The Immune Checkpoint Receptor CD96: A Local and Systemic Immune Modulator in Oral Cancer? - Trumet, Leah; Weber, Manuel; Hahn, Alina; Kunater, Lina; Geppert, Carol-Immanuel; Glajzer, Jacek; Struckmeier, Ann-Kristin; Möst, Tobias; Lutz, Rainer; Kesting, Marco Rainer; Ries, Jutta (Cancers, 2023)
Background: As immunotherapy of oral squamous cell carcinomas (OSCCs), using PD1 inhibitors, is only efficient in a small proportion of patients, additional immune checkpoints need to be identified as potential therapeutic targets. There is evidence that a blockade of CD96 might positively affect the anti-tumor immune response. The aim of this study was to analyze the gene and protein expression of CD96 in the tissue and peripheral blood of OSCC patients compared to healthy controls, while also checking for potential associations with a differential expression to the histomorphological parameters. In addition, possible correlations with the expression of PD1 and PD-L1 as well as the macrophage markers CD68 and CD163 should be tested to obtain further insights into the potential effectiveness of combined checkpoint blockage. Material and Methods: For real-time quantitative polymerase chain reaction (RT-qPCR), a total of 183 blood and tissue samples, divided into a patient and a control group, were included. Additionally, 141 tissue samples were examined by immunohistochemistry (IHC). The relative expression differences between the groups were calculated using statistical tests including the Mann–Whitney U test and AUC method. The Chi-square test was used to determine whether CD96 overexpression in individual samples is associated with malignancy. Correlation analysis was performed using the Spearman correlation test. Results: There was a significant CD96 mRNA and protein overexpression in the OSCC group compared to the controls (p = 0.001). In contrast, CD96 mRNA expression in the peripheral blood of the OSCC patients was significantly lower compared to the control group (p = 0.007). In the Chi-square test, the OSCC tissue samples showed a highly significant upregulation of CD96 mRNA expression (p < 0.001) and protein expression (p = 0.005) compared to the healthy mucosa. CD96 mRNA and protein expression correlated significantly (p = 0.005). In addition, there was a significant positive correlation of CD96 expression with PD1 (p ≤ 0.001), PD-L1 (p ≤ 0.001), and CD163 (p = 0.006) at the mRNA level. Conclusions: CD96 expression in the tumor tissue and peripheral blood of OSCC patients is differentially regulated and appears to be a relevant immune checkpoint.
CRIS-Team Scopus Importer:2023-04-28
Keywords: HNSCC; immune checkpoints; immunotherapy; OSCC; PD-1; PD-L1

The impact of body mass index on prognosis in patients with colon carcinoma - Fuchs, Julian; Schellerer, Vera S.; Brunner, Maximilian; Geppert, Carol-Immanuel; Grützmann, Robert; Weber, Klaus; Merkel, Susanne (International Journal of Colorectal Disease, 2022)
Background: The impact of body mass index (BMI) on prognosis in patients with curatively resected stage I–III colon carcinoma was analyzed. Methods: The prospectively collected data of 694 patients who underwent complete mesocolic excision between 2003 and 2014 were analyzed. BMI was classified into four categories: underweight (BMI < 18.5 kg/m2; n = 13), normal weight (BMI 18.5 to 24.9 kg/m2; n = 221), overweight (BMI 25.0 to 29.9 kg/m2; n = 309), and obese (BMI ≥ 30.0 kg/m2; n = 151). Univariate and multivariate analyses for comparison of prognosis were performed. Results: The 5-year rate of locoregional recurrence in all 694 patients was 2.1%, and no differences were found with respect to BMI (p = 0.759). For distant metastasis, the 5-year rate for all patients was 13.4%, and BMI did not have a significant impact (p = 0.593). The 5-year rate of disease-free survival for all 694 patients was 72.4%. The differences with respect to BMI were not found to be significant in univariate analysis (p = 0.222). In multivariate Cox regression analysis, disease-free survival was significantly better in obese patients (HR 0.7; p = 0.034). Regarding overall survival, the 5-year rate for all patients was 78.1%. In univariate analyses, no significant differences were found for BMI (p = 0.094). In the Cox regression analysis, overweight and obese patients had significantly better survival (overweight: HR 0.7; p = 0.027; obese: HR 0.6; p = 0.019). Conclusion: The better survival of overweight and obese patients in multivariate analyses must be interpreted with caution. It is influenced by several factors and seems to correspond to the phenomenon of the obesity paradox.
CRIS-Team Scopus Importer:2022-04-22
Keywords: Body mass index; Colon carcinoma; Obesity paradox; Overall survival; Prognosis

The impact of histopathology and NAB2-STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/hemangiopericytoma - Fritchie, Karen; Jensch, Kassandra; Moskalev, Evgeny; Caron, Alissa; Jenkins, Sarah; Link, Michael; Brown, Paul D.; Rodriguez, Fausto J.; Guajardo, Andrew; Brat, Daniel; Velázquez Vega, José E.; Perry, Arie; et al. (Acta Neuropathologica, 2018)
Meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is a rare tumor with propensity for recurrence and metastasis. Although multiple classification schemes have been proposed, optimal risk stratification remains unclear, and the prognostic impact of fusion status is uncertain. We compared the 2016 WHO CNS tumor grading scheme (CNS-G), a three-tier system based on histopathologic phenotype and mitotic count, to the 2013 WHO soft-tissue counterpart (ST-G), a two-tier system based on mitotic count alone, in a cohort of 133 patients [59 female, 74 male; mean age 54 years (range 20-87)] with meningeal SFT/HPC. Tumors were pathologically confirmed through review of the first tumor resection (n = 97), local recurrence (n = 35), or distant metastasis (n = 1). A STAT6 immunostain showed nuclear expression in 132 cases. NAB2-STAT6 fusion was detected in 99 of 111 successfully tested tumors (89%) including the single STAT6 immunonegative tumor. Tumors were classified by CNS-G as grade 1 (n = 43), 2 (n = 41), or 3 (n = 49), and by ST-G as SFT (n = 84) or malignant SFT (n = 49). Necrosis was present in 16 cases (12%). On follow-up, 42 patients had at least one subsequent recurrence or metastasis (7 metastasis only, 33 recurrence only, 2 patients had both). Twenty-nine patients died. On univariate analysis, necrosis (p = 0.002), CNS-G (p = 0.01), and ST-G (p = 0.004) were associated with recurrence-free (RFS) but not overall survival (OS). NAB2-STAT6 fusion type was not significantly associated with RFS or OS, but was associated with phenotype. A modified ST-G incorporating necrosis showed higher correlation with RFS (p = 0.0006) and remained significant (p = 0.02) when considering only the primary tumors. From our data, mitotic rate and necrosis appear to stratify this family of tumors most accurately and could be incorporated in a future grading scheme.
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The impact of surgical quality on prognosis in patients undergoing rectal carcinoma surgery after preoperative chemoradiation - Kiehlmann, Marcus; Weber, Klaus; Göhl, Jonas; Fietkau, Rainer; Agaimy, Abbas; Hohenberger, Werner; Merkel, Susanne (International Journal of Colorectal Disease, 2016)
The aim of the study was to analyse the impact of surgical quality on the prognosis of rectal carcinoma patients who underwent preoperative long-term chemoradiation and TME surgery.In a total of 314 patients, four quality indicators, including plane of surgery, pathological circumferential resection margin (pCRM), intraoperative local tumour cell dissemination and anastomotic leakage, were analysed with respect to locoregional recurrence, distant metastasis and overall survival.In 260 (82.8 %) of the patients, all four quality indicators were fulfilled. In 30 (9.6 %) of the patients, at least one quality indicator was not fulfilled; in 24 (7.6 %) of the patients, the data were not complete. Locoregional recurrence was significantly increased in patients who underwent surgery in the muscularis propria plane, who had a pCRM <= 1 mm or who experienced local tumour cell dissemination. In patients who had at least one quality indicator that was not fulfilled (suboptimal surgical quality), the 5-year rate of locoregional recurrence in those patients was 23.1 % compared to 4.8 % in patients who underwent optimal surgery (P = 0.001). In multivariate analysis, suboptimal surgery (hazard ratio (HR) 3.9; P = 0.020), abdominoperineal excision (HR 4.7; P = 0.003) and poor regression of primary tumours (HR 8.5; P < 0.001) were identified as independent prognostic factors for locoregional recurrence. In contrast to type of surgical treatment, ypT, ypN and regression grade, the quality of surgery did not significantly influence distant metastasis or overall survival.Even after preoperative chemoradiation, the surgical quality still has a strong impact on local control in patients with rectal carcinoma.
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The impact of the tumor microenvironment on the survival of penile cancer patients. - Lohse, Stefan; Mink, Jan Niklas; Eckhart, Lea; Hans, Muriel Charlotte; Jusufi, Leuart; Zwick, Anabel; Mohr, Tobias; Bley, Isabelle Ariane; Khalmurzaev, Oybek; Matveev, Vsevolod Borisovich; Loertzer, Philine; Pryalukhin, Alexey; et al. (Scientific Reports, 2024)
PeCa is a rare entity with rising incidence rates due to increased infections with human papillomaviruses (HPV). The distinct subtypes of PeCa with an individual pathogenesis demand biomarkers for a precise patient risk assessment regarding disease progression and therapeutic susceptibility. We recently identified promising candidates associated with an HPV-instructed tumor microenvironment (TME) using HPV-positive PeCa cell lines and tissue microarrays (TMA). The capacity of HPV + p63 + PeCa cells to release neutrophil-attracting CXCL-8 provided a molecular link explaining the infiltration of CD15 + myeloid cells in PeCa specimens. The candidate biomarkers HPV, p63, CD15, DKK1, and CD147 linked a tumor-promoting TME with a higher TNM classification reflecting more aggressive and metastasizing cancers. Based on immune-reactive scores (IRS) from TMA staining for these biomarkers, we calculated correlations and conducted association analyses to assess the degree of relationship between all biomarkers. We then conducted Kaplan-Meier survival estimates and Cox regression analyses to delineate the impact on PeCa patient survival. There is a notable predictive potential regarding the survival of patients with biomarker profiles beyond the potency of the individual biomarker. From all candidate biomarkers and biomarker profiles, the combination of CD147 and infiltrating CD15 + cells linked to an active HPV-driven transformation displayed cancer-immune dynamics with dismal prognosis for patients. After deciphering relevant interdependencies, the HPV + CD147 + CD15 + status was the most potent profile predicting metastasis-free survival of PeCa patients. The results of this report underscore the need for analysis of the TME and the development of multi-parameter composite scores that reflect fundamental cancer-immune relationships to tailor therapeutic interventions based on actual cancer immune dynamics.
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The importance of pancreatic inflammation in endosonographic diagnostics of solid pancreatic masses - Vitali, Francesco; Strobel, Deike; Frulloni, Luca; Heinrich, Marc Christopher; Pfeifer, Lukas; Görtz, Rüdiger; Hundorfean, Gheorghe; Wachter, David Lukas; Wachter, David; Grützmann, Robert; Bernatik, Thomas; Neurath, Markus; et al. (Medical Ultrasonography, 2018)
AIMS: Endosonography (EUS) is one of the main diagnostic tools for the differential diagnosis of pancreatic masses. The aim of our study was to describe the value of this technique in the work-up of solid pancreatic lesions, considering the influence of the morphological evidence of pancreatic inflammation in the diagnostic process. MATERIAL AND METHODS: Retrospective analysis of prospectively collected data in our tertiary University center. From March 2007 to October 2015, 218 patients underwent EUS for a suspected solid pancreatic neoplasm (based on previous cross-sectional imaging results, idiopatic acute pancreatitis, weight loss, pancreatic hyperenzymemia, painless jaundice or elevated Ca 19-9 values). RESULTS: Malignant lesions were diagnosed in 98 (45%) patients. Sensitivity of EUS for malignancy was 91% and specificity 89.2%. Signs of pancreatic inflammation in the surrounding pancreatic parenchyma around the focal lesion were present in 97 patients (44.4%)(more often in men, smokers and drinkers, and the most common etiology was focal chronic pancreatitis) and in these patients the sensitivity and sensibility dropped to 44% and 87.1%, respectively. In patients without signs of pancreatic inflammation, the pancreatic focal lesions were adenocarcinoma, neuroendocrine tumor, ventral/dorsal split, non-pancreatic pathology, pancreatic lipomatosis and autoimmune pancreatitis. CONCLUSION: Pancreatic inflammation (either focal or involving the whole gland) lowers the diagnostic sensibility of EUS in the work- up of pancreatic masses suspected for cancer, requiring further invasive diagnostic methods. Focal autoimmune pancreatitis and paraduodenal pancreatitis are still confused with pancreatic cancer, even in the absence of pancreatic inflammation.
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The Influence of Body Mass Index on Long-Term Prognosis in Patients with Colon Carcinomas - Merkel, Susanne; Fuchs, Julian; Schellerer, Vera; Brunner, Maximilian; Geppert, Carol-Immanuel; Grützmann, Robert; Weber, Klaus (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

The Influence of Different Irradiation Regimens on Inflammation and Vascularization in a Random-Pattern Flap Model - Müller-Seubert, Wibke; Ostermaier, Patrick; Horch, Raymund E.; Distel, Luitpold; Frey, Benjamin; Erber, Ramona; Arkudas, Andreas (Journal of Personalized Medicine, 2023)
Background: Irradiation plays an important role in the oncological treatment of various tumor entities. The aim of the study was to investigate the influence of different irradiation regimens on random-pattern flaps at the molecular and histopathological levels. Methods: Twenty-five rats underwent harvesting of bilateral random-pattern fasciocutaneous flaps. The right flaps received irradiation, while the left flaps served as non-irradiated intraindividual controls. Five rats served as a non-irradiated control group. Four different irradiation regimens with give rats each were tested: 20 Gy postoperatively, 3 × 12 Gy postoperatively, 20 Gy preoperatively, and 3 × 12 Gy preoperatively. Two weeks after surgery, HE staining and immunohistochemical staining for CD68 and ERG, as well as PCR analysis to detect Interleukin 6, HIF-1α, and VEGF, were performed. Results: A postoperative cumulative higher dose of irradiation appeared to result in an increase in necrosis, especially in the superficial layers of the flap compared to preoperative or single-stage irradiation. In addition, we observed increased expression of VEGF and HIF-1α in all irradiation groups. Conclusion: Even though no statistically significant differences were found between the different groups, there was a tendency for fractional postoperative irradiation with a higher total dose to have a more harmful effect compared to preoperative or single-dose irradiation.
CRIS-Team Scopus Importer:2023-11-10
Keywords: irradiation; random-pattern flaps; vascularization

The influence of postoperative complications on long-term prognosis in patients with colorectal carcinoma - Beck, Clemens; Weber, Klaus; Brunner, Maximilian; Agaimy, Abbas; Semrau, Sabine; Grützmann, Robert; Schellerer, Vera; Merkel, Susanne (International Journal of Colorectal Disease, 2020)
Background: The impact of postoperative complications (POCs) on the long-term prognosis of patients with colorectal carcinoma was analysed with respect to their severity according to the Clavien-Dindo classification (CDC). Methods: The prospectively collected data of 2158 patients who underwent curative resection of a colorectal carcinoma (1168 rectal carcinomas, 990 colon carcinomas) without distant metastases from 1995 to 2014 were analysed. The POCs were documented in a standardized form and graded with the CDC. Patients who died postoperatively (CDC grade V, 1.7%) were excluded. Results: In total, 467 patients (21.6%) had POCs: CDC I, 141 (6.5%); CDC II, 162 (7.5%); CDC III, 112 (5.2%); and CDC IV, 52 (2.4%). More POCs and higher CDC grades were found in men, ASA III-IV patients, rectal carcinoma patients, and patients who underwent abdominoperineal excisions or multivisceral resections. The 5-year locoregional recurrence rate was 5.3% in patients without POCs and 6.6% in patients with POCs. It was highest in CDC III patients (12.9%), which was confirmed in multivariate analysis (HR 2.2; p = 0.005). The 5-year distant metastasis rate was 15.9% in CDC 0 patients and 19.5% in CDC I–IV patients. In multivariate analysis, distant metastasis was highest in CDC III patients (HR 1.7; p = 0.020). The 5-year overall survival rate was 83.5% in patients without POCs and 73.5% in patients with POCs. It was worst in CDC IV patients (63.1%), which was confirmed by multivariate analysis (HR 1.9; p = 0.001). Conclusion: Patients with POCs after colorectal surgery have a poor long-term prognosis. As the CDC grade increases, survival deteriorates.
CRIS-Team Scopus Importer:2020-04-14
Keywords: Clavien-Dindo classification; Colorectal carcinoma; Postoperative complications; Prognosis

The Influence of Postoperative Complications on Long-Term Prognosis in Patients with Colorectal Carcinomas - Beck, Clemens; Schellerer, Vera; Weber, Klaus; Brunner, Maximilian; Agaimy, Abbas; Semrau, Sabine; Grützmann, Robert; Merkel, Susanne (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

The influence of tumour site on prognosis in metastatic colorectal carcinomas with primary tumour resection - Merkel, Susanne; Schellerer, Vera; Wein, Axel; Semrau, Sabine; Geppert, Carol-Immanuel; Göhl, Jonas; Hohenberger, Werner; Weber, Klaus; Grützmann, Robert (International Journal of Colorectal Disease, 2018)
PURPOSE: The aim of our study was to compare the characteristics and prognosis between right- and left-sided metastatic colorectal carcinomas. METHODS: Data from 937 patients with stage IV colorectal carcinomas (synchronous distant metastasis) who had a resection of the primary tumour between 1985 and 2014 were analysed. Carcinomas in the caecum to transverse colon were defined as right-sided (n = 250; 26.7%). They were compared to tumours located from the splenic flexure to the rectum categorised as left-sided (n = 687; 73.3%). RESULTS: In right-sided carcinomas, we observed significantly more female patients (50.8 vs 36.2%; p < 0.001), more unfavourable histological types (24.0 vs 8.6%; p < 0.001), more M1c carcinomas (metastases to the peritoneum ± others; 32.0 vs 14.4%; p < 0.001) and more emergencies (11.6 vs 7.1%; p = 0.029), while multimodal treatment was utilised in fewer patients (51.6 vs 63.8%; p = 0.001) and curative resections were less frequently (24.1 vs 35.4%; p = 0.002). Prognosis was significantly worse in patients with right-sided carcinomas (2-year-survival 27.2 vs 44.6%, p < 0.01). This difference was more pronounced after R2 resection (15.3 vs 29.7%; p < 0.001), than after macroscopic curative resection (2-year-survival 63.9 vs 71.9%; p = 0.106). In multivariate Cox regression analysis, tumour site was found to be an independent prognostic factor for overall survival (HR 1.2; 95% CI 1.0-1.5; p = 0.012). During the three 10-year periods, the prognosis improved equally in patients with right- and left-sided carcinomas, while the differences in survival remained identical. CONCLUSIONS: In a surgical patient cohort undergoing primary tumour resection, significant differences in prognosis were observed between patients with metastatic right- and left-sided colorectal carcinomas.
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The Kidney Donor Profile Index (KDPI) Correlates With Histopathologic Findings in Post-reperfusion Baseline Biopsies and Predicts Kidney Transplant Outcome - Bachmann, Quirin; Haberfellner, Flora; Büttner-Herold, Maike; Torrez, Carlos; Haller, Bernhard; Assfalg, Volker; Renders, Lutz; Amann, Kerstin Ute; Heemann, Uwe; Schmaderer, Christoph; Kemmner, Stephan (Frontiers in Medicine, 2022)
BackgroundThe increasing organ shortage in kidney transplantation leads to the necessity to use kidneys previously considered unsuitable for transplantation. Numerous studies illustrate the need for a better decision guidance rather than only the classification into kidneys from standard or expanded criteria donors referred to as SCD/ECD-classification. The kidney donor profile index (KDPI) exhibits a score utilizing a much higher number of donor characteristics. Moreover, graft biopsies provide an opportunity to assess organ quality. MethodsIn a single center analysis 383 kidney transplantations (277 after deceased and 106 after living donation) performed between January 1st, 2006, and December 31st, 2016, retrospectively underwent SCD/ECD and KDPI scoring. Thereby, the quality of deceased donor kidneys was assessed by using the KDPI and the living donor kidneys by using the living KDPI, in the further analysis merged as (L)KDPI. Baseline biopsies taken 10 min after the onset of reperfusion were reviewed for chronic and acute lesions. Survival analyses were performed using Kaplan-Meier analysis and Cox proportional hazards analysis within a 5-year follow-up. ResultsThe (L)KDPI correlated with glomerulosclerosis (r = 0.30, p < 0.001), arteriosclerosis (r = 0.33, p < 0.001), interstitial fibrosis, and tubular atrophy (r = 0.28, p < 0.001) as well as the extent of acute tubular injury (r = 0.20, p < 0.001). The C-statistic of the (L)KDPI concerning 5-year death censored graft survival was 0.692. Around 48% of ECD-kidneys were classified as (L)KDPI<85%. In a multivariate Cox proportional hazard analysis including (preformed) panel reactive antibodies, cold ischemia time, (L)KDPI, and SCD/ECD-classification, the (L)KDPI was significantly associated with risk of graft loss (hazard ratio per 10% increase in (L)KDPI: 1.185, 95% confidence interval: 1.033-1.360, p = 0.025). Survival analysis revealed decreased death censored (p < 0.001) and non-death censored (p < 0.001) graft survival in kidneys with an increasing (L)KDPI divided into groups of <35, 35-85, and >85%, respectively. ConclusionWith a higher granularity compared to the SCD/ECD-classification the (L)KDPI is a promising tool to judge graft quality. The correlation with chronic and acute histological lesions in post-reperfusion kidney biopsies underlines the descriptive value of the (L)KDPI. However, its prognostic value is limited and underlines the urgent need for a more precise prognostic tool adopted to European kidney transplant conditions.
CRIS-Team WoS Importer:2022-05-27

The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in Hypoxia: Insights into cellular transformation processes mediated by HIF-1 - Schietke, Ruth; Warnecke, Christina; Wacker, Ingrid; Schödel, Johannes; Mole, David R.; Campean, Valentina; Amann, Kerstin Ute; Goppelt-Strübe, Margarete; Behrens, Jürgen; Eckardt, Kai-Uwe; Wiesener, Michael Sean (Journal of Biological Chemistry, 2010)
Hypoxia has been shown to promote tumor metastasis and lead to therapy resistance. Recent work has demonstrated that hypoxia represses E-cadherin expression, a hallmark of epithelial to mesenchymal transition, which is believed to amplify tumor aggressiveness. The molecular mechanism of E-cadherin repression is unknown, yet lysyl oxidases have been implicated to be involved. Gene expression of lysyl oxidase (LOX) and the related LOX-like 2 (LOXL2) is strongly induced by hypoxia. In addition to the previously demonstrated LOX, we characterize LOXL2 as a direct transcriptional target of HIF-1. We demonstrate that activation of lysyl oxidases is required and sufficient for hypoxic repression of E-cadherin, which mediates cellular transformation and takes effect in cellular invasion assays. Our data support a molecular pathway from hypoxia to cellular transformation. It includes up-regulation of HIF and subsequent transcriptional induction of LOX and LOXL2, which repress E-cadherin and induce epithelial to mesenchymal transition. Lysyl oxidases could be an attractive molecular target for cancers of epithelial origin, in particular because they are partly extracellular. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
CRIS-Team Scopus Importer:2024-05-13

The marine triterpene glycoside frondoside A exhibits activity in vitro and in vivo in prostate cancer - Dyshlovoy, Sergey A.; Menchinskaya, Ekaterina S.; Venz, Simone; Rast, Stefanie; Amann, Kerstin Ute; Hauschild, Jessica; Otte, Katharina; Kalinin, Vladimir I.; Silchenko, Alexandra S.; Avilov, Sergey A.; Alsdorf, Winfried; Madanchi, Ramin; et al. (International Journal of Cancer, 2016)
Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (CRPC), outcome of patients remains poor due to the development of drug resistance. Thus, new drugs are urgently needed. We investigated efficacy, toxicity and mechanism of action of marine triterpene glycoside frondoside A (FrA) using CRPC cell lines in vitro and in vivo. FrA revealed high efficacy in human prostate cancer cells, while non-malignant cells were less sensitive. Remarkably, proliferation and colony formation of cells resistant to enzalutamide and abiraterone (due to the androgen receptor splice variant AR-V7) were also significantly inhibited by FrA. The marine compound caused cell type specific cell cycle arrest and induction of caspase-dependent or -independent apoptosis. Up-regulation or induction of several pro-apoptotic proteins (Bax, Bad, PTEN), cleavage of PARP and caspase-3 and down-regulation of anti-apoptotic proteins (survivin and Bcl-2) were detected in treated cells. Global proteome analysis revealed regulation of proteins involved in formation of metastases, tumor cell invasion, and apoptosis, like keratin 81, CrkII, IL-1? and cathepsin B. Inhibition of pro-survival autophagy was observed following FrA exposure. In vivo, FrA inhibited tumor growth of PC-3 and DU145 cells with a notable reduction of lung metastasis, as well as circulating tumor cells in the peripheral blood. Increased lymphocyte counts of treated animals might indicate an immune modulating effect of FrA. In conclusion, our results suggest that FrA is a promising new drug for the treatment of mCRPC. Induction of apoptosis, inhibition of pro-survival autophagy, and immune modulatory effects are suspected modes of actions.
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The Microphthalmia-Associated Transcription Factor p.E318K Mutation Does Not Play a Major Role in Sporadic Renal Cell Tumors from Caucasian Patients - Stoehr, Christine G.; Walter, Bernhard; Denzinger, Stefan; Ghiorzo, Paola; Sturm, Richard A.; Hinze, Raoul; Moch, Holger; Junker, Kerstin; Hartmann, Arndt; Stoehr, Robert (Pathobiology, 2016)
The transcription factor MITF (microphthalmia-associated transcription factor) is known to induce expression of hypoxia-inducible factor (HIF1-?), which is involved in renal carcinogenesis. The MITF p.E318K mutation leads to deficient SUMOylation of MITF, resulting in enhanced activation of its target genes. A case-control study on melanoma patients who coincidentally were affected by renal cell carcinoma (RCC) has revealed an elevated risk for mutation carriers to be affected by one or both of these malignancies, suggesting a possible role for MITF p.E318K in renal carcinogenesis. The same study described an MITF mutation frequency of 1.5% in a small cohort of sporadic RCC, but comprehensive data on sporadic renal cell tumors are missing. We therefore tested a large cohort of sporadic renal tumors for MITF p.E318K mutation status.Genomic DNA was extracted from 426 formalin-fixed, paraffin-embedded sporadic renal tumors that had been graded according to the 2004 WHO classification of renal tumors and staged according to the 2002 TNM classification. The tumor cohort was enriched with papillary and chromophobe RCC, and also contained benign oncocytomas. DNA was tested for MITF p.E318K by pyrosequencing.Of 403 analyzable tumors, 402 renal tumors were wild-type ones, and only 1 case showed the MITF p.E318K mutation. This tumor was a clear-cell RCC (pT3b N0 M0 G3 according to the TNM classification 2002). The affected patient was male, 61 years old, and had no known coexisting malignancies.The MITF p.E318K mutation does not appear to play a major role in sporadic RCC carcinogenesis, but is possibly restricted to a rare subpopulation of inherited RCC. © 2016 S. Karger AG, Basel.
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The modified Glasgow Prognostic Score (mGPS) can guide decisions for immunotherapy treatment beyond progression. - Saal, Jonas; Eckstein, Markus; Ritter, Manuel; Brossart, Peter; Hölzel, Michael; Grünwald, Viktor; Klümper, Niklas (European Journal of Cancer, 2025)
BACKGROUND: Treatment beyond progression (TBP) is common in patients treated with immune-checkpoint inhibitors (ICI), however, there is no biomarker to select patients that are more likely to derive benefit from TBP. Here, we investigated the potential of the modified Glasgow Prognostic Score (mGPS) as a predictive biomarker to select patients for TBP. METHODS: We performed a post-hoc analysis of the immunotherapy arms in the randomized phase 3 trials IMmotion151 (renal cell carcinoma), OAK (non-small cell lung cancer) and IMvigor211 (urothelial cancer). The main outcome was post-progression overall survival (PPOS) after the first investigator-assessed disease progression (PD), in mGPS risk groups. The mGPS classifies patients into three risk groups based on C-reactive protein (CRP) and albumin. RESULTS: We found a strong prognostic value for the mGPS when assessed at the time of PD (PD-mGPS) in all three trials. High-risk PD-mGPS was associated with significantly shorter PPOS compared to low-risk PD-mGPS (HR for death 18.3 (95 % CI 6.71-50.0, p < 0.001)) for RCC, UC: HR 4.16 (95 % CI 2.58-6.69, p < 0.001) and NSCLC HR 2.53 (95 % CI 1.70-3.77, p < 0.001). Importantly, patients within all three trials only derived benefit from ICI-TBP compared to switch to further-line treatment in the PD-mGPS low-risk group (RCC: HR 0.18 (95 % CI 0.06-0.55, p = 0.002); UC: HR 0.59 (95 % CI 0.34-1.00, p = 0.052); NSCLC: 0.62 (0.41-0.92, p = 0.018) compared to PD-mGPS intermediate/ high risk). CONCLUSIONS: These findings suggest that the mGPS measured at the time of radiologic PD can identify patients with a better prognosis who may benefit from continued atezolizumab therapy, aiding in the selection for TBP in clinical practice.
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The modified Polsby–Popper score, a novel quantitative histomorphological biomarker and its potential to predict lymph node positivity and cancer-specific survival in oral tongue squamous cell carcinoma - Csűry, Tamás Dániel; Csűry, Anna Zsófia; Balk, Matthias; Kist, Andreas; Rupp, Robin; Müller, Sarina Katrin; Sievert, Matti; Iro, Heinrich; Eckstein, Markus; Gostian, Antoniu-Oreste (Cancer Medicine, 2023)
Background: The significance of different histological spreading patterns of tumor tissue in oral tongue squamous cell carcinoma (TSCC) is well known. Our aim was to construct a numeric parameter on a continuous scale, that is, the modified Polsby–Popper (MPP) score, to describe the aggressiveness of tumor growth and infiltration, with the potential to analyze hematoxylin and eosin-stained whole slide images (WSIs) in an automated manner. We investigated the application of the MPP score in predicting survival and cervical lymph node metastases as well as in determining patients at risk in the context of different surgical margin scenarios. Methods: We developed a semiautomated image analysis pipeline to detect areas belonging to the tumor tissue compartment. Perimeter and area measurements of all detected tissue regions were derived, and a specific mathematical formula was applied to reflect the perimeter/area ratio in a comparable, observer-independent manner across digitized WSIs. We demonstrated the plausibility of the MPP score by correlating it with well-established clinicopathologic parameters. We then performed survival analysis to assess the relevance of the MPP score, with an emphasis on different surgical margin scenarios. Machine learning models were developed to assess the relevance of the MPP score in predicting survival and occult cervical nodal metastases. Results: The MPP score was associated with unfavorable tumor growth and infiltration patterns, the presence of lymph node metastases, the extracapsular spread of tumor cells, and higher tumor thickness. Higher MPP scores were associated with worse overall survival (OS) and tongue carcinoma-specific survival (TCSS), both when assessing all pT-categories and pT1-pT2 categories only; moreover, higher MPP scores were associated with a significantly worse TCSS in cases where a cancer-free surgical margin of <5 mm could be achieved on the main surgical specimen. This discriminatory capacity remained constant when examining pT1-pT2 categories only. Importantly, the MPP score could successfully define cases at risk in terms of metastatic disease in pT1-pT2 cancer where tumor thickness failed to exhibit a significant predictive value. Machine learning (ML) models incorporating the MPP score could predict the 5-year TCSS efficiently. Furthermore, we demonstrated that machine learning models that predict occult cervical lymph node involvement can benefit from including the MPP score. Conclusions: We introduced an objective, quantifiable, and observer-independent parameter, the MPP score, representing the aggressiveness of tumor growth and infiltration in TSCC. We showed its prognostic relevance especially in pT1-pT2 category TSCC, and its possible use in ML models predicting TCSS and occult lymph node metastases.
CRIS-Team Scopus Importer:2023-12-29
Keywords: computer-assisted image analysis; squamous cell carcinoma of head and neck; survival analysis; tongue cancer

The multiple signaling modalities of adhesion G protein-coupled receptor GPR126 in development - Patra, Chinmoy; Monk, Kelly R.; Engel, Felix (Receptors & Clinical Investigation, 2014)
The G protein-coupled receptor (GPCR) superfamily is the largest known receptor family in the human genome. Although the family of adhesion GPCRs comprises the second largest sub-family, their function is poorly understood. Here, we review the current knowledge about the adhesion GPCR family member GPR126. GPR126 possesses a signal peptide, a 7TM domain homologous to secretin-like GPCRs, a GPS motif and an extended N-terminus containing a CUB (Complement, Uegf, Bmp1) domain, a PTX (Pentraxin) domain, a hormone binding domain and 27 putative N-glycosylation sites. Knockdown and knockout experiments in zebrafish and mice have demonstrated that Gpr126 plays an essential role in neural, cardiac and ear development. In addition, genome-wide association studies have implicated variations at the GPR126 locus in obstructive pulmonary dysfunction, in scoliosis and as a determinant of trunk length and body height. Gpr126 appears to exert its function depending on the organ system via G protein- and/or N-terminus-dependent signaling. Here, we review the current knowledge about Gpr126, which, due to the variety of its functions and its multiple signaling modalities, provides a model adhesion GPCR to understand general functional concepts utilized by adhesion GPCRs.
EVALuna2:25482

The Myocardium in Renal Failure - Amann, Kerstin Ute (Springer International Publishing, 2020)
Patients with chronic kidney disease (CKD) suffer disproportionately from cardiovascular (cv) complications and specifically death from cardiac causes. Although the pathogenesis of this exceedingly high cv morbidity and mortality is not well understood, specific structural and functional alterations of the myocardium have been described which can contribute to the increased burden of cv disease in these patients. In the following some of these specific aspects will be discussed.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Angioadaptation; Capillary supply; CKD; Coronary arteries; Fibrosis; Heart; Hypertrophy; Myocardium

The natural course of pT2 prostate cancer with positive surgical margin: predicting biochemical recurrence - Karl, A.; Buchner, A.; Tympner, C.; Kirchner, T.; Ganswindt, U.; Belka, C.; Ganzer, R.; Burger, M.; Eder, F.; Hofstädter, F.; Schilling, D.; Sievert, K.; et al. (World Journal of Urology, 2015)
To predict biochemical recurrence respecting the natural course of pT2 prostate cancer with positive surgical margin (R1) and no adjuvant/neoadjuvant therapy.A multicenter data analysis of 956 patients with pT2R1N0/Nx tumors was performed. Patients underwent radical prostatectomy between 1994 and 2009. No patients received neoadjuvant or adjuvant therapy. All prostate specimens were re-evaluated according to a well-defined protocol. The association of pathological and clinical features, in regard to BCR, was calculated using various statistical tests.With a mean follow-up of 48 months, BCR was found in 25.4 %. In univariate analysis, multiple parameters such as tumor volume, PSA, Gleason at positive margin were significantly associated with BCR. However, in multivariate analysis, Gleason score (GS) of the prostatectomy specimen was the only significant parameter for BCR. Median time to recurrence for GS <= 6 was not reached; 5-year BCR-free survival was 82 %; and they were 127 months and 72 % for GS 3+4, 56 months and 54 % for GS 4 + 3, and 27 months and 32 % for GS 8-10. The retrospective approach is a limitation of our study.Our study provides data on the BCR in pT2R1-PCa without adjuvant/neoadjuvant therapy and thus a rationale for an individual's risk stratification. The data support patients and physicians in estimating the individual risk and timing of BCR and thus serve to personalize the management in pT2R1-PCa.
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The new semisynthetic cardenolide analog 3β-[2-(1-amantadine)-1-on-ethylamine]-digitoxigenin (AMANTADIG) efficiently suppresses cell growth in human leukemia and urologic tumor cell lines - Nolte, Elke; Sobel, Anna; Wach, Sven; Hertlein, Heidi; Ebert, Nadja; Müller-Uri, Frieder; Slany, Robert; Taubert, Helge; Wullich, Bernd; Kreis, Wolfgang (Anticancer Research, 2015)
Background/Aim: The use of cardenolides in the treatment of cardiac insufficiency is well-established. However, the potential of cardenolides in tumor therapy has not been comprehensively studied. The aim of the present study was to characterize the cytotoxic effects of the new semisynthetic cardenolide analog AMANTADIG (3β-[2-(1-amantadine)-1- on-ethylamine]-digitoxigenin), and the cardenolide digitoxin on leukemia and urological tumor cell lines. Materials and Methods: The anti-proliferative effects of AMANTADIG and digitoxin on leukemia and urological cancer cell lines were analyzed using (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium reduction viability assay. Results: AMANTADIG and digitoxin exhibited antiproliferative activities against the leukemia cell lines in the low nanomolar range. The prostate cancer and renal cell carcinoma cell lines were equally sensitive to AMANTADIG and digitoxin, however, the leukemia cell lines were more sensitive to both cardenolides. Conclusion: The new cardenolide analog AMANTADIG appears effective in cell growth inhibition of leukemia and urological tumor cell lines.
Keywords: 3β-[2-(1-Amantadine)-1-on-ethylamine]-digitoxigenin; AMANTADIG; Cardenolide analog; Human leukemia cells; Human urological cancer cells; Porcine cerebral cortex Na+/K+-ATPase

The Number of Colon Crypts in Digital Mucosal Samples: A New Independent Parameter for Diagnosing Ulcerative Colitis - Rubio, Carlos A.; Lang-Schwarz, Corinna; Matek, Christian; Kamaradova, Katerina; Vieth, Michael (Cancer Diagnosis & Prognosis, 2023)
Background/Aim: It has been demonstrated that most routine biopsies from the colon and rectum display cross-cut crypts (CCC). The aim was to assess the number of CCC in microscopic isometric digital samples (0.500 mm2) from routine colon biopsies. Patients and Methods: Colon biopsies from 224 patients were investigated: 99 in patients with ulcerative colitis (UC), 31 UC in remission (UCR), 28 infectious colitis (IC), 7 resolved IC (RIC), 19 diverticular sigmoiditis (DS), and 40 normal colon mucosa (NCM). Results: A total of 8,024 CCC were registered: 2,860 (35.6%) in UC, 1,319 UCR (16.4%), 849 (10.6%) in IC, 340 (4.2%) in RIC, 795 (9.9%) in DS, and 1,861 (23.2%) in NCM. The CCC frequencies in UC and IC were significantly lower (p<0.05) than those in UCR, RIC, DS, and NCM. Conclusion: By the simple algorithm of counting CCC in standardized isometric microscopic digital circles measuring 0.500 mm2, it was possible to differentiate between UC (long-lasting inflammation) and IC (short-lasting inflammation) on the one hand, and UCR, RIC, DS (persistent inflammation), and NCM, on the other. The counting of CCC in the algorithm by five pathologists working in three disparate European Countries, was found to be reproducible.<br
Keywords: ulcerative colitis; colon crypts; frequency; digital samples

The outcome of patients with inflammatory bowel disease-associated colorectal cancer is not worse than that of patients with sporadic colorectal cancer-a matched-pair analysis of survival - Vitali, Francesco; Wein, Axel; Rath, Timo; Eckstein, Markus; Neufert, Clemens; Siebler, Jürgen; Atreya, Raja; Hartmann, Arndt; Hohenberger, Werner; Weber, Klaus; Neurath, Markus; Grützmann, Robert; et al. (International Journal of Colorectal Disease, 2021)
Purpose Patients with inflammatory bowel disease (IBD) have an increased risk for colorectal cancer (CRC). In IBD patients, cancer is often diagnosed in advanced stages and conflicting data on survival compared to sporadic CRC have been reported. The aim of this study was to directly compare clinical characteristics and prognosis of patients with IBD-CRC and sporadic CRC. Methods The clinical and pathological data of 63 patients with IBD-CRC and 3710 patients with sporadic CRC treated at the University Hospital of Erlangen between 1995 and 2015 were compared. Forty-seven M0 patients with IBD were matched with sporadic CRC patients after curative resection (R0) according to tumor localization, stage, sex, and year of treatment. Overall and disease-free survival were compared. Results Sixty-three patients presented IBD-CRC. Fifty were affected with ulcerative colitis (UC) and 13 with Crohn's disease (CD). CRC was diagnosed within 1.45 years since last endoscopic surveillance. Twelve patients (19%) had a diagnosis of primary sclerosing cholangitis. In matched analysis, IBD patients were diagnosed with CRC at younger age compared to sporadic CRC and were more likely to have right-sided CRC (40% versus 23.3%) and rare histological subtypes (19% versus 9.2%). No differences in 5-year overall (78.7 versus 80.9 months) and 5-year disease-free survival (74.5 versus 70.2 months) were noted. Conclusion IBD-CRC patients were younger and more frequently had right-sided carcinomas compared to sporadic CRC. CRC in IBD patients did not show survival difference compared to matched-pair sporadic CRC patients without distant metastases after curative resection. Surveillance might be important for early detection of CRC in IBD patients.
CRIS-Team WoS Importer:2021-12-17

The pan-deacetylase inhibitor panobinostat affects angiogenesis in hepatocellular carcinoma models via modulation of CTGF expression - Gahr, Susanne; Mayr, Christian; Kiesslich, Tobias; Illig, Romana; Neureiter, Daniel; Alinger, Beate; Ganslmayer, Marion; Wissniowski, Till; Di Fazio, Pietro; Montalbano, Roberta; Ficker, Joachim H.; Ocker, Matthias; et al. (International Journal of Oncology, 2015)
Post-translational modifications of chromatin components are significantly involved in the regulation of tumor suppressor gene and oncogene expression. Connective tissue growth factor (CTGF) is an epigenetically regulated growth factor with functions in angiogenesis and cell-matrix interactions and plays a pivotal role in hepatocellular carcinoma (HCC). The pharmacologic inhibition of histone and protein deacetylases represents a new approach to interfere with pathways of apoptosis and angiogenesis. We investigated the effect of the pan-deacetylase inhibitor panobinostat (LBH589) on human HCC cell lines HepG2 (p53wt) and Hep3B (p53null) and in a subcutaneous xenograft model and explored the influence on angiogenesis. Specimens were characterized by quantitative real-time PCR. Protein was separated for western blotting against CTGF, VEGF, VEGF receptor-1 (VEGFR-1/FLT-1), VEGF receptor-2 (VEGFR-2/KDR), MAPK and phospho-MAPK. In vivo, HepG2 cells were xenografted to NMRI mice and treated with daily i.p. injections of 10 mg/kg panobinostat. After 1, 7 and 28 days, real-time PCR was performed. Immunohistochemistry and western blotting were examined after 28 days. An increased significant expression of CTGF was only seen after 24 h treatment with 0.1 µM panobinostat in HepG2 cells and Hep3B cells, whereas after 72 h treatment CTGF expression clearly decreased. In the xenografts, treatment with panobinostat showed a minimal CTGF expression after 1 day and 4 weeks, respectively. In vitro as well as in vivo, VEGF was not affected by panobinostat treatment at any time. In conclusion, panobinostat influences extracellular signaling cascades via CTGF-dependent pathways.
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The Phenotypic Spectrum of Nephropathies Associated with Mutations in Diacylglycerol Kinase? - Azukaitis, Karolis; Simkova, Eva; Majid, Mohammad Abdul; Galiano, Matthias; Benz, Kerstin; Amann, Kerstin Ute; Bockmeyer, Clemens; Gajjar, Radha; Meyers, Kevin E.; Cheong, Hae Ii; Lange-Sperandio, Baerbel; Jungraithnnayr, Therese; et al. (Journal of the American Society of Nephrology, 2017)
The recent discovery of mutations in the gene encoding diacylglycerol kinase ? (DGKE) identified a novel pathophysiologic mechanism leading to HUS and/or MPGN. We report ten new patients from eight unrelated kindreds with DGKE nephropathy. We combined these cases with all previously published cases to characterize the phenotypic spectrum and outcomes of this new disease entity. Most patients presented with HUS accompanied by proteinuria, whereas a subset of patients exhibited clinical and histologic patterns of MPGN without TMA. We also report the first two patients with clinical and histologic HUS/MPGN overlap. DGKE-HUS typically manifested in the first year of life but was not exclusively limited to infancy, and viral triggers frequently preceded HUS episodes. We observed signs of complement activation in some patients with DGKE-HUS, but the role of complement activation remains unclear. Most patients developed a slowly progressive proteinuric nephropathy: 80% of patients did not have ESRD within 10 years of diagnosis. Many patients experienced HUS remission without specific treatment, and a few patients experienced HUS recurrence despite complete suppression of the complement pathway. Five patients received renal allografts, with no post-transplant recurrence reported. In conclusion, we did not observe a clear genotype-phenotype correlation in patients with DGKE nephropathy, suggesting additional factors mediating phenotypic heterogeneity. Furthermore, the benefits of anti-complement therapy are questionable but renal transplant may be a feasible option in the treatment of patients with this condition.
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The Prognostic and Predictive Significance of Tumor-Infiltrating Memory T Cells Is Reversed in High-Risk HNSCC - Hartan, Rebekka; Schnellhardt, Sören; Büttner-Herold, Maike; Daniel, Christoph; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (Cells, 2022)
Tumor-infiltrating CD45RO+ memory T cells have unanimously been described as a positive prognostic factor in head and neck squamous cell carcinomas (HNSCCs). Here, we investigated the long-term prognostic relevance of CD45RO+ memory T cells in HNSCC with special regard to the influence of clinical characteristics. Pre-treatment biopsy samples from 306 patients with predominantly advanced HNSCC were analyzed. Immunohistochemistry was used to stain tissue microarrays for CD45RO+ memory T cells. CD45RO cell densities were semi-automatically registered and used for survival analysis. High CD45RO+ cell densities were clearly associated with prolonged overall survival (OS) and recurrence-free survival as well as no evidence of disease status after 10 years (p < 0.05). In contrast, the prognostic significance of tumor-infiltrating memory T cells was completely reversed in high-risk groups: in poorly differentiated tumors (G3, G4) and in cases with lymph node involvement (N+), high memory T cell densities correlated with reduced 10-year OS (p < 0.05). In conclusion, an increased density of tumor-infiltrating CD45RO+ cells in HNSCC can be a positive as well as a negative prognostic factor, depending on disease stage and histological grade. Therefore, if CD45RO+ cell density is to be used as a prognostic biomarker, further clinical characteristics must be considered.
CRIS-Team WoS Importer:2022-07-08
Keywords: CD45RO; head and neck cancer; memory T cells; prognostic value; reversal of prognostic value

The prognostic impact of Claudin 6 in papillary renal cell carcinoma - Mikuteit, Marie; Zschäbitz, Stefanie; Stöhr, Christine; Herrmann, Edwin; Polifka, Iris; Agaimy, Abbas; Trojan, Lutz; Ströbel, Philipp; Becker, Frank; Wülfing, Christian; Barth, Peter; Stöckle, Michael; et al. (Pathology Research and Practice, 2022)
Background: Claudins are promising biomarkers for diagnosis and prognosis or targets for treatment. They play a major role in signal transduction and are important in nearly all aspects of tumorigenesis. Claudin 6 is a member of the claudin family and is part of the tight junction molecule. It is reactivated in several cancer types and serves as prognostic marker in, for example, gastric, breast or non small cell lung cancer. The prognostic role of Claudin 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), is still unclear. Patients and Methods: The patients’ sample collection was a joint collaboration of the PANZAR consortium. Patients’ medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Claudin 6 was determined by immunohistochemistry. Results: In total, Claudin 6 staining was positive in 55 of 240 type 1 and 30 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed an overall survival of 84% for Claudin 6- compared to 78% for Claudin 6 + in pRCC type 1 tumors (p = 0.449, log-rank) and 68% for Claudin 6- compared to 65.4% for Claudin 6 + in pRCC type 2 tumors (p = 0.364, log-rank). Conclusion: In this study, claudin 6 expression showed no significant association regarding overall survival (OS) and therefore did not qualify as a prognostic marker in pRCC. Future studies will have to determine, whether Claudin 6 plays a prognostic role in other RCC entities. In addition, the function of Claudin 6 as a predictive marker for therapeutic approaches has to be evaluated in future studies.
CRIS-Team Scopus Importer:2022-03-11
Keywords: Claudin 6; Papillary renal cell carcinoma; Prognosis; Survival

The Prognostic Impact of PD-L2 in Papillary Renal-Cell Carcinoma. - Mondorf, Yvonne; Mikuteit, Marie; Ivanyi, Philipp; Stoehr, Christine; Herrmann, Edwin; Polifka, Iris; Agaimy, Abbas; Trojan, Lutz; Stroebel, Philipp; Becker, Frank; Wuelfing, Christian; Barth, Peter; et al. (Urologia Internationalis, 2022)
INTRODUCTION: Programmed death-1 ligand (PD-L1) has been often studied in different types of renal-cell carcinoma (RCC). For example, in clear-cell renal carcinoma it is well established that programmed death-1 receptor and PD-L1 are important prognostic markers. In contrast, the role of programmed death-2 ligand (PD-L2) as prognostic marker remains unclear. The aim of this study was to evaluate if PD-L2 expression could play a role as a prognostic marker for papillary RCC (pRCC). METHODS: The patients' sample collection was a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of PD-L2 was determined by immunohistochemistry. In total, PD-L2 staining was evaluable in 185 of 240 type 1 and 99 of 128 type 2 pRCC cases. RESULTS: PD-L2 staining was positive in 67 (36.2%) of type 1 and in 31 (31.3%) of type 2 pRCC specimens. The prevalence of PD-L2+ cells was significantly higher in high-grade type 1 tumors (p = 0.019) and in type 2 patients with metastasis (p = 0.002). Kaplan-Meier analysis disclosed significant differences in 5-year overall survival (OS) for patients with PD-L2- compared to PD-L2+ in pRCC type 1 of 88.4% compared to 73.6% (p = 0.039) and type 2 of 78.8% compared to 39.1% % (p < 0.001). However, multivariate analysis did not identify the presence of PD-L2+ cells neither in type 1 nor type 2 pRCC as an independent predictor of poor OS. DISCUSSION/CONCLUSION: PD-L2 expression did not qualify as an independent prognostic marker in pRCC. Future studies will have to determine whether anti-PD-L2-targeted treatment may play a role in pRCC and expression can potentially serve as a predictive marker for these therapeutic approaches.
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The Prognostic Value of FGFR3 Expression in Patients with T1 Non-Muscle Invasive Bladder Cancer - Sikic, Danijel; Taubert, Helge; Breyer, Johannes; Eckstein, Markus; Weyerer, Veronika; Keck, Bastian; Kubon, Jennifer; Otto, Wolfgang; Worst, Thomas S.; Kriegnnair, Maximilian C.; Erben, Philipp; Hartmann, Arndt; et al. (Cancer Management and Research, 2021)
Purpose: Fibroblast growth factor receptor 3 (FGFR3) alterations are frequent in non-muscle-invasive bladder cancer (NMIBC), although current data regarding the prognostic and therapeutic relevance are inconsistent. We analyzed the prognostic role of FGFR3 mRNA expression in stage T1 NMIBC. Patients and Methods: The mRNA expression of FGFR3 and cyclin-dependent kinase inhibitor 2A (CDKN2A) was measured by RT-qPCR in 80 patients with stage T1 NMIBC treated with transurethral resection of the bladder and correlated with clinical data and KRT5 and KRT20 expression, used as surrogate markers for basal and luminal subtypes, respectively. Results: FGFR3 and CDKN2A transcript levels were not correlated. FGFR3 expression was associated with the expression of KRT5 (p=0.002) and KRT20 (p < 0.001). CDKN2A expression was negatively correlated with KRT5 (p=0.030). In Kaplan-Meier analysis and univariable Cox regression analysis, high FGFR3 expression was associated with signifi-cantly reduced recurrence-free survival (RFS) (HR=3.78; p < 0.001) and improved overall survival (OS) (HR=0.50; p=0.043), while high CDKN2A expression was associated with reduced OS (HR=2.34; p=0.034). Patient age was the only clinicopathological parameter associated with reduced OS (HR=2.29; p=0.022). No parameter was an independent prog-nostic factor in multivariable analysis. Next, we stratified the patients depending on their lineage differentiation. In univariable analysis, the prognostic effect of FGFR3 and CDKN2A was observed primarily in patients demonstrating high expression of KRT5 or KRT20, whereas high FGFR3 expression was associated with significantly reduced RFS, irrespective of instillation therapy. Conclusion: Stage T1 NMIBC patients with high FGFR3 expression show shorter RFS but better OS than patients with low FGFR3 expression.
CRIS-Team WoS Importer:2021-09-03

The Prognostic Value of FoxP3+Tumour-Infiltrating Lymphocytes in Rectal Cancer Depends on Immune Phenotypes Defined by CD8+Cytotoxic T Cell Density - Schnellhardt, Sören; Hirneth, Johannes; Büttner-Herold, Maike; Daniel, Christoph; Haderlein, Marlen; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (Frontiers in Immunology, 2022)
Tumour-infiltrating FoxP3+ regulatory T cells have been identified as both positive and negative prognostic factors in colorectal cancer (CRC) and rectal cancer (RC). In this study we investigated whether immune phenotypes, defined by CD8+ cytotoxic T cell density, may influence the prognostic association of FoxP3+ T cell densities in RC. Tissue microarrays from 154 rectal cancer resections were immunohistochemically double stained for CD8 and FoxP3. CD8+ and FoxP3+ cell densities were measured in the stromal and intraepithelial compartment. Stromal FoxP3+ cell densities were not associated with 10-year overall survival (OS). In the "immune-desert" phenotype, defined by very low stromal CD8+ cell density, a high density of stromal FoxP3+ T cells displayed a tendency towards an association with decreased 10-year OS (p = 0.179). In "inflamed" tumours, defined by high intraepithelial CD8+ T cell infiltration, the opposite was the case and high stromal FoxP3+ T cell densities were a positive prognostic factor (p = 0.048). Additionally, patients with an increased FoxP3/CD8 cell density ratio demonstrated a strong trend towards decreased 10-year OS (p = 0.066). These contrasting findings suggest functional heterogeneity within the group of FoxP3+ T cells. They are consistent with experimental studies which reported suppressive and non-suppressive populations of FoxP3+ T cells in CRC. Furthermore, our study demonstrates that CD8 immunohistochemistry may act as an instrument to identify tumours infiltrated by possibly functionally differing FoxP3+ T cell subtypes.
CRIS-Team WoS Importer:2022-02-18

The prominent role of the S100A8/S100A9-CD147 axis in the progression of penile cancer - Mohr, Tobias; Zwick, Anabel; Hans, Muriel Charlotte; Bley, Isabelle Ariane; Braun, Felix Leon; Khalmurzaev, Oybek; Matveev, Vsevolod Borisovich; Loertzer, Philine; Pryalukhin, Alexey; Hartmann, Arndt; Geppert, Carol-Immanuel; Loertzer, Hagen; et al. (Frontiers in Oncology, 2022)
Currently, no established biomarkers are recommended for the routine diagnosis of penile carcinoma (PeCa). The rising incidence of this human papillomavirus (HPV)–related cancer entity highlights the need for promising candidates. The Calprotectin subunits S100A8 and S100A9 mark myeloid-derived suppressor cells in other HPV-related entities while their receptor CD147 was discussed to identify patients with PeCa at a higher risk for poor prognoses and treatment failure. We thus examined their expression using immunohistochemistry staining of PeCa specimens from 74 patients on tissue microarrays of the tumor center, the invasion front, and lymph node metastases. Notably, whereas the tumor center was significantly more intensively stained than the invasion front, lymph node metastases were thoroughly positive for both S100 subunits. An HPV-positive status combined with an S100A8+S100A9+ profile was related with an elevated risk for metastases. We observed several PeCa specimens with S100A8+S100A9+-infiltrating immune cells overlapping with CD15 marking neutrophils. The S100A8+S100A9+CD15+ profile was associated with dedifferentiated and metastasizing PeCa, predominantly of HPV-associated subtype. These data suggest a contribution of neutrophil-derived suppressor cells to the progression of HPV-driven penile carcinogenesis. CD147 was elevated, expressed in PeCa specimens, prominently at the tumor center and in HPV-positive PeCa cell lines. CD147+HPV+ PeCa specimens were with the higher-frequency metastasizing cancers. Moreover, an elevated expression of CD147 of HPV-positive PeCa cell lines correlated negatively with the susceptibility to IgA-based neutrophil-mediated tumor cell killing. Finally, stratifying patients regarding their HPV/S100A8/S100A9/CD15/CD147 profile may help identify patients with progressing cancer and tailor immunotherapeutic treatment strategies.
CRIS-Team Scopus Importer:2022-11-04
Keywords: calprotectin; CD147; HPV-related cancer; myeloid-derived suppressor cells; neutrophils; penile cancer; S100A8; S100A9

The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis - Neubert, Kirsten; Meister, Silke; Moser, Katrin; Weisel, Florian; Maseda, Damian; Amann, Kerstin Ute; Wiethe, Carsten; Winkler, Thomas; Kalden, Joachim; Manz, Rudolf A.; Voll, Reinhard E. (Nature Medicine, 2008)
Autoantibody-mediated diseases like myasthenia gravis, autoimmune hemolytic anemia and systemic lupus erythematosus represent a therapeutic challenge. In particular, long-lived plasma cells producing autoantibodies resist current therapeutic and experimental approaches. Recently, we showed that the sensitivity of myeloma cells toward proteasome inhibitors directly correlates with their immunoglobulin synthesis rates. Therefore, we hypothesized that normal plasma cells are also hypersensitive to proteasome inhibition owing to their extremely high amount of protein biosynthesis. Here we show that the proteasome inhibitor bortezomib, which is approved for the treatment of multiple myeloma, eliminates both short- and long-lived plasma cells by activation of the terminal unfolded protein response. Treatment with bortezomib depleted plasma cells producing antibodies to double-stranded DNA, eliminated autoantibody production, ameliorated glomerulonephritis and prolonged survival of two mouse strains with lupus-like disease, NZB/W F1 and MRL/lpr mice. Hence, the elimination of autoreactive plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases. © 2008 Nature Publishing Grou

The protective effect of prolyl-hydroxylase inhibition against renal ischaemia requires application prior to ischaemia but is superior to EPO treatment - Wang, Zhendi; Schley, Gunnar; Türkoglu, Gazi; Burzlaff, Nicolai; Amann, Kerstin Ute; Willam, Carsten; Eckardt, Kai-Uwe; Bernhardt, Wanja M. (Nephrology Dialysis Transplantation, 2012)
Background. Inhibition of the HIF regulating prolyl hydroxylation domain (PHDs) proteins prior to renal injury (preconditioning) has been shown to protect the kidney via activation of hypoxia-inducible transcription factors (HIF). Application of erythropoietin (EPO), one of the HIF target genes, has also been shown to be nephroprotective, and it remains unclear to what extent the effect of HIF induction is mediated by EPO. It is also unknown whether HIF activation after the onset of ischaemia (postconditioning) is still able to protect the kidney. Methods. Using a rat model of renal ischaemia-reperfusion injury, animals were treated with the PHD inhibitor (PHD-I) 2-(1-chloro-4- hydroxyisoquinoline-3-carboxamido) acetate (ICA), vehicle (Veh) or recombinant human EPO (300 IU/ kg) 6 h (ICA or Veh) or 30 min (EPO) prior to ischaemia (preconditioning) or with ICA prior to reperfusion (postconditioning). Renal function was assessed at baseline, 24 h and 72 h. After 72 h, kidneys were processed for histology and morphometric analysis. HIF immunohistochemistry and real-time polymerase chain reaction for HIF target genes, including EPO, were performed to evaluate ICA effects. Results. ICA treatment resulted in stabilization of HIF-1α and -2α and up-regulation of HIF target genes in a dosedependent manner. Preconditional activation of HIF by ICA significantly improved serum creatinine levels and renal morphology in comparison to Veh (P < 0.05), while postconditional ICA treatment was ineffective. EPO therapy improved tissue morphology but had no impact on the course of serum creatinine. Conclusion. These findings are in line with the concept that PHD-Is exert their protective effects through accumulation of HIF target gene products, with time requirements for increased transcription and translation of HIF-dependent genes, and suggest that their renoprotective effect is not predominately mediated by EPO. © 2011 The Author.

The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis - Lopez Posadas, Rocío; Becker, Christoph; Günther, Claudia; Tenzer, Stefan; Amann, Kerstin Ute; Billmeier, Ulrike; Atreya, Raja; Fiorino, Gionata; Vetrano, Stefania; Danese, Silvio; Ekici, Arif Bülent; Wirtz, Stefan; et al. (Journal of Clinical Investigation, 2016)
Although necrosis and necroinflammation are central features of many liver diseases, the role of programmed necrosis in the context of inflammation-dependent hepatocellular death remains to be fully determined. Here, we have demonstrated that the pseudokinase mixed lineage kinase domain-like protein (MLKL), which plays a key role in the execution of receptor-interacting protein (RIP) kinase-dependent necroptosis, is upregulated and activated in human autoimmune hepatitis and in a murine model of inflammation-dependent hepatitis. Using genetic and pharmacologic approaches, we determined that hepatocellular necrosis in experimental hepatitis is driven by an MLKL-dependent pathway that occurs independently of RIPK3. Moreover, we have provided evidence that the cytotoxic activity of the proinflammatory cytokine IFN-? in hepatic inflammation is strongly connected to induction of MLKL expression via activation of the transcription factor STAT1. In summary, our results reveal a pathway for MLKL-dependent programmed necrosis that is executed in the absence of RIPK3 and potentially drives the pathogenesis of severe liver diseases.
EVALuna2:2178

Therapeutic implications of PD-L1 expression in bladder cancer with squamous differentiation - Morsch, Ronja; Rose, Michael; Maurer, Angela; Cassataro, Maria Angela; Braunschweig, Till; Knüchel, Ruth; Vögeli, Thomas Alexander; Ecke, Thorsten; Eckstein, Markus; Weyerer, Veronika; Esposito, Irene; Ackermann, Maximilian; et al. (BMC Cancer, 2020)
BACKGROUND: Immune checkpoint inhibitors (ICI) are an integral part of bladder cancer therapy, however, the relevance of ICI treatment for mixed and pure squamous cell carcinoma of the bladder remains poorly studied. Therefore, we analysed the expression of programmed death-ligand 1 (PD-L1) in urothelial carcinomas with squamous differentiation (UC/SCC) and pure squamous cell carcinoma (SCC) of the bladder and studied a UC/SCC patient with ICI therapy. METHODS: Tissue microarrays of 45 UC/SCC and 63 SCC samples were immunohistochemically stained with four anti-PD-L1 antibodies (28-8, 22C3, SP142 and SP263). PD-L1 expression was determined for tumour cells (TP-Score), immune cells (IC-Score) and combined (CPS, combined positive score). In addition, we present clinical and histological data of an UC/SCC patient with nivolumab therapy. RESULTS: Overall, positive PD-L1 staining ranged between 4.8 and 61.9% for IC and 0 and 51.2% for TC depending on the used antibody. There were no significant differences between UC/SCC and SCC. According to current FDA guidelines for example for first line therapy of urothelial cancer with pembrolizumab (CPS ≥ 10), a subset of SCC patients up to 20% would be eligible. Finally, our UC/SCC index patient revealed excellent therapy response regarding his lung metastasis. CONCLUSIONS: Our data reveal a PD-L1 expression in squamous differentiated carcinomas comparable with current data shown for urothelial tumours. In accordance with the encouraging clinical data of the index patient we suggest ICI treatment also for mixed and pure SCC of the urinary bladder.
CRIS-Team Scopus Importer:2020-03-31
Keywords: Bladder cancer; Immunotherapy; PD-L1; Squamous cell carcinoma

Therapies for synchronous malignomas - the importance of interdisciplinary oncology - Müller, Sarina Katrin; Haderlein, Marlen; Traxdorf, Maximilian; Semrau, Sabine; Agaimy, Abbas; Lettmaier, Sebastian; Gostian, Antoniu-Oreste; Schubart, Christoph; Mantsopoulos, Konstantinos; Schmidt, Daniela; Wiesmüller, Marco; Sievert, Matti; et al. (Laryngo-Rhino-Otologie, 2021)
CRIS-Team WoS Importer:2021-08-06

Therapy response and prognosis of patients with early breast cancer with low positivity for hormone receptors – An analysis of 2765 patients from neoadjuvant clinical trials - Villegas, Sonia L.; Nekljudova, Valentina; Pfarr, Nicole; Engel, Jutta; Untch, Michael; Schrodi, Simone; Holms, Frank; Ulmer, Hans U.; Fasching, Peter; Weber, Karsten E.; Albig, Christian; Heinrichs, Clemens; et al. (European Journal of Cancer, 2021)
Aim: To evaluate HER2-negative breast cancer (BC) with a low hormone receptor (HR) expression, with regard to pathological complete response (pCR) and survival, in comparison to triple-negative BC (TNBC) and strong HR-positive BC. Methods: We compared negative [oestrogen (ER) and progesterone receptor (PR) <1%], low-positive (ER and/or PR 1–9%) and strong-positive (ER or PR 10–100%) HR-expression in neoadjuvant clinical trial cohorts (n = 2765) of BC patients. End-points were disease-free survival (DFS), distant-disease free survival (DDFS) and overall survival (OS). We performed RNA sequencing on available tumour tissue samples from patients with low-HR expression (n = 38). Results: Ninety-four (3.4%) patients had low HR-positive tumours, 1769 (64.0%) had strong HR-positive tumours, and 902 (32.6%) had TNBC. There were no significant differences in pCR rates between women with low HR-positive tumours (27.7%) and women with TNBC (35.5%). DFS and DDFS were also not different [for DFS, hazard ratio 1.26, 95%-CI (confidence interval) : 0.87–1.83, log-rank test p = 0.951; for DDFS, hazard ratio 1.17, 95%-CI: 0.78–1.76, log-rank test p = 0.774]. Patients with strong HR-positive tumours had a significantly lower pCR rate (pCR 9.4%; odds ratio 0.38, 95%-CI: 0.23–0.63), but better DFS (hazard ratio 0.48, 95%-CI: 0.33–0.70) and DDFS (hazard ratio 0.49, 95%-CI: 0.33–0.74) than patients with low HR-positive tumours. Molecular subtyping (RNA sequencing) of low HR-positive tumours classified these predominantly into a basal subtype (86.8%). Conclusion: Low HR-positive, HER2-negative tumours have a similar clinical behaviour to TNBC showing high pCR rates and poor survival and also a basal-like gene expression signature. Patients with low HR-positive tumours should be regarded as candidates for therapy strategies targeting TNBC.
CRIS-Team Scopus Importer:2021-03-26
Keywords: Breast cancer; Breast neoplasms; Cancer biomarkers; ER-negative PR-negative HER2-negative breast cancer; Hormone-dependent neoplasms; Mammary cancer; Neoadjuvant therapy; Oestrogen receptors; Progesterone receptors; Triple-negative breast cancer

The renal cancer risk allele at 14q24.2 activates a novel hypoxia-inducible transcription factor-binding enhancer of DPF3 expression - Protze, Johanna; Naas, Stephanie; Krüger, René; Stöhr, Christine; Kraus, Andre; Grampp, Steffen; Schiffer, Mario; Hartmann, Arndt; Wullich, Bernd; Schödel, Johannes; Wiesener, Michael (Journal of Biological Chemistry, 2022)
Evolution of clear cell renal cell carcinoma is guided by dysregulation of hypoxia-inducible transcription factor (HIF) pathways following loss of the von Hippel-Lindau tumor suppressor protein. Renal cell carcinoma (RCC)-associated polymorphisms influence HIF–DNA interactions at enhancers of important oncogenes thereby modulating the risk of developing renal cancer. A strong signal of genome-wide association with RCC was determined for the single nucleotide polymorphism (SNP) rs4903064, located on chr14q.24.2 within an intron of DPF3, encoding for Double PHD Fingers 3, a member of chromatin remodeling complexes; however, it is unclear how the risk allele operates in renal cells. In this study, we used tissue specimens and primary renal cells from a large cohort of RCC patients to examine the function of this polymorphism. In clear cell renal cell carcinoma tissue, isolated tumor cells as well as in primary renal tubular cells, in which HIF was stabilized, we determined genotype-specific increases of DPF3 mRNA levels and identified that the risk SNP resides in an active enhancer region, creating a novel HIF-binding motif. We then confirmed allele-specific HIF binding to this locus using chromatin immunoprecipitation of HIF subunits. Consequentially, HIF-mediated DPF3 regulation was dependent on the presence of the risk allele. Finally, we show that DPF3 deletion in proximal tubular cells retarded cell growth, indicating potential roles for DPF3 in cell proliferation. Our analyses suggest that the HIF pathway differentially operates on a SNP-induced hypoxia-response element at 14q24.2, thereby affecting DPF3 expression, which increases the risk of developing renal cancer.
CRIS-Team Scopus Importer:2022-03-18

The role of claudin-6 in chromophobe renal cell carcinoma - Erlmeier, Franziska; Zschäbitz, Stefanie; Mikuteit, Marie; Autenrieth, Michael; Weichert, Wilko; Hartmann, Arndt; Steffens, Sandra (Histology and Histopathology, 2023)
BACKGROUND: The prognostic value of Claudin-6 (CLDN6) in non clear cell renal cell carcinoma (RCC) is still unclear. AIM: To evaluate the prognostic impact of CLDN6 expression in a large cohort of chromophobe RCC (chRCC). MATERIAL AND METHODS: Patients who underwent renal surgery due to chRCC were recruited. Clinical data were retrospectively evaluated. Tumor specimens were analyzed for CLDN6 expression by immunohistochemistry. RESULTS: 81 chRCC patients were eligible for analysis, thereof 10 (12.3%) patients were positive for CLDN6. No significant associations were found for CLDN6 expression and clinical attributes in patients with chRCC. Kaplan-Meier analysis revealed no differences in overall survival (OS) for patients with CLDN6⁻ compared to CLDN6⁺ tumors (87.0% versus 62.5%; p=0.174). CONCLUSION: In chRCC CLDN6 expression is not associated with parameters of aggressiveness or survival. Due to the rare incidence of chRCC further studies with larger cohorts are warranted.
CRIS-Team Scopus Importer:2023-04-14

The role of filamins in mechanically stressed podocytes - Greiten, Jonas K.; Kliewe, Felix; Schnarre, Annabel; Artelt, Nadine; Schröder, Sindy; Rogge, Henrik; Amann, Kerstin Ute; Daniel, Christoph; Lindenmeyer, Maja T.; Cohen, Clemens D.; Endlich, Karlhans; Endlich, Nicole (The FASEB Journal, 2021)
Glomerular hypertension induces mechanical load to podocytes, often resulting in podocyte detachment and the development of glomerulosclerosis. Although it is well known that podocytes are mechanosensitive, the mechanosensors and mechanotransducers are still unknown. Since filamin A, an actin-binding protein, is already described to be a mechanosensor and mechanotransducer, we hypothesized that filamins could be important for the outside-in signaling as well as the actin cytoskeleton of podocytes under mechanical stress. In this study, we demonstrate that filamin A is the main isoform of the filamin family that is expressed in cultured podocytes. Together with filamin B, filamin A was significantly up-regulated during mechanical stretch (3 days, 0.5 Hz, and 5% extension). To study the role of filamin A in cultured podocytes under mechanical stress, filamin A was knocked down (Flna KD) by specific siRNA. Additionally, we established a filamin A knockout podocyte cell line (Flna KO) by CRISPR/Cas9. Knockdown and knockout of filamin A influenced the expression of synaptopodin, a podocyte-specific protein, focal adhesions as well as the morphology of the actin cytoskeleton. Moreover, the cell motility of Flna KO podocytes was significantly increased. Since the knockout of filamin A has had no effect on cell adhesion of podocytes during mechanical stress, we simultaneously knocked down the expression of filamin A and B. Thereby, we observed a significant loss of podocytes during mechanical stress indicating a compensatory mechanism. Analyzing hypertensive mice kidneys as well as biopsies of patients suffering from diabetic nephropathy, we found an up-regulation of filamin A in podocytes in contrast to the control. In summary, filamin A and B mediate matrix-actin cytoskeleton interactions which are essential for the adaptation of cultured podocyte to mechanical stress.
CRIS-Team Scopus Importer:2021-04-30
Keywords: diabetic nephropathy; Flna; mechanical load; mechanosensor; mechanotransducer

The role of interleukin-10 in asthma - Yang, Zuqin; Li, N.; Kölle, Julia; Rieker, Ralf; Finotto, Susetta (ALLERGY, 2020)
CRIS-Team WoS Importer:2020-10-02

The role of interleukin 3 (IL3) in allergic asthma - Kölle, Julia; Vuorinen, T.; Kiefer, Alexander; Zimmermann, Theodor; Xepapadaki, P.; Rieker, Ralf; Papadopoulos, N. G.; Finotto, Susetta (ALLERGY, 2020)
CRIS-Team WoS Importer:2020-10-02

The Role of Microsatellite Instability/DNA Mismatch Repair Deficiency and Tumor Mutational Burden as Biomarkers in Predicting Response to Immunotherapy in Castration-resistant Prostate Cancer - Klümper, Niklas; Grünwald, Viktor; Hartmann, Arndt; Hölzel, Michael; Eckstein, Markus (European Urology, 2024)
CRIS-Team Scopus Importer:2024-11-15

The Role of Palladin in Podocytes - Artelt, Nadine; Ludwig, Tim A.; Rogge, Henrik; Kavvadas, Panagiotis; Siegerist, Florian; Blumenthal, Antje; Van Den Brandt, Jens; Otey, Carol A.; Bang, Marie-Louise; Amann, Kerstin Ute; Chadjichristos, Christos E.; Chatziantoniou, Christos; et al. (Journal of the American Society of Nephrology, 2018)
Background Podocyte loss and effacement of interdigitating podocyte foot processes are the major cause of a leaky filtration barrier and ESRD. Because the complex three-dimensional morphology of podocytes depends on the actin cytoskeleton, we studied the role in podocytes of the actin bundling protein palladin, which is highly expressed therein.Methods We knocked down palladin in cultured podocytes by siRNA transfection or in zebrafish embryos by morpholino injection and studied the effects by immunofluorescence and live imaging. We also investigated kidneys of mice with podocyte-specific knockout of palladin (PodoPalld-/- mice) by immunofluorescence and ultrastructural analysis and kidney biopsy specimens from patients by immunostaining for palladin.Results Compared with control-treated podocytes, palladin-knockdown podocytes had reduced actin filament staining, smaller focal adhesions, and downregulation of the podocyte-specific proteins synaptopodin and α-actinin-4. Furthermore, palladin-knockdown podocytes were more susceptible to disruption of the actin cytoskeleton with cytochalasin D, latrunculin A, or jasplakinolide and showed altered migration dynamics. In zebrafish embryos, palladin knockdown compromised the morphology and dynamics of epithelial cells at an early developmental stage. Compared with PodoPalld+/+ controls, PodoPalld-/- mice developed glomeruli with a disturbed morphology, an enlarged subpodocyte space, mild effacement, and significantly reduced expression of nephrin and vinculin. Furthermore, nephrotoxic serum injection led to significantly higher levels of proteinuria in PodoPalld-/- mice than in controls. Kidney biopsy specimens from patients with diabetic nephropathy and FSGS showed downregulation of palladin in podocytes as well.Conclusions Palladin has an important role in podocyte function in vitro and in vivo.
EVALuna2:34432

The role of plastic reconstructive surgery in surgical therapy of soft tissue sarcomas - Götzl, Rebekka; Sterzinger, Sebastian; Arkudas, Andreas; Boos, Anja; Semrau, Sabine; Vassos, Nikolaos; Grützmann, Robert; Agaimy, Abbas; Hohenberger, Werner; Horch, Raymund E.; Beier, Justus (Cancers, 2020)
Background: Soft tissue sarcoma (STS) treatment is an interdisciplinary challenge. Along with radio(chemo)therapy, surgery plays the central role in STS treatment. Little is known about the impact of reconstructive surgery on STS, particularly whether reconstructive surgery enhances STS resection success with the usage of flaps. Here, we analyzed the 10-year experience at a university hospital’s Comprehensive Cancer Center, focusing on the role of reconstructive surgery. Methods: We performed a retrospective analysis of STS-patients over 10 years. We investigated patient demographics, diagnosis, surgical management, tissue/function reconstruction, complication rates, resection status, local recurrence and survival. Results: Analysis of 290 patients showed an association between clear surgical margin (R0) resections and higher-grade sarcoma in patients with free flaps. Major complications were lower with primary wound closure than with flaps. Comparison of reconstruction techniques showed no significant differences in complication rates. Wound healing was impaired in STS recurrence. The local recurrence risk was over two times higher with primary wound closure than with flaps. Conclusion: Defect reconstructions in STS are reliable and safe. Plastic surgeons should have a permanent place in interdisciplinary surgical STS treatment, with the full armamentarium of reconstruction methods.
CRIS-Team Scopus Importer:2020-12-04
Keywords: Plastic surgery; Reconstruction; Reconstructive surgery; Soft tissue sarcoma; STS

The role of Signal Transducer and Activator of Transcription protein 5 (STAT5) in non-small cell lung cancer (NSCLC) - Friedrich, Juliane; Heim, Lisanne; Springel, Rebekka; Mittler, Susanne; Gafencu, Dumitrita; Hartmann, Arndt; Sirbu, Horia; Finotto, Susetta (2016)
EVALuna2:25983

The role of sphingosine kinase isoforms and receptors S1P1, S1P2, S1P3, and S1P5 in primary, secondary, and recurrent glioblastomas - Quint, Karl; Stiel, Norbert; Neureiter, Daniel; Schlicker, Hans Ulrich; Nimsky, Christopher; Ocker, Matthias; Strik, Herwig; Kolodziej, Malgorzata Anna (Tumor Biology, 2014)
Sphingosine-1-phosphate (S1P), the corresponding kinases SphK1-2, and receptors S1P1-3 and S1P5 are involved in cell survival and growth. Pathway components are overexpressed in many tumors including glioblastoma. Previous studies showed that the expression of SphK1 influenced survival of glioblastoma patients, yet the roles of SphK1-2 and receptors S1P1-3 and S1P5 have not been investigated in different forms of glioblastoma. Samples from 59 patients (37 males, 22 females, age 55.1 ± 17.1 years) suffering from primary (n = 35), recurrent (n = 18), and secondary (n = 6) glioblastomas were analyzed using quantitative real-time PCR and immunohistochemistry for expression levels of SphK1 and SphK2 and S1P1-3 and S1P5. Sixteen autopsy nontumorous brain specimens were used as controls. Expression data was correlated with clinical data and patient survival. All markers were overexpressed in the glioblastoma specimens compared to the non-neoplastic brain tissue. SphK1 and all S1P receptors were expressed in increasing order of magnitude from primary, up to recurrent and secondary glioblastomas, with values of up to 44-fold compared to normal brain tissue. In contrast, SphK2 levels were highest in primary tumors (25-fold). Expression of the sphingosine signaling pathway components was influenced by radio/radiochemotherapy in distinct ways. Immunohistochemistry for SphK1 and S1P1 confirmed the overexpression in glioblastoma. Uni- and multivariate survival analyses identified S1P5 messenger RNA levels as an independent prognostic factor of survival. The sphingosine pathway is overexpressed in glioma. Its components show distinct expression patterns in the tumor subgroups. S1P5 is identified as an independent prognostic factor in multivariate analysis, and this pathway promises to be a candidate for targeted therapies.
EVALuna2:6735

The role of STAT3 (signal transducer and activator of transcription 3) in non-small cell lung cancer (NSCLC) - Heim, Lisanne; Andreev, Katerina; Balabko, Ljubov; Trufa, Denis; Sirbu, Horia; Hartmann, Arndt; Finotto, Susetta (2016)
EVALuna2:25984

The synergism of spatial metabolomics and morphometry improves machine learning-based renal tumour subtype classification. - Prade, Verena M.; Sun, Na; Shen, Jian; Feuchtinger, Annette; Kunzke, Thomas; Buck, Achim; Schraml, Peter; Moch, Holger; Schwamborn, Kristina; Autenrieth, Michael; Gschwend, Jurgen E.; Erlmeier, Franziska; et al. (Clinical and Translational Medicine, 2022)
EVALuna2:536086

The TLR9 agonist cobitolimod induces IL10 producing wound healing macrophages and regulatory T cells in ulcerative colitis - Schmitt, Heike; Ulmschneider, Julia; Billmeier, Ulrike; Scarozza, Patrizio; Sonnewald, Sophia; Reid, Stephen; Atreya, Imke; Rath, Timo; Zundler, Sebastian; Langheinrich, Melanie; Schüttler, Jürgen; Hartmann, Arndt; et al. (Journal of Crohns & Colitis, 2020)
BACKGROUND AND AIMS: The topically applied Toll-like receptor 9 (TLR9) agonist cobitolimod is a first-in-class DNA-based oligonucleotide that demonstrated therapeutic efficacy in clinical trials with ulcerative colitis (UC) patients. We here characterized its anti-inflammatory mechanism in UC. METHODS: Luminal cobitolimod administration was evaluated in an experimental DSS-induced colitis model. Cultured blood and mucosal cells from UC patients were treated with cobitolimod and analyzed via microarray, qRT-PCR, ELISA and flow cytometry. Intestinal slides of cobitolimod treated UC patients were analyzed by immunohistochemistry. RESULTS: Cobitolimod administration markedly suppressed experimental colitis activity and microarrays analyses demonstrated mucosal IL10 upregulation and suppression of IL17 signaling pathways. Cobitolimod treatment was associated with significant induction of mucosal IL10+ Tr1 and Treg cells and suppression of Th17 cells. TLR9 knockout mice indicated that cobitolimod requires TLR9 signaling for IL10 induction. In UC patients, mucosal TLR9 levels correlated with severity of inflammation. Cobitolimod inhibited IL17A and IL17F, but increased IL10 and FoxP3 expression in cultured intestinal UC T cells. Cobitolimod-mediated suppression of intestinal IL17+ T cells was abrogated by IL10 blockade. Furthermore, cobitolimod led to heightened IL10 production by wound healing macrophages. Immunohistochemistry in intestinal biopsies of cobitolimod treated UC patients indicated increased presence of IL10+ mononuclear and regulatory T cells, as well as reduction of IL17+ cells. CONCLUSION: Our studies suggest that activation of TLR9 via cobitolimod might represent a novel therapeutic approach in UC, as it suppresses Th17 cells and induces anti-inflammatory IL10+ macrophages and regulatory T cells, thereby modifying the dysregulated intestinal cytokine balance.
EVALuna2:212910
Keywords: Ulcerative colitis; TLR9; cobitolimod

The transcription factor Dach1 is essential for podocyte function - Endlich, Nicole; Kliewe, Felix; Kindt, Frances; Schmidt, Katharina; Kotb, Ahmedm.; Artelt, Nadine; Lindenmeyer, Maja T.; Cohen, Clemens D.; Doering, Franziska; Kuss, Andreas W.; Amann, Kerstin Ute; Moeller, Marcus J.; et al. (Journal of Cellular and Molecular Medicine, 2018)
Dedifferentiation and loss of podocytes are the major cause of chronic kidney disease. Dach1, a transcription factor that is essential for cell fate, was found in genome-wide association studies to be associated with the glomerular filtration rate. We found that podocytes express high levels of Dach1 in vivo and to a much lower extent in vitro. Parietal epithelial cells (PECs) that are still under debate to be a type of progenitor cell for podocytes expressed Dach1 only at low levels. The transfection of PECs with a plasmid encoding for Dach1 induced the expression of synaptopodin, a podocyte-specific protein, demonstrated by immunocytochemistry and Western blot. Furthermore, synaptopodin was located along actin fibres in a punctate pattern in Dach1-expressing PECs comparable with differentiated podocytes. Moreover, dedifferentiating podocytes of isolated glomeruli showed a significant reduction in the expression of Dach1 together with synaptopodin after 9 days in cell culture. To study the role of Dach1 in vivo, we used the zebrafish larva as an animal model. Knockdown of the zebrafish ortholog Dachd by morpholino injection into fertilized eggs resulted in a severe renal phenotype. The glomeruli of the zebrafish larvae showed morphological changes of the glomerulus accompanied by down-regulation of nephrin and leakage of the filtration barrier. Interestingly, glomeruli of biopsies from patients suffering from diabetic nephropathy showed also a significant reduction of Dach1 and synaptopodin in contrast to control biopsies. Taken together, Dach1 is a transcription factor that is important for podocyte differentiation and proper kidney function.
EVALuna2:34433

The TRPC5 receptor as pharmacological target for pain and metabolic disease - Khare, Pragyanshu; Chand, Jagdish; Ptakova, Alexandra; Liguori, Renato; Ferrazzi, Fulvia; Bishnoi, Mahendra; Vlachova, Viktorie; Zimmermann, Katharina (Pharmacology & Therapeutics, 2024)
The transient receptor potential canonical (TRPC) channels are a group of highly homologous nonselective cation channels from the larger TRP channel family. They have the ability to form homo- and heteromers with varying degrees of calcium (Ca2+) permeability and signalling properties. TRPC5 is the one cold-sensitive among them and likewise facilitates the influx of extracellular Ca2+ into cells to modulate neuronal depolarization and integrate various intracellular signalling pathways. Recent research with cryo-electron microscopy revealed its structure, along with clear insight into downstream signalling and protein-protein interaction sites. Investigations using global and conditional deficient mice revealed the involvement of TRPC5 in metabolic diseases, energy balance, thermosensation and conditions such as osteoarthritis, rheumatoid arthritis, and inflammatory pain including opioid-induced hyperalgesia and hyperalgesia following tooth decay and pulpitis. This review provides an update on recent advances in our understanding of the role of TRPC5 with focus on metabolic diseases and pain.
CRIS-Team Scopus Importer:2024-10-25
Keywords: Calcium homeostasis; Energy expenditure; Glucose homeostasis; Inflammatory pain; Metabolism; TRPC5

The tumor immune microenvironment drives a prognostic relevance that correlates with bladder cancer subtypes - Pfannstiel, Carolin; Strissel, Pamela; Chiappinelli, Katherine B.; Sikic, Danijel; Wach, Sven; Wirtz, Ralph M.; Wullweber, Adrian; Taubert, Helge; Breyer, Johannes; Otto, Wolfgang; Worst, Thomas; Burger, Maximilian; et al. (Cancer Immunology Research, 2019)
Muscle-invasive bladder cancer (MIBC) represents approximately two-thirds of invasive urothelial bladder cancers (UBC) and has high morbidity and mortality. Men are over 3-fold more frequently affected by UBC than women. Despite intensive efforts to improve patient treatment and outcome, two-thirds of patients with UBC will have a recurrence or disease progression within 5 years. We demonstrated that the quantity and spatial distribution of stromal tumor-infiltrating lymphocytes (sTIL) within the tumor immune microenvironment (TIME) predict stages of tumor inflammation, subtypes, and patient survival and correlate with expression of immune checkpoints in an analysis of 542 patients with MIBC. High sTILs indicated an inflamed subtype with an 80% 5-year DSS, and a lack of immune infiltrates identified an uninflamed subtype with a survival rate of less than 25%. A separate immune evading phenotype with upregulated immune checkpoints associated with poor survival. Within the TIME are tertiary lymphoid structures (TLS), which can mediate antitumor activity via immune cells. High TLS amounts and close tumor distance correlated significantly with an inflamed phenotype and favorable survival. The uninflamed and evasion phenotypes showed lowest TLS numbers, farthest tumor distances, and shortest survival. High inflammation also correlated with increased neoantigen load and mutational burden. Patients treated with adjuvant chemotherapy showed a favorable prognosis, which was dependent on high sTILs. Determination of sTILs and tumor subtypes may stratify therapy success and patient survival, and considering sTILs can easily be quantified using simple morphologic parameters, like hematoxylin and eosin, sTILs can be implemented for predicting patient survival in a routine manner.
CRIS-Team Scopus Importer:2019-06-21

The validation of estrogen receptor 1 mRNA expression as a predictor of outcome in patients with metastatic non-small cell lung cancer - Atmaca, Akin; Al-Batran, Salah-Eddin; Wirtz, Ralph Markus; Werner, Dominique; Zirlik, Sabine; Wiest, Gunther; Eschbach, Corinna; Claas, Silke; Hartmann, Arndt; Ficker, Joachim Hans; Jaeger, Elke; Brueckl, Wolfgang Michael (International Journal of Cancer, 2014)
The prognostic role of estrogen receptors in lung cancer is not validated. Results from patients with early stage non-small lung cancer patients indicate a prognostic role of estrogen receptor 1 (ESR1) mRNA expression in these patients. Automated RNA extraction from paraffin and RT-quantitative PCR was used for evaluation of tumoral ESR1 and progesterone receptor (PGR) mRNA expression. The test cohort consisted of 31 patients with advanced or metastatic non-small cell lung cancer (NSCLC) patients, treated in a first-line registry trial. For validation, 53 patients from a randomized multicentre first-line study with eligible tumor samples were evaluated. There was no significant correlation of ESR1 expression with clinical characteristics. ESR1 high expression was of significant positive prognostic value in the training set with a median overall survival (OS) of 15.9 versus 6.2 months for high versus low ESR1 expression patients (p = 0.0498, HR 0.39). This could be confirmed in the validation cohort with a median OS of 10.9 versus 5.0 months in ESR1 high versus low patients, respectively (p = 0.0321, HR 0.51). In the multivariate analysis adjusted for histological subtype, gender, age and performance status, ESR1 expression remained an independent prognostic parameter for survival in both cohorts. In contrast to ESR1, PGR expression was not able to separate prognostic groups or to predict outcome significantly (for OS; p = 0.94). Our study shows that ESR1 mRNA as assessed by qPCR represents a reliable method for detecting ESR1 expression in NSCLC and that ESR1 expression is an independent prognostic factor in metastatic NSCLC.
EVALuna2:1901

The WERA cancer center matrix: Strategic management of patient access to precision oncology in a large and mostly rural area of Germany - Krebs, Markus; Haller, Florian; Spörl, Silvia; Gerhard-Hartmann, Elena; Utpatel, Kirsten; Maurus, Katja; Kunzmann, Volker; Chatterjee, Manik; Venkataramani, Vivek; Maatouk, Imad; Bittrich, Max; Einwag, Tatjana; et al. (European Journal of Cancer, 2024)
Purpose: Providing patient access to precision oncology (PO) is a major challenge of clinical oncologists. Here, we provide an easily transferable model from strategic management science to assess the outreach of a cancer center. Methods: As members of the German WERA alliance, the cancer centers in Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact. Specifically, we examined the provenance of patients from WERA´s molecular tumor boards (MTBs) between 2020 and 2022 (n = 2243). As second dimension, we added the provenance of patients receiving general cancer care by WERA. Clustering our catchment area along these two dimensions set up a four-quadrant matrix consisting of postal code areas with referrals towards WERA. These areas were re-identified on a map of the Federal State of Bavaria. Results: The WERA matrix overlooked an active screening area of 821 postal code areas – representing about 50 % of Bavaria´s spatial expansion and more than six million inhabitants. The WERA matrix identified regions successfully connected to our outreach structures in terms of subsidiarity – with general cancer care mainly performed locally but PO performed in collaboration with WERA. We also detected postal code areas with a potential PO backlog – characterized by high levels of cancer care performed by WERA and low levels or no MTB representation. Conclusions: The WERA matrix provided a transparent portfolio of postal code areas, which helped assessing the geographical impact of our PO program. We believe that its intuitive principle can easily be transferred to other cancer centers.
CRIS-Team Scopus Importer:2024-06-14
Keywords: Cancer care facilities; Community health services; Health services administration; Healthcare disparities; Intersectoral collaboration; Tertiary healthcare

The World Health Organization 1973 classification system for grade is an important prognosticator in T1 non-muscle-invasive bladder cancer - van de Putte, Elisabeth E.Fransen; Bosschieter, Judith; van der Kwast, Theo H.; Bertz, Simone; Denzinger, Stefan; Manach, Quentin; Compérat, Eva M.; Boormans, Joost L.; Jewett, Michael A.S.; Stoehr, Robert; van Leenders, Geert J.L.H.; Nieuwenhuijzen, Jakko A.; et al. (Bju International, 2018)
OBJECTIVES: To compare the prognostic value of the World Health Organization (WHO) 1973 and 2004 classification systems for grade in T1 bladder cancer (T1-BC), as both are currently recommended in international guidelines. PATIENTS AND METHODS: Three uro-pathologists re-revised slides of 601 primary (first diagnosis) T1-BCs, initially managed conservatively (bacille Calmette-Guérin) in four hospitals. Grade was defined according to WHO1973 (Grade 1-3) and WHO2004 (low-grade [LG] and high-grade [HG]). This resulted in a lack of Grade 1 tumours, 188 (31%) Grade 2, and 413 (69%) Grade 3 tumours. There were 47 LG (8%) vs 554 (92%) HG tumours. We determined the prognostic value for progression-free survival (PFS) and cancer-specific survival (CSS) in Cox-regression models and corrected for age, sex, multiplicity, size and concomitant carcinoma in situ. RESULTS: At a median follow-up of 5.9 years, 148 patients showed progression and 94 died from BC. The WHO1973 Grade 3 was negatively associated with PFS (hazard ratio [HR] 2.1) and CSS (HR 3.4), whilst WHO2004 grade was not prognostic. On multivariable analysis, WHO1973 grade was the only prognostic factor for progression (HR 2.0). Grade 3 tumours (HR 3.0), older age (HR 1.03) and tumour size >3 cm (HR 1.8) were all independently associated with worse CSS. CONCLUSION: The WHO1973 classification system for grade has strong prognostic value in T1-BC, compared to the WHO2004 system. Our present results suggest that WHO1973 grade cannot be replaced by the WHO2004 classification in non-muscle-invasive BC guidelines.
EVALuna2:34812

Three-Dimensional Rotational Angiography during Catheterization of Congenital Heart Disease – A ten Years’ experience at a single center - Söder, Stephan; Wällisch, Wolfgang; Dittrich, Sven; Cesnjevar, Robert; Pfammatter, Jean Pierre; Glöckler, Martin (Scientific Reports, 2020)
This paper aims to assess the usability and advantages of three-dimensional rotational angiography (3DRA) in patients with congenital heart disease (CHD) and its application in the cath lab. Up to now, its use in CHD is not widespread or standardized. We analyzed all patients with CHD who underwent a 3DRA at our facility between January 2010 and May 2019. The 3DRAs were evaluated for radiation exposure, contrast dye consumption, diagnostic utility and image quality. We performed 872 3DRAs. 3DRA was used in 67.1% of the cases for interventional procedures and in 32.9% for diagnostic purposes. Two different acquisition programs were applied. The median dose-area product (DAP) for all 872 rotations was 54.1 µGym2 (21.7–147.5 µGym2) and 1.6 ml/kg (0.9–2.07 ml/kg) of contrast dye was used. Diagnostic utility of the generated 3D-model was rated superior to the native 3D angiography in 94% (819/872). 3DRA is an excellent and save diagnostic and interventional tool. However, 3DRA has not become a standard imaging procedure in pediatric cardiology up to now. Effort and advantage seems to be unbalanced, but new less invasive techniques may upgrade this method in future.
CRIS-Team Scopus Importer:2020-05-05

Thrombospondin-1 is a major activator of TGF-β in fibrotic renal disease in the rat in vivo - Daniel, Christoph; Wiede, Julia; Krutzsch, Henry C.; Ribeiro, Solange M. F.; Roberts, David D.; Murphy-Ullrich, Joanne E.; Hugo, Christian (Kidney International, 2004)
Background. Transforming growth factor-β (TGF-β), a profibrotic cytokine involved in many scarring processes, has to be activated extracellularly before it can bind to its receptors. Thrombospondin 1 (TSP1), a multifunctional matricellular glycoprotein, has been identified as an activator of TGF-β in in vitro systems and during mouse postnatal development in vivo. TSP1 is expressed de novo in many inflammatory disease processes, including glomerular disease. Methods. In this study we investigated whether peptides specifically interfering with the activation process of TGF-β by TSP1 may be able to block activation of TGF-β in an in vivo model of mesangial proliferative glomerulonephritis. Results. Continuous intravenous infusion of blocking peptide by minipumps significantly reduced expression of active TGF-β in glomeruli on day 7 of disease as indicated by immunohistochemistry, bioassay, and activation of the TGF-β signal transduction pathway, while total TGF-β expression was unchanged. Inhibition of glomerular TGF-β activation was accompanied by a decrease of glomerular extracellular matrix accumulation and proteinuria, but was without effect on mesangial cell proliferation or influx of monocytes/macrophages. Conclusion. TSP1 is a major endogenous activator of TGF-β in experimental inflammatory glomerular disease. Drugs interfering with the activation of TGF-β by locally produced TSP1 may be considered as a future specific treatment of scarring kidney disease.
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Keywords: Extracellular matrix; Glomerulonephritis; TGF-β activation; Thrombospondin-1

Thrombospondin-1 is an endogenous activator of TGF-β in experimental diabetic nephropathy in vivo - Daniel, Christoph; Schaub, Kathrin; Amann, Kerstin Ute; Lawler, Jack; Hugo, Christian (Diabetes, 2007)
OBJECTIVE - Transforming growth factor-β (TGF-β), the central cytokine responsible for the development of diabetic nephropathy, is usually secreted as a latent procytokine complex that has to be activated before it can bind to its receptors. Recent studies by our group demonstrated that thrombospondin-1 (TSP-1) is the major activator of latent TGF-β in experimental glomerulonephritis in the rat, but its role in diabetic nephropathy in vivo is unknown. RESEARCH DESIGN AND METHODS - Type 1 diabetes was induced in wild-type (n = 27) and TSP-1-deficient mice (n = 36) via streptozotocin injection, and diabetic nephropathy was investigated after 7, 9.5, and 20 weeks. Renal histology, TGF-β activation, matrix accumulation, and inflammation were assessed by immunohistology. Expression of fibronectin and TGF-β was evaluated using real-time PCR. Furthermore, functional parameters were examined. RESULTS - In TSP-1-deficient compared with wild-type mice, the amount of active TGF-β within glomeruli was significantly lower, as indicated by staining with specific antibodies against active TGF-β or the TGF-β signaling molecule phospho-smad2/3 or the typical TGF-β target gene product plasminogen activator inhibitor-1. In contrast, the amount of glomerular total TGF-β remained unchanged. The development of diabetic nephropathy was attenuated in TSP-1-deficient mice as demonstrated by a significant reduction of glomerulosclerosis, glomerular matrix accumulation, podocyte injury, renal infiltration with inflammatory cells, and renal functional parameters. CONCLUSIONS - We conclude that TSP-1 is an important activator of TGF-β in diabetic nephropathy in vivo. TSP-1-blocking therapies may be considered a promising future treatment option for diabetic nephropathy. © 2007 by the American Diabetes Association.
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Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in experimental glomerulonephritis in mice - Daniel, Christoph; Amann, Kerstin Ute; Hohenstein, Bernd; Bornstein, Paul; Hugo, Christian (Journal of the American Society of Nephrology, 2007)
The role of thrombospondin 2 (TSP2) was investigated in an anti-glomerular basement membrane (GBM) nephritis model that compared TSP2-null mice with wild-type (WT) controls. TSP2-null mice were analyzed for kidney function, renal cortical matrix expansion, influx of inflammatory cells, proliferation, and apoptosis, as well as for capillary rarefaction after induction of anti-GBM disease. Whereas the renal cortex of normal control WT mice did not show any detectable TSP2 staining above background, TSP2 protein expression was clearly upregulated in anti-GBM disease. TSP2 deficiency led to an accelerated and enhanced inflammatory response, as indicated by the influx of CD4+ and CD8a+ cells and monocytes/macrophages. Glomerular fibrin deposition and a matrix-remodeling response were also observed, as indicated by collagens I and IV staining and a proliferative response within the renal interstitium. These changes were accompanied by increased matrix metalloproteinase 2 activity and enhanced α-smooth muscle actin staining in the TSP2-null mice. Neither a compensatory increase in TSP1 nor increased phosphorylation of Smad 2/3, an indicator for TGF-β activity, was observed. The proliferative response of the peritubular endothelium was accelerated and enhanced, leading to a reversal of capillary rarefaction in TSP2-null mice, whereas interstitial cell death was equivalent to that in WT mice. In conclusion, the lack of the matricellular protein TSP2 in mice accelerates and enhances several responses to renal injury and reveals an important role for TSP2 as a major endogenous antiangiogenic and matrix metalloproteinase 2-regulating factor in renal disease. Copyright © 2007 by the American Society of Nephrology.
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Thrombospondin-2 therapy ameliorates experimental glomerulonephritis via inhibition of cell proliferation, inflammation, and TGF-β activation - Daniel, Christoph; Wagner, Andrea; Hohenstein, Bernd; Hugo, Christian (American Journal of Physiology-Renal Physiology, 2009)
We recently identified thrombospondin-2 (TSP-2) as an endogenous regulator of matrix remodelling and inflammation in experimental kidney disease by studying TSP-2-deficient mice. In this study, we asked whether systemic TSP-2 overexpression via thigh muscle transfection is able to ameliorate the time course of the anti-Thy1 glomerulonephritis model. After induction of anti-Thy1 nephritis, rats were transfected either with an overexpression plasmid for TSP-2 or lacZ as a control. Biopsies, urine, and blood samples were taken on days 1, 3, and 6 after disease induction. Muscular overexpression of TSP-2 reduced glomerular transforming growth factor (TGF)-β activation and glomerular extracellular matrix formation as determined by collagen IV and fibronectin. In addition, activation of mesangial cells to the myofibroblast-like phenotype was also significantly decreased in TSP-2-overexpressing animals. TSP-2 overexpression inhibited both glomerular endothelial and mesangial cell proliferation, resulting in a reduced glomerular cell number and glomerular tuft area. The inflammatory response, as monitored by T cells and antigen-presenting cells, was reduced significantly by TSP-2 overexpression, but influx of macrophages was unchanged. These data demonstrate TSP-2 as a potential therapeutic agent to inhibit the glomerular proliferative and inflammatory response as well as TGF-β activation and extracellular matrix accumulation in experimental mesangial proliferative glomerulonephritis. Copyright © 2009 the American Physiological Society.
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Keywords: Extracellular matrix; Glomerulonephritis; Proliferation; Thrombospondin-2; Transforming growth factor-β activation

Thrombospondin in renal disease - Hugo, Christian; Daniel, Christoph (Nephron Experimental Nephrology, 2009)
Thrombospondins (TSPs) are multifunctional matricellular glycoproteins which are involved in the regulation of angiogenesis, proliferation, apoptosis, the NO-cGMP-dependent protein kinase pathway and transforming growth factor (TGF) β activation. The TSP family consists of 5 members, but currently only data on effects of TSP-1 and TSP-2 in renal disease are available. Both TSPs are hardly expressed within the healthy renal cortex and can be upregulated during renal disease. Using different animal models for renal disease, TSP-1 and -2 were found to be important regulators of pathophysiological changes during renal disease with similar and contrary effects. TSP-1 is a major activator for TGF-β resulting in profibrotic effects in the injured kidney. In contrast, TSP-2 lacks the ability for its activation. Proapoptotic actions of TSP-1 were found during renal ischemia/reperfusion injury. While TSP-1 exerts proinflammatory actions, the currently available data for TSP-2 propose anti-inflammatory effects for this molecule. Both TSPs are known angiogenesis inhibitors, which could be proved for TSP-2, but antiangiogenic effects for TSP-1 were only evident by treatment with TSP-1 peptides in renal disease. In addition, TSP-2 can inhibit cell proliferation and matrix metalloproteinase 2 activity. © 2009 S. Karger AG, Basel.
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Keywords: Angiogenesis inhibitor; Thrombospondin

Thymoquinone: fifty years of success in the battle against cancer models - Schneider-Stock, Regine; Fakhoury, Isabelle H.; Zaki, Angela M.; El Baba, Chirine; Gali-Muhtasib, Hala U. (Drug Discovery Today, 2014)
Thymoquinone (TQ), the main active constituent of black seed essential oil, exhibits promising effects against inflammatory diseases and cancer. TQ, modulates signaling pathways that are key to cancer progression, and enhances the anticancer potential of clinical drugs while reducing their toxic side effects. Considering that TQ was isolated 50 years ago, this review focuses on TQ's chemical and pharmacological properties and the latest advances in TQ analog design and nanoformulation. We discuss our current state of knowledge of TQ's adjuvant potential and in vivo antitumor activity and highlight its ability to modulate the hallmarks of cancer.
EVALuna2:6619

Thymoquinone-induced conformational changes of PAK1 interrupt prosurvival MEK-ERK signaling in colorectal cancer - El Baba, Chirine; Mahadevan, Vijayalakshmi; Fahlbusch, Fabian B.; Mohan, Suma S.; Rau, Tilman; Gali-Muhtasib, Hala; Schneider-Stock, Regine (Molecular Cancer, 2014)
Thymoquinone (TQ) was shown to reduce tumor growth in several cancer models both in vitro and in vivo. So far only a few targets of TQ, including protein kinases have been identified. Considering that kinases are promising candidates for targeted anticancer therapy, we studied the complex kinase network regulated by TQ.Novel kinase targets influenced by TQ were revealed by in silico analysis of peptide array data obtained from TQ-treated HCT116wt cells. Western blotting and kinase activity assays were used to determine changes in kinase expression patterns in colorectal cancer cells (HCT116wt, DLD-1, HT29). To study the viability/apoptotic effects of combining the PAK1 inhibitor IPA-3 and TQ, crystal violet assay and AnnexinV/PI staining were employed. Interactions between PAK1 and ERK1/2 were investigated by co-immunoprecipitation and modeled by docking studies. Transfection with different PAK1 mutants unraveled the role of TQ-induced changes in PAK1 phosphorylation and TQ's effects on PAK1 scaffold function.Of the 104 proteins identified, 50 were upregulated >= 2 fold by TQ and included molecules in the AKT-MEK-ERK1/2 pathway. Oncogenic PAK1 emerged as an interesting TQ target. Time-dependent changes in two PAK1 phosphorylation sites generated a specific kinase profile with early increase in pPAK(Thr212) followed by late increase in pPAK(Thr423). TQ induced an increase of pERK1/2 and triggered the early formation of an ERK1/2-PAK1 complex. Modeling confirmed that TQ binds in the vicinity of Thr212 accompanied by conformational changes in ERK2-PAK1 binding. Transfecting the cells with the non-phosphorylatable mutant T212A revealed an increase of pPAK(Thr423) and enhanced apoptosis. Likewise, an increase in apoptosis was observed in cells transfected with both the kinase-dead K299R mutant and PAK1 siRNA. Using structural modeling we suggest that TQ interferes also with the kinase domain consequently disturbing its interaction with pPAK(Thr423), finally inhibiting MEK-ERK1/2 signaling and disrupting its prosurvival function. pERK1/2 loss was also validated in vivo.Our study shows for the first time that the small molecule TQ directly binds to PAK1 changing its conformation and scaffold function. Because TQ affects the central RAF/MEK/ERK1/2 pathway, the combination of TQ with targeted therapies is worth considering for future anticancer treatments.
EVALuna2:6620

TIGIT Expression on Intratumoral Lymphocytes Correlates with Improved Prognosis in Oral Squamous Cell Carcinoma. - Eichberger, Jonas; Spörl, Silvia; Spanier, Gerrit; Erber, Ramona; Taxis, Juergen; Schuderer, Johannes; Ludwig, Nils; Fiedler, Mathias; Nieberle, Felix; Ettl, Tobias; Geppert, Carol-Immanuel; Reichert, Torsten E.; et al. (Biomedicines, 2022)
(1) Background: T-cell immunoglobulin and ITIM domain (TIGIT) is a potential immunotherapeutic target in a variety of malignant entities, and antibody-based treatments are currently under investigation in clinical trials. While promising results were observed in patients with lung cancer, the role of TIGIT in oral squamous cell carcinoma (OSCC) as a biomarker as well as a therapeutic target remains elusive. Therefore, we evaluated the role of TIGIT as a prognostic factor in OSCC. (2) Methods: Here, we describe the results of a retrospective tissue microarray (TMA) OSCC cohort. Using immunohistochemistry, TIGIT expression was correlated with overall and recurrence-free survival (OAS and RFS, respectively). Additionally, in silico analysis was performed based on the TCGA Head and Neck Squamous Cell Carcinoma (HNSCC) cohort in order to correlate patients' survival with TIGIT and CD274 (encoding for PD-L1) gene expression levels. (3) Results: Database analysis revealed a beneficial outcome in OAS for tumor patients with high intraepithelial CD3-TIGIT-expression (n = 327). Hereby, OAS was 53.9 months vs. 30.1 months for patients with lower TIGIT gene expression levels (p = 0.033). In our retrospective OSCC-TMA cohort, elevated TIGIT levels on CD3+ cells correlated significantly with improved OAS (p = 0.025) as well as distant RFS (p = 0.026). (4) Conclusions: This study introduces TIGIT as a novel prognostic factor in OSCC, indicating the improved outcome of OSCC patients relative to their increased TIGIT expression. TIGIT might provide therapeutic implications for future immunotherapy in advanced-stage OSCC patients.
EVALuna2:513924

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes - Würfel, Franziska; Erber, Ramona; Hübner, Hanna; Hein, Alexander; Lux, Michael P.; Jud, Sebastian; Kremer, Anita; Kranich, Hannah; Mackensen, Andreas; Häberle, Lothar; Hack, Carolin; Rauh, Claudia; et al. (Breast Care, 2018)
Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triplenegative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study. Methods: Neoadjuvantly treated HER2positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype 'lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading. Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01). Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach. (C) 2018 S. Karger GmbH, Freiburg
EVALuna2:34061
Keywords: Tumor-infiltrating lymphocytes; Response; Neoadjuvant chemotherapy; TILGen study

TILGen study-immunological targets in patients with breast cancer : Influence of tumor-infiltrating lymphocytes - Erber, Ramona; Hartmann, Arndt; Beckmann, Matthias; Mackensen, Andreas; Kremer, Anita; Reimann, Hannah; Hübner, Hanna; Hein, Alexander; Lux, Michael P.; Jud, Sebastian; Häberle, Lothar; Gaß, Paul; et al. (Pathologe, 2018)
BACKGROUND: The interaction of our immune system with breast cancer (BC) cells prompted the investigation of tumor-infiltrating lymphocytes (TILs) and targeted, tumor antigen-specific immunotherapy. OBJECTIVES: Correlation between TILs and pathological complete response (pCR) after neoadjuvant systemic therapy (NACT). Tumor-specific antigens (TSAs) in HER2+ and triple negative BC and establishment of TSA-specific therapies within the interdisciplinary TILGen study. METHODS: Illustration of the TILGen study design. Assessment of TILs and correlation with pCR within this BC study. RESULTS: pCR was achieved in 38.4% (56/146) and associated with estrogen receptor/progesterone receptor negative (ER-/PR-) and HER2+ tumors. Lymphocytic predominant BC (LPBC) was found in 16.4% (24/146), particularly in ER-/PR- (ER-: 27.3% vs. ER+: 9.9%, PR-: 22.3% vs. PR+: 8.2%), large, and poorly differentiated BC. TILs were significantly correlated with pCR in multivariate analysis. In LPBC, pCR was achieved in 66.7%, whereas it was 32.8% in non-LPBC. CONCLUSIONS: First results confirm the influence of the human immune system on the response to NACT in HER2+ and triple negative BC. TSA-specific immunotherapy might improve the outcome in BC patients but there is an urgent need for comprehensive studies to further investigate this issue.
EVALuna2:35097

Time and Resources Needed to Document Patients with Breast Cancer from Primary Diagnosis to Follow-up - Results of a Single-center Study - Lux, Michael P.; Sell, C. S.; Fasching, Peter; Seidl-Ertel, Janine; Bani, Mayada; Schrauder, M. G.; Jud, Sebastian; Löhberg, Christian; Rauh, C.; Hartmann, Arndt; Schulz-Wendtland, Rüdiger; Strnad, Vratislav; et al. (Geburtshilfe und Frauenheilkunde, 2014)
Aim: Certification of breast centers helps improve the quality of care but requires additional resources, particularly for documentation. There are currently no published data on the actual staff costs and financial resources required for such documentation. The aim of this study was to determine the time and resources required to document a patient with primary breast cancer from diagnosis to the end of follow-up, to establish a database for future strategic decisions. Material and Methods: All diagnostic and therapeutic procedures of patients with primary breast cancer were recorded at the University Breast Center of Franconia. All time points for documentation were evaluated using structured interviews. The times required to document a representative number of patients were determined and combined with the staff costs of the different professional groups, to calculate the financial resources required for documentation. Results: A total of 494 time points for documentation were identified. The study also identified 21 departments and 20 different professional groups involved in the documentation. The majority (54 %) of documentation was done by physicians. 62 % of all documentation involved outpatients. The results of different scenarios for the diagnosis, therapy and follow-up of breast cancer patients in a certified breast center showed that the time required for documentation can be as much as 105 hours, costing EUR 4135. Conclusion: This analysis shows the substantial staffing and financial costs required for documentation in certified centers. A multi-center study will be carried out to compare the costs for certified breast centers of varying sizes with the costs of non-certified care facilities.
EVALuna2:6642

Time dependency of adjuvant therapy in advanced head-and-necksquamous-cell-carcinoma of unknown primary (CUP)-patients - Balk, Matthias; Rupp, Robin; Grundtner, Philipp; Müller, Sarina Katrin; Allner, Moritz; Traxdorf, Maximilian; Eckstein, Markus; Hecht, Markus; Iro, Heinrich; Gostian, Antoniu-Oreste (ORAL ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-07-16

TIMP-2 and IGFBP7 in human kidney biopsies in renal disease - Schanz, Moritz; Kimmel, Martin; Alscher, Mark Dominik; Amann, Kerstin Ute; Daniel, Christoph (Clinical Kidney Journal, 2023)
Background Tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) are markers of tubular stress and urinary [TIMP-2]*[IGFBP7] is an established biomarker for risk assessment of acute kidney injury. There are no studies of expression profiles or localization of these markers in human renal tissue with confirmed renal disease. Methods We analysed 37 kidney biopsies of patients with renal disease and 10 non-diseased control biopsies for TIMP-2 and IGFBP7 expression using immunohistochemistry. Changes in glomerular morphology were evaluated by a semi-quantitative glomerulosclerosis score (GSI) and tubular interstitial changes were graded by the tubular injury score (TSI) using periodic acid-Schiff-stained paraffin sections. Interstitial fibrosis and tubular atrophy (IF/TA) were graded according to the Banff classification. Urinary [TIMP-2]*[IGFBP7] was collected at the time of biopsy. Results TIMP-2 and IGFBP7 had significantly greater expression in kidney biopsies from patients with renal disease compared with control tissue, especially in the tubular compartment. Here, IGFBP7 was detected in proximal and distal tubules while TIMP-2 was predominantly localized in the collecting ducts. Renal injury significantly correlated with staining intensity for TIMP-2 and IGFBP7: GSI weakly correlated with glomerular TIMP-2 (r = 0.36) and IGFBP7 (r = 0.35) and TSI correlated with tubular TIMP-2 (r = 0.41) and IGFBP7 (r = 0.43). Urinary [TIMP-2]*[IGFBP7] correlated weakly with the histopathological damage score but not with glomerular and tubular expression. Conclusion Our findings underline the role of TIMP-2/IGFBP7 as an unspecific marker of renal injury that is already in use for early detection of acute kidney injury.
CRIS-Team WoS Importer:2023-03-31

TIMP3::ALK fusions characterize a distinctive myxoid fibroblastic tumor of the vocal cords: a report of 7 cases - Klubickova, Natalie; Michal, Michael; Agaimy, Abbas; Zidar, Nina; Pavlovsky, Michal; Yorita, Kenji; Grossmann, Petr; Hajkova, Veronika; Ptakova, Nikola; Steiner, Petr; Michal, Michal (Virchows Archiv, 2022)
We report 7 cases of an indolent, variably myxoid tumor of the vocal cords, characterized by overt cellular atypia with large cells containing intranuclear and intracytoplasmic vacuoles, delicate curvilinear vessels, and sparse inflammatory infiltrate. Six patients were male, aged 15 to 65 years, and 1 patient was a 54-year-old female. All tumors were located in the superficial portion of the vocal cord. One patient suffered a recurrence that was completely resected; all patients with available follow-up data currently have no evidence of disease. The tumors contained alternating areas with myxoid stroma and more compacted regions with tumor cells organized in short fascicles, interwoven with delicate curvilinear vasculature. Overt cellular atypia with large cells containing intranuclear and intracytoplasmic vacuoles or resembling ganglion cells was present in all cases but mitoses and necrosis were absent. ALK immunostaining was positive in all cases, while most tumors were negative for smooth muscle actin. Targeted RNA-sequencing revealed an identical TIMP3::ALK fusion with exon 1 of TIMP3 gene being fused with exon 12 of ALK gene in all analyzable cases. For various reasons discussed, it remains unclear whether this tumor represents a mere subtype of IMT or a separate entity. Nevertheless, it is a morphologically distinct and diagnostically challenging lesion that needs to be recognized by surgical pathologists in order to prevent overdiagnosis in this clinically very delicate area.
CRIS-Team WoS Importer:2022-08-26

Touch Imprint Cytology and Stereotactically-Guided Core Needle Biopsy of Suspicious Breast Lesions: 15-Year Follow-up - Schulz-Wendtland, Rüdiger; Fasching, Peter; Bani, Mayada; Lux, Michael P.; Jud, Sebastian; Rauh, C.; Bayer, C.; Wachter, David; Hartmann, Arndt; Beckmann, Matthias; Uder, Michael; Löhberg, Christian (Geburtshilfe und Frauenheilkunde, 2016)
Introduction: Stereotactically-guided core needle biopsies (CNB) of breast tumours allow histological examination of the tumour without surgery. Touch imprint cytology (TIC) of CNB promises to be useful in providing same-day diagnosis for counselling purposes and for planning future surgery. Having addressed the issue of accuracy of immediate microscopic evaluation of TIC, we wanted to re-examine the usefulness of this procedure in light of the present health care climate of cost containment by incorporating the surgical 15-year follow-up data and outcome. Patients and Methods: From January until December 1996 we performed TIC in core needle biopsies of 173 breast tumours in 169 patients, consisting of 122 malignant and 51 benign tumours. Histology of core needle biopsies was proven by surgical histology in all malignant and in 5 benign tumours. Surgical breast biopsy was not performed in 46 patients with 46 benign lesions, as the histological result from the core needle biopsy and the result of the TIC were in agreement with the suspected diagnosis from the complementary breast diagnostics. A 15-year follow-up of these patients followed in 2013 and follow-up data was collected from 40 women. Results: In the 15-year follow-up of the 40 benign lesions primarily confirmed using CNB and TIC, a diagnostic sensitivity, specificity, positive and negative predictive value and accuracy of 100 % was found. Conclusion: TIC and stereotactically guided CNB showed excellent long-term follow-up in patients with benign breast lesions. The use of TIC to complement CNB can therefore provide immediate cytological diagnosis of breast lesions.
EVALuna2:6752

Toward a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force - Cuvelier, Geoffrey D.E.; Schoettler, Michelle; Buxbaum, Nataliya P.; Pinal-Fernandez, Iago; Schmalzing, Marc; Distler, Jörg; Penack, Olaf; Santomasso, Bianca D.; Zeiser, Robert; Angstwurm, Klemens; MacDonald, Kelli P.A.; Kimberly, W. Taylor; et al. (Transplantation and Cellular Therapy, 2022)
Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclassical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. Although still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi-institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atypical manifestations of chronic GVHD while outlining a research framework for future studies to be undertaken within the next 3 to 7 years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features.
CRIS-Team Scopus Importer:2022-07-15
Keywords: Atypical; Chronic graft-versus-host disease; National Institutes of Health Consensus Project Task Force

Towards a Molecular Classification of Sinonasal Carcinomas: Clinical Implications and Opportunities - Taverna, Cecilia; Agaimy, Abbas; Franchi, Alessandro (Cancers, 2022)
Simple Summary In recent years, there have been several molecular and immunohistochemical additions to the pathologic diagnosis of sinonasal malignancies that could facilitate the identification of clinically relevant groups of sinonasal malignancies. Molecular profiling is progressively integrated in the histopathologic classification of sinonasal carcinomas, and it is likely to influence the management of these tumors in the near future. In this article we review the recent literature on molecular analysis and/or subtyping of sinonasal carcinomas and we discuss the possible clinical implications of a classification of sinonasal tumors based on their molecular features. Sinonasal carcinomas are a heterogeneous group of rare tumors, often with high-grade and/or undifferentiated morphology and aggressive clinical course. In recent years, with increasing molecular testing, unique sinonasal tumor subsets have been identified based on specific genetic alterations, including protein expression, chromosomal translocations, specific gene mutations, or infection by oncogenic viruses. These include, among others, the identification of a subset of sinonasal carcinomas associated with HPV infection, the identification of a subset of squamous cell carcinomas with EGFR alterations, and of rare variants with chromosomal translocations (DEK::AFF2, ETV6::NTRK and others). The group of sinonasal adenocarcinomas remains very heterogeneous at the molecular level, but some recurrent and potentially targetable genetic alterations have been identified. Finally, poorly differentiated and undifferentiated sinonasal carcinomas have undergone a significant refinement of their subtyping, with the identification of several new novel molecular subgroups, such as NUT carcinoma, IDH mutated sinonasal undifferentiated carcinoma and SWI/SNF deficient sinonasal malignancies. Thus, molecular profiling is progressively integrated in the histopathologic classification of sinonasal carcinomas, and it is likely to influence the management of these tumors in the near future. In this review, we summarize the recent developments in the molecular characterization of sinonasal carcinomas and we discuss how these findings are likely to contribute to the classification of this group of rare tumors, with a focus on the potential new opportunities for treatment.
CRIS-Team WoS Importer:2022-04-15

Towards a Synthetic Tissue Model of the Lower Urinary Tract - Preis, Alexander; Merkl, Christina; Miralles, Paula; Heer, Svenja; Benke, Elisabeth; Reitelshöfer, Sebastian; Martin, Sina; Rieker, Ralf; Franke, Jörg (Proceedings of the 16th International Joint Conference on Biomedical Engineering Systems and Technologies BIOSTEC - (Volume 1), 2023)
The development of medical devices often depends on in vivo studies to validate the proper functioning of the products. These trials provide ethical as well as economic challenges, which can be partially addressed by the usage of realistic synthetic tissue models that replicate human anatomy and the corresponding properties of the biological tissue. In this work, a silicone-based model with a fiber structure and a PVA-based model that exhibits fabrication-induced anisotropy are presented in the special context of the lower urinary tract. The analysis of the materials in the uniaxial tensile test shows the anisotropic and viscoelastic properties of the materials. Furthermore, the anatomical model of the lower urinary tract shows expected deformation in simulation as well as in the real silicone model. Additionally, a suitable artificial urine according to ISO 20696 is shown for use with the model. First experiments to change the pH of the artificial urine are successfully conducted.<br
Keywords: Anatomical Model; Urology; Lower Urinary Tract; Urinary Bladder; Urethra; Artificial Urine

Towards interactive AI-authoring with prototypical few-shot classifiers in histopathology - Kuritcyn, Petr; Kletzander, Rosalie; Eisenberg, Sophia; Wittenberg, Thomas; Bruns, Volker; Evert, Katja; Keil, Felix; Ziegler, Paul K.; Bankov, Katrin; Wild, Peter; Eckstein, Markus; Hartmann, Arndt; et al. (Journal of Pathology Informatics, 2024)
A vast multitude of tasks in histopathology could potentially benefit from the support of artificial intelligence (AI). Many examples have been shown in the literature and first commercial products with FDA or CE-IVDR clearance are available. However, two key challenges remain: (1) a scarcity of thoroughly annotated images, respectively the laboriousness of this task, and (2) the creation of robust models that can cope with the data heterogeneity in the field (domain generalization). In this work, we investigate how the combination of prototypical few-shot classification models and data augmentation can address both of these challenges. Based on annotated data sets that include multiple centers, multiple scanners, and two tumor entities, we examine the robustness and the adaptability of few-shot classifiers in multiple scenarios. We demonstrate that data from one scanner and one site are sufficient to train robust few-shot classification models by applying domain-specific data augmentation. The models achieved classification performance of around 90% on a multiscanner and multicenter database, which is on par with the accuracy achieved on the primary single-center single-scanner data. Various convolutional neural network (CNN) architectures can be used for feature extraction in the few-shot model. A comparison of nine state-of-the-art architectures yielded that EfficientNet B0 provides the best trade-off between accuracy and inference time. The classification of prototypical few-shot models directly relies on class prototypes derived from example images of each class. Therefore, we investigated the influence of prototypes originating from images from different scanners and evaluated their performance also on the multiscanner database. Again, our few-shot model showed a stable performance with an average absolute deviation in accuracy compared to the primary prototypes of 1.8% points. Finally, we examined the adaptability to a new tumor entity: classification of tissue sections containing urothelial carcinoma into normal, tumor, and necrotic regions. Only three annotations per subclass (e.g., muscle and adipose tissue are subclasses of normal tissue) were provided to adapt the few-shot model, which obtained an overall accuracy of 93.6%. These results demonstrate that prototypical few-shot classification is an ideal technology for realizing an interactive AI authoring system as it only requires few annotations and can be adapted to new tasks without involving retraining of the underlying feature extraction CNN, which would in turn require a selection of hyper-parameters based on data science expert knowledge. Similarly, it can be regarded as a guided annotation system. To this end, we realized a workflow and user interface that targets non-technical users.
CRIS-Team Scopus Importer:2024-07-12
Keywords: Colon adenocarcinoma; Data augmentation; Digital pathology; Few-shot learning; Prototypical networks; Tissue classification; Urothelial carcinoma

Towards regenerating the mammalian heart: challenges in evaluating experimentally induced adult mammalian cardiomyocyte proliferation - Zebrowski, David; Becker, Robert; Engel, Felix (American Journal of Physiology-Heart and Circulatory Physiology, 2016)
In recent years, there has been a dramatic increase in research aimed at regenerating the mammalian heart by promoting endogenous cardiomyocyte proliferation. Despite many encouraging successes, it remains unclear if we are any closer to achieving levels of mammalian cardiomyocyte proliferation for regeneration as seen during zebrafish regeneration. Furthermore, current cardiac regenerative approaches do not clarify whether the induced cardiomyocyte proliferation is an epiphenomena or responsible for the observed improvement in cardiac function. Moreover, due to the lack of standardized protocols to determine cardiomyocyte proliferation in vivo, it remains unclear if one mammalian regenerative factor is more effective than another. Here, we discuss current methods to identify and evaluate factors for the induction of cardiomyocyte proliferation and challenges therein. Addressing challenges in evaluating adult cardiomyocyte proliferation will assist in determining 1) which regenerative factors should be pursued in large animal studies; 2) if a particular level of cell cycle regulation presents a better therapeutic target than another (e.g., mitogenic receptors vs. cyclins); and 3) which combinatorial approaches offer the greatest likelihood of success. As more and more regenerative studies come to pass, progress will require a system that not only can evaluate efficacy in an objective manner but can also consolidate observations in a meaningful way.
EVALuna2:25528

Towards the introduction of the 'Immunoscore' in the classification of malignant tumours - Galon, Jerome; Mlecnik, Bernhard; Bindea, Gabriela; Angell, Helen K.; Berger, Anne; Lagorce, Christine; Lugli, Alessandro; Zlobec, Inti; Hartmann, Arndt; Bifulco, Carlo; Nagtegaal, Iris D.; Palmqvist, Richard; et al. (Journal of Pathology, 2014)
The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named 'Immunoscore' has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Toxic retrobulbar neuritis due to recurrent nonsteroidal antiinflammatory drug-exacerbated respiratory disease-based chronic sinusitis in the left sphenoid sinus: a case report - Schapher, Mirco; Brügel, Jacob; Güner, Fabian; Volbers, Bastian; Eichhorn, Philip; Agaimy, Abbas; Berger, Magdalena; Mardin, Christian; Dörfler, Arnd; Hock, Stefan (Journal of Medical Case Reports, 2023)
BACKGROUND: Abrupt visual impairment constitutes a medical urgency, necessitating an interdisciplinary diagnostic and therapeutic approach owing to the broad spectrum of potential etiologies, thereby engaging numerous medical specialties. CASE PRESENTATION: A 21-year-old Mixed White and Asian female patient, with medical history of nonsteroidal antiinflammatory drug-exacerbated respiratory disease necessitating previous sinus surgery, reported sudden monocular vision loss. Unremarkable ophthalmological examination of the fellow eye and hematological parameters, save for a slight elevation in lymphocytes and eosinophils, were observed. Imaging studies indicated recurrence of bilateral chronic rhinosinusitis with nasal polyps and a mucocele in the left sphenoid sinus, accompanied by bony structural deficits. Emergency revision sinus surgery, guided by navigation, was promptly performed. The patient received treatment with methylprednisolone, ceftriaxone, cyanocobalamin, pyridoxine, thiamine, and acetylsalicylic acid. During the hospital stay, she developed steroid-induced glaucoma, which was subsequently managed successfully. Negative microbiological swabs, along with pathohistological evidence of increased tissue eosinophilia and the patient's clinical history, led to the diagnosis of toxic retrobulbar neuritis secondary to recurrent nonsteroidal antiinflammatory drug-exacerbated respiratory disease-associated chronic rhinosinusitis of the left sphenoid sinus. CONCLUSIONS: In cases of acute unilateral vision loss, optic neuritis is a highly probable differential diagnosis and may be induced by pathologies of the paranasal sinuses. Nonsteroidal antiinflammatory drug-exacerbated respiratory disease, a subtype of chronic rhinosinusitis, is associated with type 2 inflammation, which is increasingly recognized for its role in the pathogenesis of bronchial asthma, eosinophilic esophagitis, and atopic eczema. Clinicians should consider chronic rhinosinusitis as a potential differential diagnosis in unilateral visual loss and be cognizant of the rising significance of type 2 inflammations, which are relevant to a variety of diseases.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Blindness; Case report; Inflammation mediators; Neuritis; Optic; Sinusitis

Tracking cell turnover in human brain using 15N-thymidine imaging mass spectrometry - Röder, Sebastian; Bonnin, Elisa A.; Wu, Ting Di; Guerquin-Kern, Jean Luc; Jabari, Samir; Brandner, Sebastian; Eyüpoglu, Ilker Yasin; Gollwitzer, Stephanie; Hamer, Hajo; Gerner, Stefan; Döppner, Thorsten R.; Rummel, Christoph; et al. (Frontiers in Neuroscience, 2023)
Microcephaly is often caused by an impairment of the generation of neurons in the brain, a process referred to as neurogenesis. While most neurogenesis in mammals occurs during brain development, it thought to continue to take place through adulthood in selected regions of the mammalian brain, notably the hippocampus. However, the generality of neurogenesis in the adult brain has been controversial. While studies in mice and rats have provided compelling evidence for neurogenesis occurring in the adult rodent hippocampus, the lack of applicability in humans of key methods to demonstrate neurogenesis has led to an intense debate about the existence and, in particular, the magnitude of neurogenesis in the adult human brain. Here, we demonstrate the applicability of a powerful method to address this debate, that is, the in vivo labeling of adult human patients with 15N-thymidine, a non-hazardous form of thymidine, an approach without any clinical harm or ethical concerns. 15N-thymidine incorporation into newly synthesized DNA of specific cells was quantified at the single-cell level with subcellular resolution by Multiple-isotype imaging mass spectrometry (MIMS) of brain tissue resected for medical reasons. Two adult human patients, a glioblastoma patient and a patient with drug-refractory right temporal lobe epilepsy, were infused for 24 h with 15N-thymidine. Detection of 15N-positive leukocyte nuclei in blood samples from these patients confirmed previous findings by others and demonstrated the appropriateness of this approach to search for the generation of new cells in the adult human brain. 15N-positive neural cells were easily identified in the glioblastoma tissue sample, and the range of the 15N signal suggested that cells that underwent S-phase fully or partially during the 24 h in vivo labeling period, as well as cells generated therefrom, were detected. In contrast, within the hippocampus tissue resected from the epilepsy patient, none of the 2,000 dentate gyrus neurons analyzed was positive for 15N-thymidine uptake, consistent with the notion that the rate of neurogenesis in the adult human hippocampus is rather low. Of note, the likelihood of detecting neurogenesis was reduced because of (i) the low number of cells analyzed, (ii) the fact that hippocampal tissue was explored that may have had reduced neurogenesis due to epilepsy, and (iii) the labeling period of 24 h which may have been too short to capture quiescent neural stem cells. Yet, overall, our approach to enrich NeuN-labeled neuronal nuclei by FACS prior to MIMS analysis provides a promising strategy to quantify even low rates of neurogenesis in the adult human hippocampus after in vivo15N-thymidine infusion. From a general point of view and regarding future perspectives, the in vivo labeling of humans with 15N-thymidine followed by MIMS analysis of brain tissue constitutes a novel approach to study mitotically active cells and their progeny in the brain, and thus allows a broad spectrum of studies of brain physiology and pathology, including microcephaly.
CRIS-Team Scopus Importer:2023-11-03
Keywords: adult; cell turnover; DNA-labeling; glioblastoma; hippocampus; Nano-SIMS; neurogenesis

Transcription control of DAPK - Benderska, Natalya; Schneider-Stock, Regine (Apoptosis, 2014)
Imbalanced cell death is a common phenomenon in many human diseases, including cancer. DAPK's essential function is in promoting apoptosis. DAPK interacts with stress-induced receptors through its death domain to initiate an apoptosis cascade. In addition, DAPK phosphorylates multiple cytosolic substrates and can mediate transfer of signaling pathways to the effector caspases. A series of studies demonstrated that, depending on stimuli, DAPK expression is regulated on both the transcriptional and posttranscriptional levels. Silencing of DAPK due to hypermethylation of its promoter was reported in many types of cancer. STAT3 and p52-NFkB transcription factors have been shown to down-regulate DAPK expression. In contrast, p53, C/EBP-? and Smad transcription factors bind to their specific response elements within the DAPK promoter and induce its transcription. Post-transcriptionally, DAPK undergoes alternative splicing, which results in the production of two functionally different isoforms. Moreover, miRNA 103 and miRNA 107 recently were shown to inhibit DAPK in colorectal cancer. Here we summarize our recent knowledge about transcriptional regulation of DAPK expression.
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Transcriptome and protein interaction profiling in cancer cells with mutations in histone H3.3 - Lim, Jinyeong; Park, Joo Hyun; Baude, Annika; Fellenberg, Joerg; Zustin, Jozef; Haller, Florian; Kruecken, Irene; Kang, Hyun Guy; Park, Yoon Jung; Plass, Christoph; Lindroth, Anders M. (Scientific Data, 2018)
Mutations of histone variant H3.3 are highly recurrent in childhood glioblastoma and in young adults with Giant Cell Tumor of the Bone (GCTB). The heterozygotic representation of the mutations in the tumors, and with potential histone H3 and H3.3 redundancy, suggest that the mutations are gain-of-function by nature. To address common H3.3 point mutations, we have generated data from GCTB patient samples with H3.3 G34W substitutions and engineered human GFP-tagged H3.3-mutated isogenic cell lines for high throughput data comparisons. First, a total of thirty-six patient samples and cell lines were used to acquire gene expression transcriptome data using microarray and RNA-sequencing. The expression data were validated with the orthogonal nCounter assay. Second, to uncover the H3.3-GFP interaction proteomes from the isogenic cell lines, immunoprecipitation of unmutated wild type, K27M, G34R, and G34W substitutions were performed. The RNA-sequencing data and the H3.3 interaction proteome enable potentially important functional insight into the tumorigenic process and should spur further detailed analysis.
EVALuna2:207061

Transcriptomic and metabolomic profiles in renal cell carcinoma (RCC) tumors reflect ontogeny of RCC subtypes - Fisel, Pascale; Buettner, Florian; Reustle, Anna; Klumpp, Verena; Winter, Stefan; Rausch, Steffen; Hennenlotter, Joerg; Kruck, Stephan; Stenzl, Arnulf; Wahrheit, Judith; Sonntag, Denise; Scharpf, Marcus; et al. (CANCER RESEARCH, 2018)
CRIS-Team WoS Importer:2019-06-18

Transformer-based biomarker prediction from colorectal cancer histology: A large-scale multicentric study - Wagner, Sophia J.; Reisenbüchler, Daniel; West, Nicholas P.; Niehues, Jan Moritz; Zhu, Jiefu; Foersch, Sebastian; Veldhuizen, Gregory Patrick; Quirke, Philip; Grabsch, Heike I.; van den Brandt, Piet A.; Hutchins, Gordon G.A.; Richman, Susan D.; et al. (Cancer Cell, 2023)
Deep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on convolutional neural networks (CNNs) and have mostly been validated on small patient cohorts. Here, we develop a new transformer-based pipeline for end-to-end biomarker prediction from pathology slides by combining a pre-trained transformer encoder with a transformer network for patch aggregation. Our transformer-based approach substantially improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training and evaluating on a large multicenter cohort of over 13,000 patients from 16 colorectal cancer cohorts, we achieve a sensitivity of 0.99 with a negative predictive value of over 0.99 for prediction of microsatellite instability (MSI) on surgical resection specimens. We demonstrate that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem.
CRIS-Team Scopus Importer:2023-09-15
Keywords: artificial intelligence; biomarker; colorectal cancer; deep learning; microsatellite instability; multiple instance learning; transformer

Transrectal Absorber Guide Raster-Scanning Optoacoustic Mesoscopy for Label-Free In Vivo Assessment of Colitis - Bühler, Adrian; Brown, Emma; Paulus, Lars-Philip; Eckstein, Markus; Thoma, Oana-Maria; Oraiopoulou, Mariam-Eleni; Rother, Ulrich; Hörning, André; Hartmann, Arndt; Neurath, Markus; Wölfle, Joachim; Friedrich, Oliver; et al. (Advanced Science, 2023)
Optoacoustic imaging (OAI) enables microscale imaging of endogenous chromophores such as hemoglobin at significantly higher penetration depths compared to other optical imaging technologies. Raster-scanning optoacoustic mesoscopy (RSOM) has recently been shown to identify superficial microvascular changes associated with human skin pathologies. In animal models, the imaging depth afforded by RSOM can enable entirely new capabilities for noninvasive imaging of vascular structures in the gastrointestinal tract, but exact localization of intra-abdominal organs is still elusive. Herein the development and application of a novel transrectal absorber guide for RSOM (TAG-RSOM) is presented to enable accurate transabdominal localization and assessment of colonic vascular networks in vivo. The potential of TAG-RSOM is demonstrated through application during mild and severe acute colitis in mice. TAG-RSOM enables visualization of transmural vascular networks, with changes in colon wall thickness, blood volume, and OAI signal intensities corresponding to colitis-associated inflammatory changes. These findings suggest TAG-RSOM can provide a novel monitoring tool in preclinical IBD models, refining animal procedures and underlines the capabilities of such technologies to address inflammatory bowel diseases in humans.
CRIS-Team WoS Importer:2023-05-12

Transurethral en bloc submucosal hydrodissection vs conventional resection for resection of non-muscle-invasive bladder cancer (HYBRIDBLUE): a randomised, multicentre trial - Gakis, Georgios; Karl, Alexander; Bertz, Simone; Burger, Maximillian; Fritsche, Hans Martin; Hartmann, Arndt; Jokisch, Friedrich; Kempkensteffen, Carsten; Miller, Kurt; Mundhenk, Jens; Schneevoigt, Birte Swantje; Schubert, Tina; et al. (Bju International, 2020)
Objective: To determine whether transurethral en bloc submucosal hydrodissection of bladder tumours (TUEB) improves the quality of the resection compared to conventional transurethral resection of bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC). Patients and Methods: A randomised, multicentre trial (HYBRIDBLUE) was conducted with a superiority design. Six German academic centres participated between September 2012 and August 2015. Based on literature analysis, a sample size for accurate histopathological assessment concerning muscle invasion was assumed to be feasible in 50% (P0 = 0.5) of TURBT and 80% of TUEB cases. After pre-screening of a total of 305 patients, participants were allocated to two study arms: Group I: hexaminolevulinate (HAL)-guided TUEB; Group II: conventional HAL-guided TURBT. The primary endpoint was the proportion of specimens that could be reliably evaluated pathologically concerning muscle invasiveness. Secondary endpoints included rates of histopathological completeness of the resection, muscularis propria content, recurrence, and complication rates. Results: A total of 115 patients (TUEB 56; TURBT 59) were eligible for final analysis. Adequate histopathological assessment, which included muscularis propria content and tumour margins (R0 vs R1), was present in 48/56 (86%) TUEB patients compared to 37/59 (63%; P = 0.006) in the TURBT group. R0 was confirmed in 30/56 TUEB patients (57%) and five of 59 TURBT patients (9%; P < 0.001). No complications of Grade ≥III were observed in both arms. At 3 and 12 months, three and 19 patients recurred in the TUEB group vs seven and 11 patients in the TURBT group, respectively (P = 0.33 and P = 0.08). Conclusions: In this randomised study, TUEB was shown to be clinically safe regarding perioperative endpoints. An adequate histopathological assessment concerning muscle invasion was significantly better assessable in the TUEB arm compared to standard TURBT. This finding indicates the clinical potential for reducing the rate of early re-resections. Yet, a larger study with recurrence-free survival as the primary endpoint is needed to assess the oncological efficacy between both techniques.
CRIS-Team Scopus Importer:2020-08-14
Keywords: #BladderCancer; #blcsm; bladder cancer; en bloc; hexaminolevulinate; hydrodissection; photodynamic diagnosis; transurethral; trial

Transvascular kidney biopsy in adolescent patients-safe alternative to open procedures - Utsch, Boris; Hoppe, Hanno; Dittrich, Katalin; Amann, Kerstin Ute; Gugger, Mathias; Tschumi, Sibylle; Galiano, Matthias; Plank, Christian Georg; Rascher, Wolfgang; Schmid, Axel; Uder, Michael; Dötsch, Jörg (Clinical Kidney Journal, 2021)
CRIS-Team WoS Importer:2021-05-21

Transvenous renal transplant biopsy via a transfemoral approach - Schmid, Axel; Jacobi, Johannes; Kuefner, M. A.; Lell, Michael; Wüst, Wolfgang; Mayer-Kadner, I.; Benz, Kerstin; Schmid, Matthias; Amann, Kerstin Ute; Uder, Michael (American Journal of Transplantation, 2013)
Percutaneous renal biopsy (PRB) of kidney transplants might be prevented by an elevated risk of bleeding or limited access to the allograft. In the following, we describe our initial experience with 71 transvenous renal transplant biopsies in 53 consecutive patients with unexplained reduced graft function who were considered unsuitable candidates for PRB (4.2% of all renal transplant biopsies at our institution). Biopsies were performed via the ipsilateral femoral vein with a renal biopsy set designed for transjugular renal biopsy (TJRB) of native kidneys. Positioning of the biopsy system within the transplant vein was achievable in 58 of 71 (81.7%) procedures. The specimen contained a median of 10 glomeruli (range 0-38). Tissue was considered as adequate for diagnosis in 56 of 57 (98.2%) biopsies. With respect to BANFF 50.9% of the specimen were adequate (>10 glomeruli), 47.4% marginally adequate (1-9 glomeruli) and 1.8% inadequate (no glomeruli). After implementation of real-time assessment all specimen contained glomeruli. One of the fifty-eight (1.8%) procedure-related major complications occurred (hydronephrosis requiring nephrostomy due to gross hematuria). Transfemoral renal transplant biopsy (TFRTB) is feasible and appears to be safe compared to PRB. It offers a useful new alternative for histological evaluation of graft dysfunction in selected patients with contraindications to PRB. The authors report on an experience using transvenous renal transplant biopsy to enable histological evaluation in patients unsuitable for percutaneous transplant biopsy. © 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Kidney transplant; percutaneous renal transplant biopsy; renal allograft; renal transplant biopsy; transjugular renal biopsy; transvenous biopsy

Trauma and sporadic desmoid tumor development – an approach toward real incidence and aspects of causality - Hohenberger, Peter; Menge, Franka; Hohenberger, Ralph; Kasper, Bernd; Marx, Alexander; Haller, Florian; Baumgarten, Christina; Wardelmann, Eva; Jakob, Jens (Cancer, 2023)
Objectives: The development of desmoid tumors (DT) is associated with trauma, which is an aspect with medicolegal relevance. The objective of this study was to analyze the proportion and type of trauma (surgical, blunt/fracture, implants), its lag time, and mutations of the CTNNB1 gene in patients with sporadic DT. Methods: We analyzed a prospectively kept database of 381 females and 171 males, median age at disease onset 37.7 years (females) and 39.3 years (males) with a histologically confirmed DT. Patients with germline mutation of the APC gene were excluded. Details of the history particularly of traumatic injuries to the site of DT were provided by 501 patients. Results: In 164 patients (32.7%), a trauma anteceding DT could be verified with a median lag time of 22.9 months (SD, 7.7 months; range, 9-44 months). A prior surgical procedure was relevant in 98 patients, a blunt trauma in 35 patients, a punctuated trauma (injections, trocar) in 18 patients, and site of an implant in 10 patients. In 220 patients, no trauma was reported (43.9%), and 58 females (11.6%) had a postpregnancy DT in the rectus abdominis muscle. In 42 patients (8.4%), data were inconclusive. The distribution of mutations in the CTNNB1 gene (codon 41 vs. 45) was similar in patients with and without a history of trauma before DT development. Conclusions: A significant subgroup of patients suffers from a trauma-associated DT, predominantly at a prior surgical site including implants to breast or groin, accounting for 77.9% of the cases, whereas blunt trauma was responsible in 22.1%. We found no data to support that trauma-associated DT have different molecular features in the CTNNB1 gene.
CRIS-Team Scopus Importer:2023-10-06
Keywords: beta catenin; CTNNB1; desmoid tumor; etiology; medico-legal; trauma

Treatment of Advanced or Metastatic Urothelial Cancer - Hilser, Thomas; Darr, Christopher; Bedke, Jens; Ivanyi, Philipp; Klümper, Niklas; Eckstein, Markus; Schlack, Katrin; Grünwald, Viktor (Oncology Research and Treatment, 2025)
Background: Urothelial carcinoma (UC) is a significant global health burden and shows consistent increase in incidence. The treatment landscape for advanced or metastatic urothelial carcinoma (mUC) has evolved, but significant challenges remain to prolong survival. The article is based on the content of the recent guidelines and a selective literature search. Summary: For many years in the past, cisplatin-based chemotherapy was the standard firstline therapy for eligible patients. But chemotherapy alone provides limited long-termbenefit, and a large proportion of patients either progress rapidly or are ineligible for cisplatin due to comorbidities. This demonstrates the medical need and led to the development of immune checkpoint inhibitors and antibody-drug conjugates (ADCs) in the field of mUC treatment. More recently, the introduction of ADCs further enlarged the medical armamentarium in mUC patients and was further explored as combined regimens. The combination of enfortumab vedotin (EV) and pembrolizumab was superior to standard platin-based chemotherapy as did nivolumab plus gemcitabine with cisplatin, which permanently transformed the medical treatment landscape in mUC. Today, EV plus pembrolizumab is the first-line standard in treatment of therapeutic advanced or mUC. New options are also emerging, such as molecular therapies that target the fibroblast growth factor receptor. In the future, targeted therapy could also be used in the perioperative area. Key Message: Today, EV combined with pembrolizumab sets a new standard of care in medical treatment of a/mUC patients. Compared to platinum-based therapy, EV plus pembrolizumab doubled the overall survival probability and reported a median OS of 31.5 months, which is a new hallmark of palliative medical treatment in this disease. This novel therapy in combination with molecular therapies, novel devices, and molecular markers offers a great opportunity for the next step in medical development in localized UC, and its clinical applicability is being investigated in ongoing studies.
CRIS-Team Scopus Importer:2025-05-30
Keywords: Enfortumab vedotion; Erdafitinib; Immune checkpoint inhibitor; Urothelial cancer

Treatment of generalised vitiligo with tacrolimus 0.1% ointment vs. UVB intense pulsed light phototherapy: a pilot study - Hartmann, Arndt; Löhberg, Lisa; Keikavoussi, Petra; Eichner, Saskia; Schuler, Gerold (Acta Dermato-Venereologica, 2014)
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Treatment of Membranous Nephropathy in Patients With THSD7A Antibodies Using Immunoadsorption - Weinmann-Menke, Julia; Holtz, Stefan; Sollinger, Daniel; Dörken, Mara; Boedecker, Simone; Schamberger, Beate; Pfister, Frederick; Amann, Kerstin Ute; Lutz, Jens (American Journal of Kidney Diseases, 2019)
Antibodies against THSD7A (thrombospondin type 1 domain-containing protein 7A) have been proposed to play a causal role in the development of nephrotic syndrome in patients with THSD7A antibody–positive membranous nephropathy. We hypothesized that removal of these antibodies from plasma could lead to a rapid reduction in proteinuria. Using immunoadsorption to reduce THSD7A antibodies led to a rapid reduction in proteinuria in 2 patients with THSD7A antibody–positive membranous nephropathy. Moreover, our findings support and strengthen the pathogenic role of the antibodies in the development of nephrotic syndrome in patients with THSD7A antibody–positive membranous nephropathy. Taken together, these 2 cases suggest that immunoadsorption could be a useful tool in the treatment of patients with THSD7A antibody–positive membranous nephropathy.
CRIS-Team Scopus Importer:2019-08-30
Keywords: autoantibodies; case report; immunoadsorption; kidney biopsy; malignancy-associated MN; membranous nephropathy (MN); nephrotic syndrome (NS); proteinuria; THSD7A (thrombospondin type 1 domain-containing protein 7A); urinary protein-creatinine ratio (UPCR)

Treatment of perforated colon carcinomas-outcomes of radical surgery - Daniels, Marc; Merkel, Susanne; Agaimy, Abbas; Hohenberger, Werner (International Journal of Colorectal Disease, 2015)
When patients present with a perforation of a colon cancer (CC), this situation increases the challenge to treat them properly. The question arises how to deal with these patients adequately, more restrictively or the same way as with elective cases.Between January 1995 and December 2009, 52 patients with perforated CC and 1206 nonperforated CC were documented in the Erlangen Registry of Colorectal Carcinomas (ERCRC). All these patients underwent radical resection of the primary including systematic lymph node dissection with CME. The median follow-up period was 68 months.The median age of the patients in the perforated CC group was significantly higher than in the nonperforated CC group (p = 0.010). Significantly, more patients with perforated CC were classified in ASA categories 3 and 4 (p = 0.014). Hartmann procedures were performed significantly more frequently with perforation than with the nonperforated ones (p < 0.001). If an anastomosis was performed, the leakage rate of primary anastomoses did not differ (p = 1.0). Cancer-related survival was significantly lower with perforated cancer (difference 12.8 percentage points) and by 9.6 percentage points for observed survival, if postoperative mortality was excluded.Perforated CC patients should be treated basically following the same oncologic demands, which are CME for colonic cancer including multivisceral resections, if needed. This strategy can only be performed if high-quality surgery is available, permanently.
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Treatment of vitiligo using targeted UVB-Intense Pulsed Light (IPL)- phototherapy: evaluation of variables affecting therapeutic success - Hartmann, Arndt; Schmidt-Habel, Anne; Löhberg, Lisa; Zajitschek, Jörg; Englbrecht, Matthias; Eichner, Saskia; Schuler, Gerold (European Journal of Dermatology, 2014)
Targeted UVB intense pulsed light (IPL)-phototherapy has gained interest for repigmentation of vitiligo as it allows selective treatment, sparing the surrounding skin. However, optimal treatment frequency and duration are not known.We compared the efficacy and safety of two treatment protocols, weekly and every two weeks, for a maximum of 12 months. Variables affecting treatment response were evaluated.22 patients (16 female, 6 male; aged 15 - 67 years) with generalised vitiligo were evaluated retrospectively. UVB-IPL had been administered weekly (13 patients, group A), or every second week (9 patients, group B). In cases of no response, treatment stopped after 6 months. Regimentation was evaluated qualitatively and quantitatively.After 6 months, 12/13 patients (A), 3/9 patients (B) showed repigmentation. Due to lack of success, treatment was stopped after 6 months in 1 group A patient and 6/9 group B patients. After 12 months, lesions on the face and trunk in group A showed a mean of 70 ± 27% and 60 ± 29% repigmentation, respectively. Moderate to good repigmentation was seen in 78% of group A patients on the ulnar region on the forearms and the shins. Side effects were minimal. Treatment success depended on treatment frequency, number of treatments and the anatomical site of lesions.UVB-IPL phototherapy seems to be effective and well-tolerated in non-segmental vitiligo. A treatment frequency of weekly intervals rather than every two weeks appears preferable. Our observations will help in designing a sufficiently powered prospective clinical trial to test this hypothesis.
EVALuna2:13137

Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM) - Janning, M.; Süptitz, J.; Albers-Leischner, C.; Delpy, P.; Tufman, A.; Velthaus-Rusik, J. L.; Reck, M.; Jung, A.; Kauffmann-Guerrero, D.; Bonzheim, I.; Brändlein, S.; Hummel, H. D.; et al. (Annals of Oncology, 2022)
Background: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. Patients and methods: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). Results: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1. Conclusions: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.
CRIS-Team Scopus Importer:2022-05-20
Keywords: atypical EGFR mutations; EGFR; non-small-cell lung cancer

Treatment Strategy for Newly Diagnosed T1 High-grade Bladder Urothelial Carcinoma: New Insights and Updated Recommendations - Klaassen, Zachary; Kamat, Ashish M.; Kassouf, Wassim; Gontero, Paolo; Villavicencio, Humberto; Bellmunt, Joaquim; van Rhijn, Bas W.G.; Hartmann, Arndt; Catto, James W.F.; Kulkarni, Girish S. (European Urology, 2018)
CONTEXT: High-grade T1 (T1HG) bladder cancer (BCa) has a very high likelihood of disease recurrence and progression to muscle invasion. Radical cystectomy is considered the best chance at cure, albeit with a high risk of morbidity, and is overtreatment for some patients. Treatment with bacillus Calmette-Guerin (BCG) allows bladder preservation but may risk disease progression. OBJECTIVE: To systematically review the current literature on the management of T1HG BCa and provide updated treatment recommendations. EVIDENCE ACQUISITION: Medline, EMBASE, and Epub Ahead of Print databases were searched in November 2017 to identify observational cohort studies and controlled trials, between 1946 and 2017, associated with diagnosis, treatment, and prognosis of T1HG BCa. EVIDENCE SYNTHESIS: Clinical understaging and/or persistence of disease is not uncommon at initial transurethral resection (TUR); thus, a second re-TUR is recommended for cases with T1HG BCa. Patients electing a bladder preservation approach should undergo induction BCG therapy followed by a maintenance schedule, while patients with several high-risk features should consider immediate cystectomy and those with BCG-refractory or BCG-unresponsive disease should be considered for early cystectomy. Current phase I/II clinical trials for T1HG patients may offer future bladder preservation therapy approaches. CONCLUSIONS: T1HG tumours are heterogeneous in nature and challenging to treat. Bladder preservation with BCG induction and maintenance, or radical cystectomy is the current standard treatment modality of choice for these tumours. Promising therapies for BCG-unresponsive disease are currently under investigation. PATIENT SUMMARY: Patients with high-grade T1 bladder cancer are at a high risk of tumour recurrence and progression, requiring more aggressive treatment such as bladder removal. Bladder preservation therapies are available (and new therapies are being tested in clinical trials); however, patients should be aware that currently bladder removal is considered the best opportunity for cancer cure.
EVALuna2:34613

TRICHODYSPLASIA SPINULOSA WITH DISFIGURING FACIAL FEATURES AFTER KIDNEY TRANSPLANTATION IMPROVED BY mTOR-INHIBITION - Dieterle, A.; Korn, Klaus; Büttner, Maike; Schiffer, Mario; Kiesewetter, Franklin; Wiesener, M. S. (TRANSPLANT INTERNATIONAL, 2019)
CRIS-Team WoS Importer:2019-10-29

TRIM28 haploinsufficiency predisposes to Wilms tumor - Diets, Illja J.; Hoyer, Juliane; Ekici, Arif Bülent; Popp, Bernt; Hoogerbrugge, Nicoline; van Reijmersdal, Simon V.; Bhaskaran, Rajith; Hadjihannas, Michel; Vasileiou, Georgia; Thiel, Christian; Seven, Didem; Uebe, Steffen; et al. (International Journal of Cancer, 2019)
Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified. The tumors showed an epithelial-type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss-of-heterozygosity (LOH) of the TRIM28-locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial-type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.
CRIS-Team Scopus Importer:2019-05-02
Keywords: genetic predisposition; haploinsufficiency; TRIM28; Wilms tumor

Trophoblast Cell Surface Antigen 2 (Trop2) in Chromophobe Renal Cell Carcinoma - Mikuteit, Marie; Steffens, Sandra; Zschäbitz, Stefanie; Autenrieth, Michael; Weichert, Wilko; Hartmann, Arndt; Erlmeier, Franziska (Oncology, 2022)
BACKGROUND: Overexpression of tumor-associated calcium signal transducer 2 (Trop2) is found in many tumor entities. The prognostic value of Trop2 in renal cell renal carcinoma (RCC), especially in nonclear cell RCC, is still unclear. AIM: The aim of this study was to evaluate the prognostic impact of Trop2 expression in a large cohort of patients with chromophobe (ch)RCC. MATERIALS AND METHODS: Patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimens were analyzed for Trop2 expression by immunohistochemistry. RESULTS: Eighty-one chRCC patients were eligible for analysis, of these 24 (29.6%) patients were positive for Trop2. No significant associations were found for Trop2 expression and clinical attributes in patients with chRCC. The Kaplan-Meier analysis revealed no differences in 5-year overall survival for Trop2- compared to Trop2+ (89.6% vs. 100.0%; p = 0.288). CONCLUSION: In chRCC, Trop2 expression is not associated with survival and other parameters of aggressiveness. Due to the rare incidence of chRCC, further studies with larger cohorts are warranted.
CRIS-Team Scopus Importer:2022-06-10
Keywords: Chromophobe histology; Renal cell carcinoma; Survival; Trophoblast cell surface antigen 2

Trophoblast expression dynamics of the tumor suppressor gene gastrokine 2 - Fahlbusch, Fabian B.; Ruebner, Matthias; Hübner, Hanna; Volkert, Gudrun; Bartunik, Hannah; Winterfeld, Ilona; Hartner, Andrea; Menendez-Castro, Carlos; Nögel, Stephanie; Marek, Ines; Wachter, David; Schneider-Stock, Regine; et al. (Histochemistry and Cell Biology, 2015)
Gastrokines (GKNs) were originally described as stomach-specific tumor suppressor genes. Recently, we identified GKN1 in extravillous trophoblasts (EVT) of human placenta. GKN1 treatment reduced the migration of the trophoblast cell line JEG-3. GKN2 is known to inhibit the proliferation, migration and invasion of gastric cancer cells and may interact with GKN1. Recently, GKN2 was detected in the placental yolk sac of mice. We therefore aimed to further characterize placental GKN2 expression. By immunohistochemistry, healthy first-trimester placenta showed ubiquitous staining for GKN2 at its early gestational stage. At later gestational stages, a more differentiated expression pattern in EVT and villous cytotrophoblasts became evident. In healthy third-trimester placenta, only EVT retained strong GKN2 immunoreactivity. In contrast, HELLP placentas showed a tendency of increased levels of GKN2 expression with a more prominent GKN2 staining in their syncytiotrophoblast. Choriocarcinoma cell lines did not express GKN2. Besides its trophoblastic expression, we found human GKN2 in fibrotic villi, in amniotic membrane and umbilical cord. GKN2 co-localized with smooth muscle actin in villous myofibroblasts and with HLA-G and GKN1 in EVT. In the rodent placenta, GKN2 was specifically located in the spongiotrophoblast layer. Thus, the gestational age-dependent and compartment-specific expression pattern of GKN2 points to a role for placental development. The syncytial expression of GKN2 in HELLP placentas might represent a reduced state of functional differentiation of the syncytiotrophoblast. Moreover, the specific GKN2 expression in the rodent spongiotrophoblast layer (equivalent to human EVT) might suggest an important role in EVT physiology.
EVALuna2:6725

Troponin I levels in extracorporeal membrane oxygenation following congenital heart surgery - Rüffer, André; Münch, Frank; Potapov, Sergej; Purbojo, Ariawan; Toka, Okan; Dodge-Khatami, Ali; Dittrich, Sven; Cesnjevar, Robert (World Journal for Pediatric and Congenital Heart Surgery, 2014)
Correlating postcardiotomy extracorporeal membrane oxygenation (ECMO) troponin I (TnI) levels and outcomes.Between January 2006 and August 2010, 34 patients needed postcardiotomy ECMO for low cardiac output. Bailout ECMO was required either after unsuccessful weaning from bypass (n = 17, 50%), postoperatively from prolonged hemodynamic failure (n = 8, 23.5%), or following resuscitation (n = 9, 26.5%). The TnI levels were measured following surgery or resuscitation during 10 days and compared between survivors (group I) and non-survivors (group II).Median support duration was seven days (range: 0-31). Surgery involving hypoplastic aortic arch repair (Norwood palliation; n = 7, 20.6%, or biventricular repair; n = 11, 32.4%) led to most ECMO runs. Successful weaning from ECMO and hospital survival were 76.5% and 50%, respectively. In group I, peak TnI levels were reached by 24 hours postoperatively, comparable to levels in group II (36 ± 34 vs 49 ± 38 ng/mL; P = .98). However, in group II, TnI levels formed a plateau by the second postoperative day, whereas group I showed a steep decline in TnI levels, suggesting myocardial recovery (P = .028). All patients (n = 4) who reached or maintained peak TnI levels at 48 hours died. On days 8, 9 and 10, TnI levels were significantly higher in group II (P = .024, .019, and .013, respectively).Postcardiotomy ECMO was most commonly required after aortic arch repair. In the absence of ongoing myocardial insult due to ECMO hardware issues, coronary insufficiency or residual lesions, plateau TnI levels at 48 hours may seem to indicate an unfavorable outcome due to irreversible myocardial damage.
EVALuna2:25107

Tubulocystic Carcinoma of the Kidney With Poorly Differentiated Foci: A Frequent Morphologic Pattern of Fumarate Hydratase-deficient Renal Cell Carcinoma - Smith, Steven C.; Trpkov, Kiril; Chen, Ying-Bei; Mehra, Rohit; Sirohi, Deepika; Ohe, Chisato; Cani, Andi K.; Hovelson, Daniel H.; Omata, Kei; Mchugh, Jonathan B.; Jochum, Wolfram; Colecchia, Maurizio; et al. (American Journal of Surgical Pathology, 2016)
An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase (FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes-including FH-performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12%). These tumors were aggressive, with 79% showing perinephric extension, nodal involvement in 41%, and metastasis in 86%. Of these, 16 (55%) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17%) showed a wild-type immunoprofile of FH+/2SC-. An intriguing group of 8 (28%) showed variable FH± positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FH mutations, including 5 FH-/2SC+ and 3 FH±/2SC+ cases, but none in FH+/2SC- cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31%). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term "FH-deficient RCC" as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC.
EVALuna2:6821

Tularemia lymphadenitis. An emerging differential diagnosis of necrotizing granulomatous cervical lymphadenitis - Strehl, Johanna; Schoerner, Christoph; Hartmann, Arndt; Agaimy, A. (Pathologe, 2014)
Tularemia is emerging as an important differential diagnosis of necrotizing granulomatous lymphadenitis, particularly in the head and neck region. The causal organism, Francisella tularensis is a Gram-negative coccoid bacterium. Tularemia usually presents with necrotizing granulomatous purulent lymphadenitis featuring multiple mostly small granulomas with geographic necrosis bordered by palisades of histiocytes. Diagnosis is mainly based on these characteristic but non-pathognomonic histological features in conjunction with negative tests for mycobacterial infections and serological confirmation of tularemia-specific antibodies or detection by polymerase chain reaction (PCR). This article describes our experiences with five patients with tularemia lymphadenitis and gives an overview of the diverse histopathological features and the differential diagnosis of this uncommon but possibly underrecognized disease.
EVALuna2:6582

Tumor-associated fibroblasts isolated from colorectal cancer tissues exhibit increased ICAM-1 expression and affinity for monocytes - Schellerer, Vera; Langheinrich, Melanie; Hohenberger, Werner; Croner, Roland S.; Merkel, Susanne; Rau, Tilman; Stürzl, Michael; Naschberger, Elisabeth (Oncology Reports, 2014)
Progression of colorectal cancer (CRC) is strongly associated with inflammation and other desmoplastic reactions in the tumor cell-surrounding tissue. We successfully isolated fibroblasts from the desmoplastic stroma of human CRC specimens and uninvolved colon tissue of patients treated surgically for CRC and investigated potential functional capacities. All of the isolated fibroblasts were vimentin-positive and CK-20/CD45-negative confirming the fibroblast phenotype. Differential expression patterns were detected between tumor-associated fibroblasts (TAFs) and normal tissue-associated fibroblasts (NAFs) regarding intercellular adhesion molecule-1 (ICAM-1) expression. In 11 of 12 TAF cultures, basal ICAM-1 expression was increased as compared to corresponding NAF cultures (p=0.001). After stimulation of the cultures with interleukin-1?, 8 of the 12 TAF cultures presented higher ICAM-1 levels when compared with the level in the corresponding NAF cultures (p=0.001). Moreover, the adhesive capacity of these cultures for U937 was increased in 8 out of 10 unstimulated and in 10 out of 10 stimulated cultures when TAFs and NAFs were compared. In corresponding tumor tissue sections from the same patients, the amount of ICAM-1-positive fibroblasts was significantly higher than that in the corresponding normal colon mucosa, indicating a tumor-specific effect that was maintained in the isolated cultures. These results indicate that fibroblasts from CRC tissue exhibit an increased affinity for monocytic cells. This increased intercellular interaction may contribute to elongated residence times of monocytes in CRC tissue. Therefore, these isolated fibroblasts are a useful tool for further functional investigation of desmoplastic tissue reactions in CRC.
EVALuna2:6524

Tumor-associated macrophages in classical Hodgkin lymphoma: hormetic relationship to outcome - Werner, Laura; Dreyer, Johannes H.; Hartmann, David; Barros, Mário Henrique M.; Büttner-Herold, Maike; Grittner, Ulrike; Niedobitek, Gerald (Scientific Reports, 2020)
Commonly attributed to the prevalence of M2 macrophages, tumor-associated macrophages (TAM) are linked to poor outcome in Hodgkin lymphoma (HL). MYC is supposed to control the expression of M2-specific genes in macrophages, and deficiency in MYC-positive macrophages inhibits tumor growth in mouse models. To verify this hypothesis for HL, seventy-six samples were subjected to immunohistochemical double staining using CD68 or CD163 macrophage-specific antibodies and a reagent detecting MYC. For each cell population, labelled cells were grouped according to low, intermediate and high numbers and related to disease-free survival (DFS) and overall survival (OS). MYC+ cells accounted for 21% and 18% of CD68+ and CD163+ cells, respectively. Numbers of MYC− macrophages were significantly higher in EBV+ cases while no differences were observed for MYC+ macrophages between EBV+ and EBV− cases. Cases with highest numbers of macrophages usually showed worst DFS and OS. In most scenarios, intermediate numbers of macrophages were associated with better outcome than very low or very high numbers. Our observations are reminiscent of the “hormesis hypothesis” and suggest that a relative lack of TAM may allow HL growth while macrophages display an inhibitory effect with increasing numbers. Above a certain threshold, TAM may again support tumor growth.
CRIS-Team Scopus Importer:2020-06-19

Tumor-Associated Neutrophils Are a Negative Prognostic Factor in Early Luminal Breast Cancers Lacking Immunosuppressive Macrophage Recruitment - Schmidt, Eva; Distel, Luitpold; Erber, Ramona; Büttner-Herold, Maike; Rosahl, Marie-Charlotte; Ott, Oliver; Strnad, Vratislav; Hack, Carolin; Hartmann, Arndt; Hecht, Markus; Fietkau, Rainer; Schnellhardt, Sören (Cancers, 2024)
Background: Tumor-associated neutrophils (TANs) are important modulators of the tumor microenvironment with opposing functions that can promote and inhibit tumor progression. The prognostic role of TANs in early luminal breast cancer is unclear. Methods: A total of 144 patients were treated for early-stage hormone-receptor-positive breast cancer as part of an Accelerated Partial Breast Irradiation (APBI) phase II trial. Resection samples from multiple locations were processed into tissue microarrays and sections thereof immunohistochemically stained for CD66b+ neutrophils. CD66b+ neutrophil density was measured separately in the stromal and intraepithelial compartment. Results: High stromal and intraepithelial CD66b+ TAN density was a negative prognostic factor in central tumor samples. In addition, neutrophil density in adjacent normal breast tissue and lymph node samples also correlated with reduced disease-free survival. TAN density correlated with CD163+ M2-like tumor-associated macrophage (TAM) density, which we analyzed in a previous study. TANs were a negative prognostic factor in tumors with an elevated M1/M2 TAM ratio, while this impact on patient outcome was lost in tumors with a low M1/M2 ratio. A combined multivariate analysis of TAM and TAN density revealed that only TAM polarization status was an independent prognostic factor. Conclusions: CD66b+ neutrophils were a negative prognostic factor in early-stage luminal breast cancer in single-marker analysis. Combined analysis with TAMs could be necessary to correctly evaluate their prognostic impact in future studies. TAN recruitment might act as a compensatory mechanism of immunoevasion and disease progression in tumors that are unable to sufficiently attract and polarize TAMs.
CRIS-Team Scopus Importer:2024-10-11
Keywords: breast cancer; CD66b; luminal; tumor-associated macrophages; tumor-associated neutrophils

Tumor budding and lymphovascular invasion as prognostic factors in p16-positive oropharyngeal squamous cell carcinomas. - Stögbauer, Fabian; Wirth, Markus; Lauterbach, Maren; Wollenberg, Barbara; Schmidl, Benedikt; Hoch, Cosima C.; Ourailidis, Iordanis; Hess, Jochen; Eckstein, Markus; Hartmann, Arndt; Iro, Heinrich; Gostian, Antoniu Oreste; et al. (British Journal of Cancer, 2025)
BACKGROUND: We aimed to validate the prognostic significance of tumor budding (TB) in p16-positive oropharyngeal squamous cell carcinomas (OPSCC). METHODS: We analyzed digitized H&E-stained slides from a multicenter cohort of five large university centers consisting of n = 275 cases of p16-positive OPSCC. We evaluated TB along with other histological parameters (morphology, tumor-stroma-ratio, lymphovascular invasion (LVI), perineural invasion) and calculated survival outcomes using both univariate and multivariate analyses. RESULTS: TB was identified as an independent prognostic parameter, with TB-high cases showing inferior outcomes in univariate (HR: 3.08, 95%-CI: 1.71-5.54) and multivariate analyses (HR: 4.03, 95%-CI: 1.65-9.83). Similarly, LVI remained an independent prognostic factor (HR: 3.00, 95%-CI: 1.22-7.38). A combined classification including TB and LVI stratified cases into low-, intermediate- and high-risk categories. We could not detect correlations between TB and the number of lymph node metastases or between TB and an extracapsular extension of lymph node metastases. CONCLUSIONS: In addition to LVI, we could identify TB as an independent prognostic factor in p16-positive OPSCC in this multicenter study cohort. Thus, evaluating TB along with LVI in a combined scheme for prognostication might help to establish a more personalized treatment regimen for patients with p16-positive OPSCC.
EVALuna2:578147

Tumor budding: A predictor for metastasis in the CAM xenograft model - Muenzner, Julienne K.; Ranjan, Raphela A.; Eckstein, Markus; Erber, Ramona; Kunze, Philipp; Geppert, Carol-Immanuel; Rübner, Matthias; Bäuerle, Tobias; Hartmann, Arndt; Schneider-Stock, Regine (CANCER RESEARCH, 2019)
CRIS-Team WoS Importer:2019-10-22

Tumor budding correlates with discohesive growth pattern, tumor invasiveness and is associated with worse survival of pT1 Non-Muscle-Invasive Bladder Cancer (NMIBC) - Eckstein, Markus; Kimmel, C.; Bruendl, J.; Weber, F.; Denzinger, S.; Gierth, M.; Burger, M.; Hartmann, Arndt; Otto, W.; Breyer, J. (EUROPEAN UROLOGY, 2021)
CRIS-Team WoS Importer:2021-08-20

Tumor budding correlates with tumor invasiveness and predicts worse survival in pT1 non-muscle-invasive bladder cancer - Eckstein, Markus; Kimmel, Charlotte; Bruendl, Johannes; Weber, Florian; Denzinger, Stefan; Gierth, Michael; Burger, Maximilian; Hartmann, Arndt; Otto, Wolfgang; Breyer, Johannes (Scientific Reports, 2021)
Tumor budding is defined as a single cell or a cluster of up to 5 tumor cells at the invasion front. Due to the difficulty of identifying patients at high risk for pT1 non-muscle-invasive bladder cancer (NMIBC) and the difficulties in T1 substaging, tumor budding was evaluated as a potential alternative and prognostic parameter in these patients. Tumor budding as well as growth pattern, invasion pattern and lamina propria infiltration were retrospectively evaluated in transurethral resection of the bladder (TURB) specimens from 92 patients with stage pT1 NMIBC. The presence of tumor budding correlated with multifocal tumors (p = 0.003), discontinuous invasion pattern (p = 0.039), discohesive growth pattern (p < 0.001) and extensive lamina propria invasion (p < 0.001). In Kaplan–Meier analysis, tumor budding was associated with significantly worse RFS (p = 0.005), PFS (p = 0.017) and CSS (p = 0.002). In patients who received BCG instillation therapy (n = 65), the absence of tumor budding was associated with improved RFS (p = 0.012), PFS (p = 0.011) and CSS (p = 0.022), with none of the patients suffering from progression or dying from the disease. Tumor budding is associated with a more aggressive and invasive stage of pT1 NMIBC and a worse outcome. This easy-to-assess parameter could help stratify patients into BCG therapy or early cystectomy treatment groups.
CRIS-Team Scopus Importer:2021-09-17

Tumor grade-titude: XGBoost radiomics paves the way for RCC classification - Ellmann, Stephan; von Rohr, Felicitas; Komina, Selim; Bayerl, Nadine; Amann, Kerstin Ute; Polifka, Iris; Hartmann, Arndt; Sikic, Danijel; Wullich, Bernd; Uder, Michael; Bäuerle, Tobias (European Journal of Radiology, 2025)
This study aimed to develop and evaluate a non-invasive XGBoost-based machine learning model using radiomic features extracted from pre-treatment CT images to differentiate grade 4 renal cell carcinoma (RCC) from lower-grade tumours. A total of 102 RCC patients who underwent contrast-enhanced CT scans were included in the analysis. Radiomic features were extracted, and a two-step feature selection methodology was applied to identify the most relevant features for classification. The XGBoost model demonstrated high performance in both training (AUC = 0.87) and testing (AUC = 0.92) sets, with no significant difference between the two (p = 0.521). The model also exhibited high sensitivity, specificity, positive predictive value, and negative predictive value. The selected radiomic features captured both the distribution of intensity values and spatial relationships, which may provide valuable insights for personalized treatment decision-making. Our findings suggest that the XGBoost model has the potential to be integrated into clinical workflows to facilitate personalized adjuvant immunotherapy decision-making, ultimately improving patient outcomes. Further research is needed to validate the model in larger, multicentre cohorts and explore the potential of combining radiomic features with other clinical and molecular data.
CRIS-Team Scopus Importer:2025-05-16
Keywords: Computed tomography (CT); Diagnostic performance; Feature extraction; Machine learning; Personalized immunotherapy; Radiomics; Renal cell carcinoma (RCC); Treatment decision-making; Tumor grading

Tumor Infiltrating Inflammatory Cells as a prognostic Factor in Glioblastoma - Schnellhardt, Sören; Zorob, Alexander; Polat, B.; Lisowski, D.; Daniel, Christoph; Monoranu, C-M; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Tumor-infiltrating Memory T Cells in Head and Neck Tumors: An ambivalent prognostic Factor - Hartan, R.; Schnellhardt, Sören; Büttner-Herold, Maike; Daniel, Christoph; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Tumor Infiltration with CD20+CD73+ B Cells Correlates with Better Outcome in Colorectal Cancer - Hansen, Frederik; Wu, Zhiyuan; David, Paul; Mittelstädt, Anke; Jacobsen, Anne; Podolska, Malgorzata; Ubieta Hernández, Kenia; Brunner, Maximilian; Kouhestani, Dina; Swierzy, Izabela; Roßdeutsch, Lotta; Klösch, Bettina; et al. (International Journal of Molecular Sciences, 2022)
Immunotherapy has become increasingly important in the treatment of colorectal cancer (CRC). Currently, CD73, also known as ecto-5′-nucleotidase (NT5E), has gained considerable interest as a potential therapeutic target. CD73 is one of the key enzymes catalyzing the conversion of extracellular ATP into adenosine, which in turn exerts potent immune suppressive effects. However, the role of CD73 expression on various cell types within the CRC tumor microenvironment remains unresolved. The expression of CD73 on various cell types has been described recently, but the role of CD73 on B-cells in CRC remains unclear. Therefore, we analyzed CD73 on B-cells, especially on tumor-infiltrating B-cells, in paired tumor and adjacent normal tissue samples from 62 eligible CRC patients. The highest expression of CD73 on tumor-infiltrating B-cells was identified on classswitched memory B-cells, followed by naive B-cells, whereas no CD73 expression was observed on plasmablasts. Clinicopathological correlation analysis revealed that higher CD73+ B-cells infiltration in the CRC tumors was associated with better overall survival. Moreover, metastasized patients showed a significantly decreased number of tumor-infiltrating CD73+ B-cells. Finally, neoadjuvant therapy correlated with reduced CD73+ B-cell numbers and CD73 expression on B-cells in the CRC tumors. As promising new immune therapies are being developed, the role of CD73+ B-cells and their subsets in the development of colorectal cancer should be further explored to find new therapeutic options.
CRIS-Team Scopus Importer:2022-05-20
Keywords: B-cells; CD20; CD73; colorectal cancer; neoadjuvant treatment

Tumor-in-tumor metastasis: a rare phenomenon Tumor-in-Tumor-Metastase: Ein seltenes Phänomen - Elsner, Felix; Keller, Katharina; Fuchs, Florian; Uder, Michael; Hartmann, Arndt (Die Pathologie, 2024)
CRIS-Team Scopus Importer:2025-02-04

Tumor microenvironment-dependent epigenetic imprinting in the vasculature predicts colon cancer outcome - Naschberger, Elisabeth; Fuchs, Maximilian; Dickel, Nicholas; Kunz, Meik; Popp, Bernt; Anchang, Charles Gwellem; Demmler, Richard; Lyu, Yanmin; Uebe, Steffen; Ekici, Arif Bülent; Geppert, Carol-Immanuel; Hartmann, Arndt; et al. (Cancer Communications, 2023)
CRIS-Team Scopus Importer:2023-10-27

Tumor Regression Grading After Preoperative Chemoradiotherapy as a Prognostic Factor and Individual-Level Surrogate for Disease-Free Survival in Rectal Cancer - Fokas, Emmanouil; Stroebel, Philipp; Fietkau, Rainer; Ghadimi, Michael; Liersch, Torsten; Grabenbauer, Gerhard G.; Hartmann, Arndt; Kaufmann, Marco; Sauer, Rolf; Graeven, Ullrich; Hoffmanns, Hans; Raab, Hans-Rudolf; et al. (Journal of the National Cancer Institute, 2017)
Background: We investigated tumor regression grading (TRG) as a prognostic marker and individual-level surrogate for disease-free survival (DFS) in patients with rectal carcinoma treated within the Chirurgische Arbeitsgemeinschaft fur Onkologie/Arbeitsgemeinschaft Radiologische Onkologie/Arbeitsgemeinschaft Internistische Onkologie (CAO/ARO/AIO)-04 randomized trial. Methods: TRG was recorded prospectively using the Dworak classification in 1179 patients after preoperative fluorouracil-based chemoradiotherapy (CRT) with or without oxaliplatin. Multivariable analysis was performed using Cox regression models adjusted for treatment arm, resection status, and pathologic stage. Individual-level surrogacy of TRG for DFS was examined using the four Prentice criteria (PC1-4). All statistical tests were two-sided. Results: With a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based CRT led to statistically significantly improved three-year DFS (75.9%, 95% CI = 72.3 to 79.5, vs 71.3%, 95% CI = 67.6 to 74.9, P = .04, PC 1) and a shift toward more advanced TRG groups ( P < .001, PC 2) compared with CRT with fluorouracil alone. The three-year DFS was 64.6% (95% CI = 57.3 to 71.9), 77.6% (95% CI = 74.5 to 80.7), and 92.3% (95% CI = 88.4 to 96.2) for TRG 0 + 1 (poor regression), TRG 2 + 3 (intermediate regression), and TRG 4 (complete regression), respectively ( P < .001, PC 3). TRG constituted an independent prognostic factor for DFS (TRG 2 + 3 vs TRG 0 + 1, HR = 0.68, 95% CI = 0.51 to 0.90, P = .007). Due to multicollinearity, TRG 4 and pathologic stage could not be tested within the same model. The treatment effect on DFS was captured by TRG, satisfying individual-level PC4. Conclusions: Higher TRG after preoperative CRT predicted a favorable long-term outcome. At the individual patient level, TRG was a surrogate marker for DFS. Further phase III trials are needed to validate TRG as a surrogate at trial level.
EVALuna2:32865

Tumor regression grading after preoperative chemoradiotherapy as prognostic factor and individual-level surrogate for disease-free survival in rectal cancer: Results of the CAO/ARO/AIO-04 multicentre, open-label, randomised, phase 3 trial - Fokas, E.; Stroebel, P.; Fietkau, Rainer; Ghadimi, M.; Liersch, T.; Grabenbauer, G.; Hartmann, Arndt; Kaufmann, M.; Sauer, Rolf; Graeven, U.; Hoffmanns, H.; Raab, H-R; et al. (2017)
EVALuna2:32881

Tumor–Stroma Ratio in Colorectal Cancer—Comparison between Human Estimation and Automated Assessment - Firmbach, Daniel; Benz, Michaela; Kuritcyn, Petr; Bruns, Volker; Lang-Schwarz, Corinna; Stübs, Frederik; Merkel, Susanne; Leikauf, Leah-Sophie; Braunschweig, Anna Lea; Oldenburger, Angelika; Gloßner, Laura; Abele, Niklas; et al. (Cancers, 2023)
The tumor–stroma ratio (TSR) has been repeatedly shown to be a prognostic factor for survival prediction of different cancer types. However, an objective and reliable determination of the tumor–stroma ratio remains challenging. We present an easily adaptable deep learning model for accurately segmenting tumor regions in hematoxylin and eosin (H&E)-stained whole slide images (WSIs) of colon cancer patients into five distinct classes (tumor, stroma, necrosis, mucus, and background). The tumor–stroma ratio can be determined in the presence of necrotic or mucinous areas. We employ a few-shot model, eventually aiming for the easy adaptability of our approach to related segmentation tasks or other primaries, and compare the results to a well-established state-of-the art approach (U-Net). Both models achieve similar results with an overall accuracy of 86.5% and 86.7%, respectively, indicating that the adaptability does not lead to a significant decrease in accuracy. Moreover, we comprehensively compare with TSR estimates of human observers and examine in detail discrepancies and inter-rater reliability. Adding a second survey for segmentation quality on top of a first survey for TSR estimation, we found that TSR estimations of human observers are not as reliable a ground truth as previously thought.
CRIS-Team Scopus Importer:2023-06-09
Keywords: colorectal cancer; deep learning; few-shot learning; image analysis; segmentation; tumor–stroma ratio; U-Net

Tumour immune evasion mechanism in non-small cell lung cancer by inducing Blimp-1 in CD4+CD25+Foxp-3+T regulatory cells - Neurath-Finotto, Susetta; Tausche, Patrick; Hohenberger, Katja; Neurath, Laura; Trufa, Denis; Geppert, Carol-Immanuel; Rieker, Ralf; Sirbu, Horia (JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2021-12-03

Tumour immune microenvironment drives prognostic relevance correlating with bladder cancer subtypes - Eckstein, Markus; Strissel, Pamela; Pfannstiel, C.; Chiappinelli, K.; Sikic, D.; Wach, S.; Taubert, Helge; Wullich, Bernd; Keck, Bastian; Wirtz, R.; Breyer, J.; Burger, M.; et al. (VIRCHOWS ARCHIV, 2019)
CRIS-Team WoS Importer:2019-09-27

Tumour-infiltrating inflammatory cells in early breast cancer: An underrated prognostic and predictive factor? - Schnellhardt, Sören; Erber, Ramona; Büttner-Herold, Maike; Rosahl, Marie Charlotte; Ott, Oliver; Strnad, Vratislav; Beckmann, Matthias; King, Lillian; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (International Journal of Molecular Sciences, 2020)
The role of tumour-infiltrating inflammatory cells (TIICs) in the disease progression of hormone-receptor-positive breast cancer (HR+ BC) is largely unclear since it is generally regarded as the least immunogenic BC subtype. This study investigated the prognostic significance of CD1a+ dendritic cells, CD20+ B cells, CD45RO+ memory T cells and CD4+ T-helper cells in HR+ BC. One hundred and forty-six patients were treated for early stage, distant-metastases-free HR+ BC in an accelerated partial breast irradiation (APBI) phase II trial. Immunohistochemistry was used to double-stain two adjoining sets of tissue microarrays from pre-RT (radiotherapy) tumour resection samples for CD1a/CD20 and CD45RO/CD4. Cell densities of CD1a+, CD20+, CD45RO+ and CD4+ TIICs in the stromal and intraepithelial compartment were registered semiautomatically. High densities of CD20+ and CD4+ TIICs were strongly associated with reduced disease-free survival (DFS), while high stromal CD45RO+ TIIC densities were indicators of subsequent successful treatment. An immunoscore based on CD20+ and CD45RO+ TIIC densities identified three different risk groups (p < 0.001). Thus, contrary to current assumptions, intratumoural immune cell composition might be an important prognostic indicator and a possible contributing factor in the outcome of HR+ BC and should be the subject of further research. Specifically, B-cell infiltration entailed an increased relapse rate and could play an important role in disease progression.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Accelerated partial breast irradiation; Breast cancer; CD1a; CD20; CD4; CD45RO; Hormone receptor positive; Immunoscore; Prognosis; TIL

Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy - Denkert, Carsten; Von Minckwitz, Gunter; Darb-Esfahani, Silvia; Lederer, Bianca; Heppner, Barbara I.; Weber, Karsten E.; Budczies, Jan; Huober, Jens; Klauschen, Frederick; Furlanetto, Jenny; Schmitt, Wolfgang D.; Blohmer, Jens-Uwe; et al. (Lancet Oncology, 2018)
BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal-HER2-negative breast cancer. METHODS: Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0-10% immune cells in stromal tissue within the tumour), intermediate (11-59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts. FINDINGS: In the luminal-HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0·0001 for each subtype, χ2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio [HR] 0·93 [95% CI 0·87-0·98], p=0·011) and HER2-positive breast cancer (0·94 [0·89-0·99], p=0·017), but not in luminal-HER2-negative tumours (1·02 [0·96-1·09], p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 [0·86-0·99], p=0·032), but had no association in HER2-positive breast cancer (0·94 [0·86-1·02], p=0·11), and was associated with shorter overall survival in luminal-HER2-negative tumours (1·10 [1·02-1·19], p=0·011). INTERPRETATION: Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal-HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted. FUNDING: Deutsche Krebshilfe and European Commission.
EVALuna2:34264

Tumour‐infiltrating lymphocytes (Tils) and pd‐l1 expression correlate with lymph node metastasis, high‐grade transformation and shorter metastasis‐free survival in patients with acinic cell carcinoma (acicc) of the salivary glands - Hiß, Selina; Eckstein, Markus; Segschneider, Paul; Mantsopoulos, Konstantinos; Iro, Heinrich; Hartmann, Arndt; Agaimy, Abbas; Haller, Florian; Müller, Sarina Katrin (Cancers, 2021)
Objectives: The aim of this study was to assess the number of tumour‐infiltrating lympho-cytes (TILs) and the expression of Programmed Cell Death 1 Ligand 1 (PD‐L1) in Acinic Cell Carcinoma (AciCC) of the salivary glands, to enable a correlation with clinico‐pathological features and to analyse their prognostic impact. Methods: This single centre retrospective study represents a cohort of 36 primary AciCCs with long‐term clinical follow‐up. Immunohistochemically defined immune cell subtypes, i.e., those expressing T‐cell markers (CD3, CD4 and CD8) or a B‐cell marker (CD20) were characterized on tumour tissue sections. The number of TILs was quantitatively evaluated using software for digital bioimage analysis (QuPath). PD‐L1 expression on the tumour cells and on immune cells was assessed immunohistochemically employing established scoring criteria: tu-mour proportion score (TPS), Ventana immune cell score (IC‐Score) and combined positive score (CPS). Results: Higher numbers of tumour‐infiltrating T‐ and B‐ lymphocytes were significantly associated with high‐grade transformation. Furthermore, higher counts of T‐lymphocytes correlated with node‐positive disease. There was a significant correlation between higher levels of PD‐ L1 expression and lymph node metastases as well as the occurrence of high‐grade transformation. Moreover, PD‐L1 CPS was associated with poor prognosis regarding metastasis‐free survival (p = 0.049). Conclusions: The current study is the first to demonstrate an association between PD‐L1 expression and lymph node metastases as well as grading in AciCCs. In conclusion, increased immune cell infiltration of T and B cells as well as higher levels of PD‐L1 expression in AciCC in association with high‐grade transformation, lymph node metastasis and unfavourable prognosis suggests a rel-evant interaction between tumour cells and immune cell infiltrates in a subset of AciCCs, and might represent a rationale for immune checkpoint inhibition.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Acinic cell carcinoma; Checkpoint inhibition; Immuno‐oncology; PD‐L1; Tumour‐infiltrating lymphocytes

Tumour mutational burden analysis: implementation in routine diagnostics - Kroeze, L.; Kamping, E.; Von Rhein, D.; Jansen, E.; De Voer, R.; Barberis, M.; Botling, J.; Garrido-Martin, E.; Haller, Florian; Lacroix, L.; Maes, B.; Merkelbach-Bruse, S.; et al. (VIRCHOWS ARCHIV, 2019)
CRIS-Team WoS Importer:2019-09-27

TWEAK-Fn14 Cytokine-Receptor Axis: A New Player of Myocardial Remodeling and Cardiac Failure - Novoyatleva, Tatyana; Sajjad, Amna; Engel, Felix (Frontiers in Immunology, 2014)
Tumor necrosis factor (TNF) has been firmly established as a pathogenic factor in heart failure, a significant socio-economic burden. In this review, we will explore the role of other members of the TNF/TNF receptor superfamily (TNFSF/TNFRSF) in cardiovascular diseases (CVDs) focusing on TWEAK and its receptor Fn14, new players in myocardial remodeling and heart failure. The TWEAK/Fn14 pathway controls a variety of cellular activities such as proliferation, differentiation, and apoptosis and has diverse biological functions in pathological mechanisms like inflammation and fibrosis that are associated with CVDs. Furthermore, it has recently been shown that the TWEAK/Fn14 axis is a positive regulator of cardiac hypertrophy and that deletion of Fn14 receptor protects from right heart fibrosis and dysfunction. We discuss the potential use of the TWEAK/Fn14 axis as biomarker for CVDs as well as therapeutic target for future treatment of human heart failure based on supporting data from animal models and in vitro studies. Collectively, existing data strongly suggest the TWEAK/Fn14 axis as a potential new therapeutic target for achieving cardiac protection in patients with CVDs.
EVALuna2:25479

Un- and dedifferentiated endometrial carcinoma A rare entity with a wide range of differential diagnosis - Hoehn, A. K.; Brambs, C. E.; Opitz, S.; Erber, Ramona; Hartmann, Arndt; Horn, L-C (Pathologe, 2019)
Dedifferentiated endometrial carcinomas (ECs) are composed of undifferentiated EC and a FIGO grade 1 or 2 endometrioid carcinoma. The undifferentiated component represents a malignant epithelial neoplasm with no obvious differentiation and immunohistochemical loss of PAX8, E-cadherin and focal expression of EMA and/or CK18 and the predominant presence of nuclear staining for INI1 (SMARCB1) and BRG1 (SMARCA4). The main differential diagnoses include poorly differentiated endometrioid EC, neuroendocrine carcinoma, lymphoma, plasmocytoma, high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas (UUS), carcinosarcomas, and metastases to the endometrium. The histogenesis is not yet fully understood and molecular data are still limited. Some tumors represent a loss of MHL1 and PMS2 staining due to MLH1-promotor methylation. Rare cases are associated with Lynch syndrome or POLE mutation. The un- or dedifferentiated EC represents a high-grade endometrial carcinoma that requires extended surgery and indicates a poor prognosis. In cases with mismatch repair protein deficiency or POLE mutation, immuno-oncological treatment with checkpoint inhibitors are a therapeutic option.
CRIS-Team WoS Importer:2019-10-22

Unbiased high-dimensional flow cytometry identified NK and DC immune cell signature in Luminal A-type and triple negative breast cancer - Heger, Lukas; Heidkamp, Gordon Frederik; Amon, Lukas; Nimmerjahn, Falk; Bäuerle, Tobias; Maier, Andreas; Erber, Ramona; Hartmann, Arndt; Hack, Carolin; Rübner, Matthias; Hübner, Hanna; Fasching, Peter; et al. (OncoImmunology, 2024)
Breast cancer is the most common malignancy in women worldwide and a highly heterogeneous disease. Four different subtypes are described that differ in the expression of hormone receptors as well as the growth factor receptor HER2. Treatment modalities and survival rate depend on the subtype of breast cancer. However, it is still not clear which patients benefit from immunotherapeutic approaches such as checkpoint blockade. Thus, we aimed to decipher the immune cell signature of the different breast cancer subtypes based on high-dimensional flow cytometry followed by unbiased approaches. Here, we show that the frequency of NK cells is reduced in Luminal A and B as well as triple negative breast cancer and that the phenotype of residual NK cells is changed toward regulatory CD11b−CD16− NK cells. Further, we found higher frequencies of PD-1+ CD4+ and CD8+ T cells in triple negative breast cancer. Moreover, while Luminal A-type breast cancer was enriched for CD14+ cDC2 (named type 3 DC (DC3)), CD14− cDC2 (named DC2) were more frequent in triple negative breast cancer. In contrast, HER2-enriched breast cancer did not show major alterations in the composition of the immune cell compartment in the tumor microenvironment. These findings suggest that patients with Luminal A- and B-type as well as triple negative breast cancer might benefit from immunotherapeutic approaches targeting NK cells.
CRIS-Team Scopus Importer:2024-01-12
Keywords: Breast cancer; immune cell signature; NK cells; PD-1; tumor microenvironment

Unclear tumour of the ear lobe - Dürr, Stephan; Söder, Stephan; Rösler, Wolf; Schlechtweg, Philipp; Schick, B; Alexiou, Christoph (Laryngo-Rhino-Otologie, 2014)
EVALuna2:6586

Uncovering Hereditary Tumor Syndromes: Emerging Role of Surgical Pathology - Agaimy, Abbas; Hartmann, Arndt (Seminars in Diagnostic Pathology, 2018)
With the increased use of modern next generation sequencing technologies in routine molecular pathology practice, the proportion of cancer cases with a definite or probable hereditary background seems to be steadily increasing. Currently, it is assumed that ≥10% of all malignancies develop in the setting of germline predisposition. Diagnosis and recognition of cancer predisposition syndromes relies not rarely on distinctive histopathological features that proved to be highly valuable and reproducible in uncovering those diseases that would otherwise have gone undetected by clinicians as being hereditary in nature. This is especially true in case of new mutations without suspicious family history. Example of such entities are fumarate hydratase-deficient renal cell carcinoma (RCC), succinate dehydrogenase-deficient RCC, hereditary gastrointestinal stromal tumor syndromes and many other diseases. It is remarkable that many of these inherited cancer syndromes do present as unifocal disease with highly variable age of onset so that many of them are misinterpreted as sporadic on clinical grounds. Availability of specialized cancer screening programs and disease-specific follow-up schemes for several hereditary cancer syndromes encourages the recognition of such disorders, so that "at risk patients" can be enrolled in such programs for early detection and timely intervention/ treatment of these malignancies which are in the majority of cases aggressive. In several conditions, as in familial adenomatous polyposis coli (FAP), well established prophylactic surgical interventions may be adopted to prevent the disease manifestations, highlighting the importance of the timely recognition of these potentially life-limiting neoplasms. In this review, the clinicopathological, demographic and histological features that are considered highly suggestive of a hereditary basis of "a neoplasm under consideration" are highlighted and discussed briefly. The details of some of these entities are in addition dealt with in reviews devoted to them in this special issue.
EVALuna2:33963

Under-expression of ?8 integrin aggravates experimental atherosclerosis - Menendez-Castro, Carlos; Cordasic, Nada; Neureiter, Daniel; Amann, Kerstin Ute; Marek, Ines; Volkert, Gudrun; Stintzing, Sebastian; Jahn, Angelika; Rascher, Wolfgang; Hilgers, Karl Friedrich; Hartner, Andrea (Journal of Pathology, 2015)
Integrins play an important role in vascular biology. The ?8 integrin chain attenuates smooth muscle cell migration but its functional role in the development of atherosclerosis is unclear. Therefore, we studied the contribution of ?8 integrin to atherosclerosis and vascular remodelling. We hypothesized that ?8 integrin expression is reduced in atherosclerotic lesions, and that its under-expression leads to a more severe course of atherosclerosis. ?8 Integrin was detected by immunohistochemistry and qPCR and ?8 integrin-deficient mice were used to induce two models of atherosclerotic lesions. First, ligation of the carotid artery led to medial thickening and neointima formation, which was quantified in carotid cross-sections. Second, after crossing into ApoE-deficient mice, the formation of advanced vascular lesions with atherosclerotic plaques was quantified in aortic en face preparations stained with Sudan IV. Parameters of renal physiology and histopathology were assessed: ?8 integrin was detected in the media of human and murine vascular tissue and was down-regulated in arteries with advanced atherosclerotic lesions. In ?8 integrin-deficient mice (?8(-/-) ) as well as ?8(+/-) and ?8(+/+) littermates, carotid artery ligation increased media:lumen ratios in all genotypes, with higher values in ligated ?8(-/-) and ?8(+/-) compared to ligated ?8(+/+) animals. Carotid artery ligation increased smooth muscle cell number in the media of ?8(+/+) mice and, more prominently, of ?8(-/-) or ?8(+/-) mice. On an ApoE(-/-) background, ?8(+/-) and ?8(-/-) mice developed more atherosclerotic plaques than ?8(+/+) mice. ?8 Integrin expression was reduced in ?8(+/-) animals. Renal damage with increased serum creatinine and glomerulosclerosis was detected in ?8(-/-) mice only. Thus, under-expression of ?8 integrin aggravates vascular lesions, while a complete loss of ?8 integrin results in reduced renal mass and additional renal disease in the presence of generalized atherosclerosis. Our data support the hypothesis that integrin ?8?1 has a protective role in arterial remodelling and atherosclerosis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
EVALuna2:3752

Understanding PD-L1 Testing in Breast Cancer: A Practical Approach - Erber, Ramona; Hartmann, Arndt (Breast Care, 2020)
Background: Immune checkpoint inhibitors (ICI) have changed therapy strategies for cancer patients tremendously. Some approved ICI acquire testing of PD-L1 expression on tumor and/or immune cells. However, since PD-L1 testing is a comprehensive issue with various assays, antibody clones, scoring methods, and cut-offs, we aimed to summarize the recommendations and technical and histopathological issues of diagnostic PD-L1 assessment with an emphasis on invasive breast cancer (IBC). Summary: Besides other (pre)analytical considerations, selecting the most adequate PD-L1 immunohistochemical assay/antibody clone is important. In-house assay validation, prediagnostic training, and internal and external quality assurance should be implemented. The current most relevant PD-L1 assays and scores will be explained in this review. Moreover, recommendations for PD-L1 testing in IBC are outlined. Key Messages: Atezolizumab plus nab-paclitaxel therapy is approved for adult patients with locally advanced or metastatic triple negative breast cancer (mTNBC), if the tumor-Associated immune cells express PD-L1.-This PD-L1 immune cell positivity is defined as an immune cell (IC) score, which refers to the area occupied by PD-L1 positive immune cells (lymphocytes, dendritic cells, macrophages, and granulocytes) as a percentage of the whole tumor area. The cut-off is an IC score ≥1%. In the approval study for atezolizumab in mTNBC, IC score was assessed using the Ventana PD-L1 SP142 assay. Other assays or laboratory developed tests may be used depending on country-specific drug approvals. However, harmonization studies have to show whether other PD-L1 tests are reliable and of clinical value to predict the response of breast cancer patients to ICI.
CRIS-Team Scopus Importer:2020-10-30

Undifferentiated and dedifferentiated urological carcinomas: lessons learned from the recent developments - Agaimy, Abbas; Hartmann, Arndt; Trpkov, Kiril; Hes, Ondrej (Seminars in Diagnostic Pathology, 2021)
Loss of the morphological and immunophenotypic characteristics of a neoplasm is a well-known phenomenon in surgical pathology and occurs across different tumor types in almost all organs. This process may be either partial, characterized by transition from well differentiated to undifferentiated tumor component (=dedifferentiated carcinomas) or complete (=undifferentiated carcinomas). Diagnosis of undifferentiated carcinoma is significantly influenced by the extent of sampling. Although the concept of undifferentiated and dedifferentiated carcinoma has been well established for other organs (e.g. endometrium), it still has not been fully defined for urological carcinomas. Accordingly, undifferentiated/ dedifferentiated genitourinary carcinomas are typically lumped into the spectrum of poorly differentiated, sarcomatoid, or unclassified (NOS) carcinomas. In the kidney, dedifferentiation occurs across all subtypes of renal cell carcinoma (RCC), but certain genetically defined RCC types (SDH-, FH- and PBRM1- deficient RCC) seem to have inherent tendency to dedifferentiate. Histologically, the undifferentiated component displays variable combination of four patterns: spindle cells, pleomorphic giant cells, rhabdoid cells, and undifferentiated monomorphic cells with/without prominent osteoclastic giant cells. Any of these may occasionally be associated with heterologous mesenchymal component/s. Their immunophenotype is often simple with expression of vimentin and variably pankeratin or EMA. Precise subtyping of undifferentiated (urothelial versus RCC and the exact underlying RCC subtype) is best done by thorough sampling supplemented as necessary by immunohistochemistry (e.g. FH, SDHB, ALK) and/ or molecular studies. This review discusses the morphological and molecular genetic spectrum and the recent develoments on the topic of dedifferentiated and undifferentiated genitourinary carcinomas.
CRIS-Team Scopus Importer:2021-10-08
Keywords: Dedifferentiated carcinoma; FH; Fumarate hydratase; Renal cell carcinoma; SDH; SDHB; SMARCB1; Succinate dehydrogenase; SWI/SNF; Undifferentiated carcinoma; Urothelial carcinoma

Undifferentiated large cell/rhabdoid carcinoma presenting in the intestines of patients with concurrent or recent non-small cell lung cancer (NSCLC): clinicopathologic and molecular analysis of 14 cases indicates an unusual pattern of dedifferentiated metastases - Agaimy, Abbas; Daum, Ondrej; Michal, Michal; Schmidt, Mona W.; Stöhr, Robert; Hartmann, Arndt; Lauwers, Gregory Y. (Virchows Archiv, 2021)
Undifferentiated carcinoma metastatic to the bowel is uncommon in surgical pathology practice and might be confused with primary gastrointestinal carcinoma, melanoma, lymphoma, and others. We present 14 cases of uni- (n = 9) or multifocal (n = 5) undifferentiated large cell/rhabdoid carcinoma presenting in the bowel of patients with concurrent (n = 9) or recent (diagnosed 1 to 25 months earlier; median, 4) non-small cell lung cancer (NSCLC). Patients were 6 females and 8 males, aged 52 to 85 years. Primary NSCLC was verified histologically in 10 cases and by imaging in 4. The undifferentiated histology was present in the lung biopsy in 4/10 patients (as sole pattern in 3 and combined with adenocarcinoma in 1) and was limited to the intestinal metastases in the remainder. PDL1 was strongly expressed in 7/9 cases (CPS: 41 to 100). Loss of at least one SWI/SNF subunit was detected in 7/13 cases (54%). SMARCA2 loss (n = 6) was most frequent and was combined with SMARCA4 loss in one case. PBRM1 loss was observed in one tumor. Successful molecular testing of 11 cases revealed BRAF mutations in 4 (3 were non-V600E variants), KRAS mutations in 3, and wildtype in 4. None had EGFR mutations. Analysis of 4 paired samples revealed concordant KRAS (2) and BRAF (1) mutations or wildtype (1). Our study indicates that undifferentiated carcinoma within the intestines of patients with concurrent/recent NSCLC represents dedifferentiated metastasis from the NSCLC. Recognition of this unusual presentation is cardinal to avoid misdiagnosis with inappropriate therapeutic and prognostic implications.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Anaplastic carcinoma; Gastrointestinal; Intestine; Large cell carcinoma; Metastasis; NSCLC; Rhabdoid carcinoma; SMARCA4; SWI/SNF; Undifferentiated carcinoma

Undifferenzierte und dedifferenzierte Nierenzellkarzinome: Morphomolekulare Aspekte und Differenzialdiagnose im Hinblick auf neuere Entwicklungen - Agaimy, Abbas; Hartmann, Arndt (Die Pathologie, 2025)
Histological subtyping of diverse renal cell carcinomas (RCCs) has seen significant changes during the last two decades. This resulted in the introduction of several new phenotypically and genetically defined entities, many which are also listed in the current WHO classification. Some of these well-defined entities may, under certain circumstances, undergo a process of dedifferentiation resulting in loss of their phenotypic and immunohistochemical features, hence adopting a non-descript anaplastic morphology. Accordingly, the original entity-defining tumor clone might be either totally overgrown and lost or just be missed by sampling the tumor. This final common pathway of dedifferentiation results in several oncological disadvantages and prevents a histology-tailored approach to systemic therapy. In addition, the possibility of inherited cancer as in the case of SDH- and FH-deficient RCC would be easily overlooked if the exact subtyping is not possible. This overview article illuminates the main RCC subtypes that may undergo dedifferentiation and their differential diagnostic approach.
CRIS-Team Scopus Importer:2025-01-31
Keywords: Active immunotherapy; Molecular targeted therapy; Next generation sequencing; Precision medicine; World Health Organization

Unilateral swelling of the lacrimal gland in a 15-year-old female patient - Berta, A. I.; Naumann-Bartsch, N.; Agaimy, Abbas; Metzler, Markus; Kruse, Friedrich; Holbach, L. (Ophthalmologe, 2013)
EVALuna2:6506

Uninflamed immunologic microenvironment of muscle-invasive bladder cancer associates with activating FGFR3 gene alterations. - Weyerer, Veronika; Stöhr, Robert; Strissel, Pamela; Strick, Reiner; Bolenz, Christian; Hartmann, Arndt; Erben, Philipp; Eckstein, Markus (CLINICAL CANCER RESEARCH, 2020)
CRIS-Team WoS Importer:2020-08-28

Untying the Gordian knot of composite hemangioendothelioma: Discovery of novel fusions - Linos, Konstantinos; Dermawan, Josephine K.; Pulitzer, Melissa; Hameed, Meera; Agaram, Narasimhan P.; Agaimy, Abbas; Antonescu, Cristina R. (Genes Chromosomes & Cancer, 2023)
Composite hemangioendothelioma is a rare, locally aggressive, and rarely metastasizing vascular neoplasm which affects both children and adults. Recently, a number of gene fusions including YAP1::MAML2, PTBP1::MAML2, and EPC1::PHC2 have been detected in a small subset of cases with or without neuroendocrine expression. Herein, we present four additional cases with novel in-frame fusions. The cohort comprises two females and two males with a wide age range at diagnosis (24–80 years). Two tumors were deep involving the right brachial plexus and mediastinum, while the remaining were superficial (right plantar foot and abdominal wall). The size ranged from 1.5 to 4.8 cm in greatest dimension. Morphologically, all tumors had an admixture of at least two architectural patterns including retiform hemangioendothelioma, hemangioma, epithelioid hemangioendothelioma, or angiosarcoma. The tumors were positive for endothelial markers CD31 (3/3), ERG (4/4), and D2-40 (1/4, focal), while SMA was expressed in 2/3 highlighting the surrounding pericytes. Synaptophysin showed immunoreactivity in 2/3 cases. One patient had a local recurrence after 40 months, while two patients had no evidence of disease 4 months post-resection. Targeted RNA sequencing detected novel in-frame fusions in each of the cases: HSPG2::FGFR1, YAP1::FOXR1, ACTB::MAML2, and ARID1B::MAML2. The two cases with neuroendocrine expression occurred as superficial lesions and harbored YAP1::FOXR1 and ARID1B::MAML2 fusions. Our study expands on the molecular spectrum of this enigmatic tumor, further enhancing our current understanding of the disease.
CRIS-Team Scopus Importer:2023-09-29
Keywords: ACTB; ARID1B; composite; FGFR1; FOXR1; hemangioendothelioma; HSPG2; MAML2; YAP1

Updated analysis of the phase II CheckRad-CD8 trial: First-line treatment of locally advanced head and neck squamous cell carcinoma with induction chemoimmunotherapy followed by radioimmunotherapy - Hecht, Markus; Eckstein, Markus; Kallies, Annett; von der Grün, Jens; Illmer, Thomas; Klautke, Gunther; Laban, Simon; Hautmann, Matthias; Brunner, Thomas; Tamaskovics, Bálint; Hinke, Axel; Zhou, Jianguo; et al. (35. Deutscher Krebskongress, Krebsmedizin: Schnittstellen zwischen Innovation und Versorgung, 2022)
CRIS-Team WoS Importer:2022-12-16

Update for the practicing pathologist: The International Consultation On Urologic Disease-European association of urology consultation on bladder cancer - Amin, Mahul B.; Smith, Steven C.; Reuter, Victor E.; Epstein, Jonathan I.; Grignon, David J.; Hansel, Donna E.; Lin, Oscar; Mckenney, Jesse K.; Montironi, Rodolfo; Paner, Gladell P.; Al-Ahmadie, Hikmat A.; Algaba, Ferran; et al. (Modern Pathology, 2015)
The International Consultations on Urological Diseases are international consensus meetings, supported by the World Health Organization and the Union Internationale Contre le Cancer, which have occurred since 1981. Each consultation has the goal of convening experts to review data and provide evidence-based recommendations to improve practice. In 2012, the selected subject was bladder cancer, a disease which remains a major public health problem with little improvement in many years. The proceedings of the 2nd International Consultation on Bladder Cancer, which included a 'Pathology of Bladder Cancer Work Group,' have recently been published; herein, we provide a summary of developments and consensus relevant to the practicing pathologist. Although the published proceedings have tackled a comprehensive set of issues regarding the pathology of bladder cancer, this update summarizes the recommendations regarding selected issues for the practicing pathologist. These include guidelines for classification and grading of urothelial neoplasia, with particular emphasis on the approach to inverted lesions, the handling of incipient papillary lesions frequently seen during surveillance of bladder cancer patients, descriptions of newer variants, and terminology for urine cytology reporting.
EVALuna2:6755

Update on monoclonal gammopathy of renal significance [Neues zur monoklonalen Gammopathie renaler Signifikanz] - Büttner-Herold, Maike; Pfister, F.; Amann, Kerstin Ute (Nephrologe, 2019)
The term monoclonal gammopathy of renal significance (MGRS) was recently introduced for glomerular or tubulointerstitial renal diseases that are induced by a monoclonal immunoglobulin (MIg) in the setting of a monoclonal gammopathy of uncertain significance (MGUS) which is regarded as a benign condition. Most of these MIg-associated renal diseases result from direct deposition of nephrotoxic immunoglobulins or their fragments, i. e. light and heavy chain fragments. Hereby, the nature and exact location of the immunoglobulin deposition defines the disease so that apart from light microscopy, immunohistochemistry and/or immunofluorescence and electron microscopy are of utmost importance in the workup of kidney biopsies. It is assumed that at least some members of the MGRS group of diseases, irrespective of the underlying disease, are associated with a higher progression rate which may be one reason for MGRS being considered as an indication for antineoplastic therapy.
CRIS-Team Scopus Importer:2019-05-03
Keywords: Biopsy; Electron microscopy; Immunohistochemistry; Kidney; Paraproteinemias

Update on olfactory neuroblastoma - Lopez, Fernando; Agaimy, Abbas; Franchi, Alessandro; Suárez, Carlos; Vander Poorten, Vincent; Mäkitie, Antti A.; Homma, Akihiro; Eisbruch, Avraham; Olsen, Kerry D.; Saba, Nabil F.; Nuyts, Sandra; Snyderman, Carl; et al. (Virchows Archiv, 2024)
Olfactory neuroblastomas are uncommon malignancies that arise from olfactory receptor cells located high in the nasal cavity. Accurate diagnosis plays a crucial role in determining clinical results and guiding treatment decisions. Diagnosis can be a major challenge for pathologists, especially when dealing with tumours with poor differentiation. The discovery of several molecular and immunohistochemical markers would help to overcome classification difficulties. Due to the paucity of large-scale studies, standardisation of diagnosis, treatment and prediction of outcome remains a challenge. Surgical resection by endoscopic techniques with the addition of postoperative irradiation is the treatment of choice. In addition, it is advisable to consider elective neck irradiation to minimise the risk of nodal recurrence. Molecular characterisation will help not only to make more accurate diagnoses but also to identify specific molecular targets that can be used to develop personalised treatment options tailored to each patient. The present review aims to summarise the current state of knowledge on histopathological diagnosis, the molecular biology and management of this disease.
CRIS-Team Scopus Importer:2024-03-08
Keywords: Chemotherapy; Diagnosis; Esthesioneuroblastomas; Molecular characterisation; Olfactory neuroblastomas; Outcomes; Radiotherapy; Sinonasal tumours; Staging system; Surgery

Uptake, delivery, and anticancer activity of thymoquinone nanoparticles in breast cancer cells - Fakhoury, Isabelle; Saad, Walid; Bouhadir, Kamal; Nygren, Peter; Schneider-Stock, Regine; Gali-Muhtasib, Hala (Journal of Nanoparticle Research, 2016)
Thymoquinone (TQ) is a promising anticancer molecule but its development is hindered by its limited bioavailability. Drug encapsulation is commonly used to overcome low drug solubility, limited bioavailability, and nonspecific targeting. In this project, TQ nanoparticles (TQ-NP) were synthesized and characterized. The cytotoxicity of the NP was investigated in nontumorigenic MCF-10-A breast cells, while the uptake, distribution, as well as the anticancer potential were investigated in MCF-7 and MDA-MB-231 breast cancer cells. Flash Nanoprecipitation and dynamic light scattering coupled with scanning electron microscopy were used to prepare and characterize TQ-NP prior to measuring their anticancer potential by MTT assay. The uptake and subcellular intake of TQ-NP were evaluated by fluorometry and confocal microscopy. TQ-NP were stable with a hydrodynamic average diameter size around 100 nm. Entrapment efficiency and loading content of TQ-NP were high (around 80 and 50 %, respectively). In vitro, TQ-NP had equal or enhanced anticancer activity effects compared to TQ in MCF-7 and aggressive MDA-MB-231 breast cancer cells, respectively, with no significant cytotoxicity of the blank NP. In addition, TQ and TQ-NP were relatively nontoxic to MCF-10-A normal breast cells. TQ-NP uptake mechanism was both time and concentration dependent. Treatment with inhibitors of endocytosis suggested the involvement of caveolin in TQ-NP uptake. This was further confirmed by subcellular localization findings showing the colocalization of TQ-NP with caveolin and transferrin as well as with the early and late markers of endocytosis. Altogether, the results describe an approach for the enhancement of TQ anticancer activity and uncover the mechanisms behind cell-TQ-NP interaction.
EVALuna2:33952

Uremic mouse model to study vascular calcification and “inflamm-aging” - Tölle, Markus; Henkel, Cornelia; Herrmann, Jaqueline; Daniel, Christoph; Babic, Milen; Xia, Mengdi; Schulz, Anna M.; Amann, Kerstin Ute; van der Giet, Markus; Schuchardt, Mirjam (Journal of Molecular Medicine, 2022)
Calcification and chronic inflammation of the vascular wall is a high-risk factor for cardiovascular mortality, especially in patients with chronic uremia. For the reduction or prevention of rapid disease progression, no specific treatment options are currently available. This study aimed to evaluate an adenine-based uremic mouse model for studying medial vessel calcification and senescence-associated secretory phenotype (SASP) changes of aortic tissue to unravel molecular pathogenesis and provide a model for therapy testing. The dietary adenine administration induced a stable and similar degree of chronic uremia in DBA2/N mice with an increase of uremia blood markers such as blood urea nitrogen, calcium, creatinine, alkaline phosphatase, and parathyroid hormone. Also, renal fibrosis and crystal deposits were detected upon adenine feeding. The uremic condition is related to a moderate to severe medial vessel calcification and subsequent elastin disorganization. In addition, expression of osteogenic markers as Bmp-2 and its transcription factor Sox-9 as well as p21 as senescence marker were increased in uremic mice compared to controls. Pro-inflammatory uremic proteins such as serum amyloid A, interleukin (Il)-1β, and Il-6 increased. This novel model of chronic uremia provides a simple method for investigation of signaling pathways in vascular inflammation and calcification and therefore offers an experimental basis for the development of potential therapeutic intervention studies. Graphical abstract: [Figure not available: see fulltext.].
CRIS-Team Scopus Importer:2022-08-12
Keywords: Calcification; Cardiovascular; Chronic inflammation; Chronic renal insufficiency; Inflammation; Vascular calcification

Urinary peptidomic liquid biopsy for non-invasive differential diagnosis of chronic kidney disease. - Mavrogeorgis, Emmanouil; He, Tianlin; Mischak, Harald; Latosinska, Agnieszka; Vlahou, Antonia; Schanstra, Joost P.; Catanese, Lorenzo; Amann, Kerstin Ute; Huber, Tobias B.; Beige, Joachim; Rupprecht, Harald D.; Siwy, Justyna (Nephrology Dialysis Transplantation, 2024)
BACKGROUND AND HYPOTHESIS: Specific urinary peptides hold information on disease pathophysiology, which, in combination with artificial intelligence, could enable non-invasive assessment of chronic kidney disease (CKD) aetiology. Existing approaches are generally specific for the diagnosis of single aetiologies. We present the development of models able to simultaneously distinguish and spatially visualize multiple CKD aetiologies. METHODS: The urinary peptide data of 1850 healthy control (HC) and CKD [diabetic kidney disease (DKD), immunoglobulin A nephropathy (IgAN) and vasculitis] participants were extracted from the Human Urinary Proteome Database. Uniform manifold approximation and projection (UMAP) coupled to a support vector machine algorithm was used to generate multi-peptide models to perform binary (DKD, HC) and multiclass (DKD, HC, IgAN, vasculitis) classifications. This pipeline was compared with the current state-of-the-art single-aetiology CKD urinary peptide models. RESULTS: In an independent test set, the developed models achieved 90.35% and 70.13% overall predictive accuracies, respectively, for the binary and the multiclass classifications. Omitting the UMAP step led to improved predictive accuracies (96.14% and 85.06%, respectively). As expected, the HC class was distinguished with the highest accuracy. The different classes displayed a tendency to form distinct clusters in the 3D space based on their disease state. CONCLUSION: Urinary peptide data present an effective basis for CKD aetiology differentiation using machine learning models. Although adding the UMAP step to the models did not improve prediction accuracy, it may provide a unique visualization advantage. Additional studies are warranted to further validate the pipeline's clinical potential as well as to expand it to other CKD aetiologies and also other diseases.
EVALuna2:540388

Uropathology - Hartmann, Arndt; Knuechel-Clarke, R.; Kristiansen, G. (Pathologe, 2016)
EVALuna2:6787

Urothelial Bladder Cancer: An Update on Molecular Pathology with Clinical Implications - Bertz, Simone; Eckstein, Markus; Stoehr, Robert; Weyerer, Veronika; Hartmann, Arndt (European Urology Supplements, 2017)
Urothelial bladder cancer is a heterogenous disease with distinct clinical and histopathological features. In the last few years it became clear that papillary, mostly noninvasive, disease with few molecular changes and aggressive urothelial carcinoma are genomically separate diseases. Recently, several studies found that invasive bladder cancer can also be separated into several molecular subgroups. In the present review we summarize molecular alterations, diagnostic markers, and molecular subgroups in urothelial bladder cancer and discuss their clinical relevance for prognosis, prediction of recurrence and progression, and therapeutic response to chemotherapy, radiotherapy, and immunotherapy. (C) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EVALuna2:33791

Use of NGS Gene Panel Analyzes for molecularly targeted System Therapy - Roesch, Johannes; Haller, Florian; Lettmaier, Sebastian; Haderlein, Marlen; Hartmann, Arndt; Moskalev, Evgeny; Tögel, Lars; Putz, Florian; Weissmann, T.; Schubert, P.; Höfler, Daniel; Fietkau, Rainer; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Using Probability for Pathological Complete Response (pCR) as a Decision Support Marker for Neoadjuvant Chemotherapy in HER2 Negative Breast Cancer Patients - a Survey Among Physicians - Gaß, Paul; Untch, Michael; Mueller, Volkmar; Moebus, Volker; Thomssen, Christoph; Häberle, Lothar; Erber, Ramona; Hein, Alexander; Jud, Sebastian; Lux, Michael P.; Hack, Carolin; Hartmann, Arndt; et al. (Geburtshilfe und Frauenheilkunde, 2018)
Background: In women with early breast cancer, a pathological complete response (pCR) after neoadjuvant chemotherapy is reported to be associated with an improvement of the survival. The aim of this survey among physicians was to investigate whether the probability of achieving pCR in patients with a hormone receptor-positive, HER2-negative disease encourages physicians to recommend neoadjuvant chemotherapy. Methods: The study was conducted via an online survey that was sent to 493 physicians, who were either known as members of national guideline committees, heads of breast cancer centers, being high recruiters in clinical trials or leading a private practice. Participants were asked about a specific case that should resemble patients for whom it is unclear, whether they should be treated with chemotherapy. Results: 113 (24.5%) physicians participated at the survey, out of which 96.5% had a work experience of more than 10 years and 94.7% were board certified in their specialty. A total of 84.1% would consider pCR for a decision concerning neoadjuvant chemotherapy. With regard to the pCR probability, 2.7 and 10.6% of the participants demanded at least a pCR rate of 5 and 10%, respectively, while 25.7% were satisfied with 20% probability, and another 25.7% with a pCR rate of 30%. Conclusions: The vast majority of the long-term experienced physicians would embrace the implementation of a further method such as the prediction of pCR probability in clinical routine to support decision making regarding the necessity of neoadjuvant chemotherapy. The cut-off of around 30% pCR probability seems to be a realizable rate to distinguish patient groups.
EVALuna2:34856

Uterine mesenchymal tumours harboring the KAT6B/A::KANSL1 gene fusion represent a distinct type of uterine sarcoma based on DNA methylation profiles - Kommoss, Felix K.F.; Charbel, Alphonse; Kolin, David L.; Howitt, Brooke E.; Köbel, Martin; Lee, Jen Chieh; McCluggage, W. Glenn; Agaimy, Abbas; Dickson, Brendan C.; von Deimling, Andreas; Lee, Cheng Han (Virchows Archiv, 2024)
Uterine mesenchymal tumours harboring KAT6B/A::KANSL1 gene fusions typically exhibit histological and immunophenotypic overlap with endometrial stromal and smooth muscle tumours. To date it remains uncertain whether such neoplasms should be regarded as variants of smooth muscle or endometrial stromal neoplasm, or if they constitute a distinct tumour type. In this study we investigated DNA methylation patterns and copy number variations (CNVs) in a series of uterine tumours harboring KAT6B/A::KANSL1 gene fusions in comparison to other mesenchymal neoplasms of the gynecological tract. Unsupervised hierarchical clustering and t-SNE analysis of DNA methylation data (Illumina EPIC array) identified a distinct cluster for 8/13 KAT6B/A::KANSL1 tumours (herein referred to as core cluster). The other 5 tumours (herein referred to as outliers) did not assign to the core cluster but clustered near various other tumour types. CNV analysis did not identify significant alterations in the core cluster. In contrast, various alterations, including deletions at the CDKN2A/B and NF1 loci were identified in the outlier group. Analysis of the DNA methylation clusters in relation to histological features revealed that while tumours in the core KAT6B/A::KANSL1 cluster were histologically bland, outlier tumours frequently exhibited “high-grade” histologic features in the form of significant nuclear atypia, increased mitotic activity and necrosis. Three of the five patients with outlier tumours died from their disease while clinical follow-up in the remaining two patients was limited (less than 12 months). In comparison, none of the 7 out of 8 patients with tumors in the core KAT6B/A::KANSL1 sarcoma cluster, where follow-up was available, died from disease. Furthermore, only 1 out of 7 patients recurred (mean follow-up of 30 months). In conclusion, KAT6B/A::KANSL1 uterine sarcoma is a molecularly unique type of uterine tumour that should be recognized as a distinct entity. These tumors typically exhibit low-grade histologic features but are occasionally morphologically high-grade; the latter have a DNA methylation profile different from the typical low-grade neoplasms and may be associated with aggressive behaviour.
CRIS-Team Scopus Importer:2024-10-25
Keywords: DNA methylation; KANSL1; KAT6B/A; Uterine sarcoma

Uterine sarcoma with KAT6B/A::KANSL1 fusion: an evolving entity - Fontanges, Quitterie; Croce, Sabrina; Agaimy, Abbas; McCluggage, W. Glenn (Virchows Archiv, 2025)
CRIS-Team Scopus Importer:2025-02-17

Utility of different massive parallel sequencing platforms for mutation profiling in clinical samples and identification of pitfalls using FFPE tissue - Fassunke, Jana; Haller, Florian; Hebele, Simone; Moskalev, Evgeny; Penzel, Roland; Pfarr, Nicole; Merkelbach-Bruse, Sabine; Endris, Volker (International Journal of Molecular Medicine, 2015)
In the growing field of personalised medicine, the analysis of numerous potential targets is becoming a challenge in terms of work load, tissue availability, as well as costs. The molecular analysis of non-small cell lung cancer (NSCLC) has shifted from the analysis of the epidermal growth factor receptor (EGFR) mutation status to the analysis of different gene regions, including resistance mutations or translocations. Massive parallel sequencing (MPS) allows rapid comprehensive mutation testing in routine molecular pathological diagnostics even on small formalin-fixed, paraffin-embedded (FFPE) biopsies. In this study, we compared and evaluated currently used MPS platforms for their application in routine pathological diagnostics. We initiated a first round-robin testing of 30 cases diagnosed with NSCLC and a known EGFR gene mutation status. In this study, three pathology institutes from Germany received FFPE tumour sections that had been individually processed. Fragment libraries were prepared by targeted multiplex PCR using institution-specific gene panels. Sequencing was carried out using three MPS systems: MiSeq(TM), GS Junior and PGM Ion Torrent(TM). In two institutes, data analysis was performed with the platform-specific software and the Integrative Genomics Viewer. In one institute, data analysis was carried out using an in-house software system. Of 30 samples, 26 were analysed by all institutes. Concerning the EGFR mutation status, concordance was found in 26 out of 26 samples. The analysis of a few samples failed due to poor DNA quality in alternating institutes. We found 100% concordance when comparing the results of the EGFR mutation status. A total of 38 additional mutations were identified in the 26 samples. In two samples, minor variants were found which could not be confirmed by qPCR. Other characteristic variants were identified as fixation artefacts by reanalyzing the respective sample by Sanger sequencing. Overall, the results of this study demonstrated good concordance in the detection of mutations using different MPS platforms. The failure with samples can be traced back to different DNA extraction systems and DNA quality. Unknown or ambiguous variations (transitions) need verification with another method, such as qPCR or Sanger sequencing.
EVALuna2:6746

Utility of stromal tumor infiltrating lymphocyte scoring (sTILs) for risk stratification of patients with muscle-invasive urothelial bladder cancer after radical cystectomy - Sikic, Danijel; Weyerer, Veronika; Geppert, Carol-Immanuel; Bertz, Simone; Lange, Fabienne; Taubert, Helge; Wach, Sven; Schmitz-Draeger, Bernd J.; Wullich, Bernd; Hartmann, Arndt; Eckstein, Markus (Urologic Oncology-Seminars and Original Investigations, 2021)
Background: Multi-omics analyses of muscle-invasive bladder cancer (MIBC) demonstrated that specific patterns of tumor infiltrating lymphocytes (TILs) associates with improved outcomes in patients treated with radical cystectomy. However, methodologies for simple and robust quantification of TILs, especially for daily practice purposes, are lacking. Thus, we investigated the feasibility of stromal TIL scoring on hematoxylin/eosin stained (HE) slides in MIBC. Materials and methods: sTILs were scored on HE whole slides of 241 MIBC patients treated with radical cystectomy and adjuvant chemotherapy. Median infiltration of 10% was used as objective cut-off. Additionally, immunohistochemistry was performed on spatially organized tissue microarrays to quantify key immune cell populations objectively for correlational analyses with sTIL scoring results (CD3+/Pan-T-cells, CD8+/cytotoxic T-Cells, CD56+/NK-cells, CD68+/macrophages). sTILs amounts were correlated with clinicopathological features, recurrence-free (RFS), disease-specific (DSS), and overall survival (OS). Results: sTIL amounts correlated moderately to strongly with quantitatively estimated amounts of pan-T-cells (r = 0.73, P <0.0001), cytotoxic T-cells (r = 0.73, P <0.0001), NK-cells (r = 0.68, P <0.0001), macrophages (r = 0.55, P <0.0001) and with pan-cytotoxic immune infiltration (r = 0.78, P <0.0001), thus reflecting overall infiltration with key immune cell populations. sTIL infiltration ≥10% was associated with significantly higher 5-year OS (45.5% vs. 19.8%), DSS (56.6% vs. 25.6%) and RFS (56.2% vs. 18.9%; P <0.0001 for all three comparisons) rates, and lower pT-stage (P = 0.015), lower pN-stage (P = 0.028), lower rates of lymphovascular invasion (P = 0.0003) and blood vessel invasion (P = 0.01) when compared to sTIL infiltration of <10%. Multivariable regressions models confirmed sTILs as strongest independent predictor for improved outcomes following radical cystectomy. Conclusions: HE based sTIL scoring is a reliable tool to assess MIBC inflammation status and to stratify the survival of MIBC patients undergoing radical cystectomy. sTIL amount is an independent predictor for improved survival, and might be an useful, routinely applicable tool to identify patients benefiting from perioperative platinum-based chemotherapy and checkpoint inhibitor therapy. However, external validation of our data is required.
CRIS-Team Scopus Importer:2021-09-03
Keywords: Bladder cancer; Cystectomy; Prognosis; sTILs; TILs; Urothelial cancer

Validation of a classification and scoring system for the diagnosis of laryngeal and pharyngeal squamous cell carcinomas by confocal laser endomicroscopy - Sievert, Matti; Mantsopoulos, Konstantinos; Müller-Hübner, Sarina Katrin Ursel; Rupp, Robin; Eckstein, Markus; Stelzle, Florian; Oetter, Nicolai; Maier, Andreas; Aubreville, Marc; Iro, Heinrich; Goncalves, Miguel (Brazilian Journal of Otorhinolaryngology, 2021)
Introduction: Confocal laser endomicroscopy is an optical imaging technique that allows in vivo, real-time, microscope-like images of the upper aerodigestive tract's mucosa. The assessment of morphological tissue characteristics for the correct differentiation between healthy and malignant suspected mucosa requires strict evaluation criteria. Objective: This study aims to validate an eight-point score for the correct assessment of malignancy. Methods: We performed confocal laser endomicroscopy between March and October 2020 in 13 patients. 197 sequences (11.820 images) originated from the marginal area of pharyngeal and laryngeal carcinomas. Specimens were taken at corresponding locations and analyzed in H&E staining as a standard of reference. A total of six examiners evaluated the sequences based on a scoring system; they were blinded to the histopathological examination. The primary endpoints are sensitivity, specificity, and accuracy. Secondary endpoints are interrater reliability and receiver operator characteristics. Results: Healthy mucosa showed epithelium with uniform size and shape with distinct cytoplasmic membranes and regular vessel architecture. Confocal laser endomicroscopy of malignant cells demonstrated a disorganized arrangement of variable cellular morphology. We calculated an accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 83.2%, 81.3%, 85.5%, 86.7%, and 79.7%, respectively, with a κ-value of 0.64, and an area under the curve of 0.86. Conclusion: The results confirm that this scoring system is applicable in the laryngeal and pharyngeal mucosa to classify benign and malignant tissue. A scoring system based on defined and reproducible characteristics can help translate this experimental method to broad clinical practice in head and neck diagnosis.
CRIS-Team Scopus Importer:2021-08-13
Keywords: Confocal laser endomicroscopy; Diagnosis; Head and neck cancer; Squamous cell carcinoma

Validation of a novel risk score to predict early and late recurrence in solitary fibrous tumour - Georgiesh, Tatiana; Aggerholm-Pedersen, Ninna; Schoffski, Patrick; Zhang, Yifan; Napolitano, Andrea; Bovee, Judith V. M. G.; Hjelle, Ase; Tang, Gordon; Spalek, Mateusz; Nannini, Margherita; Swanson, David; Baad-Hansen, Thomas; et al. (British Journal of Cancer, 2022)
Background Current risk models in solitary fibrous tumour (SFT) were developed using cohorts with short follow-up and cannot reliably identify low-risk patients. We recently developed a novel risk model (G-score) to account for both early and late recurrences. Here, we aimed to validate the G-score in a large international cohort with long-term follow-up. Methods Data were collected from nine sarcoma referral centres worldwide. Recurrence-free interval (RFi) was the primary endpoint. Results The cohort comprised 318 patients with localised extrameningeal SFTs. Disease recurrence occurred in 96 patients (33%). The estimated 5-year RFi rate was 72%, and the 10-year RFi rate was 52%. G-score precisely predicted recurrence risk with estimated 10-year RFi rate of 84% in low risk, 54% in intermediate risk and 36% in high risk (p < 0.001; C-index 0.691). The mDemicco (p < 0.001; C-index 0.749) and Salas(OS) (p < 0.001; C-index 0.674) models also predicted RFi but identified low-risk patients less accurate with 10-year RFi rates of 72% and 70%, respectively. Conclusions G-score is a highly significant predictor of early and late recurrence in SFT and is superior to other models to predict patients at low risk of relapse. A less intensive follow-up schedule could be considered for patients at low recurrence risk according to G-score.
CRIS-Team WoS Importer:2022-09-09

Validation of the Chick Chorioallantoic Membrane (CAM) Model for Biocompatibility Analysis of Biomaterials in the Context of the 3R‐cascade: A Pilot Study - Barbeck, Mike; Hübner, Kerstin; Burkhardt, Kim; Andreeva, Tonya; Krastev, Rumen; Schnettler, Reiner; Stojanovic, Sanja; Najman, Stevo; Jung, Ole; Schneider-Stock, Regine (In Vivo, 2025)
Background/Aim: The present study aimed to compare the tissue responses to biomaterials in the chick chorioallantoic membrane (CAM) model with those from the subcutaneous implantation model in rats at an early time point. It was especially investigated whether histopathological scoring according to DIN EN ISO 10993‑6 is also possible after biomaterial implantation using the CAM model and to what extent the values differ from the data obtained from small animal experiments. Materials and Methods: Implantation of a xenogeneic bone substitute using the CAM model for 24 h and subcutaneous implantation model in rats up to 10 days post implantation were conducted. Standardized histological and histopathological methods were used to apply for histopathological scoring according to DIN EN ISO 10993‑6. Results: The histological analysis as well as the histo‑pathological scoring revealed that the tissue responses to the xenogeneic bone substitute were completely comparable in both organisms with no visible or statistical differences. Conclusion: We suggest that bioincompatible biomaterials can already be sorted out in the context of THE preclinical in vivo test phase. Such pre‑testing before the required small animal tests might clearly contribute to the 3R‑concept to reduce the number of animals (REDUCE).
CRIS-Team Scopus Importer:2025-05-09
Keywords: 3R‑concept; Biocompatibility; biomaterial; chicken chorioallantoic membrane (CAM); DIN ISO 10993‑6; histopathology; medical device; scoring

Validation of the 'Inflammatory Bowel Disease-Distribution, Chronicity, Activity [IBD-DCA] Score' for Ulcerative Colitis and Crohn ' s Disease - Lang-Schwarz, Corinna; Angeloni, Miriam; Agaimy, Abbas; Atreya, Raja; Becker, Christoph; Dregelies, Theresa; Danese, Silvio; Flejou, Jean-Francois; Gassler, Nikolaus; Grabsch, Heike; Hartmann, Arndt; Kamaradova, Katerina; et al. (Journal of Crohns & Colitis, 2021)
Background and Aims: Histological scoring plays a key role in the assessment of disease activity in ulcerative colitis [UC] and is also important in Crohns disease [CD]. Currently, there is no common scoring available for UC and CD. We aimed to validate the Inflammatory Bowel Disease [IBD]-Distribution [D], Chronicity [C], Activity [A] score [IBD-DCA score] for histological disease activity assessment in IBD.
CRIS-Team WoS Importer:2021-11-12

Validity of tissue homogeneity in confocal laser endomicroscopy on the diagnosis of laryngeal and hypopharyngeal squamous cell carcinoma - Sievert, Matti; Aubreville, Marc; Gostian, Antoniu-Oreste; Mantsopoulos, Konstantinos; Koch, Michael; Müller-Hübner, Sarina Katrin Ursel; Eckstein, Markus; Rupp, Robin; Stelzle, Florian; Oetter, Nicolai; Maier, Andreas; Iro, Heinrich; et al. (European Archives of Oto-Rhino-Laryngology, 2022)
Purpose: Confocal laser endomicroscopy (CLE) allows imaging of the laryngeal mucosa in a thousand-fold magnification. This study analyzes differences in tissue homogeneity between healthy mucosa and squamous cell carcinoma (SCC) via CLE. Materials and methods: We included five SCC patients with planned total laryngectomy in this study between October 2020 and February 2021. We captured CLE scans of the tumor and healthy mucosa. Analysis of image homogeneity to diagnose SCC was performed by measuring the signal intensity in four regions of interest (ROI) in each frame in a total of 60 sequences. Each sequence was assigned to the corresponding histological pattern, derived from hematoxylin and eosin staining. In addition, we recorded the subjective evaluation of seven investigators regarding tissue homogeneity. Results: Out of 3600 images, 1620 (45%) correlated with benign mucosa and 1980 (55%) with SCC. ROIs of benign mucosa and SCC had a mean and standard deviation (SD) of signal intensity of, respectively, 232.1 ± 3.34 and 467.3 ± 9.72 (P < 0.001). The mean SD between the four different ROIs was 39.1 ± 1.03 for benign and 101.5 ± 2.6 for SCC frames (P < 0.001). In addition, homogeneity yielded a sensitivity and specificity of 81.8% and 86.2%, respectively, regarding the investigator-dependent analysis. Conclusions: SCC shows a significant tissue inhomogeneity in comparison to the healthy epithelium. The results support this feature’s importance in identifying malignant mucosa areas during CLE examination. However, the examiner-dependent evaluation emphasizes that homogeneity is a sub-criterion that must be considered in a broad context.
CRIS-Team Scopus Importer:2022-03-18
Keywords: Classification system; Confocal laser endomicroscopy; Head and neck cancer; Larynx; Non-invasive histological imaging; Pharynx

Value of confocal laser endomicroscopy in the diagnosis of vocal cord lesions - Goncalves, M.; Iro, Heinrich; Dittberner, A.; Agaimy, Abbas; Bohr, Christopher (European Review for Medical and Pharmacological Sciences, 2017)
The aim of this study was to assess the reliability and limitations of confocal laser endomicroscopy (CLE) for diagnosing lesions of the vocal cords and differentiating malignant from non-malignant lesions.During microlaryngoscopy, the vocal cords were scanned by probe-based CLE (pCLE: a GastroFlex probe with the Cellvizio® laser system, Mauna Technologies, Paris, France). The video recordings were analyzed and compared with the histological results. Thirty-one representative images were extracted and presented to four medical professionals (blinded examiners) for assessment.The accuracy for the category malignant/nonmalignant ranged between 58.1% and 87.1%. Overall interrater reliability was 0.29. Sensitivity ranged between 45.5 and 100%, specificity between 60.0 and 100%, PPV between 38.5% and 100% and NPV between 66.7 and 100%.CLE is a promising method for the non-invasive diagnosis of vocal cord lesions in vivo, but factors such as small penetration depth, not available contrast media for the nuclei and subjective analyses of the images limit, at the moment, its diagnostic value.
EVALuna2:6891

Value of core needle biopsy in preoperative diagnostics of soft tissue tumors: possibilities and limitations - Agaimy, A. (Pathologe, 2014)
The differential diagnosis of soft tissue swellings encompasses a variety of benign, intermediate, low-grade malignant and high-grade neoplastic lesions in addition to tumor-like reactive processes. As treatment of these heterogeneous conditions varies greatly from conservative observation and simple local excision up to extensive radical surgical resection, treatment decisions are based mainly on a precise preoperative histological diagnosis on limited biopsy material. Even for clinically unequivocal sarcomas, the importance of the preoperative histological diagnosis has been increasingly emphasized as different therapeutic regimens have been established for different sarcoma types and the indications for preoperative treatment is influenced by the tumor grade and by the entity itself. Other factors positively influencing the increasing use of core needle biopsy for preoperative tumor diagnosis in soft tissue pathology are the availability of modern high-resolution imaging modalities as well as the establishment of several new second generation immunohistochemical markers and the discovery of entity-specific translocations detected by fluorescence in situ hybridization (FISH) in several sarcoma subtypes. In this review it will be shown that a targeted approach for processing core needle biopsies oriented towards the characteristic topographical, demographic, cytomorphological and architectural features of soft tissue lesions facilitates a precise diagnosis of soft tissue neoplasms in most cases. However, profound knowledge of the different aspects of soft tissue tumor diagnostics and familiarity with the frequent as well as the less common and rare tumor entities and variants is a prerequisite for appropriate interpretation of core needle biopsy findings and for selecting a limited but well-suited marker panel. The utilization of modern immunohistochemistry and/or FISH methods is highly useful for establishing the diagnosis of rare and unusual neoplasms in core needle biopsies.
EVALuna2:6751

Variable expression of the disialoganglioside gd2 in breast cancer molecular subtypes - Erber, Ramona; Kailayangiri, Sareetha; Hübner, Hanna; Rübner, Matthias; Hartmann, Arndt; Häberle, Lothar; Meyer, Julia; Völkl, Simon; Mackensen, Andreas; Landgraf, Laura; Geppert, Carol-Immanuel; Schulz-Wendtland, Rüdiger; et al. (Cancers, 2021)
The disialoganglioside GD2 is a tumor-associated antigen that may allow for the application of targeted immunotherapies (anti-GD2 antibodies, GD2 CAR T cells) in patients with neuroblastoma and other solid tumors. We retrospectively investigated GD2 expression in a breast cancer cohort, using immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays (TMAs), and its impact on survival. GD2 expression on IHC (n = 568) and IF (n = 503) was investigated in relation to subtypes and patient outcome. Overall, 50.2% of the 568 IHC-assessed samples and 69.8% of the 503 IF-assessed samples were GD2-positive. The highest proportion of GD2-positive tumors was observed in luminal tumors. Significantly fewer GD2-positive cases were detected in triple-negative breast cancer (TNBC) compared with other subtypes. The proportion of GD2-expressing tumors were significantly lower in HER2-positive breast cancer in comparison with luminal tumors on IF staining (but not IHC). GD2 expression of IHC or IF was not significantly associated with disease-free or overall survival, in either the overall cohort or in individual subtypes. However, GD2 expression can be seen in more than 50% of breast cancer cases, with the highest frequency in hormone receptorpositive tumors. With this high expression frequency, patients with GD2-positive advanced breast cancer of all subtypes may benefit from GD2-targeting immunotherapies, which are currently subject to clinical testing.
CRIS-Team Scopus Importer:2021-11-12
Keywords: Breast cancer; Disialoganglioside; GD2; Immunofluorescence; Immunohistochemistry; Prognosis

Variant morphology and random chromosomal integration of BK polyomavirus in posttransplant urothelial carcinomas - Bertz, Simone; Enßer, Armin; Stöhr, Robert; Eckstein, Markus; Apel, Hendrik; Mayr, Doris; Büttner-Herold, Maike; Gaisa, Nadine Therese; Comperat, Eva; Wullich, Bernd; Hartmann, Arndt; Knöll, Antje (Modern Pathology, 2020)
BK polyomavirus (BKPyV) causes major complications in solid organ transplant recipients but little is known about its role in the development of urothelial carcinoma (UC) during immunosuppression. Immunohistochemistry (IHC) screening for polyomavirus large T antigen (LTag) was performed in 94 micropapillary UC (MPUC), 480 unselected UC, 199 muscle invasive UC (including 83 UC with variant differentiation), 76 cases of plasmocytoid, nested and large nested UC and 15 posttransplant UC. LTag expressing UC were reevaluated regarding their histomorphological features and characterized by IHC for p53 and HER2, chromogenic in situ hybridization for HER2 and SNaPshot analysis of the TERT promoter and HRAS. Real-time PCR and next generation sequencing (NGS) were performed to search for BKPyV-DNA and for variants in the tumor and viral genomes. We detected five LTag expressing UC which were diagnosed between 2 and 18 years after kidney (n = 4) or heart (n = 1) transplantation. 89 MPUC without history of organ transplantation and overall 755 UC (including cases with variant histology) were LTag negative. Of the five LTag expressing UC, three were MPUC, one showed extensive divergent differentiation with Mullerian type clear cell carcinoma, and one displayed focal villoglandular differentiation. All five tumors had aberrant nuclear p53 expression, 2/5 were HER2-amplified, and 3/5 had TERT promoter mutations. Within the 50 most common cancer related genes altered in UC we detected very few alterations and no TP53 mutations. BKPyV-DNA was present in 5/5 UC, chromosomal integration of the BKPyV genome was detectable in 4/5 UC. Two UC with BKPyV integration showed small deletions in the BKPyV noncoding control region (NCCR). The only UC without detectable BKPyV integration had a high viral load of human herpesvirus 6 (HHV-6). Our results suggest that LTag expression of integrated BKPyV genomes and resulting p53 inactivation lead to aggressive high-grade UC with unusual, often micropapillary morphology.
CRIS-Team WoS Importer:2020-02-28

Variation in cystectomy pathology reporting practice—results from an international survey of 212 pathologists - Griffin, Jon; Hartmann, Arndt; Comperat, Eva (Virchows Archiv, 2024)
The pathological assessment of cystectomy specimens is important for accurate prognostic information and to inform adjuvant therapy decisions. However, there is limited evidence regarding the best approach to fixation, dissection, block selection and microscopic assessment of cystectomies. We report the results of an international survey of 212 pathologists and their approach to cystectomy pathology. There is variation at all stages of the specimen journey including in fixation and dissection techniques, and in the approach to evaluating residual tumour. This is particularly evident in the post-neoadjuvant chemotherapy setting where there is variable use of response scoring systems and differing approaches to sampling. We also find variation in the use of digital and molecular pathology in cystectomy specimens. Finally, we have suggested areas for future research in cystectomy pathological assessment.
CRIS-Team Scopus Importer:2024-09-13
Keywords: Bladder cancer; Cystectomy; Dissection; Grossing; Neoadjuvant chemotherapy; Pathological response score

Vascular architecture as a diagnostic marker for differentiation of World Health Organization thymoma subtypes and thymic carcinoma - Pfister, Frederick; Hussain, Hussam; Belharazem, Djeda; Busch, Svenja; Simon-Keller, Katja; Becker, Dominic; Pfister, Eva; Rieker, Ralf; Stroebel, Philipp; Marx, Alexander (Histopathology, 2017)
Thymomas and thymic squamous cell carcinomas (TSQCCs) are rare thymic epithelial tumours. Data on angiogenesis and vascular phenotype in these tumours are limited, and no study has taken histological World Health Organization (WHO) subtypes into account. The aim of this study was to compare vascularization, pericytes coverage and expression of angiogenic growth factors in different WHO-defined subtypes of thymoma METHODS AND RESULTS: Vascular density, diameter and architecture and expression of ?-smooth muscle actin (SMA), platelet-derived growth factor (PDGF) receptor-? (PDGFR?), vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) were investigated in WHO type A, AB, B1, B2 and B3 thymomas and TSQCCs, by the use of immunostaining, quantitative morphometry, and tumour vessel isolation by trypsin digestion. Expression levels of angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), VEGF-A, PDGF-B and Hif-1? were examined by quantitative reverse transcription polymerase chain reaction. A and AB thymomas were characterized by a dense network of capillary-like vessels with tight pericyte coverage, whereas B thymomas showed a loose vascular network with increasing vascular diameters and increasing expression of SMA and PDGFR? from B1 to B3 thymomas and TSQCCs. VEGFR1 and VEGFR2 were expressed in vessels of all analysed tumour entities, and at higher levels in epithelial cells of A and B3 thymomas and TSQCCs. mRNA of Ang-2, but not of Ang-1, was significantly up-regulated in all thymoma subtypes, with the highest levels being found in A thymomas. In TSQCCs, Ang-1 and VEGF were the predominantly up-regulated growth factors. Hif-1? was only up-regulated in B3 thymomas and TSQCCs.Thymomas and TSQCCs differ significantly in their vascular architecture and expression of key angiogenic growth factors. The findings could help to improve the differential diagnosis of difficult-to-classify thymic epithelial tumours, and indicate different mechanisms of tumour angiogenesis and functional differences of tumour vessels of major thymoma subtypes and TSQCCs.
EVALuna2:6887

Vascular Calcification in Chronic Kidney Disease: The Role of Inflammation - Benz, Kerstin; Hilgers, Karl Friedrich; Daniel, Christoph; Amann, Kerstin Ute (International Journal of Nephrology, 2018)
Cardiovascular complications are extremely frequent in patients with chronic kidney disease (CKD) and death from cardiac causes is the most common cause of death in this particular population. Cardiovascular disease is approximately 3 times more frequent in patients with CKD than in other known cardiovascular risk groups and cardiovascular mortality is approximately 10-fold more frequent in patients on dialysis compared to the age- and sex-matched segments of the nonrenal population. Among other structural and functional factors advanced calcification of atherosclerotic plaques as well as of the arterial and venous media has been described as potentially relevant for this high cardiovascular morbidity and mortality. One potential explanation for this exceedingly high vascular calcification in animal models as well as in patients with CKD increased systemic and most importantly local (micro)inflammation that has been shown to favor the development of calcifying particles by multiple ways. Of note, local vascular upregulation of proinflammatory and proosteogenic molecules is already present at early stages of CKD and may thus be operative for vascular calcification. In addition, increased expression of costimulatory molecules and mast cells has also been documented in patients with CKD pointing to a more inflammatory and potentially less stable phenotype of coronary atherosclerotic plaques in CKD.
EVALuna2:35397

Vascular inflammation and media calcification are already present in early stages of chronic kidney disease - Benz, Kerstin; Varga, Ildiko; Neureiter, Daniel; Campean, Valentina; Daniel, Christoph; Heim, Christian; Reimann, Albrecht; Weyand, Michael; Hilgers, Karl Friedrich; Amann, Kerstin Ute (Cardiovascular Pathology, 2017)
While patients with chronic kidney disease (CKD) have a high prevalence of classical coronary risk factors, there is increasing evidence that atherosclerosis is different in renal compared to nonrenal patients. Therefore, the present study compares changes in different vessels obtained at cardiac surgery between patients with early and advanced CKD and nonrenal control patients.Fifty patients undergoing cardiac bypass surgery were divided into three groups: (i) 24 control patients with creatinine <1.3mg/dl, (ii) 14 patients with early CKD (creatinine 1.3-2.0mg/dl), and (iii) 12 patients with advanced CKD (creatinine >2.0mg/dl). Aorta, arteria mammaria interna, and vena saphena (V. saphena) were analyzed using morphometry, Kossa stain for vascular calcification, and immunohistochemistry for markers of inflammation and proosteogenic differentiation of vascular smooth muscle cells (VSMCs). Thereby, aortic wall thickness and calcification score of aortic intima and of V. saphena were significantly higher in advanced CKD patients than in nonrenal control patients, whereas significant vascular inflammation and proosteogenic dedifferentiation of VSMC and calcification of the aortic media were already present in early CKD. Interestingly, marked calcification of the V. saphena magna was seen in advanced CKD. Of note, calcium-phosphate product correlated well with markers of inflammation, but not with calcification itself.Early stages of CKD are already associated with local up-regulation of proinflammatory and proosteogenic molecules in the vascular wall and calcification of the aortic media. These findings point to the importance of local microinflammation in CKD and may shed new light on the potentially overestimated role of the calcium-phosphate product for vessel calcification.
EVALuna2:3941

Vascularisation for cardiac tissue engineering: the extracellular matrix - Patra, Chinmoy; Boccaccini, Aldo R.; Engel, Felix (Thrombosis and Haemostasis, 2015)
Cardiovascular diseases present a major socio-economic burden. One major problem underlying most cardiovascular and congenital heart diseases is the irreversible loss of contractile heart muscle cells, the cardiomyocytes. To reverse damage incurred by myocardial infarction or by surgical correction of cardiac malformations, the loss of cardiac tissue with a thickness of a few millimetres needs to be compensated. A promising approach to this issue is cardiac tissue engineering. In this review we focus on the problem of in vitro vascularisation as implantation of cardiac patches consisting of more than three layers of cardiomyocytes (>100 mu m thick) already results in necrosis. We explain the need for vascularisation and elaborate on the importance to include non-myocytes in order to generate functional vascularised cardiac tissue. We discuss the potential of extracellular matrix molecules in promoting vascularisation and introduce nephronectin as an, example of a new promising candidate. Finally, we discuss current biomaterial-based approaches including micropatterning, electrospinning, 3D micro-manufacturing technology and porogens. Collectively, the current literature supports the notion that cardiac tissue engineering is a realistic option for future treatment of paediatric and adult patients with cardiac disease.
Keywords: Heart; vascularisation; coronary vasculature; tissue engineering; extracellular matrix

Vascular occlusion by neutrophil extracellular traps in COVID-19 - Leppkes, Moritz; Knopf, Jasmin; Naschberger, Elisabeth; Lindemann, Aylin; Singh, Jeeshan; Herrmann, Irmgard; Stürzl, Michael; Staats, Léonie; Mahajan, Aparna; Kremer, Anita; Amann, Kerstin Ute; Evert, Katja; et al. (EBioMedicine, 2020)
Background: Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are incompletely understood. Methods: Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry. Patient findings: Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage. Interpretation: These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage. Funding: Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung
CRIS-Team Scopus Importer:2020-08-14
Keywords: Aggregated neutrophil extracellular traps; Coagulopathy; Endothelialitis; Immunothrombosis; SARS-CoV-2

Vasodilator-stimulated phosphoprotein-deficient mice demonstrate increased platelet activation but improved renal endothelial preservation and regeneration in passive nephrotoxic nephritis. - Hohenstein, Bernd; Kasperek, Laura; Kobelt, Dieter-Johannes; Daniel, Christoph; Gambaryan, Stepan; Renne, Thomas; Walter, Ulrich; Amann, Kerstin Ute; Hugo, Christian (Journal of the American Society of Nephrology, 2005)
Vasodilator-stimulated phosphoprotein (VASP), an actin cytoskeletal protein, is expressed in various cell types including renal cells. In vitro studies provide evidence for a role of VASP regarding platelet activation, cell adhesion, migration, and capillary formation. The in vivo role of VASP was investigated in experimental inflammatory renal disease. Kidneys of healthy VASP deficient (-/-) and wild-type (wt) mice were compared regarding morphology and functional parameters. Passive nephrotoxic nephritis was induced in 28 VASP -/- and 28 wt mice; kidneys were harvested; and tissues were analyzed by morphometric, immunohistochemical, and electron microscopic techniques on days 3, 7, 14, and 28. The time course of disease in VASP -/- mice differed substantially and biphasically from that in wt controls. Early on, VASP -/- mice demonstrated increased platelet influx associated with augmented glomerular and tubulointerstitial inflammation and sclerosis. Whereas renal disease continuously worsened up to day 28 in wt controls, renal disease in VASP -/- mice hardly progressed after day 3 as assessed by various injury indices. This long-term improvement of renal histology in VASP -/-compared with wt mice was associated with remarkable capillary preservation/regeneration up to day 28 mediated via an increased proliferative and a reduced apoptotic activity of VASP-negative peritubular endothelial cells. Despite an enhanced injury response early on, VASP -/- mice are protected from long-term progression of nephrotoxic nephritis, which is associated with improved renal endothelial cell preservation and regeneration. Copyright © 2005 by the American Society of Nephrology.
UnivIS-Import:2017-03-24:Pub.2005.med.MKIPIII.MKIPLA.vasodi

Vedolizumab blocks alpha 4 beta 7 integrin-mediated T cell adhesion to MAdCAM-1 in microscopic colitis - Besendorf, Laura; Müller, Tanja; Geppert, Carol-Immanuel; Schneider, Ines; Mühl, Laura; Atreya, Imke; Vitali, Francesco; Atreya, Raja; Neurath, Markus; Zundler, Sebastian (Therapeutic Advances in Gastroenterology, 2022)
Background: In Crohn's disease and ulcerative colitis, the anti-alpha 4 beta 7 integrin antibody vedolizumab has demonstrated efficacy in phase III trials and has been successfully used under real-world conditions. Occasionally, it has also been used in other forms of inflammatory bowel disease (IBD) such as microscopic colitis (MC). However, the mechanisms of vedolizumab in MC have not been studied to date. Therefore, we aimed to investigate the expression and functional role of gut-homing integrins and in particular alpha 4 beta 7 integrin in a cohort study in MC.
CRIS-Team WoS Importer:2022-07-08
Keywords: α4β7 integrin; microscopic colitis; T cell trafficking; vedolizumab

VEGFR2 Signaling Prevents Colorectal Cancer Cell Senescence to Promote Tumorigenesis in Mice With Colitis - Försch, Sebastian; Sperka, Tobias; Lindner, Christina; Taut, Astrid; Rudolph, Karl L.; Breier, Georg; Boxberger, Frank; Rau, Tilman; Hartmann, Arndt; Stürzl, Michael; Wittkopf, Nadine; Haep, Lisa; et al. (Gastroenterology, 2015)
Senescence prevents cellular transformation. We investigated whether vascular endothelial growth factor (VEGF) signaling via its receptor, VEGFR2, regulates senescence and proliferation of tumor cells in mice with colitis-associated cancer (CAC).CAC was induced in VEGFR2(?IEC) mice, which do not express VEGFR2 in the intestinal epithelium, and VEGFR2(fl/fl) mice (controls) by administration of azoxymethane followed by dextran sodium sulfate. Tumor development and inflammation were determined by endoscopy. Colorectal tissues were collected for immunoblot, immunohistochemical, and quantitative polymerase chain reaction analyses. Findings from mouse tissues were confirmed in human HCT116 colorectal cancer cells. We analyzed colorectal tumor samples from patients before and after treatment with bevacizumab.After colitis induction, VEGFR2(?IEC) mice developed significantly fewer tumors than control mice. A greater number of intestinal tumor cells from VEGFR2(?IEC) mice were in senescence than tumor cells from control mice. We found VEGFR2 to activate phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT, resulting in inactivation of p21 in HCT116 cells. Inhibitors of VEGFR2 and AKT induced senescence in HCT116 cells. Tumor cell senescence promoted an anti-tumor immune response by CD8(+) T cells in mice. Patients whose tumor samples showed an increase in the proportion of senescent cells after treatment with bevacizumab had longer progression-free survival than patients in which the proportion of senescent tumor cells did not change before and after treatment.Inhibition of VEGFR2 signaling leads to senescence of human and mouse colorectal cancer cells. VEGFR2 interacts with phosphatidylinositol-4,5-bisphosphate-3-kinase and AKT to inactivate p21. Colorectal tumor senescence and p21 level correlate with patient survival during treatment with bevacizumab.
EVALuna2:1356

Virilizing Hilus Cell Tumor of the Ovary Associated With Efferent Ductules-like Metaplasia Within Paratubal Mesonephric Remnants - Wachter, David; Burghaus, Stefanie; Beckmann, Matthias; Agaimy, Abbas (International Journal of Gynecological Pathology, 2016)
EVALuna2:6767

Vitamin D3 resolved human and experimental asthma via B lymphocyte-induced maturation protein 1 in T cells and innate lymphoid cells. - Grund, Janina; Krammer, Susanne; Yang, Zuqin; Mitländer, Hannah; Rauh, Manfred; Zirlik, Sabine; Kiefer, Alexander; Zimmermann, Theodor; Rieker, Ralf; Geppert, Carol-Immanuel; Papadopoulos, Nikolaos G.; Neurath-Finotto, Susetta (Journal of Allergy and Clinical Immunology: Global, 2023)
BACKGROUND: Vitamin D3 (VitD3) is known to have immunomodulatory functions, and VitD3 deficiency is associated with more severe asthma. OBJECTIVE: We aimed to assess the immunoregulatory effects of VitD3 food supplementation on asthma manifestation, with particular focus on T cells and type 2 innate lymphoid cells. METHODS: Preschool children and adult asthmatic cohorts were analyzed in the context of VitD3 supplementation and serum levels. In a murine model of ovalbumin-induced asthma, effects of diet VitD3 sufficiency and deficiency on T cells and type 2 innate lymphoid cells immune mechanisms were investigated. RESULTS: We found less severe and better-controlled asthma phenotypes along with reduced need for steroid medication in preschool children and asthmatic adults with VitD3 supplementation. VitD3 serum levels correlated with B lymphocyte-induced maturation protein 1 (Blimp-1) expression in blood peripheral mononuclear cells. VitD3-supplement-fed mice showed decreased asthmatic traits, with a decrease in IgE serum levels, reduced airway mucus, and increased IL-10 production by lung cells. Furthermore, we discovered an upregulation of effector T cells and Blimp-1+ lung tissue-resident memory T cells as well as induction of anti-inflammatory Blimp-1+ lung innate lymphoid cells producing IL-10. CONCLUSION: Supplementing VitD3 resulted in amelioration of clinical asthma manifestations in human studies as well as in experimental allergic asthma, indicating that VitD3 shifts proinflammatory immune responses to anti-inflammatory immune responses via upregulating Blimp-1 in lung innate lymphoid cells and tissue-resident memory cells.
EVALuna2:544627
Keywords: Allergic asthma; pediatric asthma; adult asthma; vitamin D3; vitamin D3 supplementation; TRM; ILC2s; Blimp-1; resolution of asthma

Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma - Bruns, Heiko; Büttner, Maike; Fabri, Mario; Mougiakakos, Dimitrios; Bittenbring, Joerg T.; Hoffmann, Markus; Beier, Fabian; Pasemann, Shirin; Jitschin, Regina; Hofmann, Andreas D.; Neumann, Frank; Daniel, Christoph; et al. (Science Translational Medicine, 2015)
Infiltration by macrophages represents a characteristic morphological hallmark in high-grade lymphatic malignancies such as Burkitt's lymphoma (BL). Although macrophages can, in principle, target neoplastic cells and mediate antibody-dependent cellular cytotoxicity (ADCC), tumor-associated macrophages (TAMs) regularly fail to exert direct cytotoxic functions. The underlying mechanisms responsible for this observation remain unclear. We demonstrate that inflammatory M1 macrophages kill proliferating high-grade B cell lymphoma cells by releasing the antimicrobial peptide cathelicidin in a vitamin D-dependent fashion. We show that cathelicidin directly induces cell death by targeting mitochondria of BL cells. In contrast, anti-inflammatory M2 macrophages and M2-like TAMs in BL exhibit an altered vitamin D metabolism, resulting in a reduced production of cathelicidin and consequently in inability to lyse BL cells. However, treatment of M2 macrophages with the bioactive form of vitamin D, 1,25D3, or a vitamin D receptor agonist effectively induces cathelicidin production and triggers tumoricidal activity against BL cells. Furthermore, rituximab-mediated cytotoxicity of vitamin D-treated M2 macrophages is cathelicidin-dependent. Finally, vitamin D treatment of 25-hydroxyvitamin D (25D)-deficient volunteers in vivo or primary TAMs in vitro improves rituximab-mediated ADCC against B cell lymphoma cells. These data indicate that activation of the vitamin D signaling pathway activates antitumor activity of TAMs and improves the efficacy of ADC
EVALuna2:13103

Vitamin D level and its determinants among Sudanese Women: Does it matter in a sunshine African Country? - Husain, Nazik Elmalaika; Suliman, Ahmed Abdel Badie; Abdelrahman, Ismail; Bedri, Shahinaz A.; Musa, Rasha M.; Osman, Hind E.; Mustafa, Ayda H.; Gafer, Nahla; Farah, Ehab; Satir, Ali Abdel; Ahmed, Mohamed H.; Osman, Mugtaba; et al. (Journal of Family Medicine and Primary Care, 2019)
Background: Vitamin D deficiency is a worldwide concern. The aim of the current study was to determine the vitamin D level and its contributing factors in Sudanese women. Methods: In this cross-sectional study, 251 Sudanese women attending Family Health Centers in Khartoum, Sudan were interviewed. Following the exclusion of confounding factors, samples from 190 women were analzsed. Serum 25 hydroxyvitamin D "25(OH) D" was quantified using competitive electrochemiluminescence immunoassay. Results: Participants' age ranged from 18 to 85 years with a mean age (+/- SD) of 40.2 (+/- 14.06) years. The mean (+/- SD) vitamin D level was 13.4 (+/- 6.72) ng/ml, ranged 3.00-36.5 ng/ml and the median was 12.7 ng/mL. In total, 157 out of 190 (82.6%) had vitamin D serum levels below 20 ng/ml (deficient); of whom, 52 (27.4%) were in the age group 21-30 years (P value = 0.228). The correlation between vitamin D level and residence outside Khartoum, sun-exposed face and hands, and face and limbs in comparison with being completely covered were found to be statistically significant (p values 0.008, 0.023, and 0.036). Conclusion: This study displayed a high percentage (82.6%.) of vitamin D deficiency among women in Sudan, and this in part may indicate that sunshine alone cannot guarantee vitamin D sufficiency in the tropics. Family physicians in tropical countries should screen those with clinical presentations related to vitamin D deficiency.
CRIS-Team WoS Importer:2021-10-18

Vitiligo in Childhood and Adolescence - Hartmann, Arndt (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Warm HTK donor pretreatment reduces liver injury during static cold storage in experimental rat liver transplantation - Schoening, Wenzel; Ariyakhagorn, Veeravorn; Schubert, Thomas; Olschewski, Peter; Andreou, Andreas; Neuhaus, Peter; Pratschke, Johann; Puhl, Gero (Hepatobiliary & Pancreatic Diseases International, 2015)
Organ shortage has led to an increased number of transplantations from extended criteria donors. These organs are more vulnerable to ischemia-reperfusion injury. Thus, improvement of organ preservation is needed. HTK is a widely used preservation solution for static cold storage in liver transplantation. The present study was to investigate the beneficial effect of warm HTK donor pretreatment on liver preservation.Male inbred Wistar rats (weighing 230-260 g) served as donors and recipients (n=6/group). Donors of treatment groups received i.v. 0.01 mL/g body weight (BW) warm (21 degree centigrade) HTK systemically 15 minutes prior to cold perfusion. Control groups received 0.01 mL/g BW warm (21 degree centigrade) NaCl 0.9%. Following pretreatment, donors were flushed with 4 degree centigrade cold HTK, livers were explanted and stored in 4 degree centigrade HTK for six hours. Thereafter orthotopic liver transplantation was performed. Recipients were harvested four hours, two and five days after reperfusion and blood and liver tissue samples were obtained. Blood samples were analyzed for AST, ALT, lactate dehydrogenase and bilirubin. Liver histological analysis as well as tissue analysis for pro-MMP2, MMP2 and pro-MMP9 using zymography was conducted.Treatment groups showed significantly lower ALT and lactate dehydrogenase levels as well as significantly lower activities of pro-MMP2, MMP2 and pro-MMP9. Histological analysis revealed only minor damage in all groups.The new concept of warm HTK pretreatment significantly reduced ischemia-reperfusion injury. The reduced ischemia-reperfusion injury was due to MMP inhibition. Warm HTK donor pretreatment is easy to handle and could further improve HTK's potency in liver preservation.
EVALuna2:6742

Warum Tumoren der Harnblase? - Gaisa, N. T.; Hartmann, Arndt (Die Pathologie, 2024)
CRIS-Team Scopus Importer:2024-11-08

What is new in epithelioid soft tissue tumors? - Agaimy, Abbas (Virchows Archiv, 2019)
Epithelioid cell features mimicking carcinomas characterize a variety of histogenetically, phenotypically, and molecularly distinct subsets of mesenchymal neoplasms. In a pathogenetic sense, epithelioid soft tissue tumors basically fall into three main genetic categories: (1) switch/sucrose non-fermenting (SWI/SNF) complex-deficient tumors (with epithelioid sarcoma as their prototype); (2) epithelioid neoplasms driven by specific rare gene fusions (such as sclerosing epithelioid fibrosarcoma with EWSR1 fusions and GLI1-related malignant epithelioid soft tissue neoplasms); and (3) a heterogeneous group encompassing epithelioid variants of diverse other entities. Notably, lesions in the first and third groups may display variable, occasionally prominent, rhabdoid cell morphology, thus further complicating their differential diagnosis. This review summarizes the main clinicopathological, phenotypic, and genotypic features of these diseases and discusses their pertinent differential diagnostic considerations.
CRIS-Team WoS Importer:2019-11-15

What is new in the diagnosis and therapy of renal cell carcinoma? Was ist neu bei der Diagnostik und Therapie des Nierenzellkarzinoms? - Ahrens, Marit; Hartmann, Arndt; Bergmann, Lothar (Deutsche Medizinische Wochenschrift, 2020)
Renal cell carcinomas (RCC) include different tumor entities, of which clear cell RCC is the most common tumor with approx. 75 % followed by the papillary RCC with 10-15 %. RCC are increasingly being diagnosed incidental in the context of abdominal diagnostics from other indications using sonography or cross-sectional imaging.The prognosis of metastatic RCC has improved significantly due to new therapy options, especially through the use of immune checkpoint inhibitors (IO). In the first line, combination therapies of the tyrosine kinase inhibitor (TKI) axitinib with the PD-1 antibody pembrolizumab or the PDL-1 antibody avelumab apply regardless of the risk profile and histological entity, as well as the combination of the CTLA4 antibody ipilimumab with the PD-1 antibody nivolumab in patients with intermediate and high risk as new standards in therapy. The combinations lead to a higher response rate and longer survival. In the second line and subsequent lines, there is no evidence-based data after combination therapies, but drugs can be used that were not yet part of the first-line therapy.
CRIS-Team Scopus Importer:2020-06-16

WHO 1973 grade 3 and infiltrative growth pattern proved, aberrant E-cadherin expression tends to be of predictive value for progression in a series of stage T1 high-grade bladder cancer after organ-sparing approach - Otto, Wolfgang; Breyer, Johannes; Herdegen, Sonja; Eder, Fabian; Bertz, Simone; May, Matthias; Mayr, Roman; Lausenmeyer, Eva M.; Denzinger, Stefan; van Rhijn, Bas W. G.; Burger, Maximilian; Hartmann, Arndt (International Urology and Nephrology, 2017)
Stage pT1 urothelial bladder cancer (UBC) is characterized as a challenging subentity of urothelial carcinoma with an unforeseeable clinical course. In addition to more or less established clinical and histopathological features, we evaluated the role of epithelial-mesenchymal transition (EMT) marker E-cadherin, shown to be of prognostic value in muscle-invasive disease, regarding the prognosis of stage pT1 high-grade (hg) UBC.Tissue of 226 stage pT1 hg UBC patients from transurethral resection could be immunostained for E-cadherin. Kaplan-Meier analysis and univariate and multivariate Cox regression analyses regarding progression-free (PFS) and cancer-specific survival (CSS) were performed.Aberrant expression of E-cadherin was recognized in 74% of patients. Kaplan-Meier analysis showed that aberrant E-cadherin expression was associated with worse 10-year PFS (62 vs. 90%, p = 0.045). In univariate analysis, aberrant E-cadherin staining, associated carcinoma in situ, grading 3 after WHO classification 1973 and infiltrative growth pattern at the invasion front were the statistically significant predictive factors for worse PFS, only infiltrative growth pattern for CSS. With regard to progression, grading 3 after WHO classification of 1973 (HR 6.49; CI 1.54-27.28, p = 0.011) and infiltrative tumor invasion pattern (HR 2.06; CI 1.10-3.86, p = 0.024) revealed as independent factors for PFS, and there was a trend also for E-cadherin expression (HR 0.45; CI 0.19-1.06; p = 0.068). Regarding CSS, infiltrative tumor growth pattern (HR 3.79; CI 1.67-8.60, p = 0.001) was the only statistically significantly independent predictive factor in multivariate Cox regression analysis.Beside invasion growth pattern and WHO grading 1973 that achieved to be independent prognostic factors, there was a trend for the parameter E-cadherin expression to be of predictive value for PFS in stage pT1 hg urothelial bladder carcinoma after organ-sparing approach. Further studies on genetic level are warranted to define the distinct role of EMT in early-invasive UBC.
EVALuna2:6872

WHO 2022 classification of penile and scrotal cancers: updates and evolution - Menon, S.; Moch, H.; Berney, D. M.; Cree, I. A.; Srigley, J. R.; Tsuzuki, T.; Comperat, E.; Hartmann, Arndt; Netto, G.; Rubin, M. A.; Gill, A. J.; Turajlic, S.; et al. (Histopathology, 2022)
Squamous cell carcinoma (SCC) is the most common malignant tumour of the penis. The 2022 WHO classification reinforces the 2016 classification and subclassifies precursor lesions and tumours into human papillomavirus (HPV)-associated and HPV-independent types. HPV-associated penile intraepithelial neoplasia (PeIN) is a precursor lesion of invasive HPV- associated SCC, whereas differentiated PeIN is a precursor lesion of HPV-independent SCC. Block-type positivity of p16 immunohistochemistry is the most practical daily utilised method to separate HPVassociated from HPVindependent penile SCC. If this is not feasible, the term SCC, not otherwise specified (NOS) is appropriate. Certain histologies that were previously classified as "subtypes" are now grouped, and coalesced as "patterns", under the rubric of usual type SCC and verrucous carcinoma (e.g. usual-type SCC includes pseudohyperplastic and acantholytic/pseudoglandular carcinoma, and carcinoma cuniculatum is included as a pattern of verrucous carcinoma). If there is an additional component of the usual type of invasive SCC (formerly termed hybrid histology), the tumour would be a mixed carcinoma (e.g. carcinoma cuniculatum or verrucous carcinoma with usual invasive SCC); in such cases, reporting of the relative percentages in mixed tumours may be useful. The consistent use of uniform nomenclature and reporting of percentages will inform the refinement of future reporting classification schemes and guidelines/recommendations. The classification of scrotal tumours is provided for the first time in the fifth edition of the WHO Blue book, and it follows the schema of penile cancer classification for both precursor lesions and the common SCC of the scrotum. Basal cell carcinoma of the scrotum may have a variable clinical course and finds a separate mention.
CRIS-Team WoS Importer:2022-11-25

WHO 2022 landscape of papillary and chromophobe renal cell carcinoma - Lobo, João; Ohashi, Riuko; Amin, Mahul B.; Berney, Daniel M.; Compérat, Eva M.; Cree, Ian A.; Gill, Anthony J.; Hartmann, Arndt; Menon, Santosh; Netto, George J.; Raspollini, Maria R.; Rubin, Mark A.; et al. (Histopathology, 2022)
The 5th edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems contains relevant revisions and introduces a group of molecularly defined renal tumour subtypes. Herein we present the World Health Organization (WHO) 2022 perspectives on papillary and chromophobe renal cell carcinoma with emphasis on their evolving classification, differential diagnosis, and emerging entities. The WHO 2022 classification eliminated the type 1/2 papillary renal cell carcinoma (pRCC) subcategorization, given the recognition of frequent mixed tumour phenotypes and the existence of entities with a different molecular background within the type 2 pRCC category. Additionally, emerging entities such as biphasic squamoid alveolar RCC, biphasic hyalinising psammomatous RCC, papillary renal neoplasm with reverse polarity, and Warthin-like pRCC are included as part of the pRCC spectrum, while additional morphological and molecular data are being gathered. In addition to oncocytomas and chromophobe renal cell carcinoma (chRCC), a category of ‘other oncocytic tumours’ with oncocytoma/chRCC-like features has been introduced, including emerging entities, most with TSC/mTOR pathway alterations (eosinophilic vacuolated tumour and so-called ‘low-grade’ oncocytic tumour), deserving additional research. Eosinophilic solid and cystic RCC was accepted as a new and independent tumour entity. Finally, a highly reproducible and clinically relevant universal grading system for chRCC is still missing and is another niche of ongoing investigation. This review discusses these developments and highlights emerging morphological and molecular data relevant for the classification of renal cell carcinoma.
CRIS-Team Scopus Importer:2022-06-17
Keywords: chromophobe renal cell carcinoma; emerging entities; molecular pathology; papillary renal cell carcinoma; renal tumours

WHO Classification of Tumours fifth edition: evolving issues in the classification, diagnosis, and prognostication of prostate cancer - Kench, James G.; Amin, Mahul B.; Berney, Daniel M.; Compérat, Eva M.; Cree, Ian A.; Gill, Anthony J.; Hartmann, Arndt; Menon, Santosh; Moch, Holger; Netto, George J.; Raspollini, Maria R.; Rubin, Mark A.; et al. (Histopathology, 2022)
The fifth edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems encompasses several updates to the classification and diagnosis of prostatic carcinoma as well as incorporating advancements in the assessment of its prognosis, including recent grading modifications. Some of the salient aspects include: (1) recognition that prostatic intraepithelial neoplasia (PIN)-like carcinoma is not synonymous with a pattern of ductal carcinoma, but better classified as a subtype of acinar adenocarcinoma; (2) a specific section on treatment-related neuroendocrine prostatic carcinoma in view of the tight correlation between androgen deprivation therapy and the development of prostatic carcinoma with neuroendocrine morphology, and the emerging data on lineage plasticity; (3) a terminology change of basal cell carcinoma to “adenoid cystic (basal cell) cell carcinoma” given the presence of an underlying MYB::NFIB gene fusion in many cases; (4) discussion of the current issues in the grading of acinar adenocarcinoma and the prognostic significance of cribriform growth patterns; and (5) more detailed coverage of intraductal carcinoma of prostate (IDC-P) reflecting our increased knowledge of this entity, while recommending the descriptive term atypical intraductal proliferation (AIP) for lesions falling short of IDC-P but containing more atypia than typically seen in high-grade prostatic intraepithelial neoplasia (HGPIN). Lesions previously regarded as cribriform patterns of HGPIN are now included in the AIP category. This review discusses these developments, summarising the existing literature, as well as the emerging morphological and molecular data that underpins the classification and prognostication of prostatic carcinoma.
CRIS-Team Scopus Importer:2022-08-12
Keywords: pathology; prostate carcinoma; WHO Classification

Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT) - Kosfeld, Anne; Kreuzer, Martin; Daniel, Christoph; Brand, Frank; Schaefer, Anne-Kathrin; Chadt, Alexandra; Weiss, Anna-Carina; Riehmer, Vera; Jeanpierre, Cecile; Klintschar, Michael; Braesen, Jan Hinrich; Amann, Kerstin Ute; et al. (Human genetics, 2016)
Congenital anomalies of the kidneys and urinary tract (CAKUT) are genetically highly heterogeneous leaving most cases unclear after mutational analysis of the around 30 causative genes known so far. Assuming that phenotypes frequently showing dominant inheritance, such as CAKUT, can be caused by de novo mutations, de novo analysis of whole-exome sequencing data was done on two patient-parent-trios to identify novel CAKUT genes. In one case, we detected a heterozygous de novo frameshift variant in TBC1D1 encoding a Rab-GTPase-activating protein regulating glucose transporter GLUT4 translocation. Sequence analysis of 100 further CAKUT cases yielded three novel or rare inherited heterozygous TBC1D1 missense variants predicted to be pathogenic. TBC1D1 mutations affected Ser237-phosphorylation or protein stability and thereby act as hypomorphs. Tbc1d1 showed widespread expression in the developing murine urogenital system. A mild CAKUT spectrum phenotype, including anomalies observed in patients carrying TBC1D1 mutations, was found in kidneys of some Tbc1d1 (-/-) mice. Significantly reduced Glut4 levels were detected in kidneys of Tbc1d1 (-/-) mice and the dysplastic kidney of a TBC1D1 mutation carrier versus controls. TBC1D1 and SLC2A4 encoding GLUT4 were highly expressed in human fetal kidney. The patient with the truncating TBC1D1 mutation showed evidence for insulin resistance. These data demonstrate heterozygous deactivating TBC1D1 mutations in CAKUT patients with a similar renal and ureteral phenotype, and provide evidence that TBC1D1 mutations may contribute to CAKUT pathogenesis, possibly via a role in glucose homeostasis.
EVALuna2:25497

Whorling cellular perineurioma: A previously undescribed variant closely mimicking monophasic fibrous synovial sarcoma - Michal, Michael; Kazakov, Dmitry V.; Agaimy, Abbas; Hosova, Marta; Michalova, Kvetoslava; Grossmann, Petr; Steiner, Petr; Skenderi, Faruk; Vranic, Semir; Michal, Michal (Annals of Diagnostic Pathology, 2017)
The authors present a distinctive perineurioma (PN) variant which morphologically strongly resembles monophasic fibrous synovial sarcoma (MSS). The patients were 3 males and 1 female. The age ranged from 15 to 61years (mean: 44years). Locations included the sole, lower jaw, palm and foot. The tumor size ranged from 1.3cm to 2.5cm in the largest dimension (mean 1.8cm). Morphologically, all tumors had an identical, monotonous appearance. The perineurial cells were closely packed and created a confluent cellular whorls and/or sheets in a scarce stroma, with only focally discernible long, slender cytoplasmic processes typical for perineurial differentiation. The nuclei were rounded or slightly elongated to tapered, without nuclear atypia. Mitoses were rare to completely absent. Atypical mitoses, hemorrhage, necrosis or calcifications were not present. The proliferative index (Ki-67) was 1-3%. All analyzed tumors were positive for EMA, Claudin-1, GLUT-1 and negative with S100 protein, CD34, OSCAR, CK7 and TLE-1. Two cases were tested by fluorescence in situ hybridization and neither showed alterations of the SYT gene. One case studied by electron microscopy showed characteristic features of perineurial differentiation. Follow-up was available for two patients both of which showed no evidence of disease at 8years and 6months, respectively. Based on their bland morphology, perineurial features and presumably benign clinical outcome we propose the term "whorling cellular perineurioma" for these tumors, which may represent an extremely cellular variant of sclerosing PN. Awareness of this PN subtype and its distinction from MSS is of utmost clinical significance.
EVALuna2:6857

Why and How to Diagnose Synovial Sarcoma in Head and Neck Region. A Detailed Clinicopathologic Study Emphasizing Diagnostic Utility of Immunohistochemical Markers and Poor Prognosis - Tariq, Muhammad; Din, Nasir Ud; Rani, Alka; Agaimy, Abbas (LABORATORY INVESTIGATION, 2020)
CRIS-Team WoS Importer:2020-03-24

Why is the histomorphological diagnosis of small salivary gland tumours so much more difficult? Warum ist die histomorphologische Diagnostik von Tumoren kleiner Speicheldrüsen so viel schwieriger? - Ihrler, Stephan; Agaimy, Abbas; Guntinas-Lichius, Orlando; Haas, Christian; Greber, Lukas (Die Pathologie, 2023)
There is a widespread impression among clinicians and pathologists that the histomorphological diagnosis of minor salivary gland tumours is more difficult and more frequently misdiagnosed than that of major glands. This is based on subjective clinical impression; scientific proof of and potential reasons for this difference are lacking. We identified 14 putative clinical, histopathological and combined clinical–histological reasons and four consequences, which together could explain the perceived greater difficulty of diagnosing minor gland tumours. We performed a thorough literature search and a statistical comparison of data from a personal large consultation series (biased for “difficult” cases) with cumulated data from a routine, unselected (non-consultation) series from the literature. Through this comparison, we could prove with statistical significance a series of reasons and consequences for this greater diagnostic difficulty in minor glands. Frequent incisional biopsies, almost obligatory low-grade bland cytology in malignant tumours and insufficient clinical–pathological communication emerged as the most important reasons. The special anatomic location of the hard palate contributes to further diagnostic difficulties, such as tumour necrosis, mucosal ulceration, pseudoinvasion and the “tumoural-mucosal fusion” phenomenon. Knowledge of these pitfalls in clinic and pathology can help overcome these difficulties and reduce the misdiagnosis rate in minor gland tumours. Our findings result in a series of recommendations both for the clinic and pathology.
CRIS-Team Scopus Importer:2023-07-28
Keywords: Biopsy; Diagnostic errors; Molecular pathology; Palate; Salivary gland neoplasms

Why is the histomorphological diagnosis of tumours of minor salivary glands much more difficult? - Ihrler, Stephan; Agaimy, Abbas; Guntinas-Lichius, Orlando; Haas, Christian J.; Mollenhauer, Martin; Sandison, Ann; Greber, Lukas (Histopathology, 2021)
Aims: There is a widespread perception among clinicians and pathologists that the histomorphological assessment of minor salivary gland (MinSG) tumours is more difficult and hampered by more misdiagnoses than that of major salivary gland tumours. This is based on a vague, subjective clinical impression, lacking scientific proof. The aim of the present study was to identify and statistically verify potential reasons that could explain this difference. Methods and results: We identified 14 putative clinical, pathological and combined clinicopathological reasons that, altogether, could explain the phenomenon of the perceived greater diagnostic difficulty associated with MinSG tumours. We performed a comprehensive literature search and a statistical comparison of data from a large personal consultation series (biased for difficult cases) with cumulated data from straightforward, unselected (non-consultation) series from the literature. By performing this comparison, we identified, with statistical significance, a comprehensive series of reasons, as well as of consequences, of the greater difficulty in diagnosing MinSG tumours. Conclusions: Among the 14 criteria, high frequencies of initial incisional biopsies and of a low-grade category in malignant tumours emerged as the two most important reasons for enhanced diagnostic difficulty. Very rare entities, unusual locations, shortcomings in clinicopathological communication, and pecularities of the special anatomical location of the hard palate, such as tumour necrosis, mucosal ulceration, pseudoinvasion, and the peculiar phenomenon of ‘tumoral–mucosal fusion’, contribute to further diagnostic difficulties. The awareness of these shortcomings and pitfalls enables us to provide a series of recommendations for clinicians and pathologists that might aid in assessment and reduce the rate of misdiagnosis of MinSG tumours.
CRIS-Team Scopus Importer:2021-08-27
Keywords: consultation cases; minor salivary glands; molecular testing; palate; pitfall; salivary carcinoma; second opinion

Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance - Dietrich, Peter; Koch, Andreas; Fritz, Valerie; Hartmann, Arndt; Boßerhoff, Anja Katrin; Hellerbrand, Claus (Gut, 2017)
Sorafenib is the only effective therapy for advanced hepatocellular carcinoma (HCC). Combinatory approaches targeting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)- and phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/protein-kinase B(AKT) signalling yield major therapeutic improvements. RAS proteins regulate both RAF/MAPK and PI3K/AKT signalling. However, the most important RAS isoform in carcinogenesis, Kirsten rat sarcoma (KRAS), remains unexplored in HCC.Human HCC tissues and cell lines were used for expression and functional analysis. Sorafenib-resistant HCC cells were newly generated. RNA interference and the novel small molecule deltarasin were used for KRAS inhibition both in vitro and in a murine syngeneic orthotopic HCC model.Expression of wild type KRAS messenger RNA and protein was increased in HCC and correlated with extracellular-signal regulated kinase (ERK) activation, proliferation rate, advanced tumour size and poor patient survival. Bioinformatic analysis and reporter assays revealed that KRAS is a direct target of microRNA-622. This microRNA was downregulated in HCC, and functional analysis demonstrated that KRAS-suppression is the major mediator of its inhibitory effect on HCC proliferation. KRAS inhibition markedly suppressed RAF/ERK and PI3K/AKT signalling and proliferation and enhanced apoptosis of HCC cells in vitro and in vivo. Combinatory KRAS inhibition and sorafenib treatment revealed synergistic antitumorigenic effects in HCC. Sorafenib-resistant HCC cells showed elevated KRAS expression, and KRAS inhibition resensitised sorafenib-resistant cells to suppression of proliferation and induction of apoptosis.KRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC.
EVALuna2:4776

Wntless promotes bladder cancer growth and acts synergistically as a molecular target in combination with cisplatin - Schmid, Sebastian C.; Sathe, Anuja; Guerth, Ferdinand; Seitz, Anna-Katharina; Heck, Matthias M.; Maurer, Tobias; Schwarzenboeck, Sarah M.; Krause, Bernd J.; Schulz, Wolfgang A.; Stoehr, Robert; Gschwend, Juergen E.; Retz, Margitta; et al. (Urologic Oncology-Seminars and Original Investigations, 2017)
To analyze the contribution of Wnt signaling pathway to bladder cancer growth in order to identify suitable target molecules for therapy.Expression of Wnt 2/4/7, LRP5/6, TCF1/2/4, LEF-1, and ?-actin was detected by reverse transcription polymerase chain reaction in a panel of 9 and for Wntless (WLS) in 17 bladder cancer cell lines. Protein expression of WLS was detected in 6 cell lines. Wnt/?-catenin activity was analyzed using the TOPflash/FOPflash luciferase reporter assay. Expression level of ?-catenin, WIF1, Dickkopf proteins (DKK), HSulf-2, sFRP4, and WLS was modulated by transfecting or infecting cells transiently or stably with respective shRNAs, siRNAs, or cDNAs. For protein detection, whole cell lysates were applied to sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by immunoblots. Effects on cell growth were determined by cell viability assays and BrdU/APC incorporation/staining. For 3-dimensional tumor growth, the chicken chorioallantoic membrane model was used. Tumor growth was characterized by weight.Expression of molecular components and activation of the Wnt signaling pathway could be detected in all cell lines. Expression level of ?-catenin, WIF1, DKK, WLS, and HSulf-2 influenced Wnt activity. Expression of WLS was confirmed in 17 cell lines by reverse transcription polymerase chain reaction and in 6 cell lines by immunoblotting. WLS positively regulates Wnt signaling, cell proliferation, and tumor growth in vitro and in vivo. These effects could be reversed by the expression of the Wnt antagonist WIF1 and DKK. Synergistic activity of cisplatin and WLS inactivation by genetic silencing could be observed on cell viability.The Wnt signaling pathway is ubiquitously activated in bladder cancer and regulates tumor growth. WLS might be a target protein for novel therapies in combination with established chemotherapy regimens.
EVALuna2:6905

WT1-dependent sulfatase expression maintains the normal glomerular filtration barrier - Schumacher, Valerie A.; Schlötzer-Schrehardt, Ursula; Karumanchi, S. Ananth; Shi, Xiaofeng; Zaia, Joseph; Jeruschke, Stefanie; Zhang, Dongsheng; Pavenstaedt, Hermann; Drenckhan, Astrid; Amann, Kerstin Ute; Ng, Carrie; Hartwig, Sunny; et al. (Journal of the American Society of Nephrology, 2011)
Paracrine signaling between podocytes and glomerular endothelial cells through vascular endothelial growth factor A (VEGFA) maintains a functional glomerular filtration barrier. Heparan sulfate proteoglycans (HSPGs), located on the cell surface or in the extracellular matrix, bind signaling molecules such as VEGFA and affect their local concentrations, but whether modulation of these moieties promotes normal crosstalk between podocytes and endothelial cells is unknown. Here, we found that the transcription factor Wilms' Tumor 1 (WT1) modulates VEGFA and FGF2 signaling by increasing the expression of the 6-O-endosulfatases Sulf1 and Sulf2, which remodel the heparan sulfate 6-O-sulfation pattern in the extracellular matrix. Mice deficient in both Sulf1 and Sulf2 developed age-dependent proteinuria as a result of ultrastructural abnormalities in podocytes and endothelial cells, a phenotype similar to that observed in children with WT1 mutations and in Wt1(+/-) mice. These kidney defects associated with a decreased distribution of VEGFA in the glomerular basement membrane and on endothelial cells. Collectively, these data suggest that WT1-dependent sulfatase expression plays a critical role in maintaining the glomerular filtration barrier by modulating the bioavailability of growth factors, thereby promoting normal crosstalk between podocytes and endothelial cell
EVALuna2:21045

Xanthogranulomatous epithelial tumors/keratin-positive giant cell–rich tumors involving the head and neck: report of seven cases and review of the literature - Whaley, Rumeal D.; Agaimy, Abbas; Bridge, Julia A.; Stöhr, Robert; Din, Nasir Ud; Gagan, Jeffrey; Rampisela, Debby; Folpe, Andrew L.; Bishop, Justin A. (Virchows Archiv, 2024)
Xanthogranulomatous epithelial tumor (XGET) and HMGA2::NCOR2 fusion keratin-positive giant cell–rich tumor (KPGCT) are recently described morphologically overlapping rare neoplastic entities characterized by HMGA2::NCOR2 fusions, low-grade biological behavior, and a strong predilection for young females. To date, 47 cases have been reported with only four occurring in head and neck anatomic locations. In this study, we describe the clinicopathologic, immunohistochemical, and molecular findings of seven XGET/KPGCTs occurring in the head and neck region. The patients were six females and one male, aged 3.5–59 years old (median, 25 years). The tumors involved the ear, vocal cord, skull, neck soft tissue, and sinonasal cavity. Tumor sizes ranged from 1.5 to 6.7 cm. Histologically, the tumors were characterized by xanthogranulomatous histiocytes, osteoclast-like giant cells, and keratin-positive epithelioid cells. The XGET/KPGCTs involving the ear was remarkable for more cytologic atypia than previously described. Four cases had the HMGA2::NCOR2 fusion identified by NGS and three had HMGA2 gene locus alterations by FISH. Follow-up information was available for 3 of 7 patients (range 6–46 months). The patient with a vocal cord XGET/KPGCTs developed a local recurrence treated with excision. This study illustrates that XGET/KPGCTs involves the head and neck region as well, where it may be unexpected and hence under-recognized, and expands the anatomic locations of involvement to include unreported sites (ear, vocal cord, and sinonasal tract).
CRIS-Team Scopus Importer:2024-08-30
Keywords: HMGA2::NCOR2; Keratin-positive giant cell–rich tumor; KPGCT; Xanthogranulomatous epithelial tumor; XGET

XCR1 expression distinguishes human conventional dendritic cell type 1 with full effector functions from their immediate precursors - Heger, Lukas; Hatscher, Lukas; Liang, Chunguang; Lehmann, Christian; Amon, Lukas; Lühr, Jennifer J.; Kaszubowski, Tomasz; Nzirorera, Rayk; Schaft, Niels; Dörrie, Jan; Irrgang, Pascal; Tenbusch, Matthias; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2023)
Dendritic cells (DCs) are major regulators of innate and adaptive immune responses. DCs can be classified into plasmacytoid DCs and conventional DCs (cDCs) type 1 and 2. Murine and human cDC1 share the mRNA expression of XCR1. Murine studies indicated a specific role of the XCR1-XCL1 axis in the induction of immune responses. Here, we describe that human cDC1 can be distinguished into XCR1- and XCR1+ cDC1 in lymphoid as well as nonlymphoid tissues. Steady-state XCR1+ cDC1 display a preactivated phenotype compared to XCR1- cDC1. Upon stimulation, XCR1+ cDC1, but not XCR1- cDC1, secreted high levels of inflammatory cytokines as well as chemokines. This was associated with enhanced activation of NK cells mediated by XCR1+ cDC1. Moreover, XCR1+ cDC1 excelled in inhibiting replication of Influenza A virus. Further, under DC differentiation conditions, XCR1- cDC1 developed into XCR1+ cDC1. After acquisition of XCR1 expression, XCR1- cDC1 secreted comparable level of inflammatory cytokines. Thus, XCR1 is a marker of terminally differentiated cDC1 that licenses the antiviral effector functions of human cDC1, while XCR1- cDC1 seem to represent a late immediate precursor of cDC1.
CRIS-Team Scopus Importer:2023-08-25
Keywords: antiviral immunity; cDC1; DC differentiation; IL-12; XCR1

XePhIR: the zebrafish xenograft phenotype interactive repository - Groenewoud, Arwin; Forn-Cuni, G.; Engel, Felix; Snaar-Jagalska, B. E. (Database : the Journal of Biological Databases and Curation, 2022)
Zebrafish xenografts are an established model in cancer biology, with a steadily rising number of models and users. However, as of yet, there is no platform dedicated to standardizing protocols and sharing data regarding zebrafish xenograft phenotypes. Here, we present the Xenograft Phenotype Interactive Repository (XePhIR, ) as an independent data-sharing platform to deposit, share and repurpose zebrafish xenograft data. Deposition of data and publication with XePhIR will be done after the acceptation of the original publication. This will enhance the reach of the original research article, enhance visibility and do not interfere with the publication or copyrights of the original article. With XePhIR, we strive to fulfill these objectives and reason that this resource will enhance reproducibility and showcase the appeal and applicability of the zebrafish xenograft model. Database URL:
CRIS-Team WoS Importer:2022-05-13

Xpert bladder cancer monitor to predict the need for a second TURB (MoniTURB trial) - Breyer, Johannes; Eckstein, Markus; Sikic, Danijel; Wezel, Felix; Roghmann, Florian; Brehmer, Mirco; Wirtz, Ralph M.; Jarczyk, Jonas; Erben, Philipp; Bahlinger, Veronika; Goldschmidt, Franziska; Fechner, Guido; et al. (Scientific Reports, 2023)
To determine whether Xpert bladder cancer monitor, a noninvasive PCR-based biomarker test, can predict the need for 2nd transurethral resection of the bladder (TURB) better than clinical assessment. Patients scheduled for TURB were prospectively screened. After initial TURB, patients were assigned to 2nd TURB or follow-up cystoscopy at 3 months (FU) by clinicians’ discretion. Central urine cytology and Xpert monitor tests were performed prior to the 1st TURB and 2nd TURB or FU, respectively. Statistical analysis to compare clinical assessment and Xpert monitor comprised sensitivity (SENS), specificity (SPEC), NPV and PPV. Of 756 screened patients, 171 were included (114 with 2nd TURB, 57 with FU). Residual tumors were detected in 34 patients who underwent 2nd TURB, and recurrent tumors were detected in 2 patients with FU. SENS and SPEC of Xpert monitor were 83.3% and 53.0%, respectively, PPV was 32.6% and NPV was 92.1%. Clinical risk assessment outperformed Xpert monitor. In patients with pTa disease at initial TURB, Xpert monitor revealed a NPV of 96%. Xpert monitor was not superior than clinical assessment in predicting the need for 2nd TURB. It might be an option to omit 2nd TURB for selected patients with pTa disease.
CRIS-Team Scopus Importer:2023-09-29

YAP1::KMT2A-rearranged sarcomas harbor a unique methylation profile and are distinct from sclerosing epithelioid fibrosarcoma and low-grade fibromyxoid sarcoma - Warmke, Laura M.; Ameline, Baptiste; Fritchie, Karen J.; Dehner, Carina A.; Agaimy, Abbas; Din, Nasir Ud; Miettinen, Markku M.; Dermawan, Josephine K.; Gross, John M.; Thangaiah, Judith J.; Chrisinger, John S.A.; Suster, David I.; et al. (Virchows Archiv, 2025)
Sclerosing epithelioid fibrosarcoma (SEF) was originally described as a peculiar variant of fibrosarcoma in 1995. Subsequent studies showed that conventional SEF was associated with both immunohistochemical expression of MUC4 and EWSR1/FUS gene rearrangements with CREB3L1 as the predominant fusion partner. Since then, a distinct group of fibrous tumors characterized by YAP1::KMT2A and KMT2A::YAP1 gene rearrangements and SEF-like morphology has been described. These YAP1::KMT2A-rearranged sarcomas were further shown to lack both immunohistochemical expression of MUC4 and canonical EWSR1/FUS gene rearrangements. To better understand whether the YAP1::KMT2A-rearranged sarcomas represent a subset of MUC4-negative SEF or a distinct entity, we studied 22 cases of YAP1::KMT2A-rearranged sarcomas, the largest series to date, and performed a literature review of all previously reported next-generation sequencing (NGS)-confirmed cases. These sarcomas often arose in young adults with a median age of 38 years and a male to female (M:F) ratio of 1.4:1. They predominantly involved somatic soft tissue; however, we report the first case of a tumor that primarily developed inside bone. Immunohistochemical studies showed that the tumors often demonstrated expression of YAP1 and EMA, while all tested cases were negative for MUC4. NGS confirmed the presence of YAP1::KMT2A gene fusions in all cases, some of which initially had false negative results with targeted FISH and solid tumor panel testing. Clinical follow-up information was available in 14 patients with a median follow-up of 25 months (range 1 to 170 months). Local recurrence occurred in three patients (21%) and metastasis developed in seven patients (50%). DNA methylation analysis further showed that YAP1::KMT2A-rearranged sarcomas formed a distinct cluster, which was clearly separate from both conventional SEF and low-grade fibromyxoid sarcoma (LGFMS). These results suggest that YAP1::KMT2A-rearranged sarcomas likely represent a unique sarcoma subtype with propensity for aggressive behavior.
CRIS-Team Scopus Importer:2025-02-04
Keywords: KMT2A; Methylation; MUC4; Sarcoma; Sclerosing epithelioid fibrosarcoma; YAP1

YAP1-MAML2-Rearranged Poroid Squamous Cell Carcinoma (Squamoid Porocarcinoma) Presenting as a Primary Parotid Gland Tumor - Agaimy, Abbas; Stöhr, Robert; Tögel, Lars; Hartmann, Arndt; Cramer, Thomas (Head and Neck Pathology, 2020)
Porocarcinoma (synonym: malignant eccrine poroma) is a rare aggressive carcinoma type with terminal sweat gland duct differentiation. The squamous variant of porocarcinoma is even less frequent and might be indistinguishable from conventional squamous cell carcinoma (SCC). We herein describe the first case of a carcinoma presenting as a primary parotid gland malignancy in a 24-year-old male without any other primary tumor. Total parotidectomy and neck dissection were performed followed by adjuvant chemoradiation. The patient remained alive and well 10 months after diagnosis. Histology showed keratinizing SCC infiltrating extensively the parotid gland with subtle poroid cell features. Oncogenic HPV infection was excluded by DNA-based testing. NGS analysis using the TruSight RNA fusion panel (Illumina) revealed a novel YAP1-MAML2 gene fusion. This gene fusion was reported recently in a subset of cutaneous porocarcinoma and poroma. This case of poroid SCC (or squamoid porocarcinoma) adds to the differential diagnosis of SCC presenting as parotid gland tumor and highlights the value of molecular testing in cases with unusual presentation.
CRIS-Team Scopus Importer:2020-06-16
Keywords: Head and neck; MAML2; Parotid; Porocarcinoma; Poroma; Salivary glands; Squamous cell carcinoma; YAP1

YAP1-NUTM1 Gene Fusion in Porocarcinoma of the External Auditory Canal - Agaimy, Abbas; Tögel, Lars; Haller, Florian; Zenk, Johannes; Hornung, Joachim; Märkl, Bruno (Head and Neck Pathology, 2020)
Gene fusions involving the NUTM1 gene (NUT) represent defining genetic markers of a highly aggressive carcinoma type with predilection for the midline structures of children and young adults, hence the original description as NUT midline carcinoma. Recent studies have increasingly documented involvement of the NUTM1 gene in the pathogenesis of other entities as well. We herein describe two cases of auditory canal carcinomas with features of porocarcinoma, both harboring a newly described YAP1-NUTM1 gene fusion. Patients were males aged 28 and 82 years who presented with slowly growing lesions in the external auditory canal. Histologic examination showed monomorphic basaloid and squamoid cells arranged into organoid solid aggregates, nests, ducts, small cysts, and focal pseudocribriform pattern with variable mitotic activity, infiltrative growth, and focal squamous differentiation, particularly in the most superficial part of the tumor. Immunohistochemistry revealed consistent reactivity for CK5, p63 and SOX10 and diffuse aberrant expression of TP53. CK7 expression was limited to a few luminal ductal cells. The androgen receptor and S100 were negative. Next generation sequencing (TruSight RNA fusion panel, Illumina) revealed the same YAP1-NUTM1 gene fusion in both tumors, which was subsequently confirmed by NUT-FISH and the monoclonal anti-NUT antibody. These cases represent a novel contribution to the spectrum of NUT-rearranged head and neck malignancies. This adnexal carcinoma variant should not be confused with the highly lethal NUT carcinoma based on NUT immunoreactivity alone.
CRIS-Team Scopus Importer:2020-06-02
Keywords: Auditory canal; Ear; Head and neck; Midline carcinoma; NUT carcinoma; NUTM1; YAP1

ypN0 nodal status after neoadjuvant chemoradiotherapy for rectal carcinoma is not associated with adverse prognosis as compared with pN0 after primary surgery - Erlenbach-Wuensch, Katharina; Semrau, Sabine; Fietkau, Rainer; Weber, Klaus; Hohenberger, Werner; Rau, Tilman; Hartmann, Arndt; Merkel, Susanne; Agaimy, Abbas (International Journal of Colorectal Disease, 2014)
Neoadjuvant chemoradiotherapy (nCRT) has been established as standard treatment for locally advanced rectal cancer (cT3/4 or cN+ cM0, distance from circumferential resection margin <=1 mm) to enhance local disease control and minimize the rate of locoregional recurrence. As a consequence of downstaging, a significant proportion of patients show non-viable tumor deposits within regional lymph nodes that qualify as ypN0 according to the current TNM classification irrespective of the actual pre-treatment status. Accordingly, the prognostic relevance of ypN0 status as compared with true pN0 without preceding nCRT is not known.We retrospectively analyzed 132 patients who underwent standard total mesorectal excision (TME) surgery after nCRT for rectal carcinoma and were classified as ypN0, and compared their prognoses with those of 341 patients with pN0 without nCRT.Re-evaluation of regional lymph nodes after nCRT showed no evidence of previous metastasis in 91 cases (ypN0(-)), sure but non-viable metastasis in 14 patients (ypN0(+)), and unsure status in 27 patients (ypN0(X)). The local recurrence rate, distant metastases, and disease-free, observed, and cancer-related survival were similar in all subgroups (p = 0.447, 0.695, 0.759, 0.655, and 0.354, respectively).Our results showed a similar outcome in patients with ypN0 and in the control group with pN0 regarding local recurrence rate, distant metastases, and disease-free, observed, and cancer-related survival. Validation of these results is necessary to clarify the questions regarding postoperative adjuvant chemotherapy for patients with ypN0(+).
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