%) with low-grade serous papillary ovarian cancer, 10 (5.3%) with mucinous carcinomas, nine (4.7%) with endometrioid carcinomas, six (3.1%) with clear cell carcinomas, and four (2.1%) with neuroendocrine tumors. The latter group consisted of two patients with mixed neuroendocrine-nonneuroendocrine tumors (MiNENs), one with only a small cell carcinoma (SCCO), and one with a mucinous carcinoid. The noncarcinomatous group of eight patients (4.2%) included three (1.6%) with Sertoli-Leydig cell tumor and mature cystic teratoma (MCT), one (0.5%) with a granulosa cell tumor, and one with a leiomyosarcoma. A statistically significant difference in the proportion of patients with malignant ascites was observed, at 17.7% (3/17) in those with low-grade serous papillary ovarian cancer and 91.8% (123/134) in those with high-grade serous papillary ovarian carcinomas. In both patients with MiNEN, the glandular tumor cell component was found in the ascites. Tumor cells were found in the ascitic fluid in 50% (5/10) of patients with mucinous ovarian carcinomas, 16.7% (1/6) of those with clear cell carcinomas, and 33.3% (1/3) of those with MMMTs. The two patients (2/3; 66.7%) with neoplastic squamous cell components in MCT and the only patient with a granulosa cell tumor in the SCST group (1/4; 25%) had malignant cell populations in the ascites, whereas patients with endometrioid cell carcinoma and leiomyosarcoma lacked tumor cells in the ascites. The malignant ascites was detected at the initial diagnosis in all 138 (100%) patients with ovarian neoplasms.ConclusionsHigh-grade serous papillary ovarian cancer was the main histological subtype most frequently found in ascites fluid in this series. The significant difference (P<0.00001) in the malignancy rate in comparison with low-grade serous papillary carcinoma confirms the histological distinction between the two entities. Initial evidence of ovarian cancer in ascites fluid allows correct primary diagnosis in cytology specimens and is important for staging and prognosis.
CRIS-Team WoS Importer:2019-03-08

Malignant Bone-Forming Neoplasm With NIPBL::BEND2 Fusion - Dashti, Nooshin K.; Matcuk, George; Agaimy, Abbas; Saoud, Carla; Antonescu, Cristina R. (Genes Chromosomes & Cancer, 2024)
Conventional high-grade osteosarcomas are characterized by aggressive radiologic features, cytologic pleomorphism, and complex genomics. However, rare examples of osteosarcomas remain challenging due to unusual histology, such as sclerosing or osteoblastoma-like features, which may require molecular confirmation of their complex genetic alterations. We have encountered such a case in a 17-year-old man, who presented with a third metatarsal sclerotic bone lesion, found incidentally in the work-up of a foot trauma. The initial imaging revealed a lesion with sclerotic/blastic features proximally and lucent/lytic portion distally, findings interpreted consistent with osteoblastoma. The lesion was managed intra-lesionally with curettings and cryoablation; however, the microscopic findings were non-specific, showing a bland osteoblastic proliferation embedded in a densely sclerotic matrix. Subsequently, the patient developed two rapid recurrences; the first recurrence was treated similarly despite its associated soft tissue extension radiographically, and the histologic findings remained non-specific. The 2nd recurrence showed a large mass, with bone destruction and soft tissue extension and an open biopsy revealed features of osteosarcoma with lace-like osteoid deposition, albeit with uniform cytomorphology. The subsequent below knee amputation showed features compatible with high-grade osteosarcoma, including solid growth of uniform epithelioid cells, with vesicular nuclei and scant cytoplasm, set in a lace-like meshwork of osteoid matrix. There was significant mitotic activity and tumor necrosis. Tumor cells were positive for SATB2. Further molecular work-up was performed showing an unexpected NIPBL::BEND2 fusion, which has been previously reported in two cases of phosphaturic mesenchymal tumor (PMT). FGF23 (ISH) was performed and was negative. By DNA methylation profiling, unsupervised clustering and UMAP dimensionality reduction revealed grouping with high-grade osteosarcomas and not with the PMT group. The patient received chemotherapy post-amputation and is alive without evidence of disease, with 10-month follow-up. We report an aggressive, overtly malignant acral bone-forming tumor, harboring a NIPBL::BEND2 fusion. Further studies are needed to evaluate the recurrent potential of this fusion in osteosarcomas and its relationship with PMT.
CRIS-Team Scopus Importer:2024-12-06
Keywords: BEND2; NIPBL; osteoblastic tumor; osteosarcoma; phosphaturic mesenchymal tumor; sarcoma

Malignant epithelioid peripheral nerve sheath tumor with prominent reticular/microcystic pattern in a child: a low-grade neoplasm with 18-years follow-up - Agaimy, Abbas; Stachel, Daniel; Jüngert, Jörg; Radkow, Tanja; Carbon, Roman; Metzler, Markus; Holter, Wolfgang (Applied Immunohistochemistry & Molecular Morphology, 2014)
Malignant peripheral nerve sheath tumors (MPNSTs) constitute <2% of soft tissue neoplasms in children and display a wide histologic spectrum including low-grade and epithelioid variants, although most are high-grade spindle cell sarcomas. Here, we describe an unusual case of a large retroperitoneal epithelioid MPNST diagnosed in a 7-year-old girl without family history or clinical features of neurofibromatosis type 1. The patient was treated by repeated surgical interventions, polychemotherapy, autologous stem cell transplantation, and irradiation therapy. Over the years, she developed multiple disseminated abdominal recurrences but is currently alive with very slowly progressing disseminated intra-abdominal disease 18 years from initial diagnosis. Histologically, the tumor was composed of medium-sized polygonal and ovoid-to-spindled cells set within a copious myxoid matrix with a prominent reticular and microcystic pattern reminiscent of the recently described reticular/microcystic schwannoma. Immunohistochemistry revealed strong and diffuse expression of S100, CD56, CD57, collagen IV, and neuron-specific enolase, with negativity for perineurial cell markers (claudin-1, epithelial membrane antigen, and glucose transporter-1) and other lineage-specific mesenchymal and epithelial antigens. This unusual variant of low-grade MPNST must be differentiated from a variety of other entities, in particular benign perineurioma, myxoid neurofibroma, and benign reticular/microcystic schwannoma. Confinement of the recurrent disease to the abdominal cavity emphasizes the necessity of primary curative wide excision of this highly recurring but nonmetastasizing low-grade neoplasm.
EVALuna2:6527

Malignant teratoid tumor of the thyroid gland: an aggressive primitive multiphenotypic malignancy showing organotypical elements and frequent DICER1 alterations—is the term “thyroblastoma” more appropriate? - Agaimy, Abbas; Witkowski, Leora; Stöhr, Robert; Cuenca, Joseph Christopher Castillo; González-Muller, Carlos Alberto; Brütting, Alfred; Bährle, Markus; Mantsopoulos, Konstantinos; Amin, Randa M.S.; Hartmann, Arndt; Metzler, Markus; Amr, Samir S.; et al. (Virchows Archiv, 2020)
Primary thyroid teratomas are exceedingly rare. Mature and immature variants recapitulate their gonadal counterparts (predilection for infants/children, triphasic germ layer differentiation, and favorable outcome). On the other hand, the so-called malignant teratomas affect predominantly adults and elderly, are highly aggressive, and, according to a few published cases, harbor DICER1 mutations. We describe three highly aggressive sporadic malignant teratoid thyroid tumors in 2 females (17 and 45 years) and one male (17 years). Histology showed triphasic neoplasms composed of solid nests of small primitive monomorphic cells embedded in a cellular stroma with primitive immature rhabdomyosarcoma-like (2) or pleomorphic sarcoma-like (1) phenotype. The third component was represented by TTF1+/PAX8+ primitive teratoid epithelial tubules reminiscent of primitive thyroid follicles and/or Wilms tumor, admixed with scattered respiratory- or enteric-type tubules, neuroepithelial rosettes, and fetal-type squamoid nests. Foci of cartilage were seen in two cases, but none contained mature organoid adult-type tissue or skin adnexa. SALL4 was expressed in the small cell (2) and stromal (1) component. Other germ cell markers were negative. Molecular testing revealed a known “hotspot” pathogenic DICER1 mutation in two cases. In addition, case 1 had a missense TP53 variant. This type of thyroid malignancy is distinct from genuine teratomas. The immunoprofile suggests primitive thyroid- or branchial cleft-like differentiation. Given that “blastoma” is a well-accepted terminology in the spectrum of DICER1-associated malignancies, the term “thyroblastoma” might be more convenient for these malignant teratoid tumors of the thyroid gland. Relationship of thyroblastoma to the DICER1 syndrome remains to be addressed.
CRIS-Team Scopus Importer:2020-06-16
Keywords: DICER1; Germ cell tumor; Head and neck; Malignant teratoma; Rhabdomyosarcoma; Teratocarcinosarcoma; Thyroblastoma; Thyroid

Malignant transformation of oral leukoplakia is associated with macrophage polarization - Weber, Manuel; Wehrhan, Falk; Baran, Christoph; Agaimy, Abbas; Büttner-Herold, Maike; Öztürk, Hatice Kübra; Neubauer, Kristina; Wickenhauser, Claudia; Kesting, Marco Rainer; Ries, Jutta (Journal of Translational Medicine, 2020)
BACKGROUND: Most oral squamous cell carcinomas (OSCC) occur on the basis of oral leukoplakias (OLP). The histologic degree of dysplasia is insufficient for the prediction of OLP malignant transformation. Immunologic parameters are gaining importance for prognostic assessment and therapy of cancer. M2 polarized macrophages were shown to be associated with OSCC progression and inferior prognosis. The current study aims to answer the question if OLP with malignant transformation into OSCC within 5 years differ from OLP without transformation regarding macrophage infiltration and polarization. METHODS: 201 specimens (50 transforming OLP, 53 non-transforming OLP, 49 corresponding OSCC and 49 healthy oral mucosa controls) were processed for immunohistochemistry. Samples were stained for CD68, CD163 and CD11c expression, completely digitalized and computer-assisted cell counting was performed. Epithelial and subepithelial compartments were differentially assessed. Groups were statistically compared using the Mann-Whitney U-test. A cut-off point for the discrimination of transforming and non-transforming OLP was determined and the association between macrophage infiltration and malignant transformation was calculated using the Chi-square test (χ2 test). RESULTS: Macrophage infiltration and M2 polarization in OLP with malignant transformation within 5 years was significantly increased compared to OLP without malignant transformation (p < 0.05). OSCC samples showed the highest macrophage infiltration and strongest M2 polarization (p < 0.05). Additionally, transforming OLP revealed a significant shift of macrophage infiltration towards the epithelial compartment (p < 0.05). χ2 test revealed a significant association of increased macrophage infiltration with malignant transformation (p < 0.05). CONCLUSION: Immunological changes precede malignant transformation of OLP. Increased macrophage infiltration and M2 polarization was associated with the development of oral cancer in OLP. Macrophage infiltration could serve as predictive marker for malignant transformation.
CRIS-Team Scopus Importer:2020-01-21
Keywords: Carcinogenesis; CD11c; CD163; CD68; M1; M2; Macrophage polarization; Oral cancer; Oral leukoplakia; Oral squamous cell carcinoma; OSCC

Mammary Analog Secretory Carcinoma of the Nasal Cavity Characterization of 2 Cases and Their Distinction From Other Low-grade Sinonasal Adenocarcinomas - Baneckova, Martina; Agaimy, Abbas; Andreasen, Simon; Vanecek, Tomas; Steiner, Petr; Slouka, David; Svoboda, Tomas; Miesbauerova, Marketa; Michal, Michael; Skalova, Alena (American Journal of Surgical Pathology, 2018)
Secretory carcinoma, originally described as mammary analog secretory carcinoma (MASC), is a low-grade salivary gland tumor characterized by a t(12;15)(p13;q25) translocation, resulting in an ETV6-NTRK3 gene fusion. Most MASCs are localized to the parotid gland and intraoral minor salivary glands. Moreover, ETV6-rearranged carcinomas with secretory features have been reported recently in the thyroid (with and without a history of radiation exposure), skin, and in very rare instances in the sinonasal tract. Here, we describe 2 cases of primary MASC in the sinonasal tract and provide a detailed clinical and histopathologic characterization of their morphology, immunohistochemical profile, and genetic background and highlight features allowing for its separation from its recently described molecular mimicker, ETV6-rearranged low-grade sinonasal adenocarcinoma.
EVALuna2:34876

Mammary analogue secretory carcinoma of salivary glands: diagnostic pitfall with distinct immunohistochemical profile and molecular features - Bissinger, Oliver; Goetz, Carolin; Kolk, Andreas; Bier, Henning A.; Agaimy, Abbas; Frenzel, Henning; Perner, Sven; Ribbat-Idel, Julika; Wolff, Klaus Dietrich; Weichert, Wilko; Mogler, Caroline (Rare Tumors, 2017)
Mammary analogue secretory carcinoma (MASC) is a newly defined entity among salivary gland malignancies which has just been established in the 4th edition of the WHO classification of head and neck tumors. MASC (synonym: secretory carcinoma) are characterized by a specific rearangement of the ETV6 gene locus. Here, we present a series of 3 MASC cases including clinical data with follow-up for up to 26 months. All tumours immunhistochemically displayed strong positivity for cytokeratin 7, and mammaglobin, focal positivity for S100, cytokeratin 5/6 and muc-4. In contrast, immunhistochemical stainings against cytokeratin 14, hormon receptors, Her2/neu, androgen receptor and prostate-specific antigen were consistently negative. FISH analysis showed translocation of the ETV6 gene locus in the majority of tumour cell nuclei. During clinical follow-up, no local relapse or metastasis was detected. As these carcinomas are clinically and radiologically indistinguishable from other salivary gland tumours and as therapeutic approaches and prognosis might differ, we need to be able to diagnose MASC correctly.
EVALuna2:34893

Mammographic Density and Prediction of Nodal Status in Breast Cancer Patients - Hack, Carolin; Häberle, Lothar; Geisler, K.; Schulz-Wendtland, Rüdiger; Hartmann, Arndt; Fasching, Peter; Uder, Michael; Wachter, David; Jud, Sebastian; Löhberg, Christian; Lux, Michael P.; Rauh, Claudia; et al. (Geburtshilfe und Frauenheilkunde, 2013)
Aim: Nodal status remains one of the most important prognostic factors in breast cancer. The cellular and molecular reasons for the spread of tumor cells to the lymph nodes are not well understood and there are only few predictors in addition to tumor size and multifocality that give an insight into additional mechanisms of lymphatic spread. Aim of our study was therefore to investigate whether breast characteristics such as mammographic density (MD) add to the predictive value of the presence of lymph node metastases in patients with primary breast cancer. Methods: In this retrospective study we analyzed primary, metastasis-free breast cancer patients from one breast center for whom data on MD and staging information were available. A total of 1831 patients were included into this study. MD was assessed as percentage MD (PMD) using a semiautomated method and two readers for every patient. Multiple logistic regression analyses with nodal status as outcome were used to investigate the predictive value of PMD in addition to age, tumor size, Ki-67, estrogen receptor (ER), progesterone receptor (PR), grading, histology, and multi-focality. Results: Multifocality, tumor size, Ki-67 and grading were relevant predictors for nodal status. Adding PMD to a prediction model which included these factors did not significantly improve the prediction of nodal status (p = 0.24, likelihood ratio test). Conclusion: Nodal status could be predicted quite well with the factors multifocality, tumor size, Ki-67 and grading. PMD does not seem to play a role in the lymphatic spread of tumor cells. It could be concluded that the amount of extracellular matrix and stromal cell content of the breast which is reflected by MD does not influence the probability of malignant breast cells spreading from the primary tumor to the lymph nodes. © Georg Thieme Verlag KG Stuttgart · New York.
CRIS-Team Scopus Importer:2023-03-08
Keywords: breast cancer; estrogen receptor; Ki-67; mammographic density; nodal status; progesterone receptor

Mammographic Density and Prognosis in Patients with primary Breast Cancer - Loss of Risk with increasing Age - Heindl, Felix; Fasching, Peter; Hein, Alexander; Hack, Caroline; Heusinger, K.; Gaß, Paul; Schulz-Wendtland, Rüdiger; Hartmann, Arndt; Erber, Ramona; Beckmann, Matthias; Meyer, J.; Häberle, Lothar; et al. (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Mammographic density and prognosis in primary breast cancer patients - Heindl, Felix; Fasching, Peter; Hein, Alexander; Hack, Carolin; Heusinger, Katharina; Gaß, Paul; Pöschke, Patrik; Stübs, Frederik; Schulz-Wendtland, Rüdiger; Hartmann, Arndt; Erber, Ramona; Beckmann, Matthias; et al. (BREAST, 2021)
Purpose: Mammographic density (MD) is one of the strongest risk factors for breast cancer (BC). However, the influence of MD on the BC prognosis is unclear. The objective of this study was therefore to investigate whether percentage MD (PMD) is associated with a difference in disease-free or overall survival in primary BC patients. Methods: A total of 2525 patients with primary, metastasis-free BC were followed up retrospectively for this analysis. For all patients, PMD was evaluated by two readers using a semi-automated method. The association between PMD and prognosis was evaluated using Cox regression models with disease-free survival (DFS) and overall survival (OS) as the outcome, and the following adjustments: age at diagnosis, year of diagnosis, body mass index, tumor stage, grading, lymph node status, hormone receptor and HER2 status. Results: After median observation periods of 9.5 and 10.0 years, no influence of PMD on DFS (p = 0.46, likelihood ratio test (LRT)) or OS (p = 0.22, LRT), respectively, was found. In the initial unadjusted analysis higher PMD was associated with longer DFS and OS. The effect of PMD on DFS and OS disappeared after adjustment for age and was caused by the underlying age effect. Conclusions: Although MD is one of the strongest independent risk factors for BC, in our collective PMD is not associated with disease-free and overall survival in patients with BC.
CRIS-Team Scopus Importer:2021-07-16
Keywords: Breast cancer; Breast cancer risk; Mammographic breast density; Mammographic density; Prognosis

Mammographic density is the main correlate of tumors detected on ultrasound but not on mammography - Haeberle, Lothar; Fasching, Peter; Brehm, Barbara; Heusinger, Katharina; Jud, Sebastian; Löhberg, Christian; Hack, Carolin; Preuss, Caroline; Lux, Michael P.; Hartmann, Arndt; Vachon, Celine M.; Meier-Meitinger, Martina; et al. (International Journal of Cancer, 2016)
Although mammography screening programs do not include ultrasound examinations, some diagnostic units do provide women with both mammography and ultrasonography. This article is concerned with estimating the risk of a breast cancer patient diagnosed in a hospital-based mammography unit having a tumor that is visible on ultrasound but not on mammography. A total of 1,399 women with invasive breast cancer from a hospital-based diagnostic mammography unit were included in this retrospective study. For inclusion, mammograms from the time of the primary diagnosis had to be available for computer-assisted assessment of percentage mammographic density (PMD), as well as Breast Imaging Reporting and Data System (BIRADS) assessment of mammography. In addition, ultrasound findings were available for the complete cohort as part of routine diagnostic procedures, regardless of any patient or imaging characteristics. Logistic regression analyses were conducted to identify predictors of mammography failure, defined as BIRADS assessment 1 or 2. The probability that the visibility of a tumor might be masked at diagnosis was estimated using a regression model with the identified predictors. Tumors were only visible on ultrasound in 107 cases (7.6%). PMD was the strongest predictor for mammography failure, but age, body mass index and previous breast surgery also influenced the risk, independently of the PMD. Risk probabilities ranged from 1% for a defined low-risk group up to 40% for a high-risk group. These findings might help identify women who should be offered ultrasound examinations in addition to mammography.
EVALuna2:6818

Management of Cervical Intraepithelial Neoplasia in Pregnant Women - Stübs, Frederik; Koch, Martin C.; Dietl, Anna; Schulmeyer, Carla; Behrens, Annika; Seibold, Anja; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Gaß, Paul; et al. (Anticancer Research, 2023)
BACKGROUND/AIM: The aims of the present study were to evaluate the accuracy of colposcopic findings, investigate the way in which untreated cervical intraepithelial neoplasia (CIN) 2/3 develops during pregnancy, and identify factors associated with regression, persistence, or progression rates. PATIENTS AND METHODS: In a tertiary gynecology and obstetrics department, 655 pregnant women were seen for colposcopy. The most common reason for referral was abnormal cytology findings. The follow-up findings were analyzed retrospectively on the basis of colposcopic findings and cytological and histological tests. RESULTS: The rate of accuracy for major colposcopic findings was 89.2%. Among the colposcopic findings considered "suspicious for invasion" were invasive carcinoma in 42.9% and CIN 3 in 57.1%. The persistence of CIN 3 postpartum was 80% and the rate of progression 4.1%. The rate of regression for CIN 3 was 21.9%. For CIN 2, the rate of persistence was 37.5%, with a regression rate of 31.3%. The rate of regression was higher after vaginal delivery in comparison with caesarean section. CONCLUSION: The accuracy rate of colposcopy is comparatively high, at 89.2%. This might be because pregnant women are seen by more experienced examiners in our dysplasia unit. The rate of progression is comparable with that in other studies. Vaginal delivery increases the regression rate. The newborns' birth weight or birth week did not affect the rates of regression or persistence.
CRIS-Team Scopus Importer:2023-07-07
Keywords: cervical dysplasia; High-grade squamous intraepithelial lesion (HSIL); mode of delivery; pregnancy; treatment

Management of liver metastases of gastrointestinal stromal tumors (GIST) - Vassos, Nikolaos; Agaimy, Abbas; Hohenberger, Werner; Croner, Roland S. (Annals of Hepatology, 2015)
Liver metastases (LM) are crucial prognostic manifestation of gastrointestinal stromal tumors (GIST). With the advent of tyrosine kinase inhibitors (TKI), management of metastatic GIST has radically changed. Long clinical follow-up provides an increased proportion of GIST patients with LM who are candidates for potentially curative therapy.Patients who underwent treatment for liver metastases of GIST between 2000-2009 in our department were included in the study. Mean follow-up was 84 months (range 40-145) months. In retrospective analysis we investigated clinical, macro-/microscopic and immunohistochemical criteria, surgical, interventional and TKI therapy as well.In 87 GIST-patients we identified 25 (29%) patients with metastatic disease. Of these, 12 patients (14%) suffered from LM with a mean age of 60.5 (range, 35-75) years. Primary GIST were located at stomach (n = 4, 33%) or small intestine (n = 8, 67%); all of them expressed CD117 and/or CD34. LM were multiple (83%), distributed in both lobes (67%). They were detected synchronously with primary tumor in 33% and metachronously in 77%. All patients with liver involvement were considered to treatment with TKI. LM were resected (R0) in 4 patients (33%). In recurrent (2/4) and TKI resistant cases, interventional treatment (radiofrequency ablation) and TKI escalation were carried out. During a median follow-up of 84 months (range 30-152), 2 patients died (16.5%) for progressive disease and one patient for other reasons. Nine patients (75%) were alive.Treatment of LM from GIST needs a multimodal approach. TKI-therapy is required at any case. In case of respectability, surgery must be carried out. In unresectable cases or recurrent/progressive disease, interventional treatment or TKI escalation should be considered. Therefore, these patients need to be treated in experienced centres, where multimodal approaches are established.
EVALuna2:6694

Management of spontaneous enophthalmos due to silent sinus syndrome: a case report - Nkenke, Emeka; Alexiou, Christoph; Iro, Heinrich; Amann, Kerstin Ute; Kirchner, Thomas; Häusler, Gerd; Neukam, Friedrich Wilhelm; Holbach, Benedict (International Journal of Oral and Maxillofacial Surgery, 2005)
UnivIS-Import:2015-04-14:Pub.2005.nat.dphy.optik.1optik.manage

Massive parallel sequencing of head and neck conventional squamous cell carcinomas: A comprehensive review. - Nadal, Alfons; Cardesa, Antonio; Agaimy, Abbas; Almangush, Alhadi; Franchi, Alessandro; Hellquist, Henrik; Leivo, Ilmo; Zidar, Nina; Ferlito, Alfio (Virchows Archiv, 2024)
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is a cause of significant mortality and morbidity. The epidemiology of this cancer varies worldwide due to either genetic differences in populations or differences in carcinogen exposure. The application of massive parallel sequencing-based techniques in HNSCC should provide a helpful understanding of the genetic alterations that eventually lead to HNSCC development and progression, and ideally, could be used for personalized therapy. In this review, the reader will find an overview of the mutational profile of conventional HNSCC according to published results on massive parallel sequencing data that confirm the pivotal role of TP53 and the frequent involvement of CDKN2A and PIK3CA. The reader will also find a more detailed description of the genes, such as NOTCH1 and FBXW7, that were not identified in HNSCCs before the development of these techniques, the differences that can be site-specific, such as the different mutational signatures that indicate specific carcinogens for various subsites of the head and neck, and finally, the actionability of these findings that should allow more personalized therapy for patients.
EVALuna2:578853

Massive parallel sequencing unveils homologous recombination deficiency in follicular dendritic cell sarcoma - Lorenzi, Luisa; Haferlach, Torsten; Mori, Luigi; Simbeni, Matteo; Walter, Wencke; Balzarini, Piera; Meggendorfer, Manja; Döring, Claudia; Lonardi, Silvia; Bugatti, Mattia; Agostinelli, Claudio; Mehta, Jay; et al. (Haematologica, 2024)
Standardized treatment options are lacking for patients with unresectable or multifocal follicular dendritic cell sarcoma (FDCS) and disease-related mortality is as high as 20%. Applying whole-genome sequencing (WGS) in one case and whole-exome sequencing (WES) in additional twelve cases, this study adds information on the molecular landscape of FDCS, expanding knowledge on pathobiological mechanisms and identifying novel markers of potential theragnostic significance. Massive parallel sequencing showed high frequency of mutations on oncosuppressor genes, particularly in RB1, CARS and BRCA2 and unveiled alterations on homologous recombination DNA damage repair-related genes in 70% (9/13) of cases. This indicates that patients with high-stage FDCS may be eligible for poly ADP ribose polymerase inhibition protocols. Low tumor mutational burden was confirmed in this study despite common PDL1 expression in FDCS arguing on the efficacy of immune checkpoint inhibitors. CDKN2A deletion, detected by WGS and confirmed by fluorescence in situ hybridization in 41% of cases (9/22) indicates that impairment of cell cycle regulation may sustain oncogenesis in FDCS. Absence of mutations in the RAS/RAF/MAPK pathway and lack of clonal hematopoiesis-related mutations in FDCS sanction its differences from dendritic cell-derived neoplasms of hematopoietic derivation. WGS and WES in FDCS provides additional information on the molecular landscape of this rare tumor, proposing novel candidate genes for innovative therapeutical approaches to improve survival of patients with multifocal disease.
CRIS-Team Scopus Importer:2024-06-14

Mass Spectrometry Imaging Differentiates Chromophobe Renal Cell Carcinoma and Renal Oncocytoma with High Accuracy - Kriegsmann, Mark; Casadonte, Rita; Maurer, Nadine; Stoehr, Christine; Erlmeier, Franziska; Moch, Holger; Junker, Klaus; Zgorzelski, Christiane; Weichert, Wilko; Schwamborn, Kristina; Deininger, Soeren-Oliver; Gaida, Matthias; et al. (Journal of Cancer, 2020)
Background: While subtyping of the majority of malignant chromophobe renal cell carcinoma (cRCC) and benign renal oncocytoma (rO) is possible on morphology alone, additional histochemical, immunohistochemical or molecular investigations are required in a subset of cases. As currently used histochemical and immunohistological stains as well as genetic aberrations show considerable overlap in both tumors, additional techniques are required for differential diagnostics. Mass spectrometry imaging (MSI) combining the detection of multiple peptides with information about their localization in tissue may be a suitable technology to overcome this diagnostic challenge.
CRIS-Team WoS Importer:2020-09-11

Material and shape optimization for multi-layered vocal fold models using transient loadings - Schmidt, Bastian; Leugering, Günter; Stingl, Michael; Hüttner, Björn; Agaimy, Abbas; Döllinger, Michael (Journal of the Acoustical Society of America, 2013)
Commonly applied models to study vocal fold vibrations in combination with air flow distributions are self-sustained physical models of the larynx consisting of artificial silicone vocal folds. Choosing appropriate mechanical parameters and layer geometries for these vocal fold models while considering simplifications due to manufacturing restrictions is difficult but crucial for achieving realistic behavior. In earlier work by Schmidt et al. [J. Acoust. Soc. Am. 129, 2168-2180 (2011)], the authors presented an approach in which material parameters of a static numerical vocal fold model were optimized to achieve an agreement of the displacement field with data retrieved from hemilarynx experiments. This method is now generalized to a fully transient setting. Moreover in addition to the material parameters, the extended approach is capable of finding optimized layer geometries. Depending on chosen material restriction, significant modifications of the reference geometry are predicted. The additional flexibility in the design space leads to a significantly more realistic deformation behavior. At the same time, the predicted biomechanical and geometrical results are still feasible for manufacturing physical vocal fold models consisting of several silicone layers. As a consequence, the proposed combined experimental and numerical method is suited to guide the construction of physical vocal fold models. (C) 2013 Acoustical Society of America.

Matricellular protein SPARCL1 regulates tumor microenvironment-dependent endothelial cell heterogeneity in colorectal carcinoma - Naschberger, Elisabeth; Liebl, Andrea; Schellerer, Vera; Schütz, Manuela; Britzen-Laurent, Nathalie; Kölbel, Patrick; Schaal, Ute; Haep, Lisa; Regensburger, Daniela; Wittmann, Thomas; Klein-Hitpass, Ludger; Rau, Tilman; et al. (Journal of Clinical Investigation, 2016)
Different tumor microenvironments (TMEs) induce stromal cell plasticity that affects tumorigenesis. The impact of TME-dependent heterogeneity of tumor endothelial cells (TECs) on tumorigenesis is unclear. Here, we isolated pure TECs from human colorectal carcinomas (CRCs) that exhibited TMEs with either improved (Th1-TME CRCs) or worse clinical prognosis (control-TME CRCs). Transcriptome analyses identified markedly different gene clusters that reflected the tumorigenic and angiogenic activities of the respective TMEs. The gene encoding the matricellular protein SPARCL1 was most strongly upregulated in Th1-TME TECs. It was also highly expressed in ECs in healthy colon tissues and Th1-TME CRCs but low in control-TME CRCs. In vitro, SPARCL1 expression was induced in confluent, quiescent ECs and functionally contributed to EC quiescence by inhibiting proliferation, migration, and sprouting, whereas siRNA-mediated knockdown increased sprouting. In human CRC tissues and mouse models, vessels with SPARCL1 expression were larger and more densely covered by mural cells. SPARCL1 secretion from quiescent ECs inhibited mural cell migration, which likely led to stabilized mural cell coverage of mature vessels. Together, these findings demonstrate TME-dependent intertumoral TEC heterogeneity in CRC. They further indicate that TEC heterogeneity is regulated by SPARCL1, which promotes the cell quiescence and vessel homeostasis contributing to the favorable prognoses associated with Th1-TME CRCs.
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Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging: Diagnostic Pathways and Metabolites for Renal Tumor Entities - Erlmeier, Franziska; Sun, Na; Shen, Jian; Feuchtinger, Annette; Buck, Achim; Prade, Verena M.; Kunzke, Thomas; Schraml, Peter; Moch, Holger; Autenrieth, Michael; Weichert, Wilko; Hartmann, Arndt; et al. (Oncology, 2023)
Background: Correct tumor subtyping of primary renal tumors is essential for treatment decision in daily routine. Most of the tumors can be classified based on morphology alone. Nevertheless, some diagnoses are difficult, and further investigations are needed for correct tumor subtyping. Besides histochemical investigations, high-mass-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) can detect new diagnostic biomarkers and hence improve the diagnostic. Patients and Methods: Formalin-fixed paraffin embedded tissue specimens from clear cell renal cell carcinoma (ccRCC, n = 552), papillary renal cell carcinoma (pRCC, n = 122), chromophobe renal cell carcinoma (chRCC, n = 108), and renal oncocytoma (rO, n = 71) were analyzed by high-mass-resolution MALDI fourier-transform ion cyclotron resonance (FT-ICR) MSI. The SPACiAL pipeline was executed for automated co-registration of histological and molecular features. Pathway enrichment and pathway topology analysis were performed to determine significant differences between RCC subtypes. Results: We discriminated the four histological subtypes (ccRCC, pRCC, chRCC, and rO) and established the subtype-specific pathways and metabolic profiles. rO showed an enrichment of pentose phosphate, taurine and hypotaurine, glycerophospholipid, amino sugar and nucleotide sugar, fructose and mannose, glycine, serine, and threonine pathways. ChRCC is defined by enriched pathways including the amino sugar and nucleotide sugar, fructose and mannose, glycerophospholipid, taurine and hypotaurine, glycine, serine, and threonine pathways. Pyrimidine, amino sugar and nucleotide sugar, glycerophospholipids, and glutathione pathways are enriched in ccRCC. Furthermore, we detected enriched phosphatidylinositol and glycerophospholipid pathways in pRCC. Conclusion: In summary, we performed a classification system with a mean accuracy in tumor discrimination of 85.13%. Furthermore, we detected tumor-specific biomarkers for the four most common primary renal tumors by MALDI-MSI. This method is a useful tool in differential diagnosis and biomarker detection.
CRIS-Team Scopus Importer:2023-02-17
Keywords: Chromophobe renal cell carcinoma; Clear cell renal cell carcinoma; Mass spectrometry imaging; Metabolomics; Papillary renal cell carcinoma; Renal oncocytoma

Maximizing the diagnostic information from biopsies in chronic inflammatory bowel diseases: recommendations from the Erlangen International Consensus Conference on Inflammatory Bowel Diseases and presentation of the IBD-DCA score as a proposal for a new index for histologic activity assessment in ulcerative colitis and Crohn's disease - Lang-Schwarz, Corinna; Agaimy, Abbas; Atreya, Raja; Becker, Christoph; Danese, Silvio; Flejou, Jean-Francois; Gassler, Nikolaus; Grabsch, Heike I.; Hartmann, Arndt; Kamaradova, Katerina; Kuehl, Anja A.; Lauwers, Gregory Y.; et al. (Virchows Archiv, 2020)
CRIS-Team WoS Importer:2021-01-22

MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma - Kang, Eun-Young; Millstein, Joshua; Popovic, Gordana; Meagher, Nicola S.; Bolithon, Adelyn; Talhouk, Aline; Chiu, Derek S.; Anglesio, Michael S.; Leung, Betty; Tang, Katrina; Lambie, Neil; Pavanello, Marina; et al. (Virchows Archiv, 2021)
Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naive HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naive tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naive HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.
CRIS-Team WoS Importer:2021-11-26

MDM2 is a useful diagnostic marker for nasopharyngeal carcinoma - Taverna, Cecilia; Agaimy, Abbas; Franchi, Alessandro (Pathology Research and Practice, 2022)
Background: The MDM2 gene appears to be involved in the development of nasopharyngeal carcinoma. The aim of this study was to examine MDM2 expression in a series of nasopharyngeal carcinoma biopsies to explore its potential diagnostic significance. Methods: The study cohort consisted of 26 nasopharyngeal carcinomas, including 22 EBV positive non-keratinizing squamous cell carcinomas (NKSCC), 1 EBV negative NKSCC and 3 EBV negative keratinizing SCC. For comparison, we selected 48 oropharyngeal carcinomas, including 17 HPV positive SCC (14 non-keratinizing and 3 keratinizing) and 31 HPV negative SCCs (28 keratinizing and 3 non-keratinizing). In addition, we examined MDM2 expression in a group of 26 cervical lymph node metastases, including 5 with EBV positive nasopharyngeal NKSCC and 21 from oropharyngeal carcinoma (18 non keratinizing HPV positive, 1 keratinizing HPV positive, 1 keratinizing HPV negative and 1 non-keratinizing HPV negative). Finally, 2 bone metastases from EBV positive nasopharyngeal NKSCC were also included. A tissue microarray was constructed from formalin-fixed paraffin embedded tumor tissue specimens. Sections were immunostained for MDM2 and in situ hybridization for EBER and CISH analysis for the MDM2 gene were also conducted in all cases. Results: Overall, MDM2 positivity was detected in 28 of 102 SCCs (27.2 %). MDM2 positivity was significantly more frequent in EBV positive NKSCC (80 %) than in oropharyngeal HPV positive NKSCC (6.1 %) and keratinizing SCCs (9.4 %) (p < 0.001, Pearson chi square). Considering only the primary tumors, 86.4 % of the nasopharyngeal carcinomas were positive, versus 13.5 % of the oropharyngeal carcinomas (p < 0.001, Pearson chi square). Considering the lymph node metastases, 3 of 5 EBV positive carcinomas with nasopharyngeal primary were positive, whereas only one of the HPV positive carcinomas was positive. Finally, both the bone metastases from EBV positive nasopharyngeal carcinoma were positive for MDM2. No amplification of the MDM2 gene was identified by in situ hybridization analysis. Conclusions: Our data indicate that MDM2 could be a valuable diagnostic marker to support the diagnosis of nasopharyngeal EBV positive NKSCC.
CRIS-Team Scopus Importer:2022-07-01
Keywords: Immunohistochemistry; In situ hybridization; MDM2; Nasopharyngeal carcinoma; Oropharyngeal carcinoma

MDM2 is a Useful Diagnostic Marker for the Diagnosis of Nasopharyngeal Carcinoma - Taverna, Cecilia; Agaimy, Abbas; Santucci, Marco; Franchi, Alessandro (LABORATORY INVESTIGATION, 2020)
CRIS-Team WoS Importer:2020-03-24

Mdm2 SNP309 G-Variant Is Associated with Invasive Growth of Human Urinary Bladder Cancer - Hitzenbichler, Florian; Stoehr, Christine G.; Rogenhofer, Michael; Wieland, Wolf F.; Ruemmele, Petra; Hartmann, Arndt; Stoehr, Robert (Pathobiology, 2014)
Objective: Human mouse double minute 2 (Mdm2) is essential in degrading p53 by acting as an ubiquitin ligase and therefore plays a vital role in cell cycle and survival. The G-variant of the Mdm2 SNP309, which is located within the promoter of the Mdm2 gene, increases expression of Mdm2 and thereby inhibits the p53 pathway. Several studies have investigated the influence of this SNP on disease risk and onset of various malignancies. The impact of Mdm2 SNP309 on bladder cancer is still to be established due to inconsistent data. Methods: In a case-control study we determined the distribution of Mdm2 SNP309 genotypes in 111 patients with an early-onset bladder cancer (diagnosis <45 years of age), in 113 consecutive bladder cancer patients and in a control group consisting of 140 patients without any malignancy. Results: There was no significant association between the allelic distribution of the Mdm2 SNP309 and tumor risk, early onset, gender or grade of the tumor. According to tumor stage we found a significant difference in the distribution of the Mdm2 SNP309 between patients with noninvasive and invasive (>=pT1) tumor growth (p = 0.016). In patients with invasive tumors a significant increase of the G allele was found (T/T vs. T/G + G/G; p = 0.023; OR 2.203, 95% CI 1.111-4.369). Conclusion: These data indicate that the G-variant of the Mdm2 SNP309 might influence the development of a more aggressive tumor phenotype in patients with bladder cancer without affecting the overall tumor risk. © 2013 S. Karger AG, Basel.
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Measurement of amniotic fluid steroids of midgestation via LC-MS/MS - Fahlbusch, Fabian B.; Heussner, Kirsten; Schmid, Matthias; Schild, Ralf; Rübner, Matthias; Hübner, Hanna; Rascher, Wolfgang; Dörr, Helmuth-Günther; Rauh, Manfred (Journal of Steroid Biochemistry and Molecular Biology, 2015)
Analysis of steroids by mass spectrometry (MS) has evolved into a reliable tool for the simultaneous detection of multiple steroids. As amniotic fluid (AF) and fetal serum composition of early pregnancy are closely related, the analysis of AF can yield information on the physiological status of the developing fetus. We evaluated the use of liquid-chromatography tandem mass spectrometry (LC-MS/MS) for AF steroid analysis, including the analysis of its sensitivity and accuracy for gender verification in healthy subjects.AF of 78 male and 94 female healthy newborns was analyzed by LC-MS/MS at 16 weeks of gestation. The levels of androstenedione, corticosterone, cortisol, cortisone, deoxycorticosterone, 11-deoxycortisol, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), 17-hydroxyprogesterone, progesterone (17-OHP) and testosterone were measured. Steroid levels were compared to RIA and GC-MS levels of midgestation from the literature. Cross-validated logistic regression was used to obtain statistical predictions of gender at birth from testosterone and the above steroids.LC-MS/MS analysis of AF steroids yielded comparable results with published GC-MS data. Gender specific differences were found for androstenedione and testosterone concentrations with higher levels in the male fetus. In contrast to published RIA data no gender specific differences were observed for 17-hydroxyprogesterone and dehydroepiandrosterone AF concentrations. Testosterone concentrations yielded highly accurate predictions for male gender at birth. Additional analysis of further steroids did neither increase the accuracy, sensitivity nor specificity of this prediction. The estimated optimal cut-off value for amniotic testosterone level was 0.074 ?g/L for healthy male newborns.LC-MS/MS is a reliable method for the determination of steroids in amniotic fluid. The determination of testosterone in amniotic fluid by LC-MS/MS in early pregnancy of healthy subjects can be used to offer a reliable prediction of fetal gender at birth.
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Melanoma-associated leukoderma and vitiligo cannot be differentiated based on blinded assessment by experts in the field - Lommerts, Janny E.; Teulings, Hansje-Eva; Ezzedine, Khaled; Van Geel, Nanja; Hartmann, Arndt; Speeckaert, Reinhart; Spuls, Phyllis I.; Wolkerstorfer, Albert; Luiten, Rosalie M.; Bekkenk, Marcel W. (Journal of the American Academy of Dermatology, 2016)
Melanoma-associated leukoderma (MAL) is a depigmenting disorder that can occur spontaneously in patients with melanoma. The differences in clinical presentation between MAL and vitiligo are not well defined. This may lead to misdiagnosing MAL as vitiligo, resulting in delayed detection of melanoma.The objective of this study was to assess whether experts in the field can distinguish between MAL and vitiligo, and to assess if discriminative features can be identified.We designed an image comparison study in which 4 experts in the field blindly assessed photographs followed by medical history of 11 patients with MAL and 33 with vitiligo.The assessors misdiagnosed 72.7% of MAL cases and marked 80.0% of them as typical vitiligo. The median age at onset of the leukoderma was higher (55 years, P = .001) in MAL. No discriminative features were found.Sampling bias because of inclusion in tertiary referral center is a limitation.The clinical presentation of leukoderma in patients with melanoma resembles that of vitiligo. We propose "melanoma-associated vitiligo" as the more appropriate term for leukoderma in patients with melanoma. Clinicians should be aware that depigmentation in vitiligo can also be caused by melanoma-associated vitiligo and a total body inspection should be performed.
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Membranous expression of target protein is required for ADC response in urothelial cancer - Klümper, Niklas; Brägelmann, Johannes; Bahlinger, Veronika; Hartmann, Arndt; Grünwald, Viktor; Kuppe, Christoph; Hölzel, Michael; Eckstein, Markus (European Urology, 2024)
CRIS-Team Scopus Importer:2024-08-30

Merkel Cell Carcinoma - A Rare Entity with Specific Reconstructive Challenges - Bührer, Gregor; Horch, Raymund E.; Schlabrakowski, Anne; Arkudas, Andreas (Handchirurgie, Mikrochirurgie, Plastische Chirurgie, 2016)
Merkel cell carcinoma is a rare tumor, which is associated with poor prognosis. It has been shown that radical local excision and radiotherapy are essentiell for curative therapy. To avoid compromise in tumor treatment, plastic surgery is often needed. Furthermore, using complex reconstruction methods, like free flap transplantation, has proven to be effective to avoid long and complicated clinical courses.Between 2003 and 2016 15 patients with Merkel cell carcinoma were treated in our department. In 2 cases additional resection had to take place before reconstruction was performed. In most cases, a safety margin of 2 cm was chosen. Complete excision could be achieved in 13 patients. We used different methods of reconstruction such as primary suturing, skin transplantations, local, pedicled or free flaps.In all patients defects could be reconstructed with good results, which proved to be stable even under postoperative radiation therapy.Given the modern techniques of plastic surgery the extent of local excision should not be should be chosen as radical as possible and necessary. It has been proven that interdisciplinary treatment of patients with Merkel cell carcinoma increases the chances for curative therapy while providing safe methods for reconstruction despite radiotherapy, extensive tumors or difficult localization.
EVALuna2:6765

Mesenchymal/non-epithelial mimickers of neuroendocrine neoplasms with a focus on fusion gene-associated and SWI/SNF-deficient tumors - Kasajima, Atsuko; Konukiewitz, Bjoern; Schlitter, Anna Melissa; Weichert, Wilko; Braesen, Jan Hinrich; Agaimy, Abbas; Kloeppel, Gunter (Virchows Archiv, 2021)
Mimickers of neuroendocrine neoplasms (NEN) include a number of important pitfall tumors. Here, we describe our experience with mesenchymal mimics of NENs to illustrate their spectrum and draw the attention particularly to a group of mesenchymal/non-epithelial neoplasms (MN) that combine epithelioid histology with neuroendocrine (NE-) features and peculiar genetic abnormalities. In a consultation series of 4498 cases collected between 2009 and 2021, 2099 neoplasms expressing synaptophysin and/or chromograninA were reviewed and analyzed. A total of 364 (18%) were diagnosed as non-NENs, while the remaining tumors were NEN. The group of mesenchymal/non-epithelial neoplasms with NE-features (MN-NE) included 31/364 (8%) cases. These mostly malignant neoplasms showed an epithelioid morphology. While all but one tumor expressed synaptophysin, mostly patchy, only 10/29 (34%) co-expressed chromograninA. A total of 13/31 (42%) of the MN-NE showed EWSR1-related gene fusions (6 Ewing sarcomas, 5 clear cell sarcomas, and 1 desmoplastic small round cell tumor, 1 neoplasm with FUS-CREM gene fusion) and 7 (23%) were SWI/SNF (SMARCB1 or SMARCA4)-deficient neoplasms. The remaining MN-NE included synovial sarcoma, sclerosing epithelioid mesenchymal neoplasm, melanoma, alveolar soft part sarcoma, solitary fibrous tumor, and chordoma. A total of 27/31 MN-NE were from the last 8 years, and 6 of them were located in the pancreas. Eleven MN-NE were initially diagnosed as neuroendocrine carcinomas (NECs). MN-NE with epithelioid features play an increasing role as mimickers of NECs. They mostly belong to tumors with gene fusions involving the EWSR1 gene, or with SWI/SNF complex deficiency. Synaptophysin expression is mostly patchy and chromograninA expression is infrequent in MN-NE of this series and data extracted from literature.
CRIS-Team Scopus Importer:2021-08-13
Keywords: Genetic features; Mesenchymal neoplasms; Mimics; Neuroendocrine neoplasms

Mesenchymal tumors and tumor-like lesions of the gastrointestinal tract: an overview Mesenchymale Tumoren und tumorartige Veränderungen des Gastrointestinaltraktes - Agaimy, Abbas (Pathologe, 2021)
Mesenchymal tumors and tumor-like lesions of the gastrointestinal (GI) tract are uncommon. They vary from reactive tumefactive lesions and benign neoplasms to highly aggressive sarcomas. Among them, GI stromal tumors (GISTs) are most common, followed, with less frequency, by smooth muscle and neurogenic tumors. The major challenge resides in correctly identifying GISTs and providing a comprehensive report (including risk assessment and genotyping) that represents the basis for an optimized surgical-oncological treatment and/or adjuvant therapy. On the other hand, the challenge of benign lesions is to find a good name (well understandable and reproducible diagnostic term) that helps avoid diagnostic ambiguity and prognostic uncertainty so that overprognostication and overtreatment can be prevented. Moreover, several recently described genetically defined benign and malignant entities need be correctly diagnosed due to their special “targeted” therapeutic options and to further characterize their clinicopathological and biological properties in the future. These recent entities include aggressive epithelioid inflammatory myofibroblastic sarcoma (ALK-RANBP2-driven), malignant gastrointestinal neuroectodermal tumor (EWSR1-ATF1/CREB-related), NTRK-rearranged neoplasms, and, most recently, colorectal NUTM1-rearranged sarcomas. This review highlights the major clinicopathological features of gastrointestinal mesenchymal lesions in light of recent developments.
CRIS-Team Scopus Importer:2021-12-31
Keywords: Gastrointestinal stromal tumors; Gene fusions; Imatinib; Neuroectodermal tumors; Sarcoma

Mesenchymal tumors of the mediastinum - Rieker, R. J.; Marx, A.; Agaimy, Abbas; Stroebel, P. (Pathologe, 2016)
Mesenchymal neoplasms of the thymus and mediastinum account for only 2 % of neoplasms of the mediastinum and are therefore very rare. With very few exceptions the histology, immunohistochemistry and (based on current knowledge) molecular biology of mediastinal soft tissue tumors are not different from their counterparts in other organs. Characteristic features are more concerned with clinical epidemiological and therapeutic aspects as well as the multitude of possible differential diagnoses. With the exception of organ-specific tumors, such as gastrointestinal stromal tumors (GIST), virtually all entities encountered in peripheral soft tissues can also arise in the mediastinum. Primary mediastinal soft tissue sarcomas (STS) must be distinguished from secondary radiation-induced STS after irradiation, e. g. for breast cancer and Hodgkin's lymphoma and from STS arising as somatic type malignancies in mediastinal germ cell tumors.
EVALuna2:6826

Mesenchymal tumors of the urinary bladder - Agaimy, Abbas; Hartmann, Arndt (Pathologe, 2016)
Mesenchymal tumors and tumor-like lesions of the urinary bladder are rare. They encompass a heterogeneous group of reactive pseudosarcomatous tumor-like changes and benign neoplastic lesions as well as malignant neoplasms (sarcomas) with variable biological behavior. The well-known differential diagnostic difficulties related to these conditions are mainly due to their rarity and thus limited experience and familiarity with their histological features and due to the significant morphological overlap between fully benign reactive conditions and aggressive malignant neoplasms. The distinction between them may on occasion represent a real challenge and is associated with several pitfalls. This overview summarizes the clinicopathological and differential diagnostic aspects of the most important lesions and discuss their differential diagnosis in the light of current knowledge.
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Mesothelial/monocytic incidental cardiac excrescences (cardiac MICE) associated with acute aortic dissection: a study of two cases - Strecker, Thomas; Bertz, Simone; Wachter, David Lukas; Weyand, Michael; Agaimy, Abbas (International Journal of Clinical and Experimental Pathology, 2015)
Acute aortic dissection is a life-threatening condition mainly caused by hypertension, atherosclerotic disease and other degenerative diseases of the connective tissue of the aortic wall. Mesothelial/monocytic incidental cardiac excrescences (cardiac MICE) is a rare benign reactive tumor-like lesion composed of admixture of histiocytes, mesothelial cells, and inflammatory cells set within a fibrinous meshwork without a vascular network or supporting stroma. Cardiac MICE occurring in association with aortic dissection is exceptionally rare (only one such case reported to date). We herein report on the surgical repair of two Stanford type A aortic dissections caused by idiopathic giant cell aortitis in a 66-year-old-woman and by atherosclerotic disease in a 58-year-old-man, respectively. In both cases, the dissections could be visualized via computed tomography. Histopathology showed cardiac incidental MICE within the external aortic wall near the pericardial surface which was confirmed by immunohistochemistry.
EVALuna2:6704

Metabolic and Lipidomic Reprogramming in Renal Cell Carcinoma Subtypes Reflects Regions of Tumor Origin - Schaeffeler, Elke; Büttner, Florian; Reustle, Anna; Klumpp, Verena; Winter, Stefan; Rausch, Steffen; Fisel, Pascale; Hennenlotter, Jörg; Kruck, Stephan; Stenzl, Arnulf; Wahrheit, Judith; Sonntag, Denise; et al. (European Urology Focus, 2018)
BACKGROUND: Renal cell carcinoma (RCC) consists of prognostic distinct subtypes derived from different cells of origin (eg, clear cell RCC [ccRCC], papillary RCC [papRCC], and chromophobe RCC [chRCC]). ccRCC is characterized by lipid accumulation and metabolic alterations, whereas data on metabolic alterations in non-ccRCC are limited. OBJECTIVE: We assessed metabolic alterations and the lipid composition of RCC subtypes and ccRCC-derived metastases. Moreover, we elucidated the potential of metabolites/lipids for subtype classification and identification of therapeutic targets. DESIGN, SETTING, AND PARTICIPANTS: Metabolomic/lipidomic profiles were quantified in ccRCC (n=58), chRCC (n=19), papRCC (n=14), corresponding nontumor tissues, and metastases (n=9) through a targeted metabolomic approach. Transcriptome profiling was performed in corresponding samples and compared with expression data of The Cancer Genome Atlas cohorts (patients with ccRCC, n=452; patients with papRCC, n=260; and patients with chRCC, n=59). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In addition to cluster analyses, metabolomic/transcriptomic data were analyzed to evaluate metabolic differences of ccRCC and chRCC using Welch's t test or paired t test as appropriate. Where indicated, p values were adjusted for multiple testing using Bonferroni or Benjamini-Hochberg correction. RESULTS AND LIMITATIONS: Based on their metabolic profiles, RCC subtypes clustered into two groups separating ccRCC and papRCC from chRCC, which mainly reflected the different cells of origin. ccRCC-derived metastases clustered with primary ccRCCs. In addition to differences in certain lipids (lysophosphatidylcholines and sphingomyelins), the coregulation network of lipids differed between ccRCC and chRCC. Consideration of metabolic gene expression indicated, for example, alterations of the polyamine pathway at metabolite and transcript levels. In vitro treatment of RCC cells with the ornithine-decarboxylase inhibitor difluoromethylornithine resulted in reduced cell viability and mitochondrial activity. Further evaluation of clinical utility was limited by the retrospective study design and cohort size. CONCLUSIONS: In summary, we provide novel insight into the metabolic profiles of ccRCC and non-ccRCC, thereby confirming the different ontogeny of RCC subtypes. Quantification of differentially regulated metabolites/lipids improves classification of RCC with an impact on the identification of novel therapeutic targets. PATIENT SUMMARY: Several subtypes of renal cell carcinoma (RCC) with different metastatic potentials and prognoses exist. In the present study, we provide novel insight into the metabolism of these different subtypes, which improves classification of subtypes and helps identify novel targets for RCC therapy.
EVALuna2:34809

Met amplification in non‐small cell lung cancer (Nsclc)— a consecutive evaluation using next‐generation sequencing (ngs) in a real‐world setting - Schubart, Christoph; Stöhr, Robert; Tögel, Lars; Fuchs, Florian; Sirbu, Horia; Seitz, Gerhard; Seggewiss‐bernhardt, Ruth; Leistner, Rumo; Sterlacci, William; Seidl, Christoph; Mugler, Michael; Kapp, Markus; et al. (Cancers, 2021)
In non‐small cell lung cancer (NSCLC), approximately 1–3% of cases harbor an increased gene copy number (GCN) of the MET gene. This alteration can be due to de novo amplification of the MET gene or can represent a secondary resistance mechanism in response to targeted therapies. To date, the gold standard method to evaluate the GCN of MET is fluorescence in situ hybridization (FISH). However, next‐generation sequencing (NGS) is becoming more relevant to optimize therapy by revealing the mutational profile of each NSCLC. Using evaluable n = 205 NSCLC cases of a consecutive cohort, this study addressed the question of whether an amplicon based NGS assay can completely replace the FISH method regarding the classification of MET GCN status. Out of the 205 evaluable cases, only n = 9 cases (43.7%) of n = 16 high‐level MET amplified cases assessed by FISH were classified as amplified by NGS. Cases harboring a MET GCN >10 showed the best concordance when comparing FISH versus NGS (80%). This study confirms that an amplicon‐based NGS assessment of the MET GCN detects high‐level MET amplified cases harboring a MET GCN >10 but fails to detect the various facets of MET gene amplification in the context of a therapy‐induced resistance mechanism.
CRIS-Team Scopus Importer:2021-10-22
Keywords: Amplification; Fluorescence in situ hybridization; MET; MET inhibitor; Next‐generation sequencing; NSCLC; Precision medicine; Resistance mechanism

Metastatic cutaneous squamous cell carcinoma accounts for nearly all squamous cell carcinomas of the parotid gland. - Bradley, Patrick J.; Stenman, Göran; Thompson, Lester D.R.; Skálová, Alena; Simpson, Roderick H.W.; Slootweg, Pieter J.; Franchi, Alessandro; Zidar, Nina; Nadal, Alfons; Hellquist, Henrik; Williams, Michelle D.; Leivo, Ilmo; et al. (Virchows Archiv, 2024)
Primary squamous cell carcinoma of the parotid gland (pSCCP) has long been recognized as a separate entity and is included in the WHO classifications of salivary gland tumors. However, it is widely accepted among head and neck pathologists that pSCCP is exceptionally rare. Yet, there are many publications describing series of pSCCP and data from SEER and other cancer register databases indicate erroneously an increasing incidence of pSCCP. Importantly, pSCCP and metastatic (secondary) squamous cell carcinoma to the parotid gland (mSCCP) have nearly identical histological features, and the diagnosis of pSCCP should only be made after the exclusion of mSCCP. Moreover, all of the histological diagnostic criteria proposed to be in favor of pSCCP (such as, for example, dysplasia of ductal epithelium) can be encountered in unequivocal mSCCP, thereby representing secondary growth along preexistent ducts. Squamous cell differentiation has also been reported in rare genetically defined primary parotid carcinomas, either as unequivocal histological squamous features (e.g., NUT carcinoma, mucoepidermoid carcinoma), by immunohistochemistry (e.g., in NUT carcinoma, adamantinoma-like Ewing sarcoma, basal-type salivary duct carcinoma, mucoepidermoid carcinoma), or a combination of both. Another major issue in this context is that the International Classification of Diseases (ICD) coding system does not distinguish between primary or metastatic disease, resulting in a large number of patients with mSCCP being misclassified as pSCCP. Immunohistochemistry and new molecular biomarkers have significantly improved the accuracy of the diagnosis of many salivary gland neoplasms, but until recently there were no biomarkers that can accurately distinguish between mSCCP and pSCCP. However, recent genomic profiling studies have unequivocally demonstrated that almost all SCCP analyzed to date have an ultraviolet light (UV)-induced mutational signature typical of mSCCP of skin origin. Thus, mutational signature analysis can be a very useful tool in determining the cutaneous origin of these tumors. Additional molecular studies may shed new light on this old diagnostic and clinical problem. This review presents a critical view of head and neck experts on this topic.
EVALuna2:568045

Metastatic Malignant Melanoma With Complete Loss of Differentiation Markers (Undifferentiated/Dedifferentiated Melanoma): Analysis of 14 Patients Emphasizing Phenotypic Plasticity and the Value of Molecular Testing as Surrogate Diagnostic Marker - Agaimy, Abbas; Specht, Katja; Stoehr, Robert; Lorey, Thomas; Maerkl, Bruno; Niedobitek, Gerald; Straub, Melanie; Hager, Thomas; Reis, Anna-Carinna; Schilling, Bastian; Schneider-Stock, Regine; Hartmann, Arndt; et al. (American Journal of Surgical Pathology, 2016)
Metastatic malignant melanoma is notorious for its phenotypic diversity and loss of differentiation markers. We herein summarized our experience with 14 metastatic melanomas showing complete loss of immunohistochemical melanocytic markers (with or without heterologous differentiation). Patients included 11 men and 3 women aged 24 to 78 years (median, 67 y). Thirteen patients had histologically confirmed primary skin melanoma, and 1 had metastatic melanoma of unknown primary. Undifferentiated metastasis was diagnosed synchronous to primary tumor (n=1), following skin melanoma by 3 months to 9 years (n=11) and preceding it by 1 year (n=1). Sites of undifferentiated metastases were axillary (3), inguinal (1), or submandibular (1) lymph nodes, digestive tract (2), bone/soft tissue (2), lung/pleura (2), and disseminated (n=3). Histology of metastases mimicked undifferentiated pleomorphic or spindle cell sarcoma with variable myxoid and giant cell areas (n=10) and cytokeratin-positive undifferentiated small cell sarcoma (n=1). Three cases showed heterologous dedifferentiation: pleomorphic rhabdomyosarcoma (n=1), teratocarcinosarcoma-like with prominent rhabdomyoblasts (n=1), and adenocarcinoma-like with metaplastic bone (n=1). All cases were negative for S100, melanoma cocktail, HMB45, Melan A, and SOX10. Other markers showed following results: smooth muscle actin (1/14), p16 (1/14), TP53 (2/12), pancytokeratin (4/14), desmin (5/14), h-caldesmon (0/9), and MDM2/CDK4 (0/5). SMARCB1 was intact in 8/8 cases. Genotyping showed BRAF(V600E) mutation (5/14), NRAS mutation (5/14), and BRAF/NRAS wild-type (4/14). In conclusion, undifferentiated/dedifferentiated metastatic melanoma is likely underrecognized and frequently mistaken for undifferentiated sarcoma or other neoplasms. Diagnosis of undifferentiated sarcoma at sites where melanoma metastasis are frequent (eg, inguinal and axillary region) should be made with great caution and warrants exploration of the remote history. Genotyping is a helpful surrogate marker in classifying such difficult cases. In the light of available targeted therapies, recognition of undifferentiated/dedifferentiated metastatic melanoma is mandatory for appropriate treatment.
EVALuna2:6798

Metastatic risk stratification of clear cell renal cell carcinoma patients based on genomic aberrations - Grimm, Julia; Zeuschner, Philip; Janssen, Martin; Wagenpfeil, Stefan; Hartmann, Arndt; Stöhr, Christine; Keck, Bastian; Kahlmeyer, Andreas; Stöckle, Michael; Junker, Kerstin (Genes Chromosomes & Cancer, 2019)
Prognostic markers for the definition of the individual metastatic risk in renal cell carcinoma are still missing. The aim of our study was to establish a total number of specific aberrations (TNSA) genetic score as a new prognostic test for metastatic risk evaluation. Fluorescence in situ hybridization (FISH) was performed on isolated cell nuclei of 100 ccRCCs (50 M1/50 M0) and 100 FFPE sections (second cohort, 32 M1/68 M0). For each chromosomal region (1q21.3, 7q36.3, 9p21.3p24.1, 20q11.21q13.32) cut-off values were determined by receiver-operator curve (ROC)-curve analysis. TNSA was calculated based on the dichotomized specific CNVs. The prognostic significance of CNVs was proven by Cox and logistic regression. TNSA was the best predictor of metastasis and recurrence free survival in both cohorts. We derived an algorithm for risk stratification by combining TNSA and T-category, which increased the prognostic accuracy to 87% (specificity = 86%, sensitivity = 88%). This model divides patients into two risk groups with significantly different RFS, CSS, and OS (P = 3.8×10−5, P = 5×10−6 and P = 3.57×10−8 respectively). The genetic risk model was superior to Leibovich score and was able to identify patients with metachronous metastatic spread which were incorrectly classified as “low” or “intermediate risk.” We present a new tool for individual risk stratification by combining genetic alterations with clinico-pathologic parameters. Interphase FISH proves to be a dependable method for prognostic evaluation in primary tumor tissue on isolated cell nuclei as well as on FFPE sections. Especially in organ-confined tumors the genetic score seems to be an important tool to identify patients at high risk for metastatic disease.
CRIS-Team Scopus Importer:2019-07-12
Keywords: FISH; genomics; metastasis; prognosis; renal cell carcinoma

Metastatic Uterine Leiomyosarcoma With MDM2 Amplification Mimicking Dedifferentiated Liposarcoma: A Diagnostic Pitfall - Agaimy, Abbas; Frohnauer, Judith (International Journal of Gynecological Pathology, 2015)
EVALuna2:6652

Methylomes of renal cell lines and tumors or metastases differ significantly with impact on pharmacogenes - Winter, Stefan; Fisel, Pascale; Buettner, Florian; Rausch, Steffen; D'Amico, Debora; Hennenlotter, Joerg; Kruck, Stephan; Nies, Anne T.; Stenzl, Arnulf; Junker, Kerstin; Scharpf, Marcus; Hofmann, Ute; et al. (Scientific Reports, 2016)
Current therapies for metastatic clear cell renal cell carcinoma (ccRCC) show limited efficacy. Drug efficacy, typically investigated in preclinical cell line models during drug development, is influenced by pharmacogenes involved in targeting and disposition of drugs. Here we show through genome-wide DNA methylation profiling, that methylation patterns are concordant between primary ccRCC and macro-metastases irrespective of metastatic sites (rs >= 0.92). However, 195,038 (41%) of all investigated CpG sites, including sites within pharmacogenes, were differentially methylated (adjusted P < 0.05) in five established RCC cell lines compared to primary tumors, resulting in altered transcriptional expression. Exemplarily, gene-specific analyses of DNA methylation, mRNA and protein expression demonstrate lack of expression of the clinically important drug transporter OCT2 (encoded by SLC22A2) in cell lines due to hypermethylation compared to tumors or metastases. Our findings provide evidence that RCC cell lines are of limited benefit for prediction of drug effects due to epigenetic alterations. Similar epigenetic landscape of ccRCC-metastases and tumors opens new avenue for future therapeutic strategies.
EVALuna2:6920

Metric substage according to micro and extensive lamina propria invasion improves prognostics in T1 bladder cancer - Van De Putte, Elisabeth E. Fransen; Otto, Wolfgang; Hartmann, Arndt; Bertz, Simone; Mayr, Roman; Bruendl, Johannes; Breyer, Johannes; Manach, Quentin; Comperat, Eva M.; Boormans, Joost L.; Bosschieter, Judith; Jewett, Michael A. S.; et al. (Urologic Oncology-Seminars and Original Investigations, 2018)
BACKGROUND: Reliable prognosticators for T1 bladder cancer (T1BC) are urgently needed. OBJECTIVE: To compare the prognostic value of 2 substage systems for T1BC in patients treated by transurethral resection (TUR) and adjuvant bacillus Calmette-Guérin therapy. DESIGN, SETTING, AND PARTICIPANTS: The slides of 601 primary T1BCs from four institutes were reviewed by 2 uropathologists and substaged according to 2 classifications: metric substage according to T1 microinvasive (T1m-lamina propria invasion <0.5mm) and T1 extensive invasive (pT1e-invasion ≥ 0.5mm), and according to invasion of the muscularis mucosae (MM) (T1a-invasion above or into MM/T1b). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable analyses for progression-free (PFS) and cancer-specific survival (CSS) were performed including substage, size, multiplicity, carcinoma in situ, sex, age, WHO-grade 1973, and WHO-grade 2004 as variables. RESULTS: Median follow-up was 5.9 years (interquartile range: 3.3-9.0). Progression to T2BC was observed in 148 (25%) patients and 94 (16%) died of BC. The MM was not present at the invasion front in 135 (22%) of tumors. Slides were substaged as follows: 213 T1m and 388 T1e and 281 T1a and 320 T1b. On multivariable analysis, T1m/e substage and WHO 1973 grade were the strongest prognosticators for PFS (hazard ratio [HR] = 3.8 and HR = 1.8) and CSS (HR = 2.7 and HR = 2.6), respectively. Other prognostic factors for CSS were age (HR = 1.03), and tumor size (HR = 1.8). Substage according to MM-invasion was not significant. Our study was limited by its retrospective design and that standard re-TUR was not performed if TUR was macroscopically complete and muscularis propria was present in resected specimens. CONCLUSIONS: Metric substaging of T1BC was possible in all cases of 601 T1BC patients and it was a strong independent prognosticator of both PFS and CSS.
EVALuna2:34306

Microbiome Patterns in Matched Bile, Duodenal, Pancreatic Tumor Tissue, Drainage, and Stool Samples: Association with Preoperative Stenting and Postoperative Pancreatic Fistula Development - Langheinrich, Melanie; Wirtz, Stefan; Kneis, Barbara; Gittler, Matthias M.; Tyc, Olaf; Schierwagen, Robert; Brunner, Maximilian; Krautz, Christian; Pilarsky, Christian; Trebicka, Jonel; Agaimy, Abbas; Grützmann, Robert; et al. (Journal of Clinical Medicine, 2020)
Postoperative complications after pancreatic surgery are still a significant problem in clinical practice. The aim of this study was to characterize and compare the microbiomes of different body compartments (bile duct, duodenal mucosa, pancreatic tumor lesion, postoperative drainage fluid, and stool samples; preoperative and postoperative) in patients undergoing pancreatic surgery for suspected pancreatic cancer, and their association with relevant clinical factors (stent placement, pancreatic fistula, and gland texture). For this, solid (duodenal mucosa, pancreatic tumor tissue, stool) and liquid (bile, drainage fluid) biopsy samples of 10 patients were analyzed using 16s rRNA gene next-generation sequencing. Our analysis revealed: (i) a distinct microbiome in the different compartments, (ii) markedly higher abundance of Enterococcus in patients undergoing preoperative stent placement in the common bile duct, (iii) significant differences in the beta diversity between patients who developed a postoperative pancreatic fistula (POPF B/C), (iv) patients with POPF B/C were more likely to have bacteria belonging to the genus Enterococcus, and (v) differences in microbiome composition with regard to the pancreatic gland texture. The structure of the microbiome is distinctive in different compartments, and can be associated with the development of a postoperative pancreatic fistula.
CRIS-Team WoS Importer:2020-11-06

Microbiota-derived propionate modulates megakaryopoiesis and platelet function - Schmid, Erik; Dürholz, Kerstin; Frech, Michael; Otterbein, N.; Lucas, Sébastien; Rauh, Manfred; Schett, Georg; Bruns, Heiko; Zaiss, Mario (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Microcystic adnexal carcinoma (MAC)-like squamous cell carcinoma as a differential diagnosis to Bell´s palsy: review of guidelines for refractory facial nerve palsy - Müller, Sandra; Iro, Heinrich; Lell, M.; Seifert, F.; Bohr, Christopher; Scherl, C.; Agaimy, Abbas; Traxdorf, Maximilian (Journal of Otolaryngology-Head & Neck Surgery, 2017)
Bell´s palsy is the most common cause of facial paralysis worldwide and the most common disorder of the cranial nerves. It is a diagnosis of exclusion, accounting for 60-75% of all acquired peripheral facial nerve palsies. Our case shows the first case of a microcystic adnexal carcinoma-like squamous cell carcinoma as a cause of facial nerve palsy.The patient, a 70-year-old Caucasian male, experienced subsequent functional impairment of the trigeminal and the glossopharyngeal nerve about 1½ years after refractory facial nerve palsy. An extensive clinical work-up and tissue biopsy of the surrounding parotid gland tissue was not able to determine the cause of the paralysis. Primary infiltration of the facial nerve with subsequent spreading to the trigeminal and glossopharyngeal nerve via neuroanastomoses was suspected. After discussing options with the patient, the main stem of the facial nerve was resected to ascertain the diagnosis of MAC-like squamous cell carcinoma, and radiochemotherapy was subsequently started.This case report shows that even rare neoplastic etiologies should be considered as a cause of refractory facial nerve palsy and that it is necessary to perform an extended diagnostic work-up to ascertain the diagnosis. This includes high-resolution MRI imaging and, as perilesional parotid biopsies might be inadequate for rare cases like ours, consideration of a direct nerve biopsy to establish the right diagnosis.
EVALuna2:6836

Micropapillary morphology is an indicator of poor prognosis in patients with urothelial carcinoma treated with transurethral resection and radiochemotherapy - Bertz, Simone; Wach, S.; Taubert, Helge; Merten, Ricarda; Krause, F. S.; Schick, S.; Ott, O. J.; Weigert, E.; Dworak, O.; Roedel, C.; Fietkau, Rainer; Wullich, Bernd; et al. (Virchows Archiv, 2016)
Purpose of this study was to evaluate prognostic impact of rare variants of urothelial bladder cancer (BC) after treatment with combined radiochemotherapy (RCT). To this end tumour tissue of 238 patients with urothelial carcinoma (UC) treated with transurethral resection of the bladder (TUR-B) and RCT with curative intent was collected. Histomorphological analysis included re-evaluation and semi-quantitative assessment of rare UC subtypes. Additionally, human epidermal growth factor receptor 2 (HER2) chromogenic in situ hybridisation (CISH) was performed in tumours with a micropapillary component exceeding 30 %. Long-term follow-up was available for 200 patients (range 3-282 months). Variant UC histology was found in 45 of 238 tumours, most frequently micropapillary UC (N = 17) including cases with a small fraction of tumour with micropapillary morphology. The mere presence of micropapillary morphology did not affect prognosis. In tumours with extensive (>=30 %) micropapillary morphology (N = 8) Kaplan-Meier analysis revealed significantly worse cancer specific survival (CSS) (P = 0.002) compared to conventional UC (mean survival times 97 months and 229 months, respectively). Univariate Cox regression analysis of cases with >=30 % micropapillary morphology revealed a hazard ratio of 4.726 (95 % CI 1.629-13.714) for CSS (P = 0.004). CISH revealed HER2 gene amplification in 3/10 tumours with >=30 % micropapillary component. In conclusion, for BC treated with TUR-B and RCT, the presence of micropapillary morphology in more than 30 % of the tumour is an adverse prognostic factor. Further studies are needed to evaluate a potential benefit of different, especially multimodal treatment strategies for micropapillary UC and also other subtypes of UC. Her2 represents a promising therapeutic target in a subset of micropapillary UC.
EVALuna2:6800

Micropapillary urothelial carcinoma: evaluation of HER2 status and immunohistochemical characterization of the molecular subtype - Zinnall, Ulrike; Weyerer, Veronika; Compérat, Eva; Camparo, Philippe; Gaisa, Nadine T.; Knuechel-Clarke, Ruth; Perren, Aurel; Lugli, Alessandro; Toma, Marieta; Baretton, Gustavo; Kristiansen, Glen; Wirtz, Ralph M.; et al. (Human Pathology, 2018)
Comprehensive molecular analyses of urothelial bladder cancer (UBC) have defined distinct subtypes with potential therapeutic implications. In this study, we focused on micropapillary urothelial carcinoma (MPUC), an aggressive, histomorphologically defined rare variant. Apart from genetic alterations shared with conventional UBC alterations of the HER2 gene have been reported in higher frequencies. However, only small cohorts of MPUCs have been analyzed and the real impact is still unclear. We collected a cohort of 94 MPUCs and immunohistochemically tested HER2, basal (CD44, CK5, EGFR, p63) and luminal (CD24, FOXA1, GATA3, CK20) markers to allocate MPUC to a molecular subtype. Additionally, HER2 amplification status was assigned by chromogenic in-situ-hybridization. Sanger sequencing of Exon 4 and 8 was used to test for HER2 mutations. Kruskal-Wallis test was calculated to compare marker distribution between proportions of the MPUC component. 2+/3+ HER2 staining scores were identified in 39.6% of 91 analyzed MPUCs and were not differentially distributed among the proportion of the MPUC component (P=.89). Additionally, CISH analysis revealed 30% of HER2 amplified tumors independently of the MPUC fraction. In 6/90 evaluable MPUCs a p.S310F HER2 mutation was detected. Overexpression of luminal markers was observed in the majority of MPUC. Our investigations of the largest cohort of analyzed MPUC demonstrate that HER2 overexpression and amplifications are common genetic alterations and identification of overexpressed luminal markers allows sub-classification to the luminal subtype. These findings highlight the need of histomorphological recognition of MPUC and analysis of HER2 status and the luminal molecular subtype for potential targeted therapeutic strategies.
EVALuna2:34304

Microscopic intraneural perineurial cell proliferations in patients with neurofibromatosis type 1 - Agaimy, Abbas (Annals of Diagnostic Pathology, 2014)
Benign peripheral nerve sheath tumors (PNSTs) showing more than one line of differentiation (hybrid PNSTs) have been increasingly recognized, mainly due to awareness of their existence and as a consequence of increased use of immunohistochemisty during the last decade. Two recent studies suggested overrepresentation of hybrid tumors among benign PNSTs in patients with neurofibromatosis type 1 (NF-1). This study was performed to assess the presence of perineurial cells in microscopic (early) neurofibromatous lesions and normal-looking peripheral nerves in specimens from 5 patients with NF-1 using markers of perineurial cell differentiation (epithelial membrane antigen, claudin-1, and glucose transporter 1). In 2 patients, multiple normal looking nerve fibers as well as hypertrophied nerves and microscopic tumor nodules showed variable intraneural perineurial cell proliferations that frequently occupied the whole nerve fascicle resulting in multiple microscopic reticular perineurioma-like nodules (microscopic hybrid neurofibromatosis/perineuriomatosis). None of the cases showed the onion skin pattern of intraneural perineurioma. However, other nerve fibers within the same specimens showed normal compact rim of perineurium without any detectable intraneural perineurial cells. Both patients had concurrent multiple larger PNSTs (plexiform neurofibromas, hybrid neurofibroma/perineurioma and lesions with features intermediate between the 2 types). One specimen harboring high-grade malignant PNST and 2 specimens with large solitary neurofibromas displayed no intraneural perineurial cells. These observations suggest that intraneural perineurial proliferations are part of the early lesions in the setting of constitutional NF-1 inactivation and support the concept of pure and hybrid perineuriomatous lesions as novel member of the spectrum of PNSTs in NF-1.
EVALuna2:6576

Microsecretory Adenocarcinoma of Salivary Glands: An Expanded Series of 24 Cases - Bishop, Justin A.; Sajed, Dipti P.; Weinreb, Ilan; Dickson, Brendan C.; Bilodeau, Elizabeth A.; Agaimy, Abbas; Franchi, Alessandro; Khurram, Syed Ali; Da Forno, Philip; Robledo, Juliana; Kalmar, John R.; Aguirre, Sarah; et al. (Head and Neck Pathology, 2021)
Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor with a characteristic histologic and immunophenotypic profile and recurrent MEF2C-SS18 fusions. Because only six cases of MSA have been published, its complete clinicopathologic spectrum is unclear, and its biologic behavior has not been documented. Here, we present an updated and expanded experience of 24 MSA cases. All cases of MSA were obtained from the authors' files. Immunohistochemistry for S100, SOX10, p63, p40, SMA, calponin, and mammaglobin was performed. Molecular analysis was performed by targeted RNA sequencing, SS18 break apart fluorescence in situ hybridization, and/or reverse transcriptase polymerase chain reaction for MEF2C-SS18 fusion. Clinical follow-up was obtained from medical records. A total of 24 MSA cases were collected, from 13 women and 11 men, ranging from 17 to 83 years (mean 49.5 years). The vast majority (23 of 24) arose in the oral cavity, with the palate (n = 14) and buccal mucosa (n = 6) as the most frequent subsites. Tumors showed consistent histologic features including: (1) microcystic tubules, (2) flattened intercalated duct-like cells, (3) monotonous oval hyperchromatic nuclei, (4) abundant basophilic luminal secretions, (5) fibromyxoid stroma, and (6) circumscribed borders with subtle infiltration. The tumors were very consistently positive for S100 (24 of 24), p63 (24 of 24), and SOX10 (14 of 14) and negative for p40 (0 of 21), calponin (0 of 12) and mammaglobin (0 of 16), while SMA (4 of 20) was variable. MEF2C-SS18 fusion was demonstrated in 21 of 24 cases; in the remaining 3 cases with insufficient RNA, SS18 break apart FISH was positive. Treatment information was available in 17 cases, all of which were managed with surgery only. In 14 cases with follow-up (1-216 months, mean 30), no cases recurred or metastasized. MSA is a distinct salivary gland neoplasm with remarkably consistent clinical, histologic, immunophenotypic, and genetic features that generally behaves in an indolent manner following surgery alone. These observations solidify MSA as a unique, low-grade salivary gland carcinoma that warrants inclusion in the next version of the WHO classification of head and neck tumors.
CRIS-Team WoS Importer:2021-05-28

Migration measurement of the cemented Lubinus SP II hip stem - a 10-year follow-up using radiostereometric analysis - Sesselmann, Stefan; Hong, Yutong; Schlemmer, Frank; Wiendieck, Kurt; Söder, Stephan; Hussnaetter, Isabell; Müller, Lutz Arne; Forst, Raimund; Wierer, Thomas (Biomedizinische Technik, 2016)
In a previous radiostereometric analysis (RSA) of the Lubinus SP II (Link, Hamburg, Germany), which is one of the most often used cemented hip stems worldwide, our research group detected a very small but statistically significant distal migration of -0.03±0.17 mm 2 years after surgery compared to the postoperative radiograph. Maximum subsidence occurred between 6 and 12 months. The implant appeared to have stabilized after 2 years. The mean value of maximum total point motion (MTPM) was 0.99±0.69 mm, which was detected 2 years after surgery. The purpose of this study was to analyze the migration pattern and to verify the predictive value of short-term RSA of the Lubinus SP II stem after 10 years. After a follow-up of 5 and 10 years, 38 and 27 out of 100 patients remained available for further assessment, respectively. No statistically significant implant translation or rotation was found along or about the axes of the global coordinate system 5 and 10 years after surgery with respect to the postoperative radiograph. Furthermore, the MTPM was stable in both follow-up periods. The results suggest that the Lubinus SP II hip stem is still stable 10 years after surgery, supporting that determining prognosis by short-term RSA follow-up of 2 years could be an appropriate tool for appraisal of implant behavior 10 years after surgery.
EVALuna2:6812

miR-138-5p induces aggressive traits by targeting Trp53 expression in murine melanoma cells, and correlates with poor prognosis of melanoma patients - da Cruz, Adriana Taveira; Hunger, Aline; de Melo, Fabiana Henriques Machado; Monteiro, Ana Carolina; Paré, Geneviève Catherine; Lai, Dulce; Alves-Fernandes, Débora Kristina; Ayub, Ana Luisa Pedroso; Cordero, Esteban Mauricio; Filho, José Franco da Silveira; Schneider-Stock, Regine; Strauss, Bryan Eric; et al. (Neoplasia, 2021)
Deregulation of miRNAs contributes to the development of distinct cancer types, including melanoma, an aggressive form of skin cancer characterized by high metastatic potential and poor prognosis. The expression of a set of 580 miRNAs was investigated in a model of murine melanoma progression, comprising non-metastatic (4C11-) and metastatic melanoma (4C11+) cells. A significant increase in miR-138-5p expression was found in the metastatic 4C11+ melanoma cells compared to 4C11-, which prompted us to investigate its role in melanoma aggressiveness. Functional assays, including anoikis resistance, colony formation, collective migration, serum-deprived growth capacity, as well as in vivo tumor growth and experimental metastasis were performed in 4C11- cells stably overexpressing miR-138-5p. miR-138-5p induced an aggressive phenotype in mouse melanoma cell lines leading to increased proliferation, migration and cell viability under stress conditions. Moreover, by overexpressing miR-138-5p, low-growing and non-metastatic 4C11- cells became highly proliferative and metastatic in vivo, similar to the metastatic 4C11+ cells. Luciferase reporter analysis identified the tumor suppressor Trp53 as a direct target of miR-138-5p. Using data sets from independent melanoma cohorts, miR-138-5p and P53 expression were also found deregulated in human melanoma samples, with their levels negatively and positively correlated with prognosis, respectively. Our data shows that the overexpression of miR-138-5p contributes to melanoma metastasis through the direct suppression of Trp53.
CRIS-Team Scopus Importer:2021-07-23
Keywords: Aggressiveness; Melanoma; Metastasis; miR-138-5p; Trp53

miR-186, miR-3651 and miR-494: Potential biomarkers for oral squamous cell carcinoma extracted from whole blood - Ries, Jutta; Vairaktaris, Eleftherios; Agaimy, Abbas; Kintopp, Rita; Baran, Christoph; Neukam, Friedrich Wilhelm; Nkenke, Emeka (Oncology Reports, 2014)
microRNAs (miRNAs) are aberrantly expressed in the whole blood of patients suffering from different types of cancer. Collection of whole blood samples is a minimally invasive procedure. To date, little is known concerning the altered miRNA expression in patients suffering from oral squamous cell carcinoma (OSCC). The present study aimed to evaluate the difference in miRNA expression in whole blood samples in OSCC patients as compared to healthy volunteers who served as controls. In 20 blood samples from patients and healthy volunteers, the expression patterns of 1,205 human miRNAs were examined by miRNA microarray in order to identify those with the most pronounced differential expression. The results were verified by quantitative RT-PCR (RT-qPCR) for miR-186, miR-3651 and miR-494 using 57 samples of patients and 33 samples of healthy volunteers. Receiver operating characteristic (ROC) curves and the highest Youden index were calculated in order to assess cut-off points (COPs) that allowed the distinguishing of blood samples of OSCC patients from those of healthy volunteers. Significantly different expression rates were found for miR-186 (p=0.01), miR-3651 (p=0.0001) and miR-494 (p=0.004) between the OSCC patients and healthy controls. In the OSCC patients, there was a 2-fold upregulation for miR-494 and miR-3651 and a 2-fold downregulation for miR-186. Based on the determined COPs, significant correlations between miR-3651 overexpression and lymph node status (p=0.04), tumor grade (p=0.02) and clinical stage (p=0.04) were indicated. Aberrant expression levels of miR-186, miR-494 and miR-3651 in whole blood samples of OSCC patients may provide the possibility to establish a minimally invasive screening method for OSCC.
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MiRNA-21 Expression Decreases from Primary Tumors to Liver Metastases in Colorectal Carcinoma - Feiersinger, Fabian; Nolte, Elke; Wach, Sven; Rau, Tilman; Vassos, Nikolaos; Geppert, Carol-Immanuel; Konrad, Andreas; Merkel, Susanne; Taubert, Helge; Stürzl, Michael; Croner, Roland S. (PLoS ONE, 2016)
Metastasis is the major cause of death in colorectal cancer patients. Expression of certain miRNAs in the primary tumors has been shown to be associated with progression of colorectal cancer and the initiation of metastasis. In this study, we compared miRNA expression in primary colorectal cancer and corresponding liver metastases in order to get an idea of the oncogenic importance of the miRNAs in established metastases.We analyzed the expression of miRNA-21, miRNA-31 and miRNA-373 in corresponding formalin-fixed paraffin-embedded (FFPE) tissue samples of primary colorectal cancer, liver metastasis and healthy tissues of 29 patients by quantitative real-time PCR.All three miRNAs were significantly up-regulated in the primary tumor tissues as compared to healthy colon mucosa of the respective patients (p < 0.01). MiRNA-21 and miRNA-31 were also higher expressed in liver metastases as compared to healthy liver tissues (p < 0.01). No significant difference of expression of miRNA-31 and miRNA-373 was observed between primary tumors and metastases. Of note, miRNA-21 expression was significantly reduced in liver metastases as compared to the primary colorectal tumors (p < 0.01).In the context of previous studies demonstrating increased miRNA-21 expression in metastatic primary tumors, our findings raise the question whether miRNA-21 might be involved in the initiation but not in the perpetuation and growth of metastases.
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miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis - Benderska, Natalya; Dittrich, Anna-Lena; Knaup, Sabine; Rau, Tilman; Neufert, Clemens; Wach, Sven; Fahlbusch, Fabian B.; Rauh, Manfred; Wirtz, Ralph M.; Agaimy, Abbas; Srinivasan, Swetha; Mahadevan, Vijayalakshmi; et al. (Inflammatory Bowel Diseases, 2015)
Longstanding ulcerative colitis (UC) bears a high risk for development of UC-associated colorectal carcinoma (UCC). The inflammatory microenvironment influences microRNA expression, which in turn deregulates target gene expression. microRNA-26b (miR-26b) was shown to be instrumental in normal tissue growth and differentiation. Thus, we aimed to investigate the impact of miR-26b in inflammation-associated colorectal carcinogenesis.Two different cohorts of patients were investigated. In the retrospective group, a tissue microarray with 38 samples from 17 UC/UCC patients was used for miR-26b in situ hybridization and quantitative reverse transcription polymerase chain reaction analyses. In the prospective group, we investigated miR-26b expression in 25 fresh-frozen colon biopsies and corresponding serum samples of 6 UC and 15 non-UC patients, respectively. In silico analysis, Ago2-RNA immunoprecipitation, luciferase reporter assay, quantitative reverse transcription polymerase chain reaction examination, and miR-26b mimic overexpression were employed for target validation.miR-26b expression was shown to be upregulated with disease progression in tissues and serum of UC and UCC patients. Using miR-26b and Ki-67 expression levels, an UCC was predicted with high accuracy. We identified 4 novel miR-26b targets (DIP1, MDM2, CREBBP, BRCA1). Among them, the downregulation of the E3 ubiquitin ligase DIP1 was closely related to death-associated protein kinase stabilization along the normal mucosa-UC-UCC sequence. In silico functional pathway analysis revealed that the common cellular pathways affected by miR-26b are highly related to cancerogenesis and the development of gastrointestinal diseases.We suggest that miR-26b could serve as a biomarker for inflammation-associated processes in the gastrointestinal system. Because miR-26b expression is downregulated in sporadic colon cancer, it could discriminate between UCC and the sporadic cancer type.
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Mirna expression characterizes histological subtypes and metastasis in penile squamous cell carcinoma - Ayoubian, Hiresh; Heinzelmann, Joana; Hölters, Sebastian; Khalmurzaev, Oybek; Pryalukhin, Alexey; Loertzer, Philine; Heinzelbecker, Julia; Lohse, Stefan; Geppert, Carol-Immanuel; Loertzer, Hagen; Wunderlich, Heiko; Bohle, Rainer M.; et al. (Cancers, 2021)
Although microRNAs are described as promising biomarkers in many tumor types, little is known about their role in PSCC. Thus, we attempted to identify miRNAs involved in tumor development and metastasis in distinct histological subtypes considering the impact of HPV infection. In a first step, microarray analyses were performed on RNA from formalin-fixed, paraffin-embedded tumor (22), and normal (8) tissue samples. Microarray data were validated for selected miRNAs by qRT-PCR on an enlarged cohort, including 27 tumor and 18 normal tissues. We found 876 significantly differentially expressed miRNAs (p ≤ 0.01) between HPV-positive and HPV-negative tumor samples by microarray analysis. Although no significant differences were detected between normal and tumor tissue in the whole cohort, specific expression patterns occurred in distinct histological subtypes, such as HPV-negative usual PSCC (95 differentially expressed miRNAs, p ≤ 0.05) and HPV-positive basaloid/warty subtypes (247 differentially expressed miRNAs, p ≤ 0.05). Selected miRNAs were confirmed by qRT-PCR. Furthermore, microarray data revealed 118 miRNAs (p ≤ 0.01) that were significantly differentially expressed in metastatic versus non-metastatic usual PSCC. The lower expression levels for miR-137 and miR-328-3p in metastatic usual PSCC were validated by qRT-PCR. The results of this study confirmed that specific miRNAs could serve as potential diagnostic and prognostic markers in single PSCC subtypes and are associated with HPV-dependent pathways.
CRIS-Team Scopus Importer:2021-04-02
Keywords: HPV; Microarray; MiRNA; PSCC

miRNA expression characterizes histological subtypes and metastasis in penile squamous cell carcinoma - Hiresh, A.; Heinzelmann, J.; Hoelters, S.; Khalmurzaev, O.; Pryalukhin, A.; Loertzer, P.; Heinzelbecker, J.; Lohse, S.; Geppert, Carol-Immanuel; Loertzer, H.; Wunderlich, H.; Bohle, R. M.; et al. (EUROPEAN UROLOGY, 2021)
CRIS-Team WoS Importer:2021-08-20

Misleading Germ Cell Phenotype in Pulmonary NUT Carcinoma Harboring the ZNF532-NUTM1 Fusion - Agaimy, Abbas; Haller, Florian; Renner, Andre; Niedermeyer, Jost; Hartmann, Arndt; French, Christopher A. (American Journal of Surgical Pathology, 2022)
NUT carcinoma (aka NUT midline carcinoma) is a rare, still significantly underrecognized aggressive malignancy. Although historically considered a midline malignancy of children and young adults, NUT carcinoma can originate in almost any body site and in any age group. Beside the classic BRD4-NUTM1 fusion, less common fusion partners include BRD3, NSD3, ZNF532, and ZNF592. Other fusions, including CIC, MGA, MXD4, MXD1, and BCORL1 are associated with sarcomas or cancers of unknown histogenesis. Involvement of the Z4 zinc finger protein (ZNF) family members ZNF532 and ZNF592 is exceedingly rare with only 3 recently reported cases. We herein describe a ZNF532-NUTM1-rearranged NUT carcinoma presenting as a 7.5 cm mass in the left lower lung lobe of a 65-year-old woman. Histology revealed undifferentiated monotonous small round cells with focal epithelioid and rhabdoid elements within a variably myxoid stroma. Immunohistochemistry revealed paucity of keratins and variable p63 combined with extensive CD30 and PLAP expression, leading to initial diagnoses of combined small cell carcinoma, CD30-positive unclassified hematolymphoid malignancy and malignant germ cell neoplasm. Negativity for other more specific germ cell markers justified seeking a fourth opinion, which revealed diffuse expression of the NUT antibody. The diagnosis was then confirmed by fluorescence in situ hybridization. Targeted RNA sequencing revealed the ZNF532-NUTM1 fusion. Screening of 7 NUT carcinomas (5 with BRD4-NUTM1 and 2 with NSD3-NUTM1 fusions) for germ cell markers revealed focal SALL4 reactivity in 3 cases (combined with variable AFP expression in 2), but none expressed CD30 or PLAP. An aberrant germ cell immunophenotype should be considered in NUT carcinoma to avoid misinterpretation as genuine germ cell malignancy as both diseases predominantly affect the young population, frequently involve the mediastinum and can be associated with elevated serum AFP.
CRIS-Team WoS Importer:2022-01-28

Misleading Morphologic and Phenotypic Features (Transdifferentiation) in Solitary Fibrous Tumor of the Head and Neck Report of 3 Cases and Review of the Literature - Baneckova, Martina; Michal, Michael; Hajkova, Veronika; Haller, Florian; Mosaieby, Elaheh; Salajka, Pavel; Arolt, Christoph; Nachtsheim, Lisa; Michal, Michal; Agaimy, Abbas; Skalova, Alena (American Journal of Surgical Pathology, 2022)
Solitary fibrous tumor (SFT) is a rare fibroblastic neoplasm with potentially malignant behavior that may develop in any anatomic site and may involve the head and neck (H&N) region as well. Although typical SFT has a relatively characteristic morphology, its morphologic spectrum is extraordinarily broad and also includes rare cases with dedifferentiation or transdifferentiation which result in aberrant morphologic and/or immunohistochemical features. However, since virtually all cases are molecularly characterized by NAB2::STAT6 gene fusions, molecular genetic methods or STAT6 immunohistochemistry can be effectively used in confirming the diagnosis. Herein, we report 3 diagnostically challenging H&N SFT cases with an unusual morphology and/or phenotypes closely mimicking other well-known H&N entities. The tumors originated in the oral minor salivary glands, the base of the tongue, and sinonasal tract and closely resembled hyalinizing clear cell carcinoma of the salivary gland, adenocarcinoma not otherwise specified and biphenotypic sinonasal sarcoma, respectively. All cases were positive for cytokeratins, variably expressed S100 protein, showed diffuse nuclear STAT6 positivity, and harbored NAB2::STAT6 gene fusions.
CRIS-Team WoS Importer:2022-07-29

Misses and near misses in diagnosing nodular fasciitis and morphologically related reactive myofibroblastic proliferations: experience of a referral center with emphasis on frequency of USP6 gene rearrangements - Erber, Ramona; Agaimy, Abbas (Virchows Archiv, 2018)
Although harmless, reactive and benign neoplastic myo-/fibroblastic proliferations represent a diagnostic challenge in routine surgical pathology practice as reflected by their frequency among consultation cases. In addition to resembling each other, the prototypical nodular fasciitis (NF) and NF-like lesions can be mistaken for low-grade or aggressive sarcomas. USP6 translocation was reported recently as the molecular driver and potential diagnostic marker of NF. We reviewed 71 lesions with a diagnosis of NF (n = 48) or NF-like myofibroblastic proliferations (n = 23) and screened them for USP6 translocation by fluorescence in situ hybridization (FISH). Only one third of NFs were correctly diagnosed by submitting pathologists while one third was initially judged as malignant. NF was mentioned in the differential diagnosis in only half of the cases. A high Ki67/mitotic index, misleading immunohistochemistry (false-positive h-caldesmon), and unusual sites/circumscription were main causes behind overdiagnosis as malignant. FISH analysis revealed USP6 translocation in 74.4% of NF cases. None of the reactive/reparative myofibroblastic proliferations showed USP6 translocation. NF is still significantly misdiagnosed by general surgical pathologists, with a higher tendency toward overdiagnosis of malignancy. Inclusion of NF in the differential diagnosis of any fibromyxoid soft tissue lesion and awareness of its diverse morphology are mandatory to avoid misdiagnoses with the risk of disastrous overtreatment. In the appropriate clinicopathological context, USP6 gene translocation is a valuable adjunct for diagnosis of NF, particularly in limited biopsies. Absence of the USP6 gene translocation in NF-like reparative pseudosarcomatous myofibroblastic proliferations underlines their reactive nature and distinguishes them from NF which is currently considered a benign neoplasm with a self-limiting "transient" growth phase.
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Mitophagy-associated genes PINK1 and PARK2 are independent prognostic markers of survival in papillary renal cell carcinoma and associated with aggressive tumor behavior - Simon, Adrian Georg; Tolkach, Yuri; Esser, Laura Kristin; Ellinger, Jörg; Stoehr, Christine; Ritter, Manuel; Wach, Sven; Taubert, Helge; Stephan, Carsten; Hartmann, Arndt; Kristiansen, Glen; Branchi, Vittorio; et al. (Scientific Reports, 2020)
The aim of this study was to investigate the mitophagy-related genes PINK1 and PARK2 in papillary renal cell carcinoma and their association with prognosis. In silico data of PINK1 and PARK2 were analyzed in TCGA cohorts of papillary renal cell carcinoma comprising 290 tumors and 33 corresponding non-neoplastic renal tissues. Protein expression data from a cohort of 95 papillary renal cell carcinoma patients were analyzed and associated with clinical-pathological parameters including survival. PINK1 and PARK2 were significantly downregulated in papillary renal cell carcinoma at transcript and protein levels. Reduced transcript levels of PINK1 and PARK2 were negatively associated with overall survival (p < 0.05). At the protein level, PARK2 and PINK1 expression were positively correlated (correlation coefficient 0.286, p = 0.04) and reduced PINK1 protein expression was prognostic for shorter survival. Lower PINK1 protein levels were found in tumors with metastases at presentation and in tumors of higher pT-stages. The multivariate analysis revealed mRNA expression of PINK1 and PARK2 as well as PINK1 protein expression as independent prognostic factors for shorter overall survival. The downregulation of PINK1 is a strong predictor of poor survival in papillary renal cell carcinoma. Immunohistochemical PINK1 expression in resected pRCC should be considered as an additional prognostic marker for routine practice.
CRIS-Team Scopus Importer:2020-11-13

Mitral Multifocal Papillary Fibroelastoma in a Patient with Aggressive Fibromatosis - Müller, Philipp; Agaimy, Abbas; Weyand, Michael; Heim, Christian (Thoracic and Cardiovascular Surgeon Reports, 2021)
Mitral valve fibroelastoma is a rare condition that can be associated with high morbidity rates due to thrombus formation and resulting embolic events. Causative treatment for affected patients is mitral valve surgery. An association between cardiac fibroelastoma and desmoid-type fibromatosis, an aggressive form of fibromatosis, is not yet described. We present a case of a 58-year-old man with a history of desmoid-type fibromatosis and concomitant papillary fibroelastoma of the mitral valve who consequently underwent mitral valve replacement.
CRIS-Team WoS Importer:2022-01-07

Molecular and Clinicopathologic Heterogeneity of Intracranial Tumors Mimicking Extraskeletal Myxoid Chondrosarcoma - Velz, Julia; Agaimy, Abbas; Frontzek, Karl; Neidert, Marian Christoph; Bozinov, Oliver; Wagner, Ulrich; Fritz, Christine; Coras, Roland; Hofer, Silvia; Bode-Lesniewska, Beata; Rushing, Elisabeth (Journal of Neuropathology and Experimental Neurology, 2018)
Primary intracranial neoplasms with features of extraskeletal myxoid chondrosarcomas (EMC) are extremely rare and poorly characterized tumors with only ∼12 cases described, the majority lacking molecular confirmation. There is an urgent need for the integration of molecular studies for correct subclassification of these tumors in order to predict clinical behavior, guide therapeutic decision-making, and provide novel targets for therapy. Clinical and pathologic data of 3 intracranial EMC-like myxoid neoplasms were retrospectively reviewed. In 2/3 cases, immunohistochemistry showed loss of nuclear SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1; integrase interactor 1 [INI1]) staining accompanied by monosomy of chromosome 22q (fluorescence in situ hybridization [FISH]). These 2 cases had no evidence of any fusion products by next generation sequencing (NGS). The third case had intact SMARCB1 expression and showed instead a rearrangement of the EWSR1 gene detected by FISH, with an EWSR1-CREB1 gene fusion on NGS. None of the cases showed rearrangement of the NR4A3 gene, neither by FISH nor by NGS. This small case series highlights the molecular heterogeneity of intracranial neoplasms in the morphologic spectrum of EMC. Distinct molecular alterations found in tumors with morphologic features of EMC encompass SMARCB1(INI1) loss and EWSR1-CREB gene fusions. None of the cases showed rearrangements of NR4A3 genes, suggesting they are distinct from conventional EMC.
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Molecular Characterisation of Urothelial Bladder Cancer: Will it Improve Patient Care? - Erben, P.; Hartmann, Arndt; Bolenz, C. (Aktuelle Urologie, 2015)
Urothelial bladder cancer is characterised by high recurrence and progression rates despite multimodal treatment. Only slight improvements have been achieved during the last decades. The current histopathological classification and clinical risk stratification tools are inaccurate. Hence, a better understanding of the tumour biology is essential for the improvement of patient care. The molecular characterisation of bladder cancer may be translated into useful diagnostic and predictive biomarkers. Many potential therapeutic targets have been identified such as FGFR3 (Fibroblast growth factor receptor 3), HER2 (human epidermal growth factor receptor 2) and PD1/PDL1 (programmed cell death-1). They need validation in clinical trials. We now review the molecular biology of urothelial bladder carcinoma and discuss clinical applications of biomarkers and targeted therapies.
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Molecular characterization of muellerian tumors of the urinary tract - Ortiz-Brüchle, Nadina; Wucherpfennig, Sophie; Rose, Michael; Garczyk, Stefan; Bertz, Simone; Hartmann, Arndt; Reis, Henning; Szarvas, Tibor; Kiss, András; Bremmer, Felix; Golz, Reinhard; Knüchel, Ruth; et al. (Genes, 2021)
In the 2016 WHO classification of genitourinary tumors Muellerian tumors of the urinary tract (MTUT) comprise clear cell adenocarcinomas and endometrioid carcinomas. Since these rare tumors remained understudied, we aimed to characterize their molecular background by performing DNA-and RNA-based targeted panel sequencing. All tumors (n = 11) presented single nucleotide alterations (SNVs), with ARID1A mutations being the most prevalent (5/11, 45%). Besides frequent ARID1A mutations, loss of ARID1A protein is not a suitable marker since protein expression is (partly) preserved also in mutated cases. Copy number alterations (CNVs) were found in 64% of cases (7/11), exclusively gene amplifications. Interestingly, a functionally relevant RSPO2 gene fusion/microdeletion was discovered in the endometrioid adenocarcinoma case. Comparing our findings with mutational profiles of other tumor entities, absence of TERT promoter mutations argues for a non-urothelial origin. No similarities were also found between MTUT and kidney cancers while parallels were observed for specific SNVs with endometrial carcinomas. In conclusion, immunohistochemical PAX8-positivity and lack of TERT promoter mutations could serve as key diagnostic features in difficult cases. Thus, understanding the molecular background of these tumors helps to refine treatment options and offers the possibility of targeted therapies in cases where needed.
CRIS-Team Scopus Importer:2021-07-02
Keywords: ARID1A; Clear cell adenocarcinoma; Endometrioid adenocarcinoma; Muellerian tumors; TERT

Molecular Characterization of Upper Tract Urothelial Carcinoma in the Era of Next-generation Sequencing: A Systematic Review of the Current Literature - Hassler, Melanie R.; Bray, Freddie; Catto, James W.F.; Grollman, Arthur P.; Hartmann, Arndt; Margulis, Vitaly; Matin, Surena F.; Roupret, Morgan; Sfakianos, John P.; Shariat, Shahrokh F.; Faltas, Bishoy M. (European Urology, 2020)
Context: While upper tract urothelial carcinoma (UTUC) share histological appearance with bladder cancer (BC), the former has differences in etiology and clinical phenotype consistent with characteristic molecular alterations. Objective: To systematically evaluate current genomic sequencing and proteomic data examining molecular alterations in UTUC. Evidence acquisition: A systematic review using PubMed, Scopus, and Web of Science was performed in December 2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Evidence synthesis: A total of 46 publications were selected for inclusion in this report, including 13 studies assessing genome-wide alterations, 18 studies assessing gene expression or microRNA expression profiles, three studies assessing proteomics, one study assessing genome-wide DNA methylation, and 14 studies evaluating distinct pathway alteration patterns. Differences between sporadic and hereditary UTUC, and between UTUC and BC, as well as molecular profiles associated with exposure to aristolochic acid are highlighted. Molecular pathways relevant to UTUC biology, such as alterations in FGFR3, TP53, or microsatellite instability, are discussed. Our findings are limited by tumor and patient heterogeneity and different platforms used in the studies. Conclusions: Molecular events in UTUC and BC can be shared or distinct. Consequently, molecular subtypes differ according to location. Further work is needed to define the epigenomic and proteomic features of UTUC, and understand the mechanisms by which they shape the clinical behavior of UTUC. Patient summary: We report the current data on the molecular alterations specific to upper tract urothelial carcinoma (UTUC), resulting from novel genomic and proteomic technologies. Although UTUC biology is comparable with that of bladder cancer, the rates and UTUC-enriched alterations support its uniqueness and the need for precision medicine strategies for this rare tumor type. Recent data obtained by high-throughput molecular profiling technologies underscore the distinct molecular alterations found in upper tract urothelial carcinoma (UTUC). UTUC biology shares many features with bladder cancer, but there are important specific distinctions that support the need for UTUC-targeted therapeutic strategies.
CRIS-Team Scopus Importer:2020-06-30
Keywords: Genomics; Molecular alterations; Molecular characterization; Next-generation sequencing; Proteomics; Renal pelvis; RNAseq; Transcriptomics; Ureter; Urothelial carcinoma

Molecular classification of bladder cancer. Possible similarities to breast cancer - Wirtz, R. M.; Fritz, V.; Stoehr, R.; Hartmann, Arndt (Pathologe, 2016)
Therapeutic decisions for breast cancer are increasingly becoming based on subtype-specific gene expression tests. For bladder cancer very similar subtypes have been identified by genome-wide mRNA analysis, which as for breast cancer differ with respect to the prognosis and response to therapy on the basis of their hormone dependency. At the DNA level, however, the type of mutations and their frequencies within the subtypes are strikingly different between bladder and breast cancers. It will be interesting to see whether possible driver mutations can serve as therapeutic targets in both indications. In contrast, the apparent hormone dependency of a substantial number of bladder carcinomas suggests that hormonal and anti-hormonal treatment can be valid therapy options similar to breast cancer. Moreover, gender-specific differences with respect to the incidence and aggressiveness of male compared to female bladder cancers can be explained by hormonal effects. Together with forthcoming immunomodulatory therapies these multiple therapy options raise and give new hope to efficiently combat this aggressive disease.
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Molecular Composition of Genomic TMPRSS2-ERG Rearrangements in Prostate Cancer - Krumbholz, Manuela; Agaimy, Abbas; Stöhr, Robert; Burger, Maximilian; Wach, Sven; Taubert, Helge; Wullich, Bernd; Hartmann, Arndt; Metzler, Markus (Disease Markers, 2019)
There is increasing interest in the use of cell-free circulating tumor DNA (ctDNA) as a serum marker for therapy assessment in prostate cancer patients. Prostate cancer is characterized by relatively low numbers of mutations, and, in contrast to many other common epithelial cancers, commercially available single nucleotide mutation assays for quantification of ctDNA are insufficient for therapy assessment in this disease. However, prostate cancer shares some similarity with translocation-affected mesenchymal tumors (e.g., leukemia and Ewing sarcoma), which are common in pediatric oncology, where chromosomal translocations are used as biomarkers for quantification of the tumor burden. Approximately 50% of prostate cancers carry a chromosomal translocation resulting in generation of the TMPRSS2-ERG fusion gene, which is unique to the tumor cells of each individual patient because of variability in the fusion breakpoint sites. In the present study, we examined the structural preconditions for TMPRSS2-ERG fusion sites in comparison with mesenchymal tumors in pediatric patients to determine whether the sequence composition is suitable for the establishment of tumor-specific quantification assays in prostate cancer patients. Genomic repeat elements represent potential obstacles to establishment of quantification assays, and we found similar proportions of repeat elements at fusion sites in prostate cancer to those reported for mesenchymal tumors, where genomic fusion sequences are established as biomarkers. Our data support the development of the TMPRSS2-ERG fusion gene as a noninvasive tumor marker for therapy assessment, risk stratification, and relapse detection to improve personalized therapy strategies for patients with prostate cancer.
CRIS-Team WoS Importer:2020-01-07

Molecular cross-talk between Y5-receptor and neuropeptide Y drives liver cancer - Dietrich, Peter; Wormser, Laura; Fritz, Valerie; Seitz, Tatjana; de Maria, Monica; Schambony, Alexandra; Kremer, Andreas; Günther, Claudia; Itzel, Timo; Thasler, Wolfgang E.; Teufel, Andreas; Trebicka, Jonel; et al. (Journal of Clinical Investigation, 2020)
Hepatocellular carcinoma (HCC) is clearly age-related and represents one of the deadliest cancer types worldwide. Due to globally increasing risk factors including metabolic disorders, the incidence rates of HCC are still rising. However, the molecular hallmarks of HCC remain poorly understood. Neuropeptide Y (NPY) and NPY-receptors represent a highly conserved, stress-activated system which is involved in diverse cancer-related hallmarks including aging and metabolic alterations, but its impact on liver cancer had been unclear. Here, we observed increased NPY5-receptor (Y5R) expression in HCC which correlated with tumor growth and survival. Furthermore, we found that its ligand NPY was secreted by peri-tumorous hepatocytes. Hepatocyte-derived NPY promoted HCC progression by Y5R-activation. Transforming growth factor beta 1 (TGFβ1) was identified as a regulator of NPY in hepatocytes and induced Y5R in invasive cancer cells. Moreover, NPY-conversion by dipeptidylpeptidase 4 (DPP4) augmented Y5R-activation and function in liver cancer. The TGFβ-NPY-Y5R-axis and DPP4 represent attractive therapeutic targets for controlling liver cancer progression.
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Keywords: Aging; Cancer; Hepatology

Molecular differences between arterial and venous grafts in the first year after coronary artery bypass grafting - Steger, Christina Maria; Hartmann, Arndt; Rieker, Ralf (Histochemistry and Cell Biology, 2020)
Despite commonly used for coronary artery bypass surgery, saphenous vein (SV) grafts have significantly lower patency rates in comparison to internal thoracic artery (ITA) grafts, which might be due to the structural characteristics of the vessel wall but also due to differences in oxidative stress adaptation and molecular signaling and regulation. This human post mortem study included a total of 150 human bypass grafts (75 SV grafts and 75 ITA grafts) obtained from 60 patients divided into five groups due to the time period of implantation: group 1: baseline group without grafting; group 2: 1 day; group 3: > 1 day–1 week; group 4: > 1 week–1 month; group 5: > 1 month–1 year. Pieces of 3 mm length were fixed with formaldehyde, dehydrated, wax embedded, cut into sections of 3 µm thickness, and histologically and immunohistochemically examined. Over the whole time period, we observed a lower neointima formation and a better preserved media in ITA grafts with a higher percentage of TNF-α, PDGFR-α, and VEGF-A in nearly all vessel wall layers, a higher amount of MMP-7, MMP-9, EGFR, and bFGF positive cells in SV grafts and a timely different peak not only between ITA and SV grafts but also within the various vessel wall layers of both graft types. Since most of the examined growth factors, growth factor receptors and cytokines are regulated by MAPKs, our results suggest an activation of different pathways in both vessel graft types immediately after bypass grafting.
CRIS-Team Scopus Importer:2020-07-31
Keywords: Coronary artery bypass grafting; Growth factors; ITA graft; MAPK; SV graft

Molecularly defined sinonasal malignancies: an overview with focus on the current WHO classification and recently described provisional entities. - Skálová, Alena; Agaimy, Abbas; Bradova, Martina; Poorten, Vincent Vander; Hanna, Ehab; Guntinas-Lichius, Orlando; Franchi, Alessandro; Hellquist, Henrik; Simpson, Roderick H.W.; Lopéz, Fernando; Nuyts, Sandra; Chiesa-Estomba, Carlos; et al. (Virchows Archiv, 2024)
Classification of tumors of the head and neck has evolved in recent decades including a widespread application of molecular testing in tumors of the sinonasal tract, salivary glands, and soft tissues with a predilection for the head and neck. The availability of new molecular techniques has allowed for the definition of multiple novel tumor types unique to head and neck sites. Moreover, an expanding spectrum of immunohistochemical markers specific to genetic alterations facilitates rapid identification of diagnostic molecular abnormalities. As such, it is currently possible for head and neck pathologists to benefit from a molecularly defined tumor classification while making diagnoses that are still based largely on histopathology and immunohistochemistry. This review covers the principal molecular alterations in sinonasal malignancies, such as alterations in DEK, AFF2, NUTM1, IDH1-2, and SWI/SNF genes in particular, that are important from a practical standpoint for diagnosis, prognosis, and prediction of response to treatment.
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Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups - Van Kessel, Kim E. M.; Van Der Keur, Kirstin A.; Dyrskjot, Lars; Algaba, Ferran; Welvaart, Naeromy Y. C.; Beukers, Willemien; Segersten, Ulrika; Keck, Bastian; Maurer, Tobias; Simic, Tatjana; Horstmann, Marcus; Grimm, Marc-Oliver; et al. (Clinical Cancer Research, 2018)
Purpose: The European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC.Experimental Design: We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups.Results: In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of FGFR3 mutation status and methylation of GATA2, this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%).Conclusions: We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. Clin Cancer Res; 24(7); 1586-93. ©2018 AACR.
EVALuna2:34258

Molecular profiling of clear cell myoepithelial carcinoma of salivary glands with EWSR1 rearrangement identifies frequent PLAG1 gene fusions but no EWSR1 fusion transcripts - Skálová, Alena; Agaimy, Abbas; Vanecek, Tomas; Baněčková, Martina; Laco, Jan; Ptáková, Nikola; Šteiner, Petr; Majewska, Hanna; Biernat, Wojciech; Corcione, Luigi; Eis, Václav; Koshyk, Olena; et al. (American Journal of Surgical Pathology, 2021)
Myoepithelial carcinoma of salivary glands is an underrecognized and challenging entity with a broad morphologic spectrum, including an EWSR1-rearranged clear cell variant. Myoepithelial carcinoma is generally aggressive with largely unknown genetic features. A retrospective review of Salivary Gland Tumor Registry in Pilsen searching for the key words "clear cell myoepithelial carcinoma,""hyalinizing clear cell,"and "clear cell malignant myoepithelioma"yielded 94 clear cell myoepithelial carcinomas (CCMCs) for molecular analysis of EWSR1 rearrangement using fluorescence in situ hybridization (FISH). Tumors positive for EWSR1 gene rearrangement were tested by next-generation sequencing (NGS) using fusion-detecting panels. NGS results were confirmed by reverse-transcription polymerase chain reaction or by FISH. Twenty-six tumors originally diagnosed as CCMC (26/94, 27.6%) revealed split signals for EWSR1 by FISH. Six of these tumors (6/26, 23%) displayed amplification of the EWSR1 locus. Fifteen cases were analyzable by NGS, whereas 9 were not, and tissue was not available in 2 cases. None of the CCMCs with EWSR1 rearrangements detected by FISH had an EWSR1 fusion transcript. Fusion transcripts were detected in 6 cases (6/15, 40%), including LIFR-PLAG1 and CTNNB1-PLAG1, in 2 cases each, and CHCHD7-PLAG1 and EWSR1-ATF1 fusions were identified in 1 case each. Seven cases, including those with PLAG1 fusion, were positive for PLAG1 rearrangement by FISH, with notable exception of CHCHD7-PLAG1, which is an inversion not detectable by FISH. One single case with EWSR1-ATF1 fusion in NGS showed ATF1 gene rearrangement by FISH and was reclassified as clear cell carcinoma (CCC). In addition, another 4 cases revealed ATF1 rearrangement by FISH and were reclassified as CCC as well. Moreover, 12/68 (17%) CCMCs with intact EWSR1 gene were selected randomly and analyzed by NGS. PLAG1 fusions were found in 5 cases (5/12, 41.6%) with LIFR (2 cases), FGFR1 (2 cases), and CTNNB1 (1 case) as partner genes. Overall, PLAG1 gene rearrangements were detected in 10/38 (26%) tested cases. None of the tumors had SMARCB1 loss by immunohistochemistry as a possible explanation for the EWSR1 abnormalities in FISH. Novel findings in our NGS study suggest that EWSR1-FISH positive CCMC is a gene fusion-driven disease with frequent oncogenic PLAG1 fusions, including LIFR-PLAG1 and CTNNB1-PLAG1 in most cases. Productive EWSR1 fusions are found only in a minority of EWSR1-ATF1-rearranged cases, which were in part reclassifiable as CCCs. Detectable EWSR1-FISH abnormality in CCMCs without gene fusion perhaps represents a passenger mutation with minor or no oncologic effect.
CRIS-Team Scopus Importer:2021-01-01
Keywords: Clear cell myoepithelial carcinoma; EWSR1 gene rearrangement; Gene fusion; Molecular; PLAG1; Salivary glands