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

Management of sporadic desmoid-type fibromatosis: a European consensus approach based on patients' and professionals' expertise - a sarcoma patients EuroNet and European Organisation for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group - Kasper, B.; Baumgarten, C.; Bonvalot, S.; Haas, R.; Haller, F.; Hohenberger, P.; Moreau, G.; Van Der Graaf, W. T. A.; Gronchi, A. (European Journal of Cancer, 2015)
Desmoid-type fibromatosis (DF) is a rare monoclonal, fibroblastic proliferation characterised by a variable and often unpredictable clinical course. It may affect nearly all parts of the body including extremities, trunk and abdomen. Considering the variable clinical presentations, anatomic locations and biological behaviours, an individualised treatment approach is required. No established or evidence-based approach for the treatment of this neoplasm is available as of today. Therefore, we propose a consensus treatment algorithm based on a round table meeting bringing together sarcoma experts from the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) with patient advocates from Sarcoma Patients EuroNet (SPAEN). The aim of the meeting was to develop - for the first time ever - a consensus approach based on professionals' AND patients' expertise. As a fundamental prerequisite, all patients should be discussed in a multidisciplinary setting in centres or professional networks with a specific expertise in the disease.
EVALuna2:6648

MAP2K1-MUTATED ECD/RDD-OVERLAP NON-LANGERHANS CELL HISTIOCYTOSIS RESPONDING TO COBIMETINIB - Classen, Carl Friedrich; Leyh, Jörg; Rümmele, Petra; Rosenwald, Andreas; Metzler, Markus (PEDIATRIC BLOOD & CANCER, 2021)
CRIS-Team WoS Importer:2020-12-18

Marine alkaloid Monanchocidin a overcomes drug resistance by induction of autophagy and lysosomal membrane permeabilization - Dyshlovoy, Sergey A.; Hauschild, Jessica; Amann, Kerstin Ute; Tabakmakher, Ksenia M.; Venz, Simone; Walther, Reinhard; Guzii, Alla G.; Makarieva, Tatiana N.; Shubina, Larisa K.; Fedorov, Sergey N.; Stonik, Valentin A.; Bokemeyer, Carsten; et al. (Oncotarget, 2015)
Monanchocidin A (MonA) is a novel alkaloid recently isolated from the marine sponge Monanchora pulchra. The compound reveals cytotoxic activity in genitourinary cancers including cisplatin-sensitive and -resistant germ cell tumor (GCT) cell lines, hormone-sensitive and castration-resistant prostate carcinoma cell lines and different bladder carcinoma cell lines. In contrast, non-malignant cells were significantly less sensitive. MonA is highly synergistic with cisplatin in GCT cells. Induction of autophagy at lower and lysosomal membrane permeabilization (LMP) at higher concentrations were identified as the dominating modes of action. Cytotoxicity and protein degradation could be inhibited by 3-methyladenine, an inhibitor of autophagy. LMP was confirmed by loss of acridine orange staining of lysosoms and by release of cathepsin B. In conclusion, MonA exerts cytotoxic activity by mechanisms different from "classical" apoptosis, and could be a promising new compound to overcome resistance to standard therapies in genitourinary malignancies.
EVALuna2:25492

Marine compound rhizochalinin shows high in vitro and in vivo efficacy in castration resistant prostate cancer - Dyshlovoy, Sergey A.; Otte, Katharina; Alsdorf, Winfried H.; Hauschild, Jessica; Lange, Tobias; Venz, Simone; Bauer, Christiane K.; Baehring, Robert; Amann, Kerstin Ute; Mandanchi, Ramin; Schumacher, Udo; Schroeder-Schwarz, Jennifer; et al. (Oncotarget, 2016)
Development of drug resistance is an inevitable phenomenon in castration-resistant prostate cancer (CRPC) cells requiring novel therapeutic approaches. In this study, efficacy and toxicity of Rhizochalinin (Rhiz) - a novel sphingolipid-like marine compound - was evaluated in prostate cancer models, resistant to currently approved standard therapies. In vitro activity and mechanism of action of Rhiz were examined in the human prostate cancer cell lines PC-3, DU145, LNCaP, 22Rv1, and VCaP. Rhiz significantly reduced cell viability at low micromolar concentrations showing most pronounced effects in enzalutamide and abiraterone resistant AR-V7 positive cells. Caspase-dependent apoptosis, inhibition of pro-survival autophagy, downregulation of AR-V7, PSA and IGF-1 expression as well as inhibition of voltage-gated potassium channels were identified as mechanisms of action. Remarkably, Rhiz re-sensitized AR-V7 positive cells to enzalutamide and increased efficacy of taxanes.In vivo activity and toxicity were evaluated in PC-3 and 22Rv1 NOD SCID mouse xenograft models using i.p. administration. Rhiz significantly reduced growth of PC-3 and 22Rv1 tumor xenografts by 27.0% (p = 0.0156) and 46.8% (p = 0.047) compared with controls with an increased fraction of tumor cells showing apoptosis secondary to Rhiz exposure. In line with the in vitro data, Rhiz was most active in AR-V7 positive xenografts in vivo. In animals, no severe side effects were observed.In conclusion, Rhiz is a promising novel marine-derived compound characterized by a unique combination of anticancer properties. Its further clinical development is of high impact for patients suffering from drug resistant prostate cancer especially those harboring AR-V7 mediated resistance to enzalutamide and abiraterone.
EVALuna2:25524

Massively parallel sequencing fails to detect minor resistant subclones in tissue samples prior to tyrosine kinase inhibitor therapy - Heydt, Carina; Kumm, Niklas; Fassunke, Jana; Kuenstlinger, Helen; Ihle, Michaela Angelika; Scheel, Andreas; Schildhaus, Hans-Ulrich; Haller, Florian; Buettner, Reinhard; Odenthal, Margarete; Wardelmann, Eva; Merkelbach-Bruse, Sabine (BMC Cancer, 2015)
Personalised medicine and targeted therapy have revolutionised cancer treatment. However, most patients develop drug resistance and relapse after showing an initial treatment response. Two theories have been postulated; either secondary resistance mutations develop de novo during therapy by mutagenesis or they are present in minor subclones prior to therapy. In this study, these two theories were evaluated in gastrointestinal stromal tumours (GISTs) where most patients develop secondary resistance mutations in the KIT gene during therapy with tyrosine kinase inhibitors.We used a cohort of 33 formalin-fixed, paraffin embedded (FFPE) primary GISTs and their corresponding recurrent tumours with known mutational status. The primary tumours were analysed for the secondary mutations of the recurrences, which had been identified previously. The primary tumours were resected prior to tyrosine kinase inhibitor therapy. Three ultrasensitive, massively parallel sequencing approaches on the GS Junior (Roche, Mannheim, Germany) and the MiSeq(TM) (Illumina, San Diego, CA, USA) were applied. Additionally, nine fresh-frozen samples resected prior to therapy were analysed for the most common secondary resistance mutations.With a sensitivity level of down to 0.02%, no pre-existing resistant subclones with secondary KIT mutations were detected in primary GISTs. The sensitivity level varied for individual secondary mutations and was limited by sequencing artefacts on both systems. Artificial T > C substitutions at the position of the exon 13 p.V654A mutation, in particular, led to a lower sensitivity, independent from the source of the material. Fresh-frozen samples showed the same range of artificially mutated allele frequencies as the FFPE material.Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary KIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.
EVALuna2:6723

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 Blood Vessel Integrity and Antagonizes Inflammatory Bowel Disease - Regensburger, Daniela; Tenkerian, Clara; Pürzer, Victoria; Schmid, Benjamin; Wohlfahrt, Thomas; Stolzer, Iris; Lopez Posadas, Rocío; Günther, Claudia; Waldner, Maximilian; Becker, Christoph; Sticht, Heinrich; Petter, Katja; et al. (Inflammatory Bowel Diseases, 2021)
Background The understanding of vascular plasticity is key to defining the role of blood vessels in physiologic and pathogenic processes. In the present study, the impact of the vascular quiescence marker SPARCL1 on angiogenesis, capillary morphogenesis, and vessel integrity was evaluated. Methods Angiogenesis was studied using the metatarsal test, an ex vivo model of sprouting angiogenesis. In addition, acute and chronic dextran sodium sulfate colitis models with SPARCL1 knockout mice were applied. Results This approach indicated that SPARCL1 inhibits angiogenesis and supports vessel morphogenesis and integrity. Evidence was provided that SPARCL1-mediated stabilization of vessel integrity counteracts vessel permeability and inflammation in acute and chronic dextran sodium sulfate colitis models. Structure-function analyses of purified SPARCL1 identified the acidic domain of the protein necessary for its anti-angiogenic activity. Conclusions Our findings inaugurate SPARCL1 as a blood vessel–derived anti-angiogenic molecule required for vessel morphogenesis and integrity. SPARCL1 opens new perspectives as a vascular marker of susceptibility to colitis and as a therapeutic molecule to support blood vessel stability in this disease. <br
Keywords: angiogenesis; blood vessel; DSS colitis; endothelial cell; inflammatory bowel disease; permeability; SPARCL1

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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Mechanisms of everolimus‐induced glomerulosclerosis after glomerular injury in the rat - Daniel, Christoph; Renders, L.; Amann, Kerstin Ute; Schulze-Lohoff, Eckhard; Hauser, Ingeborg A.; Hugo, Christian (American Journal of Transplantation, 2005)
Despite the lack of nephrotoxicity, adverse effects of the new antiproliferative immunosuppressant everolimus have been reported. By varying time point and dose of everolimus treatment as well as the degree of glomerular injury, the specific conditions and potential mechanisms leading to adverse actions in the anti-Thy1 model have been determined. Only the combination of early and high-dose everolimus treatment (1-3 mg/kg bw) with a severe glomerular lesion ('full-dose' anti-Thy1 model) caused adverse effects with a high mortality rate, progressive apoptosis, crescent formation and glomerulosclerosis. In contrast, either later start or low-dose (0.3 mg/kg bw) therapy or treatment of a less severe lesion ('reduced dose' anti-Thy1 model) appeared to be relatively safe for the glomerular architecture. The adverse effects of everolimus were linked to its marked inhibition of endothelial cell, but not necessarily mesangial cell proliferation. In addition, everolimus markedly inhibited the angiogenic cytokine vascular endothelial growth factor in nephritic glomeruli in vivo. These experimental results suggest special caution regarding the use of everolimus in all situations of severe glomerular cell injury requiring extensive capillary repair, where at least adaption to a low dose needs to be considered. Copyright © Blackwell Munksgaard 2005.
Created from Fastlane, Scopus look-up
Keywords: Anti-Thy1 model; Glomerular endothelial cell proliferation; Glomerular regeneration; Rapamycin derivative everolimus; Renal microvascular injury

Mechanisms of pathogenicity and the quest for genetic modifiers of kidney disease in branchiootorenal syndrome - Sewerin, Sebastian; Aurnhammer, Charlotte; Skubic, Cene; Cokan, Kaja Blagotinšek; Jeruc, Jera; Rozman, Damjana; Pfister, Frederick; Dittrich, Katalin; Mayer, Brigitte; Schönauer, Ria; Petzold, Friederike; Halbritter, Jan (Clinical Kidney Journal, 2024)
Backgound. Branchiootorenal (BOR) syndrome is an autosomal dominant disorder caused by pathogenic EYA1 variants and clinically characterized by auricular malformations with hearing loss, branchial arch anomalies, and congenital anomalies of the kidney and urinary tract. BOR phenotypes are highly variable and heterogenous. While random monoallelic expression is assumed to explain this phenotypic heterogeneity, the potential role of modifier genes has not yet been explored. Methods. Through thorough phenotyping and exome sequencing, we studied one family with disease presentation in at least four generations in both clinical and genetic terms. Functional investigation of the single associated EYA1 variant c.1698+1G>A included splice site analysis and assessment of EYA1 distribution in patient-derived fibroblasts. The candidate modifier gene CYP51A1 was evaluated by histopathological analysis of murine Cyp51+/− and Cyp51−/− kidneys. As the gene encodes the enzyme lanosterol 14α-demethylase, we assessed sterol intermediates in patient blood samples as well. Results. The EYA1 variant c.1698+1G>A resulted in functional deletion of the EYA domain by exon skipping. The EYA domain mediates protein-protein interactions between EYA1 and co-regulators of transcription. EYA1 abundance was reduced in the nuclear compartment of patient-derived fibroblasts, suggesting impaired nuclear translocation of these protein complexes. Within the affected family, renal phenotypes spanned from normal kidney function in adulthood to chronic kidney failure in infancy. By analyzing exome sequencing data for variants that potentially play roles as genetic modifiers, we identified a canonical splice site alteration in CYP51A1 as the strongest candidate variant. Conclusion. In this study, we demonstrate pathogenicity of EYA1 c.1698+1G>A, propose a mechanism for dysfunction of mutant EYA1, and conjecture CYP51A1 as a potential genetic modifier of renal involvement in BOR syndrome.
CRIS-Team Scopus Importer:2024-01-26
Keywords: branchiootorenal syndrome; chronic kidney disease; modifier genes; patient-derived fibroblasts; phenotypic heterogeneity

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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Melatonin as a cardioprotective therapy following ST-segment elevation myocardial infarction: is it really promising? Reply - Hausenloy, Derek J.; Garcia-Dorado, David; Botker, Hans Erik; Davidson, Sean M.; Downey, James; Engel, Felix; Jennings, Robert; Lecour, Sandrine; Leor, Jonathan; Madonna, Rosalinda; Ovize, Michel; Perrino, Cinzia; et al. (Cardiovascular Research, 2017)
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Membranoproliferative glomerulonephritis and C3 glomerulopathy - Hohenstein, B.; Amann, Kerstin Ute; Menne, J. (Internist, 2019)
Based on an increasingly better pathophysiological understanding over the last 10 years, in 2010 a new classification of glomerulonephritis with dominant or codominant C3 deposits was introduced and the predominant subgoup was termed C3 glomerulopathy (C3G). In the current classification, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) form a disease spectrum which is very heterogeneous in terms of pathophysiology and the clinical course. Recent evidence suggests that IC-MPGN and C3G share more pathophysiological aspects with respect to secondary causes, autoantibodies and genetic aspects than had been suggested with the creation of the new classification. Knowledge of the underlying pathophysiology is important for guiding the diagnostic steps for clarification of secondary causes. Comprehensive complement analysis, accompanied by antibody screening and genetic analysis, should be consistently carried out. Although not systematically validated in clinical trials, the published evidence provides a robust foundation for the use of available treatment approaches for these diseases that are often rapidly progressive and often return after renal transplantation.
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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.
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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.
EVALuna2:6784

Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract - Shaikh, Haroon; Vargas, Juan Gamboa; Mokhtari, Zeinab; Jarick, Katja J.; Ulbrich, Maria; Mosca, Josefina Pena; Viera, Estibaliz Arellano; Graf, Caroline; Le, Duc-Dung; Heinze, Katrin G.; Büttner-Herold, Maike; Rosenwald, Andreas; et al. (Frontiers in Immunology, 2021)
Mesenteric lymph nodes (mLNs) are sentinel sites of enteral immunosurveillance and immune homeostasis. Immune cells from the gastrointestinal tract (GIT) are constantly recruited to the mLNs in steady-state and under inflammatory conditions resulting in the induction of tolerance and immune cells activation, respectively. Surgical dissection and transplantation of lymph nodes (LN) is a technique that has supported seminal work to study LN function and is useful to investigate resident stromal and endothelial cell biology and their cellular interactions in experimental disease models. Here, we provide a detailed protocol of syngeneic mLN transplantation and report assays to analyze effective mLN engraftment in congenic recipients. Transplanted mLNs allow to study T cell activation and proliferation in preclinical mouse models. Donor mLNs proved viable and functional after surgical transplantation and regenerated blood and lymphatic vessels. Immune cells from the host completely colonized the transplanted mLNs within 7-8 weeks after the surgical intervention. After allogeneic hematopoietic cell transplantation (allo-HCT), adoptively transferred allogeneic CD4+ T cells from FVB/N (H-2q) mice homed to the transplanted mLNs in C57BL/6 (H-2b) recipients during the initiation phase of acute graft-versus-host disease (aGvHD). These CD4+ T cells retained full proliferative capacity and upregulated effector and gut homing molecules comparable to those in mLNs from unmanipulated wild-type recipients. Wild type mLNs transplanted into MHCII deficient syngeneic hosts sufficed to activate alloreactive T cells upon allogeneic hematopoietic cell transplantation, even in the absence of MHCII+ CD11c+ myeloid cells. These data support that orthotopically transplanted mLNs maintain physiological functions after transplantation. The technique of LN transplantation can be applied to study migratory and resident cell compartment interactions in mLNs as well as immune reactions from and to the gut under inflammatory and non-inflammatory conditions.
CRIS-Team Scopus Importer:2021-08-20
Keywords: acute graft-versus host disease; alloreactive T cells; lymph node stromal cells; lymph node transplantation; mesenteric lymph node; mouse models

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

MIA/CD-RAP Regulates MMP13 and Is a Potential New Disease-Modifying Target for Osteoarthritis Therapy - Stäbler, Sebastian; Lichtblau, Adrian; Gurbiel, Slavyana; Schubert, Thomas; Riechers, Alexander; Rottensteiner-Brandl, Ulrike; Boßerhoff, Anja Katrin (Cells, 2023)
Melanoma inhibitory activity/cartilage-derived retinoicacid-sensitive protein (MIA/CD-RAP) is a protein expressed and secreted by chondrocytes and cartilaginous tissues. MIA/CD-RAP-deficient mice develop milder osteoarthritis than wildtype mice. In this study, we investigated MIA/CD-RAP downstream targets to explain this reduced disease development. As a possible mediator, we could detect matrix metalloproteinase 13 (MMP13), and the influence of MIA/CD-RAP on MMP13 regulation was analyzed in vitro using SW1353 chondrosarcoma cells and primary chondrocytes. The femoral head cartilage of WT and MIA/CD-RAP −/− mice were cultured ex vivo to further investigate MMP13 activity. Finally, osteoarthritis was surgically induced via DMM in C57BL/6 mice, and the animals were treated with an MIA/CD-RAP inhibitory peptide by subcutaneously implanted pellets. MMP13 was regulated by MIA/CD-RAP in SW1353 cells, and MIA/CD-RAP −/− murine chondrocytes showed less expression of MMP13. Further, IL-1β-treated MIA/CD-RAP −/− chondrocytes displayed less MMP13 expression and activity. Additionally, MIA/CD-RAP-deficient ex vivo cultured cartilage explants showed less MMP13 activity as well as reduced cartilage degradation. The mice treated with the MIA/CD-RAP inhibitory peptide showed less osteoarthritis development. Our findings revealed MIA/CD-RAP as a new regulator of MMP13 and highlighted its role as a potential new target for osteoarthritis therapy.
CRIS-Team Scopus Importer:2023-02-03
Keywords: MIA/CD-RAP; MMP13; osteoarthritis; signaling; therapeutic

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

Microfluidically fabricated fibers containing pancreatic islets and mesenchymal stromal cells improve longevity and sustained normoglycemia in diabetic rats - Navaei-Nigjeh, Mona; Mirzababaei, Soheyl; Ghiass, Mohammad Adel; Roshanbinfar, Kaveh; Gholami, Mahdi; Abdollahi, Mohammad (Biofabrication, 2022)
Type 1 diabetes mellitus is an autoimmune disease characterized by the loss of pancreatic isletβcells. Insulin injections and pancreas transplants are currently available therapies. The former requires daily insulin injections, while the latter is constrained by donor organ availability. Islet transplantation is a promising alternative treatment for type 1 diabetes mellitus that may overcome the limitations of previous techniques. Two challenges, however, must be addressed: limited cell retention as a result of the immune response and limited function of the transplanted cells that survive. To address these problems, we developed a microfluidic technology for a one-step generation of islet-laden fibers to protect them from the immune response. This approach enables continuous generation of microfibers with a diameter suitable for islet encapsulation (275µm). We, then, transplanted islet-laden fibers into diabetic Wistar rats. While islet-laden fibers alone were unable to restore normoglycemia in diabetic rats, adding mesenchymal stromal cells (MSCs) restored normoglycemia for an extended time. It increased the animals' lifespan by up to 75 d. Additionally, it improved the glucose-stimulated response of islets to the point where there was no significant difference between the treatment group and the healthy animals. Additionally, the presence of MSCs suppressed the immune response, as seen by decreased levels of pro-inflammatory cytokines such as tumor necrosis factor-α. Taken together, these fibers including islet and MSCs provide a versatile platform for concurrently improving cell preservation and functioning followingin vivotransplantation.
CRIS-Team Scopus Importer:2022-12-16
Keywords: cell encapsulation; cell-laden fiber; diabetes; mesenchymal stromal cells; microfiber; microfluidics; pancreatic islet transplantation

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 gastrointestinal stromal tumors in the gastric antrum - Agaimy, Abbas; Bihl, Michel P. (Human Pathology, 2014)
EVALuna2:6590

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

Microtubule Organization in Striated Muscle Cells - Becker, Robert; Leone, Marina; Engel, Felix (Cells, 2020)
Distinctly organized microtubule networks contribute to the function of differentiated cell types such as neurons, epithelial cells, skeletal myotubes, and cardiomyocytes. In striated (i.e. skeletal and cardiac) muscle cells, the nuclear envelope acts as the dominant microtubule-organizing center (MTOC) and the function of the centrosome-the canonical MTOC of mammalian cells-is attenuated, a common feature of differentiated cell types. We summarize the mechanisms known to underlie MTOC formation at the nuclear envelope, discuss the significance of the nuclear envelope MTOC for muscle function and cell cycle progression, and outline potential mechanisms of centrosome attenuation.
CRIS-Team Scopus Importer:2020-06-16
Keywords: cardiomyocytes; cell cycle; centrosome; microtubules; MTOC; non-centrosomal MTOC; skeletal muscle

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

Mild Salt-Sensitive Hypertension in Genetically Determined Low Nephron Number is Associated with Chloride but Not Sodium Retention - Benz, Kerstin; Schlote, Julia; Daniel, Christoph; Kopp, Christoph; Dahlmann, Anke; Schröder, Agnes; Cordasic, Nada; Klanke, Bernd; Hilgers, Karl Friedrich; Titze, Jens; Amann, Kerstin Ute (Kidney & Blood Pressure Research, 2018)
BACKGROUND/AIMS: One potential pathomechanism how low nephron number leads to hypertension in later life is altered salt handling. We therefore evaluated changes in electrolyte and water content in wildtype (wt) and GDNF+/- mice with a 30% reduction of nephron number. METHODS: 32 GDNF+/- and 36 wt mice were fed with low salt (LSD, 0.03%, normal drinking water) or high salt (HSD, 4%, 0.9% drinking water) diet for 4 weeks. Blood pressure was continuously measured by telemetry in a subgroup. At the end of the experiment and after standardized ashing processes electrolyte- and water contents of the skin and the total body were determined. RESULTS: We found higher blood pressure in high salt treated GDNF+/-compared to wt mice. Of interest, we could not confirm an increase in total-body sodium as predicted by prevailing explanations, but found increased total body and skin chloride that interestingly correlated with relative kidney weight. CONCLUSION: We hereby firstly report significant total body and skin chloride retention in salt sensitive hypertension of GDNF+/-mice with genetically determined lower nephron number. Thus, in contrast to the prevailing opinion our data argue for the involvement of non-volume related mechanisms.
EVALuna2:34423

Minimalinvasives Implantat für die Harninkontinenztherapie - Preis, Alexander; Benke, Elisabeth; Reitelshöfer, Sebastian; Rieker, Ralf (2024)
Der Weg von der Forschungsidee zum zulassungsfähigen Medizinprodukt ist zeit-, kosten- und ressourcenintensiv. Dies zeigt das Beispiel eines Projektes am Lehrstuhl FAPS der Friedrich-Alexander-Universität Erlangen-Nürnberg. Hier arbeitet ein Forscherteam seit einigen Jahren gemeinsam mit medizinischen Partnern an der Entwicklung eines minimalinvasiven Implantats zur Harninkontinenztherapie. Für die Forscher stellt das Vorhaben eine spezielle Anforderung dar, da für wissenschaftliches Arbeiten und eine angestrebte Unternehmensgründung oftmals konträre Wege beschritten werden müssen. Mit der richtigen Unterstützung, strukturellen Voraussetzungen und dem richtigen Mindset aber können beide Ziele erfolgreich vereint werde
Keywords: Harninkontinenztherapie; Forschungstransfer; Start-up; Implantat; Medizinproduktentwicklung

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.
EVALuna2:6555

MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer - Kalogirou, C.; Linxweiler, J.; Schmucker, P.; Snaebjornsson, M. T.; Schmitz, W.; Wach, S.; Krebs, M.; Hartmann, E.; Puhr, M.; Müller, A.; Spahn, M.; Seitz, A. K.; et al. (Nature Communications, 2021)
Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.
CRIS-Team Scopus Importer:2021-08-27

miR-27a/b is a posttranscriptional regulator of Gpr126 (Adgrg6) - Musa, Gentian; Srivastava, Swati; Petzold, Jana; Cazorla-Vazquez, Salvador; Engel, Felix (Annals of the New York Academy of Sciences, 2019)
Gpr126 (Adgrg6), a member of the adhesion G protein-coupled receptor family, has been associated with a variety of human diseases. Yet, despite its clinical importance, the mechanisms regulating Gpr126 expression are poorly understood. Here, we aimed at identifying upstream regulatory mechanisms of Gpr126 expression utilizing the heart as model organ in which Gpr126 regulates trabeculation. Here, we focused on possible regulation of Gpr126 regulation by microRNAs, which have emerged as key players in regulating development, have a critical role in disease progression, and might serve as putative therapeutic targets. In silico analyses identified one conserved binding site in the 3 ' UTR of Gpr126 for microRNA 27a and 27b (miR-27a/b). In addition, miR-27a/b and Gpr126 expression were differentially expressed during rat heart development. A regulatory role of miR-27a/b in controlling Gpr126 expression was substantiated by reduced Gpr126 mRNA levels upon ectopic expression of miR-27a/b in HEK293T cells and miR-27b in zebrafish embryos. Regulation of Gpr126 expression by direct binding of miR-27a/b to the 3 ' UTR of Gpr126 was verified by luciferase reporter assays in HEK293T cells. Finally, the modulation of gpr126 expression in zebrafish by injection of either miR-27b or miR-27b inhibitor in single cell-stage embryos resulted in hypo- or hypertrabeculation, respectively. Collectively, the data indicate that Gpr126 expression is regulated by miR-27a/b.
CRIS-Team WoS Importer:2019-10-22

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.
EVALuna2:6831

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.
EVALuna2:1970

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.
EVALuna2:34872

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

Mitosis domain generalization in histopathology images — The MIDOG challenge - Aubreville, Marc; Stathonikos, Nikolas; Bertram, Christof A.; Klopfleisch, Robert; ter Hoeve, Natalie; Ciompi, Francesco; Wilm, Frauke; Marzahl, Christian; Donovan, Taryn A.; Maier, Andreas; Breen, Jack; Ravikumar, Nishant; et al. (Medical Image Analysis, 2023)
The density of mitotic figures (MF) within tumor tissue is known to be highly correlated with tumor proliferation and thus is an important marker in tumor grading. Recognition of MF by pathologists is subject to a strong inter-rater bias, limiting its prognostic value. State-of-the-art deep learning methods can support experts but have been observed to strongly deteriorate when applied in a different clinical environment. The variability caused by using different whole slide scanners has been identified as one decisive component in the underlying domain shift. The goal of the MICCAI MIDOG 2021 challenge was the creation of scanner-agnostic MF detection algorithms. The challenge used a training set of 200 cases, split across four scanning systems. As test set, an additional 100 cases split across four scanning systems, including two previously unseen scanners, were provided. In this paper, we evaluate and compare the approaches that were submitted to the challenge and identify methodological factors contributing to better performance. The winning algorithm yielded an F1 score of 0.748 (CI95: 0.704-0.781), exceeding the performance of six experts on the same task.
CRIS-Team Scopus Importer:2022-12-16
Keywords: Challenge; Deep Learning; Domain generalization; Histopathology; Mitosis

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

Modeling Hemolytic-Uremic Syndrome: In-Depth Characterization of Distinct Murine Models Reflecting Different Features of Human Disease - Dennhardt, Sophie; Pirschel, Wiebke; Wissuwa, Bianka; Daniel, Christoph; Gunzer, Florian; Lindig, Sandro; Medyukhina, Anna; Kiehntopf, Michael; Rudolph, Wolfram W.; Zipfel, Peter F.; Gunzer, Matthias; Figge, Marc Thilo; et al. (Frontiers in Immunology, 2018)
Diarrhea-positive hemolytic-uremic syndrome (HUS) is a renal disorder that results from infections with Shiga-toxin (Stx)-producing Escherichia coli. The aim of this study was to establish well-defined refined murine models of HUS that can serve as preclinical tools to elucidate molecular mechanisms of disease development. C57BL/6J mice were subjected to different doses of Stx2 purified from an E. coli O157:H7 patient isolate. Animals received 300 ng/kg Stx2 and were sacrificed on day 3 to establish an acute model with fast disease progression. Alternatively, mice received 25 ng/kg Stx2 on days 0, 3, and 6, and were sacrificed on day 7 to establish a subacute model with moderate disease progression. Indicated by a rise in hematocrit, we observed dehydration despite volume substitution in both models, which was less pronounced in mice that underwent the 7-day regime. Compared with sham-treated animals, mice subjected to Stx2 developed profound weight loss, kidney dysfunction (elevation of plasma urea, creatinine, and neutrophil gelatinase-associated lipocalin), kidney injury (tubular injury and loss of endothelial cells), thrombotic microangiopathy (arteriolar microthrombi), and hemolysis (elevation of plasma bilirubin, lactate dehydrogenase, and free hemoglobin). The degree of complement activation (C3c deposition), immune cell invasion (macrophages and T lymphocytes), apoptosis, and proliferation were significantly increased in kidneys of mice subjected to the 7-day but not in kidneys of mice subjected to the 3-day regime. However, glomerular and kidney volume remained mainly unchanged, as assessed by 3D analysis of whole mount kidneys using CD31 staining with light sheet fluorescence microscopy. Gene expression analysis of kidneys revealed a total of only 91 overlapping genes altered in both Stx2 models. In conclusion, we have developed two refined mouse models with different disease progression, both leading to hemolysis, thrombotic microangiopathy, and acute kidney dysfunction and damage as key clinical features of human HUS. While intrarenal changes (apoptosis, proliferation, complement deposition, and immune cell invasion) mainly contribute to the pathophysiology of the subacute model, prerenal pathomechanisms (hypovolemia) play a predominant role in the acute model. Both models allow the further study of the pathomechanisms of most aspects of human HUS and the testing of distinct novel treatment strategies.
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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 peripheral arterial disease in proximal extremity arteries - Croner, Roland S.; Balzer, Klaus; Schellerer, Vera; Mueller, Volker; Schlabrakowsi, Anne; Stürzl, Michael; Naschberger, Elisabeth; Lang, Werner (Journal of Surgical Research, 2012)
Purpose: Although risk factors for atherosclerosis in peripheral arterial disease (PAD) are well defined, the underlying mechanisms are poorly understood and no medication exists for causal therapy. Molecular pathways that could be targeted have not been identified so far. To address this issue, we compared the molecular profiles of healthy versus PAD proximal femoral arteries. Methods: Gene expression profiles from proximal femoral arteries of patients with PAD (Fontaine stage IIb-IV; n = 20) and femoral arteries from healthy controls (CO) (n = 3) were compared by microarray technology. We evaluated all samples by histopathology and performed microdissection on the CO tissue before molecular analysis. We analyzed genes regarding their cellular localization, molecular function, and risk factors such as hypercholesterolemia, smoking, and diabetes. We used a selected panel of genes for polymerase chain reaction validation of microarray results and compared the data with previously published studies. Results: Most genes overexpressed in PAD versus CO were located in the cytoplasm, membrane, and nucleus. Functionally, they had binding activity to nucleotides, cytoskeletal proteins, and transcription factors. They were mainly involved in immune regulation (e.g., interleukin-8, chemokine ligand 18, and allograft-inflammatory factor-1) (P < 0.01). Down-regulated genes in PAD versus CO were located in the extracellular region. They had transporter and G-protein receptor activity. They were associated with signaling, cell growth, and tissue formation (e.g., myosin VB, marker for differentiated aortic smooth muscle, myosin 11) (P < 0.01). Polymerase chain reaction successfully validated the expression of the differences among 10 selected genes (e.g., chemokine ligand 18, common leukocyte antigen, killer cell lectin-like receptor subfamily B, member 1, and interleukin-8). Conclusions: Genes enrolled in immune regulation and inflammatory response were identified as key players in PAD. Various membrane-bound molecules with binding activity are hereunder. Identification of such molecules may elucidate relevant players that act as candidates for therapeutic targets or prognostic markers in the future. © 2012 Elsevier Inc. All rights reserved.
Created from Fastlane, Scopus look-up
Keywords: Artheriosclerosis; Microarray; Molecular marker; Peripheral arterial disease

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 diagnosis of kidney transplant failure based on urine - Wiesener, Antje; Knaup, Karl; Büttner-Herold, Maike; Dieterle, Anne; Stoeckert, Johanna; Riedl, Bernhard; Morath, Christian; Wald, Alexandra; Vondran, Florian; Braun, Felix; Schödel, Johannes; Schüler, Markus; et al. (American Journal of Transplantation, 2020)
In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor's disease of oral-facial-digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient ' s urine more than 10 years after transplantation. Next-generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long-term outcome was enabled for 5 recipients.
CRIS-Team WoS Importer:2020-01-31

MOLECULAR DIAGNOSIS OF KIDNEY TRANSPLANT FAILURE BY THE URINE - Knaup, Karl; Wiesener, A.; Buettner-Herold, M.; Dieterle, A.; Morath, C.; Vondran, F. W. R.; Wald, A.; Braun, F.; Schüler, Markus; Schödel, Johannes; Schiffer, Mario; Reis, André; et al. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

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.
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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

Molecular Profiling of Salivary Oncocytic Mucoepidermoid Carcinomas Helps to Resolve Diagnostic Dilemma with Low-Grade Oncocytic Lesions - Stanowska, Olga; Agaimy, Abbas; Ardighieri, Laura; Steiner, Petr; Nicolai, Piero; Durzynska, Monika; Majewska, Hanna; Prochorec-Sobieszek, Monika; Bakula-Zalewska, Elwira; Baneckova, Martina; Michal, Michal; Skalova, Alena (LABORATORY INVESTIGATION, 2020)
CRIS-Team WoS Importer:2020-03-24

Molecular Profiling of Salivary Oncocytic Mucoepidermoid Carcinomas Helps to Resolve Differential Diagnostic Dilemma with Low-grade Oncocytic Lesions - Skálová, Alena; Agaimy, Abbas; Stanowska, Olga; Baneckova, Martina; Ptáková, Nikola; Ardighieri, Laura; Nicolai, Piero; Lombardi, Davide; Durzynska, Monika; Corcione, Luigi; Laco, Jan; Koshyk, Olena; et al. (American Journal of Surgical Pathology, 2020)
Oncocytic mucoepidermoid carcinoma (OMEC) is a rare but diagnostically challenging variant of mucoepidermoid carcinoma (MEC). OMEC is notable for differential diagnostic considerations that are raised as a result of overlap with other benign and low-grade oncocytic salivary gland tumors. Diffuse and strong immunoreactivity of p63 protein may be useful in distinguishing OMEC from its mimics. However, focal p63 staining can be present in benign oncytomas. Presence of mucin-containing cells, mucinous cystic formation, and foci of extravasated mucin are considered a hallmark of MEC. True mucocytes may be, however, very few and hardly discernable in OMECs. Recent evidence has shown that most MECs harbor gene fusions involving MAML2. A retrospective review of archived pathology files and the authors' own files was conducted to search for "low-grade/uncertain oncocytic tumor,""oncocytoma,"and "oncocytic carcinoma"in the period from 1996 to 2019. The tumors with IHC positivity for p63 and/or p40, and S100 negativity, irrespective of mucicarmine staining, were tested by next-generation sequencing using fusion-detecting panels to detect MAML2 gene rearrangements. Two index cases from consultation practice (A.S. and A.A.) of purely oncocytic low-grade neoplasms without discernible mucinous cells showed a CRTC1-MAML2 fusion using next-generation sequencing, and were reclassified as OMEC. In total, 22 cases of oncocytic tumors, retrieved from the authors' files, and from the Salivary Gland Tumor Registry, harbored the MAML2 gene rearrangements. Presence of mucocytes, the patterns of p63 and SOX10 immunopositivity, and mucicarmine staining were inconsistent findings. Distinguishing OMEC devoid of true mucinous cells from oncocytoma can be very challenging, but it is critical for proper clinical management. Diffuse and strong positivity for p63 and visualization of hidden mucocytes by mucicarmine staining may be misleading and does not always suffice for correct diagnosis. Our experience suggests that ancillary studies for the detection of MAML2 rearrangement may provide useful evidence in difficult cases.
CRIS-Team Scopus Importer:2020-11-13
Keywords: CRTC1-MAML2; gene fusion; MAML2; mucoepidermoid carcinoma; oncocytic; oncocytoma; salivary gland neoplasms

Molecular profiling of single circulating tumor cells with diagnostic intention - Polzer, Bernhard; Medoro, Gianni; Pasch, Sophie; Fontana, Francesca; Zorzino, Laura; Pestka, Aurelia; Andergassen, Ulrich; Meier-Stiegen, Franziska; Czyz, Zbigniew T.; Alberter, Barbara; Treitschke, Steffi; Schamberger, Thomas; et al. (Embo Molecular Medicine, 2014)
Several hundred clinical trials currently explore the role of circulating tumor cell (CTC) analysis for therapy decisions, but assays are lacking for comprehensive molecular characterization of CTCs with diagnostic precision. We therefore combined a workflow for enrichment and isolation of pure CTCs with a non-random whole genome amplification method for single cells and applied it to 510 single CTCs and 189 leukocytes of 66 CTC-positive breast cancer patients. We defined a genome integrity index (GII) to identify single cells suited for molecular characterization by different molecular assays, such as diagnostic profiling of point mutations, gene amplifications and whole genomes of single cells. The reliability of > 90% for successful molecular analysis of high-quality clinical samples selected by the GII enabled assessing the molecular heterogeneity of single CTCs of metastatic breast cancer patients. We readily identified genomic disparity of potentially high relevance between primary tumors and CTCs. Microheterogeneity analysis among individual CTCs uncovered pre-existing cells resistant to ERBB2-targeted therapies suggesting ongoing microevolution at late-stage disease whose exploration may provide essential information for personalized treatment decisions and shed light into mechanisms of acquired drug resistance.
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Molecular signature for lymphatic metastasis in colorectal carcinomas. - Croner, Roland S.; Förtsch, Thomas; Brueckl, Wolfgang M.; Roedel, Franz; Roedel, Claus; Papadopoulos, Thomas; Brabletz, Thomas; Kirchner, Thomas; Sachs, Martin; Behrens, Jürgen; Klein-Hitpass, Ludger; Stürzl, Michael; et al. (Annals of Surgery, 2008)
Fifty differently expressed genes between stage UICC I, II versus III CRC were identified respecting the selection criteria by allowing for multiple testing. The data validation by the independent clinical study confirmed our results. In comparison to MC, the genes were over- or underexpressed. They belong to various functional groups such as cellular adhesion, transporters, signaling, metabolism, protein synthesis, gene control, and immune system. Forty tumor samples of stage UICC I, II CRC, 40 samples of stage III CRC, and 25 biopsies of healthy mucosa (MC) were shock frozen in liquid nitrogen and underwent cryotomy after manual dissection for tumor tissue or MC enrichment. Isolated RNA was hybridized to GeneChips (HG-U133A, Affymetrix). Preprocessing of the microarray results was done by the robust multichip average method, and differentially expressed genes were selected by the maximum Wilcoxon statistic over 22,215 probe sets. The results were validated at an independent clinical study. Our large patient cohort and the data validation on an independent study identified 50 differentially expressed genes between CRC of different histopathologic stages. These findings indicate that molecular staging of CRC may be possible, which could help to guide individual CRC treatment before surgery. TNM-staging of colorectal carcinomas (CRC) relies on the histopathologic workup of the surgically removed specimen. If valid preoperative staging methods existed, patients could be selected for adequate individual therapy before surgery. Microarray techniques provide a promising tool to identify stage-specific molecular signatures on primary tumor biopsies. RESULTS MATERIAL AND METHODS CONCLUSION PURPOSE

Molecular staging of lymph node-negative colon carcinomas by one-step nucleic acid amplification (OSNA) results in upstaging of a quarter of patients in a prospective, European, multicentre study - Croner, R. S.; Geppert, Carol-Immanuel; Bader, F. G.; Nitsche, U.; Spaeth, C.; Rosenberg, R.; Zettl, A.; Matias-Guiu, Xavier; Tarragona, J.; Gueller, U.; Stürzl, Michael; Zuber, M. (British Journal of Cancer, 2014)
Background:Current histopathological staging procedures in colon carcinomas depend on midline division of the lymph nodes with one section of haematoxylin & eosin (H&E) staining only. By this method, tumour deposits outside this transection line may be missed and could lead to understaging of a high-risk group of stage UICC II cases, which recurs in 20% of cases. A new diagnostic semiautomated system, one-step nucleic acid amplification (OSNA), detects cytokeratin (CK) 19 mRNA in lymph node metastases and enables the investigation of the whole lymph node. The objective of this study was to assess whether histopathological pN0 patients can be upstaged to stage UICC III by OSNA.Methods:Lymph nodes from patients who were classified as lymph node negative after standard histopathology (single (H&E) slice) were subjected to OSNA. A result revealing a CK19 mRNA copy number >250, which makes sure to detect mainly macrometastases and not isolated tumour cells (ITC) or micrometastases only, was regarded as positive for lymph node metastases based on previous threshold investigations.Results:In total, 1594 pN0 lymph nodes from 103 colon carcinomas (median number of lymph nodes per patient: 14, range: 1-46) were analysed with OSNA. Out of 103 pN0 patients, 26 had OSNA-positive lymph nodes, resulting in an upstaging rate of 25.2%. Among these were 6/37 (16.2%) stage UICC I and 20/66 (30.3%) stage UICC II patients. Overall, 38 lymph nodes were OSNA positive: 19 patients had one, 3 had two, 3 had three, and 1 patient had four OSNA-positive lymph nodes.Conclusions:OSNA resulted in an upstaging of over 25% of initially histopathologically lymph node-negative patients. OSNA is a standardised, observer-independent technique, allowing the analysis of the whole lymph node. Therefore, sampling bias due to missing investigation of certain lymph node tissue can be avoided, which may lead to a more accurate staging.
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Molecular Subtyping of Invasive Breast Cancer Using a PAM50-Based Multigene Expression Test-Comparison with Molecular-Like Subtyping by Tumor Grade/Immunohistochemistry and Influence on Oncologist's Decision on Systemic Therapy in a Real-World Setting - Erber, Ramona; Angeloni, Miriam; Stöhr, Robert; Lux, Michael P.; Ulbrich-Gebauer, Daniel; Pelz, Enrico; Bankfalvi, Agnes; Schmid, Kurt W.; Walter, Robert F. H.; Vetter, Martina; Thomssen, Christoph; Mayr, Doris; et al. (International Journal of Molecular Sciences, 2022)
In intermediate risk hormone receptor (HR) positive, HER2 negative breast cancer (BC), the decision regarding adjuvant chemotherapy might be facilitated by multigene expression tests. In all, 142 intermediate risk BCs were investigated using the PAM50-based multigene expression test Prosigna (R) in a prospective multicentric study. In 119/142 cases, Prosigna (R) molecular subtyping was compared with local and two central (C1 and C6) molecular-like subtypes relying on both immunohistochemistry (IHC; HRs, HER2, Ki-67) and IHC + tumor grade (IHC+G) subtyping. According to local IHC, 35.4% were Luminal A-like and 64.6% Luminal B-like subtypes (local IHC+G subtype: 31.9% Luminal A-like; 68.1% Luminal B-like). In contrast to local and C1 subtyping, C6 classified >2/3 of cases as Luminal A-like. Pairwise agreement between Prosigna (R) subtyping and molecular-like subtypes was fair to moderate depending on molecular-like subtyping method and center. The best agreement was observed between Prosigna (R) (53.8% Luminal A; 44.5% Luminal B) and C1 surrogate subtyping (Cohen's kappa = 0.455). Adjuvant chemotherapy was suggested to 44.2% and 88.6% of Prosigna (R) Luminal A and Luminal B cases, respectively. Out of all Luminal A-like cases (locally IHC/IHC+G subtyping), adjuvant chemotherapy was recommended if Prosigna (R) testing classified as Prosigna (R) Luminal A at high / intermediate risk or upgraded to Prosigna (R) Luminal B.
CRIS-Team WoS Importer:2022-08-26

Molecular weight and molar substitution are more important in HES-induced renal impairment than concentration after hemorrhagic and septic shock - Simon, T P; Thiele, C; Schuerholz, T; Fries, M; Stadermann, F; Haase, G; Amann, Kerstin Ute; Marx, G (Minerva Anestesiologica, 2015)
Clinical studies have raised concerns about the safety of 6% hydroxyethylstarch (HES) 130/0.42, but the pathomechanisms of this renal impairment remain unknown. To evaluate the effects of different HES concentrations, molar substitutions and molecular weights in HES-induced renal impairment, we used a porcine two-hit model that combined haemorrhagic and septic shock.We conducted a prospective, randomised, double-blinded, controlled study in a university animal laboratory. Thirty anaesthetised and ventilated pigs were randomised to receive volume replacement therapy using 6% HES130/0.42, 6% HES200/0.5, 10% HES130/0.42 or 10% HES200/0.5, all dissolved in 0.9% NaCl rather than 0.9% NaCl alone. First, we bled the animals until they reached half of their baseline mean arterial pressure (MAP) for 45 minutes followed by fluid resuscitation. As a second hit, sepsis was induced using an Escherichia coli-laden clot 6 hours after haemorrhagic shock. Volume resuscitation started with a delay of two hours and a central venous pressure goal of 12 mmHg.At the end of the study, the groups showed no difference in cardiac output or MAP, but the volume balance (mL/kg BW) was significantly higher in the 0.9% NaCl group (346±90; P<=0.05) than in the other groups (6% HES130, 125±26; 6% HES200, 105±15; 10% HES130, 114±17; 10% HES200, 96±23). Creatinine clearance (mL/min) was significantly lower in the 6% HES200 (26±33) and 10% HES200 (15±18) groups compared to the 0.9% NaCl group (104±46; P<=0.05) but not in the HES 130 formulations (6% HES130: 64±51; 10% HES130: 58±38) at the end of the study.In this porcine two-hit shock model, treatment with 0.9% NaCl, HES 130/0.42 or HES 200/0.5 led to a similar maintenance of haemodynamic values. Despite this similar maintenance of the haemodynamic values, volume replacement with 6% and 10% HES 200/0.5 led to an accumulation of HES, higher colloid osmotic pressure and significantly reduced renal function after haemorrhagic and septic shock. These facts support the presumption that not the concentration but the degree of substitution and the molecular weight play a decisive role in HES-induced renal impairment.
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Molekular definierte Nierenzellkarzinome 2025 - Stöhr, Christine; Fiegl, August; Bercebal, C.; Agaimy, Abbas; Hartmann, Arndt (Die Pathologie, 2025)
BACKGROUND: The latest edition of the WHO classification of urinary and male genital tumours was published in 2022. The revision was based on the newest scientific literature. This article summarizes the updated recommendations regarding the classification of molecularly defined tumours. RESULTS AND CONCLUSIONS: The current edition of the WHO classification of tumours introduced the new category of molecularly defined tumours. This category includes TFE3-rearranged RCC, TFEB-altered RCC, ELOC-mutated RCC, FH-deficient RCC, SDH-deficient RCC, ALK-rearranged RCC and SMARCB1-deficient RCC. The change reflects the importance of the respective alterations with regard to tumour biology and future treatment options. Simultaneously, the diagnosis of these tumours, which sometimes can show equivocal morphologies, is facilitated.
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Molekulare Testung bei mesenchymalen Neoplasien: Was, wann und wie testen? Eine Übersicht mit besonderem Fokus auf den Stellenwert der Next-Generation-Immunhistochemie als Alternative für molekulare Testung - Agaimy, Abbas (Die Pathologie, 2024)
With the widespread use of diverse modern molecular testing tools, the last two decades have seen significant advances in the classification of soft tissue neoplasms. Specifically, numerous molecularly defined new entities have been introduced and many established older entities have received more insightful molecular studies that have developed their classification further. The discrepant therapeutic and prognostic implications of this evolving complexity of the nosology of neoplastic diseases make the precise subtyping of soft tissue neoplasms unavoidable. However, these rapid developments of the modern diagnostic molecular pathology did not only offer efficient solutions to many complex classification issues, but they were accompanied by similarly complex and diverse emerging problems. Most importantly, these advances have not only challenged the historical dogma of some phenotypes that were once considered specific, but they also have questioned the value of diagnostic immunohistochemistry compared to emerging modern diagnostic molecular tools. Moreover, the central question of when to test, what to test, and how to test became more confusing. This review addresses the major molecular categories in soft tissue neoplasms, their characteristics, and the criteria to be used for selecting the most appropriate molecular diagnostic tool to be used in individual cases with a special focus on the value of next generation immunohistochemistry as a substitute for molecular testing.
CRIS-Team Scopus Importer:2024-12-06
Keywords: Classification; High-precision medicine; Sarcoma; Targeted RNA sequencing; NGS; Targeted therapy

Molekularpathologie bei urologischen Tumoren: Empfehlungen der Konsenskonferenz der Internationalen Gesellschaft für Uropathologie (ISUP) 2019 - Hommerding, Oliver; Allory, Yves; Argani, Pedram; Bismar, Tarek A.; Bubendorf, Lukas; Canete-Portillo, Sofía; Chaux, Alcides; Chen, Ying Bei; Cheng, Liang; Cubilla, Antonio L.; Egevad, Lars; Gill, Anthony J.; et al. (Pathologe, 2021)
Comprehensive understanding of molecular principles in cancer and the diversification of oncological therapy promise individual therapeutic concepts, which have not yet found their way into urogenital cancer therapy. In March 2019 the International Society of Urogenital Pathology (ISUP) therefore held a consensus conference on recommendations for molecular diagnostics of genitourinary tumors, which were published in five separate manuscripts and are summarized in this article. In preparation for the conference, a comprehensive survey of current practices for molecular testing of urogenital tumors was carried out by members of the ISUP. At the conference, the results and the corresponding background information were presented by five working groups and recommendations for action for diagnostics were developed. An agreement between 66% of the conference participants was defined as consensus.
CRIS-Team Scopus Importer:2021-01-15
Keywords: Bladder cancer; Kidney cancer; Molecular biomarker; Prostate cancer; Targeted therapy

MONITORING OF GENERAL IMMUNE STATUS AND SARS-COV-2 REACTIVE T-CELL AND HUMORAL IMMUNITY FACILITATES THE CLINICAL DECISION IN A SEVERE SARS-COV-2-ASSOCIATED PNEUMONIA, MENINGOENCEPHALITIS AND GASTROENTERITIS IN A PANCREAS-KIDNEY TRANSPLANT PATIENT - Babel, N.; Stervbo, U.; Seibert, F.; Bauer, F.; Anft, M.; Rohn, B.; Winnekendonk, G.; Dittmer, U.; Schenker, P.; Amann, Kerstin Ute; Viebahn, R.; Westhoff, T. (TRANSPLANT INTERNATIONAL, 2020)
CRIS-Team WoS Importer:2020-11-06

Mononuclear phagocytes orchestrate prolyl hydroxylase inhibition-mediated renoprotection in chronic tubulointerstitial nephritis - Schley, Gunnar; Klanke, Bernd; Kalucka, Joanna; Schatz, Valentin; Daniel, Christoph; Mayer, Marleen; Goppelt-Strübe, Margarete; Herrmann, Martin; Thorsteinsdottir, Margret; Palsson, Runolfur; Beneke, Angelika; Katschinski, Dörthe M.; et al. (Kidney International, 2019)
Prolyl hydroxylase domain enzyme inhibitors (PHDIs) stabilize hypoxia-inducible factors (HIFs), and are protective in models of acute ischemic and inflammatory kidney disease. Whether PHDIs also confer protection in chronic inflammatory kidney disease models remains unknown. Here we investigated long-term effects of PHDI treatment in adenine-induced nephropathy as a model for chronic tubulointerstitial nephritis. After three weeks, renal dysfunction and tubulointerstitial damage, including proximal and distal tubular injury, tubular dilation and renal crystal deposition were significantly attenuated in PHDI-treated (the isoquinoline derivative ICA and Roxadustat) compared to vehicle-treated mice with adenine-induced nephropathy. Crystal-induced renal fibrosis was only partially diminished by treatment with ICA. Renoprotective effects of ICA treatment could not be attributed to changes in adenine metabolism or urinary excretion of the metabolite 2,8-dihydroxyadenine. ICA treatment reduced inflammatory infiltrates of F4/80+ mononuclear phagocytes in the kidneys and supported a regulatory, anti-inflammatory immune response. Furthermore, interstitial deposition of complement C1q was decreased in ICA-treated mice fed an adenine-enriched diet. Tubular cell-specific HIF-1α and myeloid cell-specific HIF-1α and HIF-2α expression were not required for the renoprotective effects of ICA. In contrast, depletion of mononuclear phagocytes with clodronate largely abolished the nephroprotective effects of PHD inhibition. Thus, our findings indicate novel and potent systemic anti-inflammatory properties of PHDIs that confer preservation of kidney function and structure in chronic tubulointerstitial inflammation and might counteract kidney disease progression.
CRIS-Team Scopus Importer:2019-06-04
Keywords: adenine; chronic inflammation; chronic kidney disease; hypoxia-inducible factor; mononuclear phagocyte; PHD inhibitor

More than just sound: Harnessing metadata to improve neural network classifiers for medical auscultation - Matek, Christian (Patterns, 2022)
Label-efficient algorithms are of central importance for machine learning applications in many medical fields, where obtaining expert annotations is often expensive and time-consuming. Soni et al. show how contrastive learning can help build classifiers for one of the oldest and most revered methods of clinical medicine: auscultation of heart and lung sounds.
CRIS-Team Scopus Importer:2022-02-25

Morphological features useful in the differential diagnosis between undifferentiated carcinoma and gastrointestinal stromal tumor - Vankova, Bohuslava; Behenska, Kristyna; Bauer, Meret; Sedivcova, Monika; Daumova, Magdalena; Agaimy, Abbas; Michal, Michal; Daum, Ondrej (Annals of Diagnostic Pathology, 2020)
Undifferentiated (sarcomatoid) carcinomas may closely mimic gastrointestinal stromal tumors (GISTs) due to possible histological and immunohistochemical overlap between these two entities. To avoid unnecessary employment of a wide spectrum of immunohistochemical stainings and molecular genetics and thus decrease costs, finding simple morphological features to target further investigation of such neoplasms of the gastrointestinal tract would be helpful. Five cases classified as undifferentiated (sarcomatoid) carcinomas with a definite proof of the diagnosis, i. e. the presence of a differentiated carcinomatous component, were retrieved from archives of several institutions. For comparison, 84 cases of GIST mutated in KIT or PDGFRA genes served as the control group. Hematoxylin and eosin stained slides were evaluated for the presence of patterns which might discriminate between sarcomatoid carcinoma and GIST. Lymphatic invasion and entrapment of fat tissue strongly favor the diagnosis of undifferentiated carcinoma, as it was found in all or almost all cases of undifferentiated carcinoma, but in no GIST. Alternation of low- and high- grade areas, formation of angiosarcomatous-like spaces, and the presence of yolk sac-like areas were also detected in all cases of undifferentiated carcinoma, but only in 1.2%, 2.4% and 7.2% of the GISTs, respectively. Furthermore, DOG1 was negative in all cases of undifferentiated carcinoma. According to this study, the presence of the histological findings listed above should prompt extensive tumor sampling in order to find a differentiated carcinomatous component. However, due to the small number of cases of undifferentiated carcinoma available for the study, a larger multi-institutional study is warranted.
CRIS-Team Scopus Importer:2020-05-12
Keywords: Differential diagnostics; Gastrointestinal stromal tumor; GIST; Sarcomatoid carcinoma; Undifferentiated carcinoma

Morphological subtypes of colorectal low-grade intraepithelial neoplasia: Diagnostic reproducibility, frequency and clinical impact - Lang-Schwarz, Corinna; Büttner-Herold, Maike; Burian, Stephan; Erber, Ramona; Hartmann, Arndt; Jesinghaus, Moritz; Kamarádová, Kateina; Rubio, Carlos A.; Seitz, Gerhard; Sterlacci, William; Vieth, Michael; Bertz, Simone (Journal of Clinical Pathology, 2023)
Aims: Special histomorphological subtypes of colorectal low-grade intraepithelial neoplasia (LGIN) with variable prognostic impact were recently described in patients with inflammatory bowel disease (IBD) referred to as non-conventional dysplasia. However, they can also be found in patients without IBD. We aimed to analyse the reproducibility, frequency and prognostic impact of non-conventional colorectal LGIN in patients with and without IBD. Methods: Six pathologists evaluated 500 specimens of five different LGIN-cohorts from patients with and without IBD. Non-conventional LGIN included hypermucinous, goblet cell-deficient, Paneth cell-rich and crypt cell dysplasia. A goblet cell-rich type and non-conventional LGIN, not otherwise specified were added. Results were compared with the original expert-consented diagnosis from archived pathology records. Results: Four or more pathologists agreed in 86.0% of all cases. Non-conventional LGIN was seen in 44.4%, more frequently in patients with IBD (52%; non-IBD: 39.3%, p=0.005). In patients with IBD non-conventional LGIN associated with more frequent and earlier LGIN relapse (p=0.006, p=0.025), high-grade intraepithelial neoplasia (p=0.003), larger lesion size (p=0.001), non-polypoid lesions (p=0.019) and additional risk factors (p=0.034). Results were highly comparable with expert-consented diagnoses. In patients without IBD, non-conventional LGIN may indicate a higher risk for concurrent or subsequent colorectal carcinoma (CRC, p=0.056 and p=0.061, respectively). Frequencies and association with high-grade intraepithelial neoplasia or CRC varied between the different LGIN subtypes. Conclusions: Non-conventional histomorphology in colorectal LGIN is frequent and highly reproducible. Our results indicate an increased risk for CRC in patients with non-conventional LGIN, probably independent of IBD. We recommend reporting non-conventional LGIN in routine pathology reports.
CRIS-Team Scopus Importer:2023-12-29
Keywords: Histology; Inflammatory Bowel Diseases; Intestine; Large; NEOPLASMS

Morphology of non cutaneous head and neck squamous cell carcinoma - Weichert, W.; Ihrler, S.; Boxberg, M.; Agaimy, Abbas; Mollenhauer, M.; Hartmann, Arndt (Pathologe, 2018)
Head and neck squamous cell carcinoma (HNSCC) is by far the most frequent malignant tumor in this anatomic region. Today, HNSCC is divided into two morphologically, molecularly and clinically fundamentally different entities: conventional and virus-associated (HPV/EBV) neoplasms. Premalignant lesions of nonvirus-associated HNSCC include conventional leukoplakia, dysplasia and proliferative verrucous hyperplasia with an increasing risk for malignant transformation. The morphology of HNSCC comprises a spectrum of growth patterns. In addition, special types of HNSCC must be delineated. Recently, for virus-associated HNSCC, some important clinicopathological specifics have become relevant including a separate staging system for these neoplasms. For non-virus associated HNSCC, new grading procedures have been proposed, which significantly impact on prognosis. These issues will be discussed in this review.
EVALuna2:34262

Moving from “single gene” concept to “functionally homologous multigene complex”: The SWI/SNF paradigm - Agaimy, Abbas (Seminars in Diagnostic Pathology, 2021)
CRIS-Team Scopus Importer:2021-03-19

mRNA-Expression of KRT5 and KRT20 Defines Distinct Prognostic Subgroups of Muscle-Invasive Urothelial Bladder Cancer Correlating with Histological Variants - Eckstein, Markus; Wirtz, Ralph Markus; Gross-Weege, Matthias; Breyer, Johannes; Otto, Wolfgang; Stoehr, Robert; Sikic, Danijel; Keck, Bastian; Eidt, Sebastian; Burger, Maximilian; Bolenz, Christian; Nitschke, Katja; et al. (International Journal of Molecular Sciences, 2018)
Recently, muscle-invasive bladder cancer (MIBC) has been subclassified by gene expression profiling, with a substantial impact on therapy response and patient outcome. We tested whether these complex molecular subtypes of MIBC can be determined by mRNA detection of keratin 5 (KRT5) and keratin 20 (KRT20). Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was applied to quantify gene expression of KRT5 and KRT20 using TaqMan (R)-based assays in 122 curatively treated MIBC patients (median age 68.0 years). Furthermore, in silico analysis of the MD Anderson Cancer Center (MDACC) cohort (GSE48277 + GSE47993) was performed. High expression of KRT5 and low expression of KRT20 were associated with significantly improved recurrence-free survival (RFS) and disease-specific survival disease specific survival (DSS: 5-year DSS for KRT5 high: 58%; 5-year DSS for KRT20 high: 29%). KRT5 and KRT20 were associated with rates of lymphovascular invasion and lymphonodal metastasis. The combination of KRT5 and KRT20 allowed identification of patients with a very poor prognosis (KRT20(+)/KRT5(-), 5-year DSS 0%, p < 0.0001). In silico analysis of the independent MDACC cohorts revealed congruent results (5-year DSS for KRT20 low vs. high: 84% vs. 40%, p = 0.042). High KRT20-expressing tumors as well as KRT20(+)/KRT- tumors were significantly enriched with aggressive urothelial carcinoma variants (micropapillary, plasmacytoid, nested).
EVALuna2:35878

MSI status plus immunoscore to select metastatic colorectal cancer patients for immunotherapies - Galon, J.; Mlecnik, B.; Hermitte, F.; Marliot, F.; Bifulco, C.; Lugli, A.; Nagtegaal, I. D.; Hartmann, Arndt; Van Den Eynde, M.; Roehrl, M.; Ohashi, P.; Zavadova, E.; et al. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-06

MSI testing: What is new? What should be considered? German version MSI-Testung: Was ist neu? Was ist zu beachten? - Rüschoff, Josef; Baretton, Gustavo; Bläker, Hendrik; Dietmaier, Wolfgang; Dietel, Manfred; Hartmann, Arndt; Horn, Lars Christian; Jöhrens, Korinna; Kirchner, Thomas; Knüchel, Ruth; Mayr, Doris; Merkelbach-Bruse, Sabine; et al. (Pathologe, 2021)
Based on new trial data regarding immune checkpoint inhibitors (ICIs), the detection of high-grade microsatellite instability (MSI-H) or underlying deficient mismatch repair protein (dMMR) is now becoming increasingly important for predicting treatment response. For the first time, a PD‑1 ICI (pembrolizumab) has been approved by the European Medicines Agency (EMA) for first-line treatment of advanced (stage IV) dMMR/MSI‑H colorectal cancer (CRC). Further indications, such as dMMR/MSI‑H endometrial carcinoma (EC), have already succeeded (Dostarlimab, 2nd line treatment) and others are expected to follow before the end of 2021. The question of optimal testing in routine diagnostics should therefore be re-evaluated. Based on a consideration of the strengths and weaknesses of the widely available methods (immunohistochemistry and PCR), a test algorithm is proposed that allows quality assured, reliable, and cost-effective dMMR/MSI‑H testing. For CRC and EC, testing is therefore already possible at the primary diagnosis stage, in line with international recommendations (NICE, NCCN). The clinician is therefore enabled from the outset to consider not only the predictive but also the prognostic and predispositional implications of such a test when counseling patients and formulating treatment recommendations. As a basis for quality assurance, participation in interlaboratory comparisons and continuous documentation of results (e.g., QuIP Monitor) are strongly recommended.
CRIS-Team Scopus Importer:2021-06-11
Keywords: DNA mismatch repair; Endometrial carcinoma; Immune checkpoint inhibitors; Microsatellite instability; Prognosis

MSI testing What's new? What should be considered? - Rueschoff, Josef; Baretton, Gustavo; Blaeker, Hendrik; Dietmaier, Wolfgang; Dietel, Manfred; Hartmann, Arndt; Horn, Lars-Christian; Joehrens, Korinna; Kirchner, Thomas; Knuechel, Ruth; Mayr, Doris; Merkelbach-Bruse, Sabine; et al. (Pathologe, 2021)
Based on new trial data regarding immune checkpoint inhibitors (ICIs), the detection of high-grade microsatellite instability (MSI-H) or underlying deficient mismatch repair protein (dMMR) is now becoming increasingly important for predicting treatment response. For the first time, a PD-1 ICI (pembrolizumab) has been approved by the European Medicines Agency (EMA) for first-line treatment of advanced (stage IV) dMMR/MSI-H colorectal cancer (CRC). Further indications, such as dMMR/MSI-H endometrial carcinoma (EC), have already succeeded (Dostarlimab, 2nd line treatment) and others are expected to follow before the end of 2021. The question of optimal testing in routine diagnostics should therefore be re-evaluated. Based on a consideration of the strengths and weaknesses of the widely available methods (immunohistochemistry and PCR), a test algorithm is proposed that allows quality assured, reliable, and cost-effective dMMR/MSI-H testing. For CRC and EC, testing is therefore already possible at the primary diagnosis stage, in line with international recommendations (NICE, NCCN). The clinician is therefore enabled from the outset to consider not only the predictive but also the prognostic and predispositional implications of such a test when counseling patients and formulating treatment recommendations. As a basis for quality assurance, participation in interlaboratory comparisons and continuous documentation of results (e.g., QuIP Monitor) are strongly recommended.
CRIS-Team WoS Importer:2021-09-17

MUC4 as a potential marker for differentiating MASC and PLGA in minor salivary glands - Taverna, C.; Franchi, A.; Santucci, M.; Baneckova, M.; Skalova, A.; Agaimy, Abbas (VIRCHOWS ARCHIV, 2019)
CRIS-Team WoS Importer:2019-09-27

MUC4 is a valuable marker for distinguishing secretory carcinoma of the salivary glands from its mimics - Taverna, Cecilia; Baneckova, Martina; Lorenzon, Monica; Palomba, Annarita; Franchi, Alessandro; Skalova, Alena; Agaimy, Abbas (Histopathology, 2020)
Aims Secretory carcinoma (SC) (synonym: mammary analogue secretory carcinoma) is a low-grade salivary gland tumour that occurs in both major and minor salivary glands. SC is known for its wide morphological, architectural and immunohistochemical spectrum, which overlaps with those of several salivary gland neoplasms, including acinic cell carcinoma (AciCC) and intercalated duct-type intraductal carcinoma (IDC) in major salivary glands, and polymorphous adenocarcinoma (PAC) in minor salivary glands. These tumours share with SC some morphological features and SOX10 immunoreactivity; also, with the exception of AciCC, they all coexpress S100 and mammaglobin.
CRIS-Team WoS Importer:2020-11-27

Mucosal Mast Cell Distribution in the Gastrointestinal Tract of Children: A Preliminary Study for Establishing Reference Values - Ehrsam, Christoph; Rechenauer, Tobias; Allabauer, Ida; Siebenlist, Gregor; Kaspar, Sonja; Rieger, Daniel; Schmid, Margit; Ruckel, Aline; Wölfle, Joachim; Hartmann, Arndt; Rieker, Ralf; Raithel, Martin; et al. (Journal of Pediatric Gastroenterology and Nutrition, 2022)
Objectives: The physiological number and distribution of mast cells (MCs) in the pediatric gastrointestinal (GI) tract is not well defined and reference values of normality are missing. To define a physiological and disease defining cut-off, a systematic histological exploration of MC distribution from the esophagus to the rectum in healthy as well as in patients with gastrointestinal food allergies (GFA) was performed. Methods: Nine pediatric subjects that exhibited unremarkable histopathological evaluations or underwent endoscopy for surveillance reasons after a previous polypectomy of single colonic juvenile polyps served as reference cohort. In all of these subjects, a chronic inflammatory disease (eg, inflammatory bowel disease, celiac disease) or allergy was excluded. In addition, a group of 15 patients with gastrointestinal complaints suspected to be caused by a GFA were investigated. Immunohistochemistry was performed from all biopsies using CD117 (c-Kit) as a reliable marker to identify MCs in the lamina propria. Results: There were distinct differences of MC counts in all parts of the pediatric GI tract. The highest counts of MCs in both symptomatic patients and control cohort, were found in the duodenum, terminal ileum, cecum and ascending colon. The lowest counts were found in the esophagus. Significant disparities between GFA and healthy subjects were found in the gastric corpus (22.1 +/- 4.0/ high power field [HPF] vs 32.0 +/- 10.1/HPF; P = 0.034) and ascending colon (44.8 +/- 10.4/HPF vs 60.4 +/- 24.3/HPF; P = 0.047). Conclusions: Mucosal MC counts in the pediatric GI tract are higher than previously reported, with a considerable overlap between healthy and GFA patients. These results provide detailed information on distribution and numbers of MCs in pediatric allergic patients while allowing estimates of physiological values in childhood for the first time. With regard to diagnostic procedures in GFA further laboratory parameters have to be integrated.
CRIS-Team WoS Importer:2022-01-07

Mucosal tumor vaccination delivering endogenous tumor antigens protects against pulmonary breast cancer metastases - Oltmanns, Friederike; Vieira Antao, Ana Isabel; Irrgang, Pascal; Viherlehto, Vera; Jörg, Leticia; Schmidt, Anna; Wagner, Jannik; Rückert, Michael; Flohr, Ann-Sophie; Geppert, Carol-Immanuel; Frey, Benjamin; Bayer, Wibke; et al. (Journal for ImmunoTherapy of Cancer, 2024)
Background Generally, early-stage breast cancer has a good prognosis. However, if it spreads systemically, especially with pulmonary involvement, prospects worsen dramatically. Importantly, tumor-infiltrating T cells contribute to tumor control, particularly intratumoral T cells with a tissue-resident memory phenotype are associated with an improved clinical outcome. Methods Here, we use an adenoviral vector vaccine encoding endogenous tumor-associated antigens adjuvanted with interleukin-1β to induce tumor-specific tissue-resident memory T cells (TRM) in the lung for the prevention and treatment of pulmonary metastases in the murine 4T1 breast cancer model. Results The mucosal delivery of the vaccine was highly efficient in establishing tumor-specific TRM in the lung. Concomitantly, a single mucosal vaccination reduced the growth of pulmonary metastases and improved the survival in a prophylactic treatment. Vaccine-induced TRM contributed to these protective effects. In a therapeutic setting, the vaccination induced a pronounced T cell infiltration into metastases but resulted in only a minor restriction of the disease progression. However, in combination with stereotactic radiotherapy, the vaccine increased the survival time and rate of tumor-bearing mice. Conclusion In summary, our study demonstrates that mucosal vaccination is a promising strategy to harness the power of antitumor TRM and its potential combination with state-of-the-art treatments.
CRIS-Team Scopus Importer:2024-03-22

Multi-Center Assessment of Lymph-Node Density and Nodal-Stage to Predict Disease-Specific Survival in Patients with Bladder Cancer Treated by Radical Cystectomy. - van Gennep, Erik J.; Claps, Francesco; Bostrom, Peter J.; Shariat, Shahrokh F.; Neuzillet, Yann; Zlotta, Alexandre R.; Trombetta, Carlo; Eckstein, Markus; Mertens, Laura S.; Bussani, Rossana; Burger, Maximilian; Boormans, Joost L.; et al. (Bladder Cancer, 2024)
BACKGROUND: Prognostic tools in pathological-node (pN) patients after radical cystectomy (RC) are needed. OBJECTIVES: To evaluate the prognostic impact of lymph node (LN)-density on disease-specific survival (DSS) in patients with bladder cancer (BC) undergoing RC with pelvic lymph node dissection. METHODS: We analyzed a multi-institutional cohort of 1169 patients treated with upfront RC for cT1-4aN0M0 urothelial BCat nine centers. LN-densitywas calculated as the ratio of the number of positive LNs×100% to the number of LNs removed. The optimal LN-density cut-off value was defined by creating a time-dependent receiver operating characteristic (ROC) curve in pN patients. Univariable and multivariable Cox' regression analyses were used to assess the effect of conventional Tumor Nodes Metastasis (TNM) nodal staging system, LN-density and other LN-related variables on DSS in the pN-positive cohort. RESULTS: Of the 1169 patients, 463 (39.6%) patients had LN-involvement. The area under the ROC curve was 0.60 and the cut-off for LN-density was set at 20%, 223 of the pN-positive patients (48.2%) had a LN-density ≥ 20%. In multivariable models, the number of LN-metastases (HR 1.03, p = 0.005) and LN-density, either as continuous (HR 1.01, p = 0.013) or as categorical variable (HR 1.37, p = 0.014), were independently associated with worse DSS, whereas pN-stage was not. CONCLUSIONS: LN-density ≥ 20% was an independent predictor of worse DSS in BC patients with LN-involvement at RC. The integration of LN-density and other LN-parameters rather than only conventional pN-stage may contribute to a more refined risk-stratification in BC patients with nodal involvement.
EVALuna2:570127
Keywords: Bladder cancer; radical cystectomy; survival; lymph node density; urothelial neoplasm

Multicenter evaluation of an automated, multiplex, RNA-based molecular assay for detection of ALK, ROS1, RET fusions and MET exon 14 skipping in NSCLC - Melchior, Linea; Hirschmann, Astrid; Hofman, Paul; Bontoux, Christophe; Concha, Angel; Mrabet-Dahbi, Salima; Vannuffel, Pascal; Watkin, Emmanuel; Putzová, Martina; Scarpino, Stefania; Cayre, Anne; Martin, Paloma; et al. (Virchows Archiv, 2024)
The current study assessed the performance of the fully automated RT-PCR-based Idylla™ GeneFusion Assay, which simultaneously covers the advanced non-small cell lung carcinoma (aNSCLC) actionable ALK, ROS1, RET, and MET exon 14 rearrangements, in a routine clinical setting involving 12 European clinical centers. The Idylla™ GeneFusion Assay detects fusions using fusion-specific as well as expression imbalance detection, the latter enabling detection of uncommon fusions not covered by fusion-specific assays. In total, 326 archival aNSCLC formalin-fixed paraffin-embedded (FFPE) samples were included of which 44% were resected specimen, 46% tissue biopsies, and 9% cytological specimen. With a total of 179 biomarker-positive cases (i.e., 85 ALK, 33 ROS1, 20 RET fusions and 41 MET exon 14 skipping), this is one of the largest fusion-positive datasets ever tested. The results of the Idylla™ GeneFusion Assay were compared with earlier results of routine reference technologies including fluorescence in situ hybridization, immunohistochemistry, reverse-transcription polymerase chain reaction, and next-generation sequencing, establishing a high sensitivity/specificity of 96.1%/99.6% for ALK, 96.7%/99.0% for ROS1, 100%/99.3% for RET fusion, and 92.5%/99.6% for MET exon 14 skipping, and a low failure rate (0.9%). The Idylla™ GeneFusion Assay was found to be a reliable, sensitive, and specific tool for routine detection of ALK, ROS1, RET fusions and MET exon 14 skipping. Given its short turnaround time of about 3 h, it is a time-efficient upfront screening tool in FFPE samples, supporting rapid clinical decision making. Moreover, expression-imbalance-based detection of potentially novel fusions may be easily verified with other routine technologies without delaying treatment initiation.
CRIS-Team Scopus Importer:2024-05-10
Keywords: ALK fusion; Idylla; MET exon 14 skipping; NSCLC; RET fusion; ROS1 fusion

Multicenter International Society for Immunotherapy of Cancer Study of the Consensus Immunoscore for the Prediction of Survival and Response to Chemotherapy in Stage III Colon Cancer - Mlecnik, Bernhard; Bifulco, Carlo; Bindea, Gabriela; Marliot, Florence; Lugli, Alessandro; Lee, J. Jack; Zlobec, Inti; Rau, Tilman T.; Berger, Martin D.; Nagtegaal, Iris D.; Vink-Borger, Elisa; Hartmann, Arndt; et al. (Journal of Clinical Oncology, 2020)
PURPOSEThe purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR).METHODSAn international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy.RESULTSPatients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high v low], 0.48; 95% CI, 0.32 to 0.71; P = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all P < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high v low], 0.41; 95% CI, 0.25 to 0.67; P = .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high v low], 0.36; 95% CI, 0.21 to 0.62; P = .0003). Immunoscore had the strongest contribution 2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy v no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; P = .0011) and high-risk (HR [chemotherapy v no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; P = .0015) patients, in contrast to the low-Immunoscore group (P > .12).CONCLUSIONThis study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.
CRIS-Team WoS Importer:2020-11-27

Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer - Mlecnik, Bernhard; Lugli, Alessandro; Bindea, Gabriela; Marliot, Florence; Bifulco, Carlo; Lee, Jiun Kae Jack; Zlobec, Inti; Rau, Tilman T.; Berger, Martin D.; Nagtegaal, Iris D.; Vink-Börger, Elisa; Hartmann, Arndt; et al. (Cancers, 2023)
Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p < 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.
CRIS-Team Scopus Importer:2023-02-03
Keywords: colon cancer; early-stage; Immunoscore; predictive biomarkers; prognosis; tumor microenvironment

Multicentric Analytical and Inter-observer Comparability of Four Clinically Developed Programmed Death-ligand 1 Immunohistochemistry Assays in Advanced Clear-cell Renal Cell Carcinoma - Sommer, Ulrich; Eckstein, Markus; Ammann, Johannes; Braunschweig, Till; Macher-Göppinger, Stephan; Schwamborn, Kristina; Hieke-Schulz, Stefanie; Harlow, Greg; Flores, Mike; Wullich, Bernd; Wirth, Manfred; Roth, Wilfried; et al. (Clinical Genitourinary Cancer, 2020)
Background: Previous studies have suggested increased clinical benefit with inhibition of programmed death-ligand 1 (PD-L1)/programmed death-1 in patients with PD-L1–positive locally advanced/metastatic renal cell carcinoma (RCC). We examined the analytical and inter-observer comparability of PD-L1–positivity across 4 clinically developed immunohistochemistry assays in clear-cell RCC (CCRCC). Materials and Methods: Randomly selected archived, formalin-fixed, paraffin-embedded nephrectomy specimens from 201 patients with locally advanced CCRCC were screened using VENTANA SP142. From these, 30 cases were selected based on their tumor-infiltrating immune cell (IC) PD-L1 status (PD-L1-IC–positivity of < 1%, 1%-5%, or > 5%; 10 cases each). These cases were stained for PD-L1 using VENTANA SP142 and SP263, and DAKO 22C3 and 28-8, and scored for PD-L1 expression on IC and tumor cells (TC) by trained readers at 5 sites. Results: Adjusted mean percentages of PD-L1-IC–positivity and PD-L1-TC–positivity varied from 4.0% to 4.9% and from 1.3% to 10.7%, respectively, between assays. Inter-assay differences in PD-L1-IC–positivity were small and non-significant (P = .1938 to .9963); for PD-L1-TC–positivity, significant differences were observed between VENTANA SP142 and the other assays (P ≤ .0001) and between VENTANA SP263 and DAKO 28-8 (P = .0248). Intra-class correlation values showed moderate-to-high inter-reader agreement for each assay for PD-L1-IC–positivity and for 3 assays for PD-L1-TC–positivity. Conclusions: In this first multicenter analytical comparison study of PD-L1 assays in CCRCC, PD-L1–positivity could be assessed reproducibly using all 4 assays for IC and for 3 of the 4 assays for TC.
CRIS-Team Scopus Importer:2020-03-27
Keywords: CCRC; Inter-observer variability; PD-L1; PD-L1 assay; Technical comparability; Uropathology

Multicentric analytical comparability study of programmed death-ligand 1 expression on tumor-infiltrating immune cells and tumor cells in urothelial bladder cancer using four clinically developed immunohistochemistry assays - Schwamborn, Kristina; Ammann, Johannes U.; Knüchel, Ruth; Hartmann, Arndt; Baretton, Gustavo; Lasitschka, Felix; Schirmacher, Peter; Braunschweig, Till; Tauber, Robert; Erlmeier, Franziska; Hieke-Schulz, Stefanie; Weichert, Wilko (Virchows Archiv, 2019)
Programmed death-ligand 1 (PD-L1) expression on tumor cells (TC) or tumor-infiltrating immune cells (IC) correlated in several studies with PD-L1/programmed death-1 (PD-1) checkpoint inhibitor efficacy. Since June 2018, a positive PD-L1 status is required for atezolizumab or pembrolizumab treatment of patients with advanced or metastasized urothelial bladder cancer, who are ineligible for cisplatin-containing therapy. We examined technical comparability and inter-reader agreement of four clinically developed PD-L1 assays in locally advanced disease. Archived, formalin-fixed, paraffin-embedded sections from 30 patients (73.3% cystectomies, 26.7% transurethral resections) were stained by PD-L1 immunohistochemistry using VENTANA SP142, VENTANA SP263, DAKO 22C3, and DAKO 28-8 at two sites per manufacturers’ protocols and scored blinded at five sites for PD-L1 expression on IC (% per tumor area) and TC (%). Small, non-significant inter-assay differences were observed for IC. For TC, SP142 showed significantly lower staining percentages. Pairwise comparisons revealed − 0.3 to 1.6% differences in adjusted means between assays for IC, and for TC, − 10.5 to − 7.8% (SP142 versus others) and − 1.9 to 2.7% (other comparisons). Inter-reader and inter-assay agreement was moderate to high for both IC and TC. Allocation to binary cutoffs (1%, 5%, 10%) showed substantial to high Kappa agreement scores (0.440–0.923) for IC and TC between assays for each reader. This first multicenter study, with five independent readers blinded with respect to the assay used, suggests that all four currently clinically relevant assays are analytically similar for evaluation of PD-L1-stained IC and three (SP263, 22C3, and 28-8) for PD-L1-stained TC. Inter-observer agreement for trained readers in scoring of both IC and TC positivity was generally high.
CRIS-Team Scopus Importer:2019-07-19
Keywords: Immunohistochemistry; PD-L1; Programmed death-ligand 1; Tumor-infiltrating immune cells; Urothelial bladder cancer

Multi-colour FISH in oesophageal adenocarcinoma-predictors of prognosis independent of stage and grade - Geppert, Carol-Immanuel; Ruemmele, P.; Sarbia, M.; Langer, R.; Feith, M.; Morrison, L.; Pestova, E.; Schneider-Stock, Regine; Hartmann, Arndt; Rau, Tilman (British Journal of Cancer, 2014)
Oesophageal adenocarcinoma or Barrett's adenocarcinoma (EAC) is increasing in incidence and stratification of prognosis might improve disease management. Multi-colour fluorescence in situ hybridisation (FISH) investigating ERBB2, MYC, CDKN2A and ZNF217 has recently shown promising results for the diagnosis of dysplasia and cancer using cytological samples.To identify markers of prognosis we targeted four selected gene loci using multi-colour FISH applied to a tissue microarray containing 130 EAC samples. Prognostic predictors (P1, P2, P3) based on genomic copy numbers of the four loci were statistically assessed to stratify patients according to overall survival in combination with clinical data.The best stratification into favourable and unfavourable prognoses was shown by P1, percentage of cells with less than two ZNF217 signals; P2, percentage of cells with fewer ERBB2- than ZNF217 signals; and P3, overall ratio of ERBB2-/ZNF217 signals. Median survival times for P1 were 32 vs 73 months, 28 vs 73 months for P2; and 27 vs 65 months for P3. Regarding each tumour grade P2 subdivided patients into distinct prognostic groups independently within each grade, with different median survival times of at least 35 months.Cell signal number of the ERBB2 and ZNF217 loci showed independence from tumour stage and differentiation grade. The prognostic value of multi-colour FISH-assays is applicable to EAC and is superior to single markers.
EVALuna2:6597

Multi-institutional re-evaluation of prognostic factors in chromophobe renal cell carcinoma: proposal of a novel two-tiered grading scheme - Ohashi, Riuko; Martignoni, Guido; Hartmann, Arndt; Caliò, Anna; Segala, Diego; Stöhr, Christine; Wach, Sven; Erlmeier, Franziska; Weichert, Wilko; Autenrieth, Michael; Schraml, Peter; Rupp, Niels J.; et al. (Virchows Archiv, 2019)
A histological grading system of chromophobe renal cell carcinoma (chRCC) is highly desirable to identify approximately 5–10% of tumors at risk for progression. Validation studies failed to demonstrate a correlation between the four-tiered WHO/ISUP grade and outcome. Previous proposals with three-tiered chromophobe grading systems could not be validated. In this study, the presence of sarcomatoid differentiation, necrosis, and mitosis was analyzed in a Swiss cohort (n = 42), an Italian cohort (n = 103), a German cohort (n = 54), a Japanese cohort (n = 119), and The Cancer Genome Atlas cohort (n = 64). All 3 histological parameters were significantly associated with shorter time to tumor progression and overall survival in univariate analysis. Interobserver variability for identification of these parameters was measured by Krippendorff’s alpha coefficient and showed high concordance for the identification of sarcomatoid differentiation and tumor necrosis, but only low to medium concordance for the identification of mitosis. Therefore, we tested a two-tiered tumor grading system (low versus high grade) based only on the presence of sarcomatoid differentiation and/or necrosis finding in the combined cohorts (n = 382). pT stage, patient’s age (> 65 vs ≤ 65), lymph node and/or distant metastasis, and the two-tiered grading system (low versus high grade) were significantly associated with overall survival and were independent prognostic parameters in multivariate analysis (Cox proportional hazard). This multi-institutional evaluation of prognostic parameters suggests tumor necrosis and sarcomatoid differentiation as reproducible components of a two-tiered chromophobe tumor grading system.
CRIS-Team Scopus Importer:2019-12-03
Keywords: Chromophobe renal cell carcinoma; Kidney; Mitosis; Necrosis; Prognosis; Sarcomatoid differentiation; The Cancer Genome Atlas (TCGA); Tumor grade

Multilocular cystic leiomyoma of the anterolateral abdominal wall: A case report and literature review - Yorita, Kenji; Tanaka, Yu; Hirano, Koki; Kuwahara, Michio; Nakatani, Kimiko; Fukunaga, Masaharu; Agaimy, Abbas (Medicine, 2017)
RATIONALE: Leiomyomas arising from the anterolateral abdominal wall are uncommon, and their pathogenesis remains unknown. We present the 15th case of such a tumor, having this unique tumor morphology, followed by a detailed discussion on disease pathogenesis. PATIENT CONCERNS: A 48-year-old, asymptomatic perimenopausal, multiparous Japanese woman presented with a left-sided pelvic mass. She had no history of previous surgeries or uterine leiomyomas. Although a transabdominal ultrasonogram raised suspicions of an ovarian tumor, a transvaginal ultrasonogram confirmed normal ovaries. Radiological images showed a multilocular cystic mass with enhanced solid lesions connected to the uterus. Retrospective radiological evaluation showed that the mass was largely connected to the peritoneum of the anterolateral abdominal wall. INTERVENTIONS: Intraoperatively, the mass appeared as a dome-like protrusion from the left lower quadrant of the abdominal wall, without connection to the uterus, ovaries, or the left round ligament. No other peritoneal masses were seen. The mass was easily enucleated from the abdominal wall. Pathology confirmed that the mass was a leiomyoma with hydropic and myxoid degeneration. No striated muscle tissues were noted between the tumor and resection margin, but a thin smooth muscle layer, positive for hormone receptors, was present at the periphery, suggesting the origin of the tumor. LESSONS: Benign leiomyomas of the anterolateral abdominal wall likely originate from Müllerian-like smooth muscle remnants in this region. They should be considered in the differential diagnosis of solid and cystic masses and be distinguished from uterine and ovarian masses on imaging to avoid unnecessary organ resection.
EVALuna2:34889

Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden - Peneder, Peter; Stütz, Adrian M.; Surdez, Didier; Krumbholz, Manuela; Semper, Sabine; Chicard, Mathieu; Sheffield, Nathan C.; Pierron, Gaelle; Lapouble, Eve; Tötzl, Marcus; Ergüner, Bekir; Barreca, Daniele; et al. (Nature Communications, 2021)
Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.
CRIS-Team Scopus Importer:2021-06-11

Multimodal histopathologic models stratify hormone receptor-positive early breast cancer - Boehm, Kevin M.; El Nahhas, Omar S.M.; Marra, Antonio; Waters, Michele; Jee, Justin; Braunstein, Lior; Schultz, Nikolaus; Selenica, Pier; Wen, Hannah Y.; Weigelt, Britta; Paul, Evan D.; Cekan, Pavol; et al. (Nature Communications, 2025)
The Oncotype DX® Recurrence Score (RS) is an assay for hormone receptor-positive early breast cancer with extensively validated predictive and prognostic value. However, its cost and lag time have limited global adoption, and previous attempts to estimate it using clinicopathologic variables have had limited success. To address this, we assembled 6172 cases across three institutions and developed Orpheus, a multimodal deep learning tool to infer the RS from H&E whole-slide images. Our model identifies TAILORx high-risk cases (RS > 25) with an area under the curve (AUC) of 0.89, compared to a leading clinicopathologic nomogram with 0.73. Furthermore, in patients with RS ≤ 25, Orpheus ascertains risk of metastatic recurrence more accurately than the RS itself (0.75 vs 0.49 mean time-dependent AUC). These findings have the potential to guide adjuvant therapy for high-risk cases and tailor surveillance for patients at elevated metastatic recurrence risk.
CRIS-Team Scopus Importer:2025-03-14

Multinational proficiency tests for EGFR exon 20 insertions reveal that the assay design matters - Ihle, Michaela A.; Heydt, Carina; Schultheis, Anne Maria; Stöhr, Robert; Haller, Florian; Herold, Sylvia; Aust, Daniela; Dietmaier, Wolfgang; Evert, Matthias; Eszlinger, Markus; Haak, Anja; Laßmann, Silke; et al. (Scientific Reports, 2024)
Insertion mutations in exon 20 of the epidermal growth factor receptor gene (EGFR exon20ins) are rare, heterogeneous alterations observed in non-small cell lung cancer (NSCLC). With a few exceptions, they are associated with primary resistance to established EGFR tyrosine kinase inhibitors (TKIs). As patients carrying EGFR exon20ins may be eligible for treatment with novel therapeutics—the bispecific antibody amivantamab, the TKI mobocertinib, or potential future innovations—they need to be identified reliably in clinical practice for which quality-based routine genetic testing is crucial. Spearheaded by the German Quality Assurance Initiative Pathology two international proficiency tests were run, assessing the performance of 104 participating institutes detecting EGFR exon20ins in tissue and/or plasma samples. EGFR exon20ins were most reliably identified using next-generation sequencing (NGS). Interestingly, success rates of institutes using commercially available mutation-/allele-specific quantitative (q)PCR were below 30% for tissue samples and 0% for plasma samples. Most of these mutation-/allele-specific (q)PCR assays are not designed to detect the whole spectrum of EGFR exon20ins mutations leading to false negative results. These data suggest that NGS is a suitable method to detect EGFR exon20ins in various types of patient samples and is superior to the detection spectrum of commercially available assays.
CRIS-Team Scopus Importer:2024-06-14

Multiphoton Microscopy Reveals DAPK1‐Dependent Extracellular Matrix Remodeling in a Chorioallantoic Membrane (CAM) Model - Kunze, Philipp; Kreiß, Lucas; Novosadová, Vendula; Roehe, Adriana V.; Steinmann, Sara; Prochazka, Jan; Geppert, Carol-Immanuel; Hartmann, Arndt; Schürmann, Sebastian; Friedrich, Oliver; Schneider-Stock, Regine (Cancers, 2022)
Cancer cells facilitate tumor growth by creating favorable tumor micro‐environments (TME), altering homeostasis and immune response in the extracellular matrix (ECM) of surrounding tissue. A potential factor that contributes to TME generation and ECM remodeling is the cytoskeleton‐associated human death‐associated protein kinase 1 (DAPK1). Increased tumor cell motility and de‐adhesion (thus, promoting metastasis), as well as upregulated plasminogen-signaling, are shown when functionally analyzing the DAPK1 ko‐related proteome. However, the systematic investigation of how tumor cells actively modulate the ECM at the tissue level is experimentally challenging since animal models do not allow direct experimental access while artificial in vitro scaffolds cannot simulate the entire complexity of tissue systems. Here, we used the chorioallantoic membrane (CAM) assay as a natural, collagen‐rich tissue model in combination with all‐optical experimental access by multiphoton microscopy (MPM) to study the ECM remodeling potential of colorectal tumor cells with and without DAPK1 in situ and even in vivo. This approach demonstrates the suitability of the CAM assay in combination with multiphoton microscopy for studying collagen remodeling during tumor growth. Our results indicate the high ECM remodeling potential of DAPK1 ko tumor cells at the tissue level and support our findings from proteomics.
CRIS-Team Scopus Importer:2022-05-20
Keywords: collagen; colon cancer; ECM remodeling; MPM; uPAR

Multiplex gene analysis reveals T-cell and antibody-mediated rejection-specific upregulation of complement in renal transplants - Vonbrunn, Eva; Ries, Tajana; Söllner, Stefan; Müller-Deile, Janina; Büttner, Maike; Amann, Kerstin Ute; Daniel, Christoph (Scientific Reports, 2021)
In renal transplantation, complement is involved in ischemia reperfusion injury, graft rejection and dysfunction. However, it is still unclear how induction of complement and its activation are initiated. Using allograft biopsies of a well-characterized cohort of 28 renal transplant patients with no rejection (Ctrl), delayed graft function (DGF), acute T-cell-mediated (TCMR) or antibody-mediated rejection (ABMR) we analyzed differences in complement reaction. For that mRNA was isolated from FFPE sections, quantified with a multiplex gene expression panel and correlated with transplant conditions and follow-up of patients. Additionally, inflammatory cells were quantified by multiplex immunohistochemistry. In allograft biopsies with TCMR and ABMR gene expression of C1QB was 2-4 fold elevated compared to Ctrl. In TCMR biopsies, mRNA counts of several complement-related genes including C1S, C3, CFB and complement regulators CFH, CR1 and SERPING1 were significantly increased compared to Ctrl. Interestingly, expression levels of about 75% of the analyzed complement related genes correlated with cold ischemia time (CIT) and markers of inflammation. In conclusion, this study suggest an important role of complement in transplant pathology which seems to be at least in part triggered by CIT. Multiplex mRNA analysis might be a useful method to refine diagnosis and explore new pathways involved in rejection.
CRIS-Team Scopus Importer:2021-08-13

Multi-Prototype Few-shot Learning in Histopathology - Deuschel, Jessica; Firmbach, Daniel; Geppert, Carol-Immanuel; Eckstein, Markus; Hartmann, Arndt; Bruns, Volker; Kuritcyn, Petr; Dexl, Jakob; Hartmann, David; Perrin, Dominik; Wittenberg, Thomas; Benz, Michaela (2021 IEEE/CVF INTERNATIONAL CONFERENCE ON COMPUTER VISION WORKSHOPS (ICCVW 2021), 2021)
CRIS-Team WoS Importer:2022-02-25

Multiregion human bladder cancer sequencing reveals tumour evolution, bladder cancer phenotypes and implications for targeted therapy - Heide, Timon; Maurer, Angela; Eipel, Monika; Knoll, Katrin; Geelvink, Mirja; Veeck, Juergen; Knuechel, Ruth; van Essen, Julius; Stoehr, Robert; Hartmann, Arndt; Altmueller, Janine; Graham, Trevor A.; et al. (Journal of Pathology, 2019)
We present an evolutionary analysis of the relative time of genetic events underlying tumorigenesis in human bladder cancers from 10 whole cystectomy specimens using multiregional whole-exome sequencing. We timed bladder cancer drivers, mutational signatures, ploidy and copy number alterations, provided evidence for kataegis and correlated alterations with tumour areas and histological phenotypes. We found that: (1) heterogeneous tumour areas/phenotypes had distinct driver mutations, (2) papillary-invasive tumours divided early into two parallel evolving branches and (3) parallel evolution of subclonal driver mutations occurred. APOBEC mutational signatures were found to be very early events, active in carcinoma in situ, and often remained a dominant source of mutations throughout tumour evolution. Genetic progression from carcinoma in situ followed driver mutations in NA13/FAT1, ZBTB7B or EP300/USP28/KMT2D. Our results point towards a more diverse mutational trajectory of bladder tumorigenesis and underpin the importance of timing of mutational processes and clonal architecture in bladder cancer as important aspects for successful prognostication and therapy. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
CRIS-Team Scopus Importer:2019-05-28
Keywords: bladder cancer; kataegis; phylogenetic analysis; tumour evolution; tumour heterogeneity; tumour phenotype

Multispectral optoacoustic tomography enables assessment of disease activity in paediatric inflammatory bowel disease - Regensburger, Adrian; Eckstein, Markus; Wetzl, Matthias; Raming, Roman; Paulus, Lars-Philip; Bühler, Adrian; Nedoschill, Emmanuel; Danko, Vera; Jüngert, Jörg; Wagner, Alexandra; Schnell, Alexander; Rückel, Aline; et al. (Photoacoustics, 2024)
Multispectral optoacoustic tomography (MSOT) allows non-invasive molecular disease activity assessment in adults with inflammatory bowel disease (IBD). In this prospective pilot-study, we investigated, whether increased levels of MSOT haemoglobin parameters corresponded to inflammatory activity in paediatric IBD patients, too. 23 children with suspected IBD underwent MSOT of the terminal ileum and sigmoid colon with standard validation (e.g. endoscopy). In Crohn‘s disease (CD) and ulcerative colitis (UC) patients with endoscopically confirmed disease activity, MSOT total haemoglobin (HbT) signals were increased in the terminal ileum of CD (72.1 ± 13.0 a.u. vs. 32.9 ± 15.4 a.u., p = 0.0049) and in the sigmoid colon of UC patients (62.9 ± 13.8 a.u. vs. 35.1 ± 16.3 a.u., p = 0.0311) as compared to controls, respectively. Furthermore, MSOT haemoglobin parameters correlated well with standard disease activity assessment (e.g. SES-CD and MSOT HbT (rs =0.69, p = 0.0075). Summarizing, MSOT is a novel technology for non-invasive molecular disease activity assessment in paediatric patients with inflammatory bowel disease.
CRIS-Team Scopus Importer:2023-12-15
Keywords: Multispectral optoacoustic tomography; Optoacoustic imaging; Paediatric inflammatory bowel disease

Multispectral Optoacoustic Tomography for Assessment of Crohn's Disease Activity - Knieling, Ferdinand; Neufert, Clemens; Hartmann, Arndt; Claussen, Jing; Urich, Alexander; Egger, Cornelia; Vetter, Marcel; Fischer, Sarah; Pfeifer, Lukas; Hagel, Alexander; Kielisch, Christian; Görtz, Rüdiger; et al. (New England Journal of Medicine, 2017)
EVALuna2:33821

Multispectral Optoacoustic Tomography in Crohn's disease - A First-in-human Diagnostic Clinical Trial - Knieling, Ferdinand; Hartmann, Arndt; Uter, Wolfgang; Urich, Alexander; Claussen, Jing; Atreya, Raja; Rascher, Wolfgang; Waldner, Maximilian (2017)
EVALuna2:33902

Multispectral Optoacoustic Tomography in Ulcerative Colitis - A First-in-human Diagnostic Clinical Trial - Knieling, Ferdinand; Hartmann, Arndt; Claussen, Jing; Urich, Alexander; Atreya, Raja; Rascher, Wolfgang; Waldner, Maximilian (2017)
EVALuna2:33901

Multistain deep learning for prediction of prognosis and therapy response in colorectal cancer - Foersch, Sebastian; Glasner, Christina; Woerl, Ann-Christin; Eckstein, Markus; Wagner, Daniel-Christoph; Schulz, Stefan; Kellers, Franziska; Fernandez, Aurelie; Tserea, Konstantina; Kloth, Michael; Hartmann, Arndt; Heintz, Achim; et al. (Nature Medicine, 2023)
Although it has long been known that the immune cell composition has a strong prognostic and predictive value in colorectal cancer (CRC), scoring systems such as the immunoscore (IS) or quantification of intraepithelial lymphocytes are only slowly being adopted into clinical routine use and have their limitations. To address this we established and evaluated a multistain deep learning model (MSDLM) utilizing artificial intelligence (AI) to determine the AImmunoscore (AIS) in more than 1,000 patients with CRC. Our model had high prognostic capabilities and outperformed other clinical, molecular and immune cell-based parameters. It could also be used to predict the response to neoadjuvant therapy in patients with rectal cancer. Using an explainable AI approach, we confirmed that the MSDLM’s decisions were based on established cellular patterns of anti-tumor immunity. Hence, the AIS could provide clinicians with a valuable decision-making tool based on the tumor immune microenvironment.
CRIS-Team Scopus Importer:2023-03-03

"Multisystem Inflammatory Syndrome in Children"-Like Disease after COVID-19 Vaccination (MIS-V) with Potential Significance of Functional Active Autoantibodies Targeting G-Protein-Coupled Receptors (GPCR-fAAb) for Pathophysiology and Therapy. - Schmidt, Marius; Hébert, Steven; Wallukat, Gerd; Ponader, Rolf; Krickau, Tobias; Galiano, Matthias; Reutter, Heiko Martin; Wölfle, Joachim; Agaimy, Abbas; Mardin, Christian; Hörning, André; Hohberger, Bettina (Children, 2023)
BACKGROUND: An infection with SARS-CoV-2 can trigger a systemic disorder by pathological autoimmune processes. A certain type of this dysregulation is known as Multisystemic inflammatory syndrome in children (MIS-C). However, similar symptoms may occur and have been described as Multisystemic inflammatory syndrome after SARS-CoV-2 Vaccination (MIS-V) following vaccination against SARS-CoV-2. We report the case of a 12-year-old boy who was identified with MIS-C symptoms without previous SARS-CoV-2 infection after receiving two doses of the Pfizer-BioNTech COVID-19 vaccine approximately one month prior to the onset of symptoms. He showed polyserositis, severe gastrointestinal symptoms and, consequently, a manifestation of a multiorgan failure. IgG antibodies against spike proteins of SARS-CoV-2 were detected, indicating a successful vaccination, while SARS-CoV-2 Nucleocapsid protein antibodies and SARS-CoV-2 PCR were not detected. Several functional, active autoantibodies against G-protein-coupled receptors (GPCR-fAAb), previously associated with Long COVID disease, were detected in a cardiomyocyte bioassay. Immunosuppression with steroids was initiated. Due to side effects, treatment with steroids and later interleukin 1 receptor antagonists had to be terminated. Instead, immunoadsorption was performed and continued with tacrolimus and mycophenolic acid therapy, leading to improvement and discharge after 79 days. GPCR-fAAb decreased during therapy and remained negative after clinical curing and under continued immunosuppressive therapy with tacrolimus and mycophenolic acid. Follow-up of the patient showed him in good condition after one year. CONCLUSIONS: Infection with SARS-CoV-2 shows a broad and severe variety of symptoms, partly due to autoimmune dysregulation, which, in some instances, can lead to multiorgan failure. Despite its rarity, post-vaccine MIS-C-like disease may develop into a serious condition triggered by autoimmune dysregulation. The evidence of circulating GPCR-fAAb and their disappearance after therapy suggests a link of GPCR-fAAb to the clinical manifestations. Thus, we hypothesize a potential role of GPCR-fAAb in pathophysiology and their potential importance for the therapy of MIS-C or MIS-V. However, this observation needs further investigation to prove a causative correlation.
EVALuna2:547545

Murine cytomegalovirus reactivation concomitant with acute graft-versus-host disease is controlled by antibodies. - Seefried, Martina; Hundhausen, Nadine; Kroeger, Irena; Büttner-Herold, Maike; Hoffmann, Petra; Edinger, Matthias; Ullrich, Evelyn; Berberich-Siebelt, Friederike; Britt, William J.; Mach, Michael; Winkler, Thomas (JCI Insight, 2023)
Reactivation of human cytomegalovirus (HCMV) from latency is a frequent complication following hematopoietic stem cell transplantation (HSCT). The development of acute graft-versus-host disease (GVHD) is a significant risk factor for HCMV disease. Using a murine GVHD model in animals latently infected with murine CMV (MCMV), we studied preventive and therapeutic interventions in this high-risk scenario of HSCT. Mice latently infected with MCMV experienced reactivated MCMV and developed disseminated MCMV infection concomitant with the manifestations of GVHD. Dissemination was accompanied by accelerated mortality. We demonstrate that MCMV reactivation and dissemination was modulated by MCMV-specific antibodies, thus demonstrating in vivo protective activity of antiviral antibodies. However, the efficacy of serum therapy required repetitive doses of high-titer immune serum secondary to the shortened serum half-life of IgG in animals with GVHD. In a complementary approach, treatment of GVHD by adoptive transfer of donor-derived Tregs facilitated production of MCMV-specific antibodies from newly developing donor-derived B cells. Together, our findings strongly suggest that antibodies play a major role in controlling recurrent MCMV infection that follows GVHD, and they argue for reassessing the potential of antibody treatments as well as therapeutic strategies that enhance de novo antibody development against HCMV.
EVALuna2:527934

Mutational frequencies of CD79B and MYD88 vary greatly between primary testicular DLBCL and gastrointestinal DLBCL - Frick, Mareike; Bettstetter, Marcus; Bertz, Simone; Schwarz-Furlan, Stephan; Hartmann, Arndt; Richter, Thomas; Lenze, Dido; Hummel, Michael; Dreyling, Martin; Lenz, Georg; Gaumann, Andreas (Leukemia & Lymphoma, 2018)
EVALuna2:34062

Mutations in BRCA1/2 and Other Panel Genes in Patients With Metastatic Breast Cancer -Association With Patient and Disease Characteristics and Effect on Prognosis - Fasching, Peter; Yadav, Siddhartha; Hu, Chunling; Wunderle, Marius; Häberle, Lothar; Hart, Steven N.; Rübner, Matthias; Polley, Eric C.; Lee, Kun Y.; Gnanaolivu, Rohan D.; Hadji, Peyman; Hübner, Hanna; et al. (Journal of Clinical Oncology, 2021)
PURPOSE: Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome. PATIENTS AND METHODS: Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed. RESULTS: Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC. CONCLUSION: Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.
CRIS-Team Scopus Importer:2021-06-04

Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome - Vasileiou, Georgia; Vergarajauregui, Silvia; Endele, Sabine; Popp, Bernt; Büttner, Christian; Ekici, Arif Bülent; Gerard, Marion; Bramswig, Nuria C.; Albrecht, Beate; Clayton-Smith, Jill; Morton, Jenny; Tomkins, Susan; et al. (American Journal of Human Genetics, 2018)
Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.

Mutations in the BAF-complex subunit DPF2 are associated with Coffin-Siris syndrome - Vasileiou, G.; Vergarajauregui, S.; Endele, Sabine; Popp, Bernt; Büttner, Christian; Ekici, Arif Bülent; Gerard, M.; Bramswig, N. C.; Albrecht, B.; Clayton-Smith, J.; Morton, J.; Tomkins, S.; et al. (EUROPEAN JOURNAL OF HUMAN GENETICS, 2019)
CRIS-Team WoS Importer:2019-10-25

Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations - Kosfeld, Anne; Brand, Frank; Weiss, Anna-Carina; Kreuzer, Martin; Goerk, Michaela; Martens, Helge; Schubert, Stephanie; Schaefer, Anne-Kathrin; Riehmer, Vera; Hennies, Imke; Braesen, Jan Hinrich; Pape, Lars; et al. (Human Molecular Genetics, 2017)
Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. As CAKUT is a genetically heterogeneous disorder and most cases are genetically unexplained, we aimed to identify new CAKUT causing genes. Using whole-exome sequencing and trio-based de novo analysis, we identified a novel heterozygous de novo frameshift variant in the leukemia inhibitory factor receptor (LIFR) gene causing instability of the mRNA in a patient presenting with bilateral CAKUT and requiring kidney transplantation at one year of age. LIFR encodes a transmembrane receptor utilized by IL-6 family cytokines, mainly by the leukemia inhibitory factor (LIF). Mutational analysis of 121 further patients with severe CAKUT yielded two rare heterozygous LIFR missense variants predicted to be pathogenic in three unrelated patients. LIFR mutants showed decreased half-life and cell membrane localization resulting in reduced LIF-stimulated STAT3 phosphorylation. LIFR showed high expression in human fetal kidney and the human ureter, and was also expressed in the developing murine urogenital system. Lifr knockout mice displayed urinary tract malformations including hydronephrosis, hydroureter, ureter ectopia, and, consistently, reduced ureteral lumen and muscular hypertrophy, similar to the phenotypes observed in patients carrying LIFR variants. Additionally, a form of cryptorchidism was detected in all Lifr-/- mice and the patient carrying the LIFR frameshift mutation. Altogether, we demonstrate heterozygous novel or rare LIFR mutations in 3.3% of CAKUT patients, and provide evidence that Lifr deficiency and deactivating LIFR mutations cause highly similar anomalies of the urogenital tract in mice and humans.
EVALuna2:25536

Mutations in WDR19 encoding the intraflagellar transport component IFT144 cause a broad spectrum of ciliopathies - Fehrenbach, Henry; Decker, Christian; Eisenberger, Tobias; Frank, Valeska; Hampel, Tobias; Walden, Ulrike; Amann, Kerstin Ute; Krueger-Stollfuss, Ingrid; Bolz, Hanno J.; Haeffner, Karsten; Pohl, Martin; Bergmann, Carsten (Pediatric Nephrology, 2014)
An emerging number of clinically and genetically heterogeneous diseases now collectively termed ciliopathies have been connected to the dysfunction of primary cilia. We describe an 8-year-old girl with a complex phenotype that did not clearly match any familiar syndrome.Hypotonia, facial dysmorphism and retardation were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Renal biopsy revealed tubular atrophy, interstitial fibrosis and segmental glomerulosclerosis. After exclusion of a chromosomal abnormality by array-comparative genomic hybridization (CGH), we performed next-generation sequencing (NGS) using a customized panel that targeted 131 genes known or hypothesized to cause ciliopathies. We identified the novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) that affects an evolutionarily highly conserved residue in the intraflagellar transport protein IFT144, is absent from databases and is predicted to be pathogenic by all bioinformatic sources used.Mutations in WDR19 encoding the intraflagellar transport component IFT144 have recently been described in single families with the clinically overlapping skeletal ciliopathies Jeune and Sensenbrenner syndromes, combined or isolated nephronophthisis (NPHP) and retinitis pigmentosa (RP) (Senior-Loken syndrome). Our patient emphasizes the usefulness and efficiency of a comprehensive NGS panel approach in patients with unclassified ciliopathies. It further suggests that WDR19 mutations can cause a broad spectrum of ciliopathies that extends to Jeune and Sensenbrenner syndromes, RP and renal NPHP-like phenotypes.
EVALuna2:25461

Mutation status of the mediator complex subunit 12 (MED12) in uterine leiomyomas and concurrent/metachronous multifocal peritoneal smooth muscle nodules (leiomyomatosis peritonealis disseminata) - Rieker, Ralf; Agaimy, Abbas; Moskalev, Evgeny; Hebele, Simone; Hein, Alexander; Mehlhorn, Grit; Beckmann, Matthias; Hartmann, Arndt; Haller, Florian (Pathology, 2013)
Aims: The pathogenesis and classification of multicentric smooth muscle tumours with benign appearance and concurrent/metachronous uterine and peritoneal involvement is controversial and may on occasion be diagnostically challenging. Leiomyomatosis peritonealis disseminata (LPD) is a rare condition affecting women of reproductive age, characterised by the occurrence of multiple small peritoneal smooth muscle nodules with bland histology. Methods: We investigated a total of 12 uterine and seven concurrent/metachronous peritoneal smooth muscle nodules with benign appearance from two females for mutations in the mediator complex subunit 12 (MED12), which has recently been identified as the most frequent genetic aberration in uterine leiomyomas. Results: The first case harboured different MED12 mutations in the peritoneal nodules. Mutational status of peritoneal nodules was discordant with that of the uterine leiomyomas. The second case displayed the same MED12 mutation in all five peritoneal nodules, but this mutation was not detected in her current uterine leiomyomas. Conclusions: Our results suggest that smooth muscle neoplasms with benign appearance of the primary and secondary mü llerian system share a similar genetic background of MED12 mutation in combination with oestrogen dependency. Analysis of MED12 mutation status might be a valuable adjunct tool for the future classification of these sometimes diagnostically challenging multicentric tumours. © 2013 Royal College of Pathologists of Australasia.
CRIS-Team Scopus Importer:2021-07-19
Keywords: Leiomyomatosis peritonealis disseminata; MED12; Uterine leiomyoma

MyD88 Is Required for Efficient Control of Coxiella burnetii Infection and Dissemination - Kohl, Lisa; Hayek, Inaya; Daniel, Christoph; Schulze-Luehrmann, Jan; Bodendorfer, Barbara; Lührmann, Anja; Lang, Roland (Frontiers in Immunology, 2019)
The intracellular pathogen Coxiella (C.) burnetii causes Q fever, a usually self-limiting respiratory infection that becomes chronic and severe in some patients. Innate immune recognition of C. burnetii and its role in the decision between resolution and chronicity is not understood well. However, TLR2 is important for the response to C. burnetii in mice, and genetic polymorphisms in Myd88 have been associated with chronic Q fever in humans. Here, we have employed MyD88-deficient mice in infection models with the attenuated C. burnetii Nine Mile phase II strain (NMII). Myd88(-/-) macrophages failed to restrict the growth of NMII in vitro, and to upregulate production of the cytokines TNF, IL-6, and IL-10. Following intraperitoneal infection, NMII bacterial burden was significantly higher on day 5 and 20 in organs of Myd88(-/-) mice. After infection via the natural route by intratracheal injection, a higher bacterial load in the lung and increased dissemination of NMII to other organs was observed in MyD88-deficient mice. While wild-type mice essentially cleared NMII on day 27 after intratracheal infection, it was still readily detectable on day 42 in multiple organs in the absence of MyD88. Despite the elevated bacterial load, Myd88(-/-) mice had less granulomatous inflammation and expressed significantly lower levels of chemoattractants, inflammatory cytokines, and of several IFN gamma-induced genes relevant for control of intracellular pathogens. Together, our results show that MyD88-dependent signaling is essential for early control of C. burnetii replication and to prevent systemic spreading. The continued presence of NMII in the organs of Myd88(-/-) mice constitutes a new mouse model to study determinants of chronicity and resolution in Q fever.
CRIS-Team WoS Importer:2019-02-21

Myeloid sarcoma with RBM15::MRTFA (MKL1) mimicking vascular neoplasm - Gündoğdu, Fatma; Agaimy, Abbas; Aytaç, Selin; Hazar, Volkan; Üner, Ayşegül; Kösemehmetoğlu, Kemal (Virchows Archiv, 2024)
Extramedullary involvement of acute myeloid leukemia (AML), aka myeloid sarcoma, is a rare phenomenon in acute megakaryoblastic leukemia with RBM15:: MRTFA(MKL1) fusion, which might mimic non-hematologic malignancies. A 7-month-old infant presented with leukocytosis, hepatosplenomegaly, multiple lymphadenopathies, and a solid mass in the right thigh. Initially, the patient was diagnosed with a malignant vascular tumor regarding the expression of vascular markers from the biopsy of the right thigh lesion that was performed after the inconclusive bone marrow biopsy. The second bone marrow biopsy, which was performed due to the partial response to sarcoma treatment, showed hypercellular bone marrow with CD34 and CD61-positive spindle cell infiltration and > 20% basophilic blasts with cytoplasmic blebs. RNA sequencing of soft tissue biopsy revealed the presence of RBM15::MRTFA(MKL1) fusion. Based on these findings, myeloid sarcoma/AML with RBM15::MRTFA(MKL1) fusion diagnosis was made. AML with RBM15::MRTFA(MKL1) fusion can initially present as extramedullary lesions and might cause misdiagnosis of non-hematologic malignancies.
CRIS-Team Scopus Importer:2024-05-17
Keywords: Acute megakaryoblastic leukemia; Children; Malignant mesenchymal tumor; Myeloid sarcoma; RBM15::MRTFA(MKL1) fusion; Vascular neoplasm

Myocardial infarction with a preserved ejection fraction—the impaired function of the cardio-renal baroreflex - Pickny, Lisa; Hindermann, Martin; Ditting, Tilmann; Hilgers, Karl Friedrich; Linz, Peter; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Rodionova, Kristina (Frontiers in Physiology, 2023)
Introduction: In experimental myocardial infarction with reduced ejection fraction causing overt congestive heart failure, the control of renal sympathetic nerve activity (RSNA) by the cardio-renal baroreflex was impaired. The afferent vagal nerve activity under these experimental conditions had a lower frequency at saturation than that in controls. Hence, by investigating respective first neurons in the nodose ganglion (NG), we wanted to test the hypothesis that after myocardial infarction with still-preserved ejection fraction, the cardiac afferent nerve pathway is also already impaired. Material and methods: A myocardial infarction was induced by coronary artery ligature. After 21 days, nodose ganglion neurons with cardiac afferents from rats with myocardial infarction were cultured. A current clamp was used to characterize neurons as “tonic,” i.e., sustained action potential (AP) firing, or “phasic,” i.e., <5 APs upon current injection. Cardiac ejection fraction was measured using echocardiography; RSNA was recorded to evaluate the sensitivity of the cardiopulmonary baroreflex. Renal and cardiac histology was studied for inflammation and fibrosis markers. Results: A total of 192 neurons were investigated. In rats, after myocardial infarction, the number of neurons with a tonic response pattern increased compared to that in the controls (infarction vs. control: 78.6% vs. 48.5%; z-test, *p < 0.05), with augmented production of APs (23.7 ± 2.86 vs. 15.5 ± 1.86 APs/600 ms; mean ± SEM, t-test, *p < 0.05). The baseline activity of RSNA was subtly increased, and its control by the cardiopulmonary baroreflex was impaired following myocardial infarction: the fibrosis marker collagen I augmented in the renal interstitium. Discussion: After myocardial infarction with still-preserved ejection fraction, a complex impairment of the afferent limb of the cardio-renal baroreflex caused dysregulation of renal sympathetic nerve activity with signs of renal fibrosis.
CRIS-Team Scopus Importer:2023-05-05
Keywords: cardiac afferent neurons after myocardial infarction cardiac afferent innervation; congestive heart failure; myocardial infarction; neuronal cell culture; preserved ejection fraction; renal innervation

Myogenin controls via AKAP6 non-centrosomal microtubule-organizing center formation at the nuclear envelope - Becker, Robert; Vergarajauregui, Silvia; Billing, Florian; Sharkova, Maria; Lippolis, Eleonora; Mamchaoui, Kamel; Ferrazzi, Fulvia; Engel, Felix (eLife, 2021)
Non-centrosomal microtubule-organizing centers (MTOCs) are pivotal for the function of multiple cell types, but the processes initiating their formation are unknown. Here, we find that the transcription factor myogenin is required in murine myoblasts for the localization of MTOC proteins to the nuclear envelope. Moreover, myogenin is sufficient in fibroblasts for nuclear envelope MTOC (NE-MTOC) formation and centrosome attenuation. Bioinformatics combined with loss- and gain-of-function experiments identified induction of AKAP6 expression as one central mechanism for myogenin-mediated NE-MTOC formation. Promoter studies indicate that myogenin preferentially induces the transcription of muscle- and NE-MTOC-specific isoforms of Akap6 and Syne1, which encodes nesprin-1 alpha, the NE-MTOC anchor protein in muscle cells. Overexpression of AKAP6 beta and nesprin-1 alpha was sufficient to recruit endogenous MTOC proteins to the nuclear envelope of myoblasts in the absence of myogenin. Taken together, our results illuminate how mammals transcriptionally control the switch from a centrosomal MTOC to an NE-MTOC and identify AKAP6 as a novel NE-MTOC component in muscle cells.
CRIS-Team WoS Importer:2021-11-05

Myositis ossificans mimicking metaplastic breast cancer on core needle biopsy - Schmitz, Klaus Jürgen; Losch, Matthias; Agaimy, Abbas (Human Pathology, 2019)
Myositis ossificans (MO) is an uncommon myofibroblastic proliferation that may closely mimic sarcoma. A 33-year old woman presented with a 2-cm breast mass. A core needle biopsy showed highly cellular spindle cell proliferations with atypia and high proliferation activity. Focal areas of immature osteoid-like matrix were seen. After immunohistochemical analysis, a diagnosis of metaplastic breast cancer was made. Because of the proximity of the tumor to the rib, resection of the tumor including partial resection of the rib was carried out. Complete examination of the excised lesion allowed the correct diagnosis of MO. Only the resection specimens contained a predominance of mature organoid bone tissue admixed with variably cellular myofibroblastic proliferations with the typical zonal pattern, characteristic of MO. The diagnosis of MO was not possible on the initially performed core needle biopsy because biopsy material reflected only the central proliferative portion of the lesion showing increased pleomorphism and early osteoid formation. This case highlights the pitfall related to this unusual presentation of a benign lesion and points to the necessity to include MO in the differential diagnosis of triple-negative metaplastic breast cancer.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Breast tumor; Myositis ossificans; Osteosarcoma; Pitfalls; Pseudosarcoma; USP6

Myxoide Weichgewebstumoren: Ein Algorithmus zur Differenzialdiagnose - Agaimy, Abbas (Pathologe, 2019)
Soft tissue neoplasms with myxoid features are collectively not uncommon. Their often complex differential diagnosis makes them significantly over-represented among consultation cases. This applies not only to sarcomas but in particular to benign lesions as well. Generally, myxoid soft tissue lesions are divided into two major groups: (1) myxoid lesions by definition (which can however rarely be non-myxoid) and (2) rare myxoid variants of otherwise non-myxoid entities. Four major diagnostic challenges are responsible for the complexity of myxoid soft tissue neoplasms: (1) Diagnosis of malignancy in many cases is not based on conventional malignancy criteria but is defined by the entity itself, making under-diagnosis of malignancy likely in entities such as low-grade fibromyxoid sarcoma. (2) On the other hand, harmless myxoid lesions with features of high proliferation, e.g. nodular and proliferative fasciitis, tend to be over-diagnosed as malignant by the unworried. (3) The necessity to assess not only cellular morphology/differentiation, but also the stromal, vascular and architectural characteristics adds to the complexity of the differential diagnostic algorithm. (4) Last but not least, recognition of unexpected myxoid variants of non-myxoid entities is basically impossible if focal conventional areas are absent, underlining the need for high suspicion index and sufficient sampling. This review illuminates the various aspects related to the differential diagnostic workup of these challenging entities.
CRIS-Team Scopus Importer:2019-06-21
Keywords: Differential diagnosis; Fibrosarcoma; Myxoma; Myxosarcoma; Soft tissue neoplasms

Myxoid Inflammatory Myofibroblastic Sarcoma: Clinicopathologic Analysis of 25 Cases of a Distinctive Sarcoma With Deceptively Bland Morphology and Aggressive Clinical Behavior - Papke, David J.; Odintsov, Igor; Dickson, Brendan C.; Nucci, Marisa R.; Agaimy, Abbas; Fletcher, Christopher D.M. (American Journal of Surgical Pathology, 2024)
The number of recognized sarcoma types harboring targetable molecular alterations continues to increase. Here we present 25 examples of a distinctive myofibroblastic tumor, provisionally termed "myxoid inflammatory myofibroblastic sarcoma,"which might be related to inflammatory myofibroblastic tumor, and which occurred in 13 males (52%) and 12 females at a median age of 37 years (range: 7 to 79 years). Primary tumor sites were peritoneum (18 patients; 72%), paratesticular (2; 8%), chest wall (1), upper extremity (1), esophagus (1), retroperitoneum (1), and uterus (1). Nine peritoneal tumors (50%) were multifocal at presentation; all other tumors were unifocal. Tumors showed bland-to-mildly-atypical neoplastic myofibroblasts in a myxoid stroma, with prominent inflammatory infiltrates in 22 cases (88%). Most tumors showed delicate branching stromal vessels like those of myxoid liposarcoma, and most showed infiltrative growth through non-neoplastic tissue. Immunohistochemistry demonstrated expression of SMA (19/25 tumors; 76%), desmin (13/22; 59%), and CD30 (5/11; 45%), while ALK was expressed in 1 tumor (of 25; 4%) that was negative for ALK rearrangement. Sequencing of 11 tumors showed seven to harbor tyrosine kinase fusions (4 PDGFRB, 2 PML::JAK1, 1 SEC31A::PDGFRA). Two instead harbored hot spot KRAS mutations (G12V and Q61H), and 2 were negative for known driving alterations. Clinical follow-up was available for 18 patients (72%; median: 2.7 years; range: 4 mo-12.3 years). Nine patients (50%) were alive with no evidence of disease, 5 (28%) died of disease, and 4 (22%) were alive with disease. Seven patients (39%) experienced peritoneal relapse or distant metastasis. Two patients showed disease progression on conventional, nontargeted chemotherapy. The patient whose tumor harbored SEC31A::PDGFRA was treated after multiple relapses with imatinib and sunitinib therapy, with progression-free periods of 5 and 2 years, respectively. Despite its bland appearance, myxoid inflammatory myofibroblastic sarcoma harbors a significant risk for disseminated disease, particularly when it occurs in the peritoneum. Targeted therapy could be considered for patients with disseminated disease.
CRIS-Team Scopus Importer:2024-07-26
Keywords: JAK1; KRAS; myxoid inflammatory myofibroblastic sarcoma; PDGFRA; PDGFRB; PML

NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors - Eschbacher, Kathryn L.; Tran, Quynh T.; Moskalev, Evgeny; Jenkins, Sarah; Fritchie, Karen; Stöhr, Robert; Caron, Alissa; Link, Michael J.; Brown, Paul D.; Guajardo, Andrew; Brat, Daniel J.; Wu, Ashley; et al. (Brain Pathology, 2024)
Meningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow-up (median 9.9 years; range 15 days–43 years), we performed extensive molecular characterization including genome-wide DNA methylation profiling (n = 80) and targeted TERT promoter mutation testing (n = 98). Associations were examined with NAB2::STAT6 fusion status (n = 101 cases; 51 = ex5-7::ex16-17, 26 = ex4::ex2-3; 12 = ex2-3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. NAB2::STAT6 fusion breakpoints (fusion type) were significantly associated with metastasis-free survival (MFS) (p = 0.03) and, on multivariate analysis, disease-specific survival (DSS) when adjusting for CNS WHO grade (p = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (n = 38), Cluster 2 (n = 22), and Cluster 3 (n = 20). Methylation clusters were significantly associated with fusion type (p < 0.001), with Cluster 2 harboring ex4::ex2-3 fusion in 16 (of 20; 80.0%), nearly all TERT promoter mutations (7 of 8; 87.5%), and predominantly an “SFT” histologic phenotype (15 of 22; 68.2%). Clusters 1 and 3 were less distinct, both dominated by tumors having ex5-7::ex16-17 fusion (respectively, 25 of 33; 75.8%, and 12 of 18; 66.7%) and with variable histological phenotypes. Methylation clusters were significantly associated with MFS (p = 0.027), but not overall survival (OS). In summary, NAB2::STAT6 fusion type was significantly associated with MFS and DSS, suggesting that tumors with an ex5::ex16-17 fusion may have inferior patient outcomes. Methylation clusters were significantly associated with fusion type, TERT promoter mutation status, histologic phenotype, and MFS.
CRIS-Team Scopus Importer:2024-04-12
Keywords: CNS WHO grade; meningeal solitary fibrous tumor; NAB2::STAT6; solitary fibrous tumor; TERT

NAB2-STAT6 Gene Fusion in Meningeal Hemangiopericytoma and Solitary Fibrous Tumor - Fritchie, Karen J.; Jin, Long; Rubin, Brian P.; Burger, Peter C.; Jenkins, Sarah M.; Barthelmeß, Sarah; Moskalev, Evgeny; Haller, Florian; Oliveira, Andre M.; Giannini, Caterina (Journal of Neuropathology and Experimental Neurology, 2016)
Meningeal solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) are considered to be distinct entities in the WHO Classification of CNS Tumours (2007). They harbor NAB2-STAT6 fusions similar to their soft tissue counterparts, supporting the view that they are part of a tumor continuum. We examined 30 meningeal-based tumors originally diagnosed as either SFT or HPC. These showed a spectrum of morphologic features and were diagnosed as SFTs, malignant SFTs, HPCs, or tumors with "intermediate" features. All of the tumors showed nuclear expression of STAT6. SFTs consistently expressed diffuse CD34, while HPCs and intermediate tumors had heterogeneous staining. NAB2-STAT6 fusions were identified in 20 cases, including 7 with exon 4-exon 3, 9 with exon 6-exon 17, and 4 with exon 6-exon 18 fusions. NAB2 exon 4-STAT6 exon 3 fusion correlated with classic SFT morphology and older age and showed a trend toward less mitotic activity; there was also a trend toward more aggressive behavior in tumors lacking NAB2 exon 4-STAT6 exon 3. Thus, despite their clinical and morphologic differences, meningeal-based SFTs, HPCs, and tumors with intermediate features, similar to their soft tissue counterparts, form a histopathologic spectrum unified by STAT6 immunoexpression and NAB2-STAT6 fusion.
EVALuna2:6771

Nanofibrous Composite with Tailorable Electrical and Mechanical Properties for Cardiac Tissue Engineering - Roshanbinfar, Kaveh; Vogt, Lena; Ruther, Florian; Roether, Judith; Boccaccini, Aldo R.; Engel, Felix (Advanced Functional Materials, 2019)
Cardiac tissue engineering is a promising strategy to prevent functional deterioration or even to enhance cardiac function upon myocardial infarction. Here, electrospun fiber mats containing different combinations of electrically conductive polyaniline, collagen, and/or hyaluronic acid are assessed regarding material properties and compatibility with cardiomyocyte attachment and function. Microstructure analysis reveals that collagen fiber mats contain a wide range of fiber diameters after crosslinking (from ≈300 nm to ≈5 µm); all other fiber mats contain fibers in the range of ≈120 to ≈300 nm. Fiber mats exhibit comparable electrical conductivity to and greater mechanical properties than the native human myocardium, which is considered beneficial. Cell–matrix interaction analysis utilizing postnatal rat cardiomyocytes reveals that the fiber mats are non-cytotoxic and permit cell attachment and contraction. Fiber mats containing collagen (9.89%), hyaluronic acid (1.1%), and polyaniline (PANi, 1.34%) exhibit the most favorable properties with longer contraction time, higher contractile amplitude, and lower beating rates. Improved contraction is accompanied by increased connexin 43 expression. Importantly, this fiber mat is a suitable material for human-induced pluripotent stem cell–derived cardiomyocytes regarding cytotoxicity, cell attachment, and function. Collectively, these data demonstrate that fiber mats made of collagen, hyaluronic acid, and polyaniline are promising materials for cardiac tissue engineering.
CRIS-Team Scopus Importer:2019-12-31
Keywords: collagen; electroconductive; electrospinning; heart; hyaluronic acid; polyaniline; tissue engineering

NAR score as surrogate for disease-free survival in the CAO/ARO/AIO-04 phase 3 rectal cancer trial - Fokas, E.; Fietkau, Rainer; Hartmann, Arndt; Hohenberger, Werner; Grützmann, Robert; Ghadimi, M.; Liersch, T.; Stroebel, P.; Grabenbauer, G.; Wittekind, C.; Sauer, Rolf; Kaufmann, M.; et al. (2018)
EVALuna2:36513

Nasal and sinonasal tumors formed by atypical adenomatous lesions arising in respiratory epithelial adenomatoid hamartoma/seromucinous hamartoma - Michal, Michal; Skálová, Alena; Hyrcza, Martin; Laco, Jan; Vaněček, Tomáš; Rupp, Niels J.; Michal, Michael; Michalová, Květoslava; Agaimy, Abbas; Bradová, Martina (Virchows Archiv, 2023)
Two benign adenomatous lesions are commonly recognized within the sinonasal tract, namely respiratory epithelial adenomatoid hamartoma (REAH) and seromucinous hamartoma (SH). We present 10 hitherto unrecognized benign polypoid nasal and sinonasal tumoriform lesions having in average 3.6 cm in largest dimension, which are histogenetically related to SH and REAH. In addition to typical structures of REAH and SH, these lesions contained an additional characteristic and slightly atypical adenomatous component, which we termed atypical sinonasal glands arising in SH (ASGSH). ASGSH often produced deep red colored secretion with peripheral clearing similar to that seen in thyroid follicles. In contrast to SH, ASGSH was endowed by both secretory and myoepithelial layers and had mostly angulated shapes with snout-like protrusions into the lumens. Both layers were formed by an irregular, disorganized, and often incomplete cell lining, which had slightly atypical cytological features without mitoses. In 3 cases, ASGSHs revealed sebaceous differentiation, and in 3 cases the stroma produced a well-differentiated cartilage. Neoplastic nature of ASGSH was supported by finding of various mutations as revealed by next generation sequencing in five cases. In two cases each, we found identical mutations in BRAF gene (Val600Glu), and RET gene (Arg912Trp), respectively and in one case FAT1 gene alteration (Pro1665Leu).
CRIS-Team Scopus Importer:2023-12-22
Keywords: Atypical adenomatous lesions arising in REAH/seromucinous hamartoma; REAH; Respiratory adenomatoid hamartoma; Sebaceous differentiation; Seromucinous hamartoma

Navigating Through Whole Slide Images With Hierarchy, Multi-Object, and Multi-Scale Data - Tran, Manuel; Wagner, Sophia; Weichert, Wilko; Matek, Christian; Boxberg, Melanie; Peng, Tingying (IEEE Transactions on Medical Imaging, 2025)
Building deep learning models that can rapidly segment whole slide images (WSIs) using only a handful of training samples remains an open challenge in computational pathology. The difficulty lies in the histological images themselves: many morphological structures within a slide are closely related and very similar in appearance, making it difficult to distinguish between them. However, a skilled pathologist can quickly identify the relevant phenotypes. Through years of training, they have learned to organize visual features into a hierarchical taxonomy (e.g., identifying carcinoma versus healthy tissue, or distinguishing regions within a tumor as cancer cells, the microenvironment,...). Thus, each region is associated with multiple labels representing different tissue types. Pathologists typically deal with this by analyzing the specimen at multiple scales and comparing visual features between different magnifications. Inspired by this multi-scale diagnostic workflow, we introduce the Navigator, a vision model that navigates through WSIs like a domain expert: it searches for the region of interest at a low scale, zooms in gradually, and localizes ever finer microanatomical classes. As a result, the Navigator can detect coarse-grained patterns at lower resolution and fine-grained features at higher resolution. In addition, to deal with sparsely annotated samples, we train the Navigator with a novel semi-supervised framework called S5CL v2. The proposed model improves the F1 score by up to 8% on various datasets including our challenging new TCGA-COAD-30CLS and Erlangen cohorts.
CRIS-Team Scopus Importer:2025-02-07
Keywords: Contrastive learning; hierarchical labels; multi-class; multi-object; multi-scale; semi-supervision

NCOA4-RET and TRIM27-RET are Characteristic Gene Fusions in Salivary Intraductal Carcinoma, Including Invasive and Metastatic Tumors: Is "intraductal" Correct? - Skálová, Alena; Ptáková, Nikola; Santana, Thalita; Agaimy, Abbas; Ihrler, Stephan; Uro-Coste, Emmanuelle; Thompson, Lester D.R.; Bishop, Justin A.; Baněčkova, Martina; Rupp, Niels J.; Morbini, Patrizia; De Sanctis, Stefano; et al. (American Journal of Surgical Pathology, 2019)
Intraductal carcinoma (IC) is the new WHO designation for tumors previously encompassed by "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma (SDC) is controversial, even though they are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with histopathological features reminiscent of atypical ductal hyperplasia or ductal carcinoma in situ of the breast, showing diffuse S100 protein and mammaglobin positivity, while it is partially defined genetically. Recently, RET rearrangements including NCOA4-RET and TRIM27-RET have been described in IC. Here, we genetically characterize the largest cohort of IC to date (33 cases) including 8 cases with focal or widespread invasive growth and 1 case with lymph node metastasis. Thirty-three cases of IC were analyzed by next-generation sequencing (NGS) using the FusionPlex Solid Tumor kit (ArcherDX). Identified gene fusions were confirmed using fluorescence in situ hybridization break-apart and fusion probes and an reverse transcription polymerase chain reaction designed specifically for the detected breakpoints. Ten cases of SDC were analyzed for comparison using NGS panels that detect mutations and fusion transcripts. NGS analysis detected an NCOA4-RET fusion transcript in 11 cases of intercalated duct-type IC joining exon 7 or 8 of NCOA4 gene and exon 12 of the RET gene. Eight cases of IC had an invasive growth pattern, including one with widespread invasion and lymph node metastasis. Three invasive ICs harbored an NCOA4-RET fusion transcript, while 1 case was negative, and 2 cases were not analyzable. In addition, a novel TRIM27-RET fusion transcript between exon 3 of TRIM27 and exon 12 of RET was identified in 2 cases of IC with apocrine features, and one of them displayed invasive growth. Two IC cases with invasive growth harbored novel fusions TUT1-ETV5 and KIAA1217-RET, respectively. A total of 42.4% of the cases in this series of IC harbored fusions involving RET. Such fusion transcripts were not detected in any of the 10 SDC cases. We have confirmed NCOA4-RET as a predominant fusion in intercalated duct-type IC, including 3 cases with invasive growth pattern. A novel finding in our series was a case of widely invasive intercalated duct-type IC, with a single lymph node metastasis that revealed an NCOA4-RET fusion transcript. We also demonstrated that a subset of apocrine ICs harbored a TRIM27-RET gene fusion, including one case with invasive growth. In contrast, neither NCOA4-RET nor TRIM27-RET fusions were detected in any tested SDCs. Thus, the distinct molecular findings in IC and SDC support that the tumors are separate malignant salivary tumor entities. The presence of tumor-type-specific NCOA4-RET or TRIM27-RET translocations in a subset of widely invasive carcinomas with intercalated duct-like immunoprofiles suggests that a recharacterization of IC including its redesignation as "intercalated duct carcinoma, invasive or noninvasive" may be appropriate.
CRIS-Team Scopus Importer:2019-06-18
Keywords: apocrine; cohort studies; gene fusion; intercalated duct carcinoma; intraductal carcinoma; NCOA4-RET; RET -targeted therapy; salivary gland neoplasms; TRIM27-RET

Nebenwirkungen neuer onkologischer Immuntherapien - Braun, G. S.; Kirschner, M.; Ruebben, A.; Wahl, R. U.; Amann, Kerstin Ute; Benesova, K.; Leipe, J. (Nephrologe, 2020)
Systemic treatment with immune checkpoint inhibitors (ICI) has revolutionized the treatment of hematological and oncological diseases in recent years. The mechanism of action hinges on enhancing the natural ability of the immune system to eliminate malignant cells. The most important substances in this arena include inhibitors of PD-1, PD-L1 and CTLA-4. As a consequence, the spectrum of treatment-associated adverse reactions is shifting away from classical cytotoxic effects (e.g. pancytopenia and polyneuropathy) towards novel entities of immune-mediated complex diseases. These so-called immune-related adverse events (irAEs) can involve any organ system and mimic known classical autoimmune conditions. Timely recognition of irAEs is the key for rapid initiation of a suitable treatment and is especially challenging in the clinical routine as it requires an intensive interdisciplinary management. Nephrologists are particularly confronted with this kind of problem due to the highly interdisciplinary nature of their work. This article summarizes the broad spectrum of currently known renal and more frequently occuring non-renal forms of irAEs and aims to prime the reader on diagnostic and therapeutic options.
CRIS-Team WoS Importer:2020-05-15

Neoadjuvant chemoradiation combined with regional hyperthermia in locally advanced or recurrent rectal cancer - Ott, Oliver; Gani, Cihan; Lindner, Lars H.; Schmidt, Manfred; Lamprecht, Ulf; Abdel-Rahman, Sultan; Hinke, Axel; Weissmann, Thomas; Hartmann, Arndt; Issels, Rolf D.; Zips, Daniel; Belka, Claus; et al. (Cancers, 2021)
Background: To prospectively analyze feasibility and pathological complete response (pCR) rates of neoadjuvant chemoradiotherapy combined with regional hyperthermia (RHT) in patients with locally advanced (LARC) or recurrent (LRRC) rectal cancer. Methods: between 2012 and 2018, 111 patients with UICC stage IIB-IV or any locally recurrent rectal cancer were included (HyRec-Trial, ClinicalTrials.gov Identifier: NCT01716949). Patients received radiotherapy with concurrent 5-Fluororuracil (5-FU)/Capecitabine and Oxaliplatin, and RHT. Stage 1 feasibility analysis evaluated dose-limiting toxicities (DLT) after 19 patients, stage 2 after 59 evaluable patients. Analysis of the pCR rate was based on histopathological reports. Results: the feasibility rates for stages 1 and 2 were 90% (17/19) and 73% (43/59), respectively. In the intention-to-treat population the pCR rate was 19% (20/105; 90% confidence interval (CI) 13.0–26.5). In the per-protocol-analysis, complete tumor regression was seen in 28% (18/64) and 38% (3/8) of the patients with LARC and LRRC, respectively. Complete resection rates (R0) among patients with LARC and LRRC who received surgery were 99% (78/84) and 67% (8/12). Conclusions: the intensified neoadjuvant and multimodality treatment schedule was feasible and led to comparable early toxicity rates as described by other trials that used the similar chemoradiation protocol. The presented treatment regimen resulted in a very high pCR rate and appears as a promising option for patients with LRRC.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Complete remission rate; Concurrent chemoradiation; Locally advanced rectal cancer; Locally recurrent rectal cancer; Regional hyperthermia; Tumor regression grading

Neoadjuvant chemotherapy in breast cancer: Which diagnostic procedures can be used? - Löhberg, Christian; Lux, Michael P.; Ackermann, Sven; Pöhls, Uwe G.; Bani, Mayada; Schulz-Wendtland, Rüdiger; Papadopoulos, Thomas; Schmucker, Martin; Beckmann, Matthias; Fasching, Peter (Anticancer Research, 2005)
BACKGROUND To improve breast cancer treatment, the evaluation of predictive factors is in the focus of clinical research. Significant discrepancies between the clinical assessment of response to neoadjuvant chemotherapy (NACT) and the pathological assessment of response from post-therapy surgical specimens have been demonstrated. We focused on comparing the value of various diagnostic methods used in medical routine. PATIENTS AND METHODS A clinical evaluation of the primary tumour and regional lymph nodes before and after NACT was performed in 139 patients by physical examination, sonography and mammography. RESULTS Mammography and physical examination correlated best with pathological findings in the measurement of the tumour, whereas sonography was the most accurate predictor of the status for axillary lymph nodes. CONCLUSION Mammography and physical examination are the best non-invasive predictors of the real size of the primary breast cancer, whereas sonography correlates better with the proven status of axillary lymph nodes.
Keywords: Neoadjuvant chemotherapy; breast cancer; mammography; sonography

Neoadjuvant concurrent chemoradiotherapy with and without hyperthermia in retroperitoneal sarcomas: feasibility, efficacy, toxicity, and long-term outcome - Willner, Alexander; Fechner, Katja; Agaimy, Abbas; Haller, Florian; Eckstein, Markus; Ott, Oliver; Putz, Florian; Gaipl, Udo; Kersting, S.; Meidenbauer, Norbert; Grützmann, Robert; Fietkau, Rainer; et al. (Strahlentherapie und Onkologie, 2021)
Purpose Retroperitoneal (RPS) sarcomas are associated with poor local and abdominal tumor control. However, the benefit of preoperative radio- or chemotherapy alone for these entities is currently unclear. Moreover, as intermediate- and high-grade sarcomas have a tendency toward early metastasis, exploration of neoadjuvant strategies is of high importance. This analysis reports the results of our 20-year single-institution experience with preoperative neoadjuvant concurrent chemoradiation. Methods From 2000-2019, 27 patients with intermediate- or high-grade RPS (12 dedifferentiated liposarcoma, 10 leiomyosarcoma, 5 others) were treated with radiotherapy (median dose: 50.4 Gy; range 45-75 Gy) and two cycles of chemotherapy (doxorubicin 50 mg/m(2) BSA/d3 q28 and ifosfamide 1.5 g/m(2) BSA/d1-5 q28) in neoadjuvant intent. Chemotherapy consisted of doxorubicin alone in two cases and ifosfamide alone in one case. Fifteen patients (56%) additionally received deep regional hyperthermia. Results The median follow-up time was 53 months (+/- 56.7 months). 92% of patients received two cycles of chemotherapy as planned and 92% underwent surgery. At 5 and 10 years, abdominal-recurrence-free survival was 74.6% (+/- 10.1%) and 66.3% (+/- 11.9%), distant metastasis-free survival was 67.2% (+/- 9.7%) and 59.7% (+/- 11.1%), and overall survival was 60.3% (+/- 10.5%) and 60.3% (+/- 10.5%), respectively. CTC grade III and IV toxicities were leukocytopenia (85%), thrombocytopenia (33%), and anemia (11%). There were no treatment-related deaths. Conclusion Neoadjuvant chemoradiotherapy with and without hyperthermia for retroperitoneal sarcomas is feasible and provided high local control of intermediate- and high-grade sarcoma.
CRIS-Team WoS Importer:2021-11-12

Neoadjuvant Immunotherapy of Oral Squamous Cell Carcinoma: Case Report and Assessment of Histological Response - Olmos, Manuel; Glajzer, Jacek; Büntemeyer, Tjark-Ole; Frohwitter, Gesche; Ries, Jutta; Eckstein, Markus; Hecht, Markus; Lutz, Rainer; Kesting, Marco Rainer; Weber, Manuel (Frontiers in Oncology, 2021)
Background: The treatment of oral cancer remains challenging due to its infiltrative nature and a high tendency for tumour relapse leading to an overall poor prognosis. In the case of early recurrence, the patient’s prognosis deteriorates dramatically, with survival rate dropping to below 30%. Minimal improvements in survival trends in recurrent and advanced stage tumours have been reported in recent decades. Neoadjuvant immunotherapy may represent a new therapeutic approach changing the standard of care in advanced oral cancer therapy. Case Presentation: We describe the case of a woman in her late 30’s who presented in mid-2019 with oral squamous cell carcinoma (OSCC) localized to the floor of the mouth. After initial R0 resection, selective neck dissection, and adjuvant brachytherapy, an early recurrence of OSCC located between the hyoid bone and the mandible was diagnosed at the end of 2019. An off-label treatment regimen was performed with neoadjuvant use of Pembrolizumab 19 days prior to salvage surgery. Radiological and histological assessment of T-cell and programmed cell death protein 1 ligand 1 (PD-L1) expression was performed before and after checkpoint inhibitor application. Neoadjuvant immunotherapy resulted in increased T-cell infiltration and PD-L1 expression, as well as a significant tumour necrosis rate. One cycle of Pembrolizumab led to significant regressive tumour changes with increases in immune infiltration, sclerosis, and necrosis of 75% of the tumour mass with only 25% vital tumour cells remaining. By June 2020, the patient remained without recurrence. Conclusions: The case presented outlines the potential effects of neoadjuvant immunotherapy in recurrent or advanced OSCC prior to definitive surgical tumour treatment. The benefit of additional adjuvant treatment after histologic response will be discussed. The case is also analysed considering ongoing clinical trials of neoadjuvant immunotherapy for head and neck malignancies.
CRIS-Team Scopus Importer:2021-08-13
Keywords: case report; immune checkpoint inhibitors; immunotherapy; neoadjuvant; oral cancer; OSCC; PD-1 - PD-L1 axis; pembrolizumab

Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer—Analyses of CD68, CD163, TGF-β1, GLUT-1 and HIF-1α Expressions - Weber, Manuel; Ries, Jutta; Braun, Kristina; Wehrhan, Falk; Distel, Luitpold; Geppert, Carol-Immanuel; Lutz, Rainer; Kesting, Marco Rainer; Trumet, Leah (Cells, 2024)
Background: The first-line treatment of oral squamous cell carcinoma (OSCC) involves surgical tumor resection, followed by adjuvant radio(chemo)therapy (R(C)T) in advanced cases. Neoadjuvant radio- and/or chemotherapy has failed to show improved survival in OSCC. Recently, neoadjuvant immunotherapy has shown promising therapeutic efficacy in phase 2 trials. In this context, the addition of radio- and chemotherapy is being reconsidered. Therefore, a better understanding of the tumor-biologic effects of neoadjuvant RCT would be beneficial. The current study was conducted on a retrospective cohort of patients who received neoadjuvant RCT for the treatment of oral cancer. The aim of the study was to evaluate the influence of neoadjuvant RCT on the immunological tumor microenvironment (TME) and hypoxic and glucose metabolisms. Methods: A cohort of 45 OSSC tissue samples from patients were analyzed before and after RCT (total 50.4 Gy; 1.8 Gy 5× weekly; Cisplatin + 5-Fluorouracil). Immunohistochemistry for CD68, CD163, TGF-β, GLUT-1 and HIF-1α was performed using tissue microarrays and automated cell counting. Differences in expression before and after RCT and associations with histomorphological parameters (T-status, N-status) were assessed using the Mann–Whitney U test. Results: Tumor resection specimens after neoadjuvant RCT showed a significant decrease in CD68 infiltration and a significant increase in CD163 cell density. The CD68/CD163 ratio was significantly lower after RCT, indicating a shift toward M2 polarization. The GLUT-1 and HIF-1α expressions were significantly lower after RCT. Larger tumors (T3/T4) showed a lower GLUT-1 expression. Other biomarkers were not associated with the T- and N-status. Conclusions: Neoadjuvant RCT with 50.4 Gy induced a shift toward the M2 polarization of macrophages in the TME. This change in immune composition is not favorable and may be prognostically negative and counteract immunotherapeutic approaches. In addition, the decreased expressions in GLUT-1 and HIF-1α indicate reductions in the glucose metabolism and hypoxic energy metabolism in response to “high dose” neoadjuvant RCT, which may be therapeutically desirable.
CRIS-Team Scopus Importer:2024-03-22
Keywords: head and neck squamous cell carcinoma; HNSCC; hypoxia; immune tolerance; induction therapy; macrophage polarization; metabolism; oral squamous cell carcinoma; OSCC; RCT

Neoadjuvant Radiochemotherapy Followed by Curative Resection in Patients with Advanced Non-Small Cell Lung Cancer in Stage IIIA/IIIB: Prognostic Factors and Results - Schreiner, Waldemar; Dudek, Wojciech; Lettmaier, S.; Gavrychenkova, S.; Rieker, R.; Fietkau, Rainer; Sirbu, Horia (Zentralblatt für Chirurgie, 2016)
The role of surgical lung resection following neo-adjuvant radio-chemotherapy (RCT) in patients with locally advanced non-small cell lung cancer (NSCLC) is yet not clearly defined. The aim of our study was to analyze the postoperative survival and to identify relevant prognostic factors. 46 patients underwent curative resections after neo-adjuvant RCT for locally advanced NSCLC (IIIA/IIIB) between February 2008 and February 2015. A retrospective data analysis regarding preoperative regression status, perioperative mortality, postoperative survival, patho-histological remission, relapse pattern and other prognostic factors was performed. A neo-adjuvant RCT with a median radiation dose of 50.4 [range, 45-60] Gy was performed in 44 (96 %) patients. Partial and/or complete regression was observed in 32 (70 %) patients. R0-resection was achieved in 44 (96 %) patients. The 30-day mortality was 4 % and the perioperative morbidity was 37 %. The overall and progression free 5-year survival rate was 47 % and respectively 45 % [in median 58 months]. The 5-year survival rate of 64 % in the "responder"-group was significantly better when compared with 24 % in the "non-responder"-group (p = 0.038). The tri-modality therapy improved the prognosis in patients with locally advanced NSCLC (stage IIIA/IIIB). The complete patho-histological remission is an important prognostic factor for better long term survival. Dividing the patients in "responder" and "non-responder" after neo-adjuvant RCT may have large therapeutically consequences in the future.
EVALuna2:6809

Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial - Fokas, E.; Fietkau, Rainer; Hartmann, Arndt; Hohenberger, Werner; Grützmann, Robert; Ghadimi, M.; Liersch, T.; Stroebel, P.; Grabenbauer, G. G.; Graeven, U.; Hofheinz, R-D; Koehne, C-H; et al. (Annals of Oncology, 2018)
Background: Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial. Patients and methods: Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. Results: After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106-7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4. Conclusion: Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.
EVALuna2:34609

Nephronectin Is Required for Vascularization in Zebrafish and Sufficient to Promote Mammalian Vessel-Like Structures in Hydrogels for Tissue Engineering. - Patra, Chinmoy; Rayrikar, Amey; Wagh, Ganesh; Kleefeldt, Florian; Roshanbinfar, Kaveh; Cop, Florian; Nikolic, Iva; Schmidt, Mirko H.H.; Acker-Palmer, Amparo; Ergün, Süleyman; Engel, Felix (Journal of the American Heart Association, 2025)
BACKGROUND: Organs and tissues need to be vascularized during development. Similarly, vascularization is required to engineer thick tissues. How vessels are formed during organogenesis is not fully understood, and vascularization of engineered tissues remains a significant challenge. METHODS AND RESULTS: Here, we show that the extracellular matrix protein nephronectin is required for vascularization during zebrafish development as well as adult fin regeneration and is sufficient to promote mammalian vessel formation and maturation. Nephronectin a morphants and mutants exhibit diminished axial vein sprouting and posterior intersegmental vessel growth. Notably, the angiogenesis-associated integrins itgav and itgb3.1 are coexpressed with nephronectin a in the region of the caudal vein plexus and posterior somites; nephronectin binds to integrin alpha-V/integrin beta-3.1 (ITGAV/ITGB3.1), and itgav morphants phenocopy nephronectin a mutants. In addition, nephronectin a mutants showed decreased vessel maturation compared with wild-type siblings during caudal fin regeneration in adult zebrafish. Moreover, nephronectin promotes mammalian endothelial cell migration and tube formation in 2D and 3-dimensional in vitro tissue culture. Further, nephronectin enhances vascular endothelial growth factor-induced periaortic vascular capillary interconnectivity, vessel diameter, and vessel stability. CONCLUSIONS: Collectively, our results identify nephronectin as a proangiogenic factor during embryonic development, which can be used to improve the vascularization of engineered tissues.
EVALuna2:583978

Nephron-specific knockout of TMEM16A leads to reduced number of glomeruli and albuminuria - Schenk, Laura K.; Buchholz, Björn; Henke, Sebastian F.; Michgehl, Ulf; Daniel, Christoph; Amann, Kerstin Ute; Kunzelmann, Karl; Pavenstaedt, Hermann (American Journal of Physiology-Renal Physiology, 2018)
TMEM16A is a transmembrane protein from a conserved family of calcium activated proteins, which is highly expressed in the kidney. TMEM16A confers calcium-activated chloride channel activity which is of importance for various cellular functions in secretory epithelia and involved in secretion-dependent renal cyst growth. However, its specific function in renal physiology has remained elusive so far. Therefore we generated conditional nephron specific TMEM16A knockout mice and found that these animals suffered from albuminuria. Kidney histology demonstrated an intact corticomedullary differentiation and absence of cysts. Electron microscopy showed a normal slit diaphragm. However, the total number of glomeruli and total nephron count was decreased in TMEM16A knockout animals. At the same time, glomerular diameter was increased, presumably as a result of the hyperfiltration in the remaining glomeruli. TUNEL and PCNA stainings showed increased cell death and increased proliferation. Proximal tubular cilia were intact in young animals but the number of properly ciliated cells was decreased in older, albuminuric animals. Taken together, our data suggests that TMEM16A may be involved in ureteric bud branching and proper nephron endowment. Loss of TMEM16A resulted in reduced nephron number and, subsequently, albuminuria and tubular damage.
EVALuna2:35395
Keywords: albuminuria; Ano1; kidney; nephron number; TMEM16A

Nephropathologie - Amann, Kerstin Ute; Wolf, G. (Nephrologe, 2019)
CRIS-Team Scopus Importer:2019-05-03

Nephropathologie infektiöser Erkrankungen - Büttner-Herold, Maike; Amann, Kerstin Ute; Velden, Joachim (Die Pathologie, 2024)
Infections can affect the kidney via different pathways. Urinary tract infections can directly involve the renal tissue by spreading along pre-existing canalicular structures. Such an ascending infection can manifest as a highly active and purulent or even abscessing interstitial nephritis or as a chronic-fibrosing process in recurrent pyelonephritis. Viral infections can also use the canalicular route as in polyomavirus nephropathy or spread via the blood stream in a hematogenous manner as in the case of cytomegalovirus or hantavirus infections. Likewise, bacterial infections can reach the kidney via the blood in the case of systemic infection. Another large group of nephropathies taking place as a sequel of infections includes infection-related glomerulonephritides (IRGN), which are mediated by a series of immunological mechanisms. These IRGN can be subdivided according to their temporal association with the infectious process, occurring either after the infection has healed (postinfectious) or accompanying the ongoing infectious process (parainfectious). The latter, in particular, is of increasing importance in the daily practice of nephropathologists, especially in older patients. A number of other glomerulonephritis forms, i.e., membranous or membranoproliferative forms, can occur as a consequence of infection. In addition, infections can trigger nephropathies, such as thrombotic microangiopathy. The present article gives an overview of morphologic changes in renal parenchyma that take place as a consequence of infectious processes, with particular focus on IRGN.
CRIS-Team Scopus Importer:2024-05-17
Keywords: Immune complex; Infection-related glomerulonephritis; Path of infection; Pathogen spectrum; Urinary tract infection

Nephropathology Nephropathologie - Wolf, Gunter; Amann, Kerstin Ute (Die Nephrologie, 2022)
CRIS-Team Scopus Importer:2024-12-16

Nephropathy in illicit drug abusers: a postmortem analysis - Büttner, Maike; Toennes, Stefan W.; Buettner, Stefan; Bickel, Markus; Allwinn, Regina; Geiger, Helmut; Bratzke, Hansjuergen; Amann, Kerstin Ute; Jung, Oliver (American Journal of Kidney Diseases, 2014)
Illicit drug abuse is an independent risk factor for chronic kidney disease, but the pathogenic consequences of long-term exposure to illicit drugs and contaminants under unsterile conditions remains unclear.Case series.All deceased persons (n 5 129) who underwent forensic autopsy because of suspected connection with illicit drug abuse between January 1, 2009, and April 30, 2011, in Frankfurt/Main, Germany.Clinical characteristics and patterns of drug abuse.Histopathologic alterations of the kidney.Hematoxylin and eosin, periodic acid-Schiff, Sirius, and Congo Red stainings and immunoglobulin A immunohistochemistry of all cases; additional histochemical stainings or immunohistochemistry and electron microscopy in selected cases.Individuals were mostly white (99.2%), were male (82.2%), and had intravenous drug use (IVDU) (81.4%). Median age at death was 39 years and duration of drug abuse was 17 years. The majority (79.1%) took various drugs in parallel as assessed by toxicologic analysis. Despite a young age, the deceased had a high burden of comorbid conditions, especially cardiovascular disease, liver cirrhosis, and infections. Evaluation of the kidneys demonstrated a broad spectrum of pathologic alterations predominated by arteriosclerotic and ischemic damage, mild interstitial inflammation, calcification of renal parenchyma, and interstitial fibrosis and tubular atrophy, with hypertensive-ischemic nephropathy as the most common cause of nephropathy. Interstitial inflammation (OR, 16.59; 95% CI, 3.91-70.39) and renal calcification (OR, 2.43; 95% CI, 1.03- 5.75) were associated with severe IVDU, whereas hypertensive and ischemic damage were associated with cocaine abuse (OR, 6.00; 95% CI, 1.27-28.44). Neither specific glomerular damage indicative for heroin and hepatitis C virus-related disease nor signs of analgesic nephropathy were found.White population, lack of a comparable control group, incomplete clinical data, and absence of routine immunohistochemistry and electron microscopy.Illicit drug abuse is associated with a broad but unspecific spectrum of pathologic alterations of the kidneys. Cocaine abuse has a deleterious role in this setting by promoting hypertensive and ischemic damage.
EVALuna2:25464

Nephrotic syndrome and thrombotic microangiopathy caused by cobalamin C deficiency - Koenig, Jens C.; Rutsch, Frank; Bockmeyer, Clemens; Baumgartner, Matthias; Beck, Bodo B.; Kranz, Brigitta; Konrad, Martin (Pediatric Nephrology, 2015)
Cobalamin C (CblC) defects are inherited autosomal recessive disorders of vitamin B12 metabolism due to mutations in the MMACHC gene. Renal manifestations include thrombotic microangiopathy (TMA), acute or chronic renal failure, tubulointerstitial nephritis, and proximal renal tubular acidosis. However, reports about glomerular pathologies are scarce.A 4-year-old boy presented with nephrotic syndrome, arterial hypertension, and chronic anemia but no signs of hemolysis. Renal biopsy showed TMA with ischemic glomerular collapse, foot process effacement, and tubulointerstitial fibrosis. Elevated serum levels of homocysteine suggested a cobalamin C disorder. This was confirmed by the identification of compound heterozygous mutations in the MMACHC gene. Initial therapy consisted of antihypertensive treatment including angiotensin converting enzyme inhibitor (ACEi) leading to blood pressure control and a significant reduction of proteinuria. After a definite diagnosis of CblC deficiency, hydroxocobalamin was introduced. Thereafter, homocysteine levels decreased, anemia resolved, and a further decline of proteinuria with normalization of serum protein levels was noted. Renal function remained stable.Although uncommon, the clinical picture of CblC defects may be ruled by nephrotic syndrome mimicking glomerulonephritis, minimal change disease, or primary focal and segmental glomerulosclerosis. Key to a correct diagnosis is elevated serum levels of homocysteine, and a definite diagnosis can be confirmed by genetic testing.
EVALuna2:25496

Nephrotic syndrome in antibody deficiency syndrome in CLL - Strutz, Frank; Amann, Kerstin Ute; Wittmann, Gertraud; Beck, Joachim (Die Nephrologie, 2022)
CRIS-Team WoS Importer:2022-12-16

Nephrotisches Syndrom nach COVID-19-Impfung: Drei neue Fälle aus Deutschland - Dormann, Harald; Knüppel-Ruppert, Anja; Amann, Kerstin Ute; Erley, Christiane (Deutsches Ärzteblatt international, 2021)
CRIS-Team Scopus Importer:2021-10-29

Nestin expression in repopulating mesangial cells promotes their proliferation - Daniel, Christoph; Albrecht, Heinz; Lüdke, Andrea; Hugo, Christian (Laboratory Investigation, 2008)
We investigated whether the intermediate filament protein and neural stem cell marker nestin characterizes the glomerular progenitor/reserve cell population immigrating the glomerulus after mesangial cell (MC) injury in the rat (anti-Thy1 nephritis). Nestin expression was investigated by immunohistochemistry and real-time PCR during anti-Thy1 nephritis. Migration and proliferation assays were used to characterize the function of nestin in isolated MCs after nestin knockdown by siRNA. After MC injury during anti-Thy1 nephritis, glomerular nestin was transiently increased during the repopulation phase. At the peak of mesangial proliferation and expansion (day 5) most OX-7-positive MCs expressed nestin largely colocalizing with the activation marker α-smooth muscle actin and the proliferation marker PCNA. In contrast to a healthy, non-injured mesangium in vivo, MCs in culture are considered to be in an 'activated, injured state' and express nestin in a generalized distribution with condensed localization around the nucleus as well as intensive staining of cell protrusions such as filopodia. During cell cycle, the percentage of MCs with high nestin levels was increased during S- aupnd G2-phase. Blocking of nestin using specific siRNA resulted in inhibition of cell proliferation but not cell migration. In conclusion, nestin is constitutively expressed in podocytes, but is a marker for repopulating MCs after experimental MC injury in vivo. Nestin promotes MC proliferation in vitro, suggesting a supporting role for nestin during repair reaction. © 2008 USCAP, Inc All rights reserved.
Created from Fastlane, Scopus look-up
Keywords: Nestin; Podocytes; Proliferation; Repopulation; Stem cells

Neues aus der Uropathologie - Hartmann, Arndt (Die Pathologie, 2025)
CRIS-Team Scopus Importer:2025-02-17

'Neuroendocrine' middle ear adenomas: consistent expression of the transcription factor ISL1 further supports their neuroendocrine derivation - Agaimy, Abbas; Lell, Michael; Schaller, Tina; Märkl, Bruno; Hornung, Joachim (Histopathology, 2015)
Neuroendocrine middle ear adenoma (MEA) is a rare epithelial neoplasm of uncertain histogenesis that frequently shows neuroendocrine features. To date, <120 cases have been reported. The aims of the current study were to describe our experience with neuroendocrine MEA, to assess the frequency of specific neuroendocrine differentiation, and to test these lesions for transcription factors known to be expressed in a variety of other neuroendocrine tumours.We investigated six cases of neuroendocrine MEA, and stained them, for the first time, for the transcription factors CDX2, TTF1, PAX8, and ISL1 (islet-1). The patients were four men and two women (mean age, 39 years; range, 27-53 years). Two of four patients with extended follow-up (4.5-22 years) experienced recurrence at 92 months, and at 9 and 22 years, respectively. One case extending into the external ear coexisted with cholesteatoma. Histological examination showed trabecular, solid, acinar, glandular, cribriform, organoid, nested, diffuse non-cohesive plasmacytoid and pseudoalveolar patterns in varying combinations. Immunohistochemistry showed consistent expression of vimentin (4/4), pancytokeratin (6/6), synaptophysin (6/6), CD56 (4/4), and ISL1 (6/6). A CK7 antibody stained scattered cells in two of five cases. The myoepithelial markers and transcription factors TTF1, CDX2 or PAX8 were not expressed in any of the cases.Middle ear adenoma is an indolent, locally recurring, but generally non-metastasizing neoplasm with uniform expression of synaptophysin and ISL1, indicating true neuroendocrine differentiation. Because of its highly varied cellular and architectural appearance, MEA should be distinguished from tympanic paraganglioma and a variety of rare benign and malignant lesions at this site.
EVALuna2:6634

Neuroendocrine neoplasms of the head and neck - Konukiewitz, B.; Agaimy, Abbas; Weichert, W.; Kloeppel, G. (Pathologe, 2018)
Common to all neuroendocrine neoplasms (NENs), irrespective of their site of origin, is the expression of synaptophysin and chromogranin A. NENs of the head and neck region derive either from epithelial or neural/neuroectodermal tissues. The epithelial-type NENs express cytokeratins and include the well-differentiated typical and atypical carcinoids (also called low- and intermediate-grade neuroendocrine carcinomas by WHO), the poorly differentiated high-grade neuroendocrine carcinomas of small and large cell type and the mixed neuroendocrine-nonneuroendocrine neoplasms. The neural-neuroectodermal-type NENs comprise olfactory neuroblastoma and paraganglioma, each of them with distinct clinicopathological characteristics. Olfactory neuroblastomas show a spectrum of histologic differentiation and are prognostically classified by Hyams grading. Paragangliomas often occur multiple and show a familial background. Most head and neck NENs occur in the upper respiratory system. Their diagnosis follows the general guidelines for NENs, focusing on immunohistochemical profiling. Molecular examinations are so far only required in individual cases.
EVALuna2:34881

Neurogenic substance P-influences on action potential production in afferent neurons of the kidney? - Rodionova, Kristina; Hilgers, Karl Friedrich; Linz, Peter; Schaetzl, Johannes; Raschke, Giulia; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Ditting, Tilmann (Pflügers Archiv: European Journal of Physiology, 2021)
We recently showed that a substance P (SP)-dependent sympatho-inhibitory mechanism via afferent renal nerves is impaired in mesangioproliferative nephritis. Therefore, we tested the hypothesis that SP released from renal afferents inhibits the action potential (AP) production in their dorsal root ganglion (DRG) neurons. Cultured DRG neurons (Th11-L2) were investigated in current clamp mode to assess AP generation during both TRPV1 stimulation by protons (pH 6) and current injections with and without exposure to SP (0.5 mu mol) or CGRP (0.5 mu mol). Neurons were classified as tonic (sustained AP generation) or phasic (<= 4 APs) upon current injection; voltage clamp experiments were performed for the investigation of TRPV1-mediated inward currents due to proton stimulation. Superfusion of renal neurons with protons and SP increased the number of action potentials in tonic neurons (9.6 +/- 5 APs/10 s vs. 16.9 +/- 6.1 APs/10 s, P < 0.05, mean +/- SD, n = 7), while current injections with SP decreased it (15.2 +/- 6 APs/600 ms vs. 10.2 +/- 8 APs/600 ms, P < 0.05, mean +/- SD, n = 29). Addition of SP significantly reduced acid-induced TRPV1-mediated currents in renal tonic neurons (- 518 +/- 743 pA due to pH 6 superfusion vs. - 82 +/- 50 pA due to pH 6 with SP superfusion). In conclusion, SP increased action potential production via a TRPV1-dependent mechanism in acid-sensitive renal neurons. On the other hand, current injection in the presence of SP led to decreased action potential production. Thus, the peptide SP modulates signaling pathways in renal neurons in an unexpected manner leading to both stimulation and inhibition of renal neuronal activity in different (e.g., acidic) environmental contexts.
CRIS-Team WoS Importer:2021-04-16

Neurogenic tachykinin mechanisms in experimental nephritis of rats - Rodionova, Kristina; Hilgers, Karl Friedrich; Paulus, Eva-Maria; Tiegs, Gisa; Ott, Christian; Schmieder, Roland; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Ditting, Tilmann (Pflügers Archiv: European Journal of Physiology, 2020)
We demonstrated earlier that renal afferent pathways combine very likely "classical" neural signal transduction to the central nervous system and a substance P (SP)-dependent mechanism to control sympathetic activity. SP content of afferent sensory neurons is known to mediate neurogenic inflammation upon release. We tested the hypothesis that alterations in SP-dependent mechanisms of renal innervation contribute to experimental nephritis. Nephritis was induced by OX-7 antibodies in rats, 6 days later instrumented for recording of blood pressure (BP), heart rate (HR), drug administration, and intrarenal administration (IRA) of the TRPV1 agonist capsaicin to stimulate afferent renal nerve pathways containing SP and electrodes for renal sympathetic nerve activity (RSNA). The presence of the SP receptor NK-1 on renal immune cells was assessed by FACS. IRA capsaicin decreased RSNA from 62.4 +/- 5.1 to 21.6 +/- 1.5 mV s (*p < 0.05) in controls, a response impaired in nephritis. Suppressed RSNA transiently but completely recovered after systemic administration of a neurokinin 1 (NK1-R) blocker. NK-1 receptors occurred mainly on CD11(+)dendritic cells (DCs). An enhanced frequency of CD11c(+)NK1R(+)cell, NK-1 receptor(+)macrophages, and DCs was assessed in nephritis. Administration of the NK-1R antagonist aprepitant during nephritis reduced CD11c(+)NK1R(+)cells, macrophage infiltration, renal expression of chemokines, and markers of sclerosis. Hence, SP promoted renal inflammation by weakening sympathoinhibitory mechanisms, while at the same time, substance SP released intrarenally from afferent nerve fibers aggravated immunological processes i.e. by the recruitment of DCs.
CRIS-Team WoS Importer:2020-11-06

Neuropilin-2 and its ligand VEGF-C predict treatment response after transurethral resection and radiochemotherapy in bladder cancer patients - Keck, Bastian; Wach, S.; Taubert, Helge; Zeiler, S.; Ott, O. J.; Kunath, F.; Hartmann, Arndt; Bertz, Simone; Weiss, C.; Hoenscheid, P.; Schellenburg, S.; Roedel, C.; et al. (International Journal of Cancer, 2015)
The standard treatment for invasive bladder cancer is radical cystectomy. In selected patients, bladder-sparing therapy can be performed by transurethral resection (TURBT) and radio-chemotherapy (RCT) or radiotherapy (RT). Our published in vitro data suggest that the Neuropilin-2 (NRP2)/VEGF-C axis plays a role in therapy resistance. Therefore, we studied the prognostic impact of NRP2 and VEGF-C in 247 bladder cancer patients (cN0M0) treated with TURBT and RCT (n = 198) or RT (n = 49) and a follow-up time up to 15 years. A tissue microarray was analyzed by immunohistochemistry. NRP2 expression emerged as a prognostic factor in overall survival (OS; HR: 3.42; 95% CI: 1.48 - 7.86; p = 0.004) and was associated with a 3.85-fold increased risk of an early cancer specific death (95% CI: 0.91 - 16.24; p = 0.066) in multivariate analyses. Cancer specific survival (CSS) dropped from 166 months to 85 months when NRP2 was highly expressed (p = 0.037). Patients with high VEGF-C expression have a 2.29-fold increased risk of shorter CSS (95% CI: 1.03-5.35; p = 0.043) in univariate analysis. CSS dropped from 170 months to 88 months in the case of high VEGF-C expression (p = 0.041). Additionally, NRP2 and VEGF-C coexpression is a prognostic marker for OS in multivariate models (HR: 7.54; 95% CI: 1.57-36.23; p = 0.012). Stratification for muscle invasiveness (T1 vs. T2-T4) confirmed the prognostic role of NRP2 and NRP2/VEGF-C co-expression in patients with T2-T4 but also with high risk T1 disease. In conclusion, immunohistochemistry for NRP2 and VEGF-C has been determined to predict therapy outcome in bladder cancer patients prior to TURBT and RCT.
EVALuna2:6641

Neutrophil extracellular traps characterize caseating granulomas - Zlatar, Leticija; Knopf, Jasmin; Singh, Jeeshan; Wang, Han; Muñoz-Becerra, Marco; Herrmann, Irmgard; Chukwuanukwu, Rebecca; Eckstein, Markus; Eichhorn, Philip; Rieker, Ralf; Naschberger, Elisabeth; Burkovski, Andreas; et al. (Cell Death & Disease, 2024)
Tuberculosis (TB) remains one of the top 10 causes of death worldwide and still poses a serious challenge to public health. Recent attention to neutrophils has uncovered unexplored areas demanding further investigation. Therefore, the aim of this study was to determine neutrophil activation and circulatory neutrophil extracellular trap (NET) formation in various types of TB. Sera from TB patients (n = 91) and healthy controls (NHD; n = 38) were analyzed for NE-DNA and MPO–DNA complexes, cell-free DNA (cfDNA), and protease activity (elastase). We show that these NET parameters were increased in TB sera. Importantly, NET formation and NE activity were elevated in TB patients with extensive tissue damage when compared to those with minor damage and in patients with relapse, compared to new cases. We discuss the importance of balancing NET formation to prevent tissue damage or even relapse and argue to analyze circulating NET parameters to monitor the risk of disease relapse. To investigate the tissues for NETs and to find the source of the circulating NET degradation products, we collected sections of granulomas in lung and lymph node biopsies. Samples from other diseases with granulomas, including sarcoidosis (SARC) and apical periodontitis (AP), served as controls. Whereas NET formation characterizes the caseating granulomas, both caseating and non-caseating granulomas harbor DNA with unusual conformation. As TB is associated with hypercoagulation and thromboembolism, we further imaged the pulmonary vessels of TB patients and detected vascular occlusions with neutrophil aggregates. This highlights the dual role of neutrophils in the pathology of TB.
CRIS-Team Scopus Importer:2024-08-09

Neutrophil extracellular traps drive epithelial‐mesenchymal transition of human colon cancer - Stehr, Antonia; Wang, Guangxia; Demmler, Richard; Stemmler, Marc; Straube, Julia; Tripal, Philipp; Schmid, Benjamin; Geppert, Carol-Immanuel; Hartmann, Arndt; Munoz, Luis Enrique; Schoen, Janina; Völkl, Simon; et al. (Journal of Pathology, 2021)
Neutrophil extracellular traps (NETs) are extracellular structures, composed of nuclear DNA and various proteins released from neutrophils. Evidence is growing that NETs exert manifold functions in infection, immunity, and cancer. Recently, NETs have been detected in colorectal cancer (CRC) tissues but their association with disease progression and putative functional impact on tumourigenesis remained elusive. Using high-resolution stimulated emission depletion (STED) microscopy we showed that citrullinated histone H3 (H3cit) is sufficient to specifically detect citrullinated NETs in colon cancer tissues. Among other evidence this was supported by the close association of H3cit with de-condensed extracellular DNA, the hallmark of NETs. Extracellular DNA was reliably differentiated from nuclear condensed DNA by staining with an anti-DNA-antibody providing a novel and valuable tool to detect NETs in FFPE tissues. Using these markers, the clinical association of NETs has been investigated in a cohort of 85 patients with colon cancer. NETs were frequently detected (n = 37/n = 85, 44%) in colon cancer tissue sections and preferentially localized either only in the tumour centre or both, in the tumour centre and the invasive front. Of note, citrullinated NETs were significantly associated with high histopathologic tumour grades and lymph node metastasis. In vitro, purified NETs induced filopodia formation and cell motility in CRC cell lines. This was associated with increased expression of mesenchymal marker mRNAs (vimentin [VIM], fibronectin [FN1]) and epithelial- mesenchymal transition (EMT) promoting transcription factors (ZEB1 and Slug [SNAI2]) as well as decreased expression of the epithelial markers E-cadherin (CDH1) and EpCAM (EPCAM). These findings indicated that NETs activate an EMT-like process in CRC cells and may contribute to the metastatic progression of CRC.
Keywords: epithelial–mesenchymal transition (EMT); colorectal neoplasms; stimulated emission depletion (STED) microscopy; neutrophils; migration; extracellular traps

Neutrophils in HNSCC Can Be Associated with Both a Worse or Favorable Prognosis - Brunkhorst, Hendrik; Schnellhardt, Sören; Büttner-Herold, Maike; Daniel, Christoph; Fietkau, Rainer; Distel, Luitpold (Biomolecules, 2024)
The prognostic significance of tumor-infiltrating neutrophils in head and neck squamous cell carcinoma (HNSCC) is poorly understood. It is unclear how the presence of neutrophils affects prognosis due to their polarization into cytotoxic N1 or immunosuppressive N2. Therefore, we determined the number of CD66b+ neutrophil granulocytes separately in the stromal and epithelial compartments in cancer tissues from 397 patients with HNSCC. Tumor samples from six historical patient groups were processed into tissue microarrays and stained immunohistochemically. In total, 21.9% were HPV positive (p16+). Neutrophil counts were much lower in the stromal compartment (372 ± 812) than in the epithelial cancer compartment (1040 ± 1477) (p < 0.001), with large differences between groups. In three groups with high neutrophil infiltration, high rates were associated with a favorable prognosis, whereas in two groups, high rates were a negative prognostic factor. In p16- oropharyngeal and hypopharyngeal cancer high infiltration was associated with a favorable prognosis. Cancers with an exclusion of neutrophils in the epithelial compartment were associated with improved prognosis. In oropharyngeal and hypopharyngeal HPV-negative cancer high neutrophil infiltration rates were clearly associated with prolonged survival. Neutrophil granulocytes in HNSCC may contribute to a favorable or unfavorable prognosis.
CRIS-Team Scopus Importer:2024-03-08
Keywords: CD66b+; head and neck cancer; HNSCC; hypopharynx; larynx; neutrophils; oral cavity; oropharynx; prognosis; tumor-associated neutrophils

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia - Trpkov, Kiril; Hes, Ondrej; Williamson, Sean R.; Adeniran, Adebowale J.; Agaimy, Abbas; Alaghehbandan, Reza; Amin, Mahul B.; Argani, Pedram; Chen, Ying-Bei; Cheng, Liang; Epstein, Jonathan I.; Cheville, John C.; et al. (Modern Pathology, 2021)
The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.
CRIS-Team WoS Importer:2021-04-09

New functions and signaling mechanisms for the class of adhesion G protein-coupled receptors - Liebscher, Ines; Ackley, Brian; Arac, Demet; Ariestanti, Donna M.; Aust, Gabriela; Bae, Byoung-Il; Bista, Bigyan R.; Bridges, James P.; Duman, Joseph G.; Engel, Felix; Giera, Stefanie; Goffinet, Andre M.; et al. (Annals of the New York Academy of Sciences, 2014)
The class of adhesion G protein-coupled receptors (aGPCRs), with 33 human homologs, is the second largest family of GPCRs. In addition to a seven-transmembrane ?-helix-a structural feature of all GPCRs-the class of aGPCRs is characterized by the presence of a large N-terminal extracellular region. In addition, all aGPCRs but one (GPR123) contain a GPCR autoproteolysis-inducing (GAIN) domain that mediates autoproteolytic cleavage at the GPCR autoproteolysis site motif to generate N- and a C-terminal fragments (NTF and CTF, respectively) during protein maturation. Subsequently, the NTF and CTF are associated noncovalently as a heterodimer at the plasma membrane. While the biological function of the GAIN domain-mediated autocleavage is not fully understood, mounting evidence suggests that the NTF and CTF possess distinct biological activities in addition to their function as a receptor unit. We discuss recent advances in understanding the biological functions, signaling mechanisms, and disease associations of the aGPCRs.
EVALuna2:25477

New information about tumours of the salivary glands: WHO classification 2022 Neues zu Tumoren der Speicheldrüsen: WHO-Klassifikation 2022 - Ihrler, Stephan; Jurmeister, Philipp; Haas, Christian; Greber, Lukas; Agaimy, Abbas (Die Pathologie, 2023)
The WHO 2022 classification of head and neck tumours contains another slight increase in the number of listed benign and malignant tumour entities of the salivary glands. This includes conceptual changes and alterations in the terminology of some entities. While some new features are regarded as preliminary or provisional, others are strongly disputed (for example the terminology of intraductal carcinoma). The impact of molecular findings, mainly recurrent gene fusions, continues to increase rapidly and some have been included in the definition of certain tumour entities. The significance of molecular findings is, however, still largely restricted to diagnostic aspects. Newly included entities include microsecretory carcinoma (defined by an SS18::MEF2C fusion), sclerosing microcystic adenocarcinoma (similar to skin adnexal tumours of the same name) and mucinous adenocarcinoma (characterized by AKT1 mutations with heterogeneous morphology).
CRIS-Team Scopus Importer:2023-07-07
Keywords: Adenocarcinoma; Gene fusion; Head and neck neoplasms; Molecular pathology; World Health Organization

New insights in predictive determinants of the tumor immune microenvironment for immune checkpoint inhibition: a never ending story? - Eckstein, Markus; Gupta, Shilpa (Annals of Translational Medicine, 2019)
CRIS-Team WoS Importer:2019-09-17

New oleoyl hybrids of natural antioxidants: Synthesis and in vitro evaluation as inducers of apoptosis in colorectal cancer cells - Carullo, Gabriele; Mazzotta, Sarah; Koch, Anna Maria; Hartmann, Kristin; Friedrich, Oliver; Gilbert, Daniel; Vega-Holm, Margarita; Schneider-Stock, Regine; Aiello, Francesca (Antioxidants, 2020)
Nowadays, the beneficial role of a healthy lifestyle, particularly emphasizing the quality of foods and cancer management, is accepted worldwide. Polyphenols and oleic acid play a key role in this context, but are still scarcely used as anti-cancer agents due to their bio-accessibility limits. Therefore, we aimed to synthesize a set of new oleoyl-hybrids of quercetin, morin, pinocembrin, and catechin to overcome the low bioavailability of polyphenols, throughout a bio-catalytic approach using pancreatic porcine lipase as a catalyst. The in vitro assays, using a wide panel of human cancer cell lines showed, mainly for two novel regioisomer oleoyl-hybrids of quercetin, a remarkable increase in apoptotic cell populations. We suggested that the DNA damage shown as GH2AX signals might be the major cause of apoptotic cell death. Finally, we demonstrated convincing data about two novel polyphenol-based hybrids displaying a highly selective anti-cancer cytotoxicity and being superior compared to their reference/parental compounds.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Apoptosis; Colorectal cancer; Cytotoxicity; DNA damage; HCT-116; Oleic acid; Pancreatic porcine lipase; Polyphenol hybrids; Quercetin

New prognostic and predictive markers for breast cancer - Wachter, David (Pathologe, 2016)
Breast cancer can be divided into four molecular subtypes with different prognoses using immunohistochemical markers in the routine clinicopathological work-up. The protein Ki-67 is of central importance in this context, in particular to distinguish between luminal A and luminal B carcinomas. Determination of the Ki-67 index of a carcinoma also allows a prediction of the likelihood of the response to chemotherapy. Additionally, the expression of certain cytokeratins in tumor cells is associated with a poor response to chemotherapy. The heterogeneity of molecular subtypes with regard to the histological appearance indicates an even greater diversity of breast cancer. We were able to show that a high proportion of luminal B carcinomas display neuroendocrine differentiation. Further studies with particular emphasis on histomorphological criteria should be performed to attain a more accurate classification of breast cancer and to pave the way towards targeted therapies for a better prognosis in the future.
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[New WHO classification 2022: urinary bladder cancer]. - Gaisa, Nadine Therese; Hartmann, Arndt; Knuechel-Clarke, Ruth (Die Pathologie, 2023)
The new World Health Organization (WHO) classification of urogenital tumors is still primarily based on anatomic location, but is also a hierarchical taxonomic classification without separate chapters for tumors of the upper urinary tract and the urethra. It clarifies aspects regarding grading and noninvasive entities. It consolidates the use of the Paris system for urinary cytology as well as various subtypes/special types of neoplasms, and incorporates general concepts of the 5th edition of the WHO blue book. In addition to mesenchymal tumors, well-differentiated neuroendocrine tumors and neuroendocrine carcinomas are addressed in separate chapters. Papillary non-invasive low- and high-grade carcinomas and carcinoma in situ remain, while dysplasia and urothelial proliferation of unknown malignant potential (UPUMP) are no longer treated as separate entities. Former variants of urothelial carcinoma are now called subtypes and aberrant differentiation and special types are more precisely defined.
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Next generation sequencing and functional analysis of patient urine renal progenitor-derived podocytes to unravel the diagnosis underlying refractory lupus nephritis - Romagnani, Paola; Giglio, Sabrina; Angelotti, Maria Lucia; Provenzano, Aldesia; Becherucci, Francesca; Mazzinghi, Benedetta; Mueller, Susanna; Amann, Kerstin Ute; Weidenbusch, Marc; Romoli, Simone; Lazzeri, Elena; Anders, Hans-Joachim (Nephrology Dialysis Transplantation, 2016)
Often the cause of refractory lupus nephritis (RLN) remains unclear. We performed next-generation sequencing for podocyte genes in an RLN patient and identified compound heterozygosity for APOL1 risk alleles G1 and G2 and a novel homozygous c.[1049C>T]+[1049C>T] NPHS1 gene variant of unknown significance. To test for causality renal progenitor cells isolated from urine of this patient were differentiated into podocytes in vitro. Podocytes revealed aberrant nephrin trafficking, cytoskeletal structure and lysosomal leakage, and increased detachment as compared with podocytes isolated from controls. Thus, lupus podocytopathy can be confirmed as a cause of RLN by functional genetics on patient-derived podocytes.
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NFATc1 Promotes Antitumoral Effector Functions and Memory CD8+ T-cell Differentiation during Non-Small Cell Lung Cancer Development - Heim, Lisanne; Friedrich, Juliane; Engelhardt, Marina; Trufa, Denis; Geppert, Carol-Immanuel; Rieker, Ralf; Sirbu, Horia; Finotto, Susetta (Cancer Research, 2018)
Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor activated by T-cell receptor (TCR) and Ca2+ signaling that affects T-cell activation and effector function. Upon tumor antigen challenge, TCR and calcium-release-activated channels are induced, promoting NFAT dephosphorylation and translocation into the nucleus. In this study, we report a progressive decrease of NFATc1 in lung tumor tissue and in tumor-infiltrating lymphocytes (TIL) of patients suffering from advanced-stage non-small cell lung cancer (NSCLC). Mice harboring conditionally inactivated NFATc1 in T cells (NFATc1ΔCD4) showed increased lung tumor growth associated with impaired T-cell activation and function. Furthermore, in the absence of NFATc1, reduced IL2 influenced the development of memory CD8+ T cells. We found a reduction of effector memory and CD103+ tissue-resident memory (TRM) T cells in the lung of tumor-bearing NFATc1ΔCD4 mice, underlining an impaired cytotoxic T-cell response and a reduced TRM tissue-homing capacity. In CD4+ICOS+ T cells, programmed cell death 1 (PD-1) was induced in the draining lymph nodes of these mice and associated with lung tumor cell growth. Targeting PD-1 resulted in NFATc1 induction in CD4+ and CD8+ T cells in tumor-bearing mice and was associated with increased antitumor cytotoxic functions. This study reveals a role of NFATc1 in the activation and cytotoxic functions of T cells, in the development of memory CD8+ T-cell subsets, and in the regulation of T-cell exhaustion. These data underline the indispensability of NFATc1 for successful antitumor immune responses in patients with NSCLC.Significance: The multifaceted role of NFATc1 in the activation and function of T cells during lung cancer development makes it a critical participant in antitumor immune responses in patients with NSCLC. Cancer Res; 78(13); 3619-33. ©2018 AACR.
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