ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer - Menche, Constantin; Schuhwerk, Harald; Armstark, Isabell; Gupta, Pooja; Fuchs, Kathrin; van Roey, Ruthger; Mosa, Mohammed H.; Hartebrodt, Anne; Hajjaj, Yussuf; Clavel Ezquerra, Ana; Selvaraju, Manoj K.; Geppert, Carol-Immanuel; et al. (EMBO Reports, 2024)
(Figure presented.) Fibroblast-specific Zeb1 knock-out in colorectal cancer models leads to a shift in myCAF and iCAF populations, promoting immune infiltration. This increases colitis-associated tumorigenesis, reduces progression and metastasis and renders tumors susceptible to immune checkpoint blockade. Zeb1 loss in cancer-associated fibroblasts (CAFs) accelerates inflammation-driven colorectal tumorigenesis. In sporadic tumors CAF-specific Zeb1-loss results in decreased progression and metastasis. Impaired myofibroblast and increased inflammation result in increased immune cell infiltration and checkpoint activation. Zeb1 deficiency in CAFs sensitizes colorectal cancers to immune checkpoint inhibition.
CRIS-Team Scopus Importer:2024-07-19
Keywords: Cancer-Associated Fibroblast Plasticity; Colorectal Cancer; Immune Checkpoint Blockade; Tumor Microenvironment

Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition - Schwab, Annemarie; Rao, Zhigang; Zhang, Jie; Gollowitzer, André; Siebenkäs, Katharina; Bindel, Nino; D’Avanzo, Elisabetta; van Roey, Ruthger; Hajjaj, Yussuf; Özel, Ece; Armstark, Isabell; Bereuter, Leonhard; et al. (Nature Cell Biology, 2024)
Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial–mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1. We demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic polyunsaturated fatty acids over cyto-protective monounsaturated fatty acids by modulating the differential expression of the underlying crucial enzymes stearoyl-Co-A desaturase 1 (SCD), fatty acid synthase (FASN), fatty acid desaturase 2 (FADS2), elongation of very long-chain fatty acid 5 (ELOVL5) and long-chain acyl-CoA synthetase 4 (ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis sensitivity preferentially in high-Zeb1-expressing cancer cells. Our data are of potential translational relevance and suggest a combination of ferroptosis activators and SCD inhibitors for the treatment of aggressive cancers expressing high Zeb1.
CRIS-Team Scopus Importer:2024-08-02

Zoledronate causes a systemic shift of macrophage polarization towards M1 in vivo - Weber, Manuel; Homm, Andi; Müller, Stefan; Frey, Silke; Amann, Kerstin Ute; Ries, Jutta; Geppert, Carol-Immanuel; Preidl, Raimund; Möst, Tobias; Kämmerer, Peer W.; Kesting, Marco Rainer; Wehrhan, Falk (International Journal of Molecular Sciences, 2021)
Background: Immunomodulatory properties of bisphosphonates (BP) are suggested to contribute to the development of medication‐associated osteonecrosis of the jaw (MRONJ). Further-more, bisphosphonate‐derived immune modulation might contribute to the anti‐metastatic effect observed in breast cancer patients. Macrophages are potential candidates for the mediation of immunomodulatory effects of bisphosphonates. The study aimed to investigate the influence of bisphosphonates alone and in combination with surgical trauma on systemic macrophage polarization (M1 vs. M2) using an in vivo rat model. Methods: A total of 120 animals were divided into four groups. Groups 2 and 4 were treated with 8 × 40 μg/kg body weight of the BP Zoledronate i.p. (week 0–7). Groups 3 and 4 were exposed to surgical trauma (week 8, tooth extraction + tibia fracture), whereas in Group 1 neither medication nor surgical trauma was applied. After 8, 10, 12 and 16 weeks, skin, lung and spleen were immunohistochemically examined for macrophage polarization via expression analysis of CD68, CD163 and iNOS using a tissue microarray (TMA). Results: A significant shift of macrophage polarization towards M1 was observed in skin, spleen and lung tissue of animals, with and without surgical trauma, treated with BP when compared to those without BP application. Surgical trauma did not cause a significant increase towards M1 polarization. Conclusions: BP application leads to a systemic pro‐inflammatory situation in vivo, independent of surgical trauma, as evidenced by the shift in macrophage polarization towards M1 in various somatic tissues. This provides a possible explanation for the clinically observed anti‐tumor effect of bisphosphonates and might also contribute to pathogenesis of MRONJ.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Antiresorptives; Bisphosphonate; Immune modulation; M1; M2; Macrophage polarization; Zoledronate

Zoledronate Shifts Macrophage Polarization towards M1 in Vivo - An Animal Study on Wistar Rats - Weber, Manuel; Amann, Kerstin Ute; Homm, Andi; Müller, Stefan; Ries, Jutta; Geppert, Carol-Immanuel; Preidl, Raimund; Kesting, Marco Rainer; Wehrhan, Falk (2020)
EVALuna2:216186

Zukunft mammographie-basierter Bildgebung [Future of mammography-based imaging] - Schulz-Wendtland, Rüdiger; Wittenberg, Thomas; Michel, Thilo; Hartmann, Arndt; Beckmann, Matthias; Rauh, Claudia; Judt, Sebastian; Brehm, Barbara; Meier-Meitinger, Martina; Anton, Gisela; Uder, Michael; Fasching, Peter (Radiologe, 2014)
Mammography is the central diagnostic method for clinical diagnostics of breast cancer and the breast cancer screening program. In the clinical routine complementary methods, such as ultrasound, tomosynthesis and optional magnetic resonance imaging (MRI) are already combined for the diagnostic procedure. Future developments will utilize investigative procedures either as a hybrid (combination of several different imaging modalities in one instrument) or as a fusion method (the technical fusion of two or more of these methods) to implement fusion imaging into diagnostic algorithms. For screening there are reasonable hypotheses to aim for studies that individualize the diagnostic process within the screening procedure. Individual breast cancer risk prediction and individualized knowledge about sensitivity and specificity for certain diagnostic methods could be tested. The clinical implementation of these algorithms is not yet in sight. (orig.) [German] Die Mammographie ist die zentrale diagnostische Methode der klinischen symptombezogenen Abklaerung von Brusterkrankungen und des Brustkrebsscreenings. In der klinischen Diagnostik wird sie heute schon oft durch zusaetzliche Untersuchungsmethoden wie dem Ultraschall, der Tomosynthese und ggf. auch der MRT-Bildgebung unterstuetzt. Zukuenftige Entwicklungen gehen in die Richtung, dass diese Kombination aus 2 oder mehr Untersuchungsverfahren entweder in Hybrid- (Aufnahme mehrerer unterschiedlicher Bildmodalitaeten in einem einzigen Geraet) oder in Fusionsmethoden (Zusammenfuehrung und Registrierung von Bilddaten aus verschiedenen Modalitaeten) technisch professionalisiert werden. Des Weiteren koennten an subgruppenbezogene Erkrankungsrisiken und individuelle Sensitivitaeten und Spezifitaeten angepasste Diagnostikkombinationen fuer eine Screeningdiagnostik Gegenstand kuenftiger Studien sein. Wir stellen die aktuellen Entwicklungen auf diesen Gebieten und deren momentane Relevanz fuer die klinische Praxis und Entwicklungspotenzial fuer die Zukunft dar. (orig
UnivIS-Import:2015-04-14:Pub.2014.tech.IMMD.IMMD9.zukunf
Keywords: MAMMOgraphy

Zymogen-locked mutant prostasin (Prss8) leads to incomplete proteolytic activation of the epithelial sodium channel (ENaC) and severely compromises triamterene tolerance in mice - Essigke, Daniel; Ilyaskin, Alexandr; Wörn, Matthias; Bohnert, Bernhard N.; Xiao, Mengyun; Daniel, Christoph; Amann, Kerstin Ute; Birkenfeld, Andreas L.; Szabo, Roman; Bugge, Thomas H.; Korbmacher, Christoph; Artunc, Ferruh (Acta physiologica (Oxford, England), 2021)
Aim: The serine protease prostasin (Prss8) is expressed in the distal tubule and stimulates proteolytic activation of the epithelial sodium channel (ENaC) in co-expression experiments in vitro. The aim of this study was to explore the role of prostasin in proteolytic ENaC activation in the kidney in vivo. Methods: We used genetically modified knockin mice carrying a Prss8 mutation abolishing proteolytic activity (Prss8-S238A) or a mutation leading to a zymogen-locked state (Prss8-R44Q). Mice were challenged with low sodium diet and diuretics. Regulation of ENaC activity by Prss8-S238A and Prss8-R44Q was studied in vitro using the Xenopus laevis oocyte expression system. Results: Co-expression of murine ENaC with Prss8-wt or Prss8-S238A in oocytes caused maximal proteolytic ENaC activation, whereas ENaC was activated only partially in oocytes co-expressing Prss8-R44Q. This was paralleled by a reduced proteolytic activity at the cell surface of Prss8-R44Q expressing oocytes. Sodium conservation under low sodium diet was preserved in Prss8-S238A and Prss8-R44Q mice but with higher plasma aldosterone concentrations in Prss8-R44Q mice. Treatment with the ENaC inhibitor triamterene over four days was tolerated in Prss8-wt and Prss8-S238A mice, whereas Prss8-R44Q mice developed salt wasting and severe weight loss associated with hyperkalemia and acidosis consistent with impaired ENaC function and renal failure. Conclusion: Unlike proteolytically inactive Prss8-S238A, zymogen-locked Prss8-R44Q produces incomplete proteolytic ENaC activation in vitro and causes a severe renal phenotype in mice treated with the ENaC inhibitor triamterene. This indicates that Prss8 plays a role in proteolytic ENaC activation and renal function independent of its proteolytic activity.
CRIS-Team Scopus Importer:2021-03-19
Keywords: ENaC; epithelial sodium channel; Prostasin; Prss8; Prss8-R44Q; Prss8-S238A

Zyxin is important for the stability and function of podocytes, especially during mechanical stretch - Kliewe, Felix; Siegerist, Florian; Hammer, Elke; Al-Hasani, Jaafar; Amling, Theodor Rolf Jakob; Hollemann, Jonas Zeno Eddy; Schindler, Maximilian; Drenic, Vedran; Simm, Stefan; Amann, Kerstin Ute; Daniel, Christoph; Lindenmeyer, Maja; et al. (Communications Biology, 2024)
Podocyte detachment due to mechanical stress is a common issue in hypertension-induced kidney disease. This study highlights the role of zyxin for podocyte stability and function. We have found that zyxin is significantly up-regulated in podocytes after mechanical stretch and relocalizes from focal adhesions to actin filaments. In zyxin knockout podocytes, we found that the loss of zyxin reduced the expression of vinculin and VASP as well as the expression of matrix proteins, such as fibronectin. This suggests that zyxin is a central player in the translation of mechanical forces in podocytes. In vivo, zyxin is highly up-regulated in patients suffering from diabetic nephropathy and in hypertensive DOCA-salt treated mice. Furthermore, zyxin loss in mice resulted in proteinuria and effacement of podocyte foot processes that was measured by super resolution microscopy. This highlights the essential role of zyxin for podocyte maintenance in vitro and in vivo, especially under mechanical stretch.
CRIS-Team Scopus Importer:2024-04-19

α4β7 integrin-dependent adhesion of T cells to MAdCAM-1 is blocked by vedolizumab in patients with chronic refractory pouchitis - Melde, Michaela; Müller, Tanja; Schneider, Ignaz Hans Friedrich; Geppert, Carol-Immanuel; Mühl, Laura; Besendorf, Laura; Allner, Clarissa; Becker, Emily; Atreya, Imke; Vitali, Francesco; Atreya, Raja; Neurath, Markus; et al. (Therapeutic Advances in Gastroenterology, 2021)
Background: The anti-α4β7 integrin antibody vedolizumab is an established therapeutic option for the treatment of inflammatory bowel disease (IBD). It has also been successfully used in patients with chronic antibiotic-refractory pouchitis following proctocolectomey with ileal pouch-anal anastomosis. However, the expression and function of gut-homing markers as well as strategies to predict the response to vedolizumab in pouchitis are understudied so far. Methods: We used flow cytometry and dynamic adhesion assays to study the expression and function of gut-homing integrins on T cells from patients with pouchitis and controls as well as longitudinally during therapy of pouchitis with vedolizumab. Moreover, we describe clinical effects of vedolizumab in a cohort of patients with pouchitis. Results: T cells from patients with pouchitis express a specific profile of gut-homing integrins. Integrin α4β7 on T cells from patients with pouchitis mediates adhesion to mucosal addressin cell adhesion molecule (MAdCAM)-1, which can be blocked by vedolizumab in vitro. Vedolizumab efficiently treats pouchitis in a portion of patients and response correlates with dynamic adhesion profiles to MAdCAM-1. Conclusion: Our data suggest that T cell trafficking seems to be important for the pathogenesis of pouchitis and support the therapeutic use of vedolizumab. Integrin function might serve as a biomarker to predict response to vedolizumab.
CRIS-Team Scopus Importer:2021-12-17
Keywords: ileal pouch-anal anastomosis; pouchitis; proctocolectomy; T cells trafficking; vedolizumab

β2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression - Hofbauer, Daniel; Mougiakakos, Dimitrios; Broggini, Luca; Zaiss, Mario; Büttner-Herold, Maike; Bach, Christian; Spriewald, Bernd; Neumann, Frank; Bisht, Savita; Nolting, Jens; Zeiser, Robert; Hamarsheh, Shaima'a; et al. (Immunity, 2021)
As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1β (IL-1β) and IL-18. This process depends on activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencing of β2m in MM cells abrogates inflammasome activation in a murine MM model. Finally, we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolytic bone destruction normally promoted by β2m-induced inflammasome signaling. Our results provide mechanistic evidence for β2m's role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.
CRIS-Team Scopus Importer:2021-08-13
Keywords: inflammation; macrophages; multiple myeloma; NLRP3; phagocytosis; tumor-associated macrophages

A20 undermines alternative NF-kappa B activity and expression of anti-apoptotic genes in Helicobacter pylori infection - Lim, Michelle C. C.; Maubach, Gunter; Birkl-Toeglhofer, Anna M.; Haybaeck, Johannes; Vieth, Michael; Naumann, Mchael (Cellular and Molecular Life Sciences, 2022)
A hallmark of infection by the pathogen Helicobacter pylori, which colonizes the human gastric epithelium, is the simultaneous activation of the classical and alternative nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) pathways, underlying inflammation and cell survival. Here, we report that the classical NF-kappa B target gene product A20 contributes to the negative regulation of alternative NF-kappa B signaling in gastric epithelial cells infected by H. pylori. Mechanistically, the de novo synthesized A20 protein interacts with tumor necrosis factor receptor-associated factor-interacting protein with forkhead-associated domain (TIFA) and thereby interferes with the association of TIFA with the NIK regulatory complex. We also show that alternative NF-kappa B activity contributes to the up-regulation of anti-apoptotic genes, such as baculoviral IAP repeat containing 2 (BIRC2), BIRC3 and B-cell lymphoma 2-related protein A1 (BCL2A1) in gastric epithelial cells. Furthermore, the observed over-expression of RelB in human gastric biopsies with type B gastritis and RelB-dependent suppression of apoptotic cell death emphasize an important role of the alternative NF-kappa B pathway in H. pylori infection.
CRIS-Team WoS Importer:2022-02-11

Comparative analysis on the effect of low-thermal plasma dissection device (PEAK PlasmaBlade) vs conventional electrosurgery in post-bariatric abdominoplasty: A retrospective randomised clinical study - Schlosshauer, Torsten; Kiehlmann, Marcus; Riener, Marc-Oliver; Sader, Robert; Rieger, Ulrich M. (International Wound Journal, 2019)
Post-bariatric patients undergoing abdominoplasty have a relatively high risk of complications due to residual obesity and major comorbidities. Also, conventional electrosurgery and the associated thermal tissue damage may compromise outcomes. This retrospective randomised clinical study evaluated the effect of low-thermal plasma dissection device (PEAK [pulsed electron avalanche knife] PlasmaBlade) in comparison with conventional electrosurgery. A total of 52 post-bariatric patients undergoing abdominoplasty were randomised to PEAK PlasmaBlade (n = 26) and to monopolar electrosurgery (n = 26). Wounds of 20 patients per group were examined histologically for acute thermal injury depth. In PEAK PlasmaBlade incisions, acute thermal damage was significantly reduced compared with standard of care (40% vs 75%; P = .035). Also, acute thermal injury depth from PEAK PlasmaBlade was less than that from electrosurgery (2780 mu m vs 4090 mu m). Significantly less total complication rate (30.8% vs 69.2%; P = .012) was found by PEAK PlasmaBlade compared with electrosurgery. Moreover, the PEAK PlasmaBlade showed less than half as many wound healing problems (19.2% vs 46.2%; P = .075), far fewer secondary bleeding (7.7% vs 30.8%; P = .075), and no seroma compared with four seroma with the standard of care (0% vs 15.4%; P = .11). PEAK PlasmaBlade appears to be superior to traditional monopolar electrosurgery for post-bariatric abdominoplasty, because it demonstrated significantly less tissue damage, less total complication rate, and fewer postoperative seroma resulting in faster wound healing.
CRIS-Team WoS Importer:2019-10-04

DNA methylation-based classification of sinonasal tumors - Jurmeister, Philipp; Glöß, Stefanie; Roller, Renée; Leitheiser, Maximilian; Schmid, Simone; Mochmann, Liliana H.; Payá Capilla, Emma; Fritz, Rebecca; Dittmayer, Carsten; Friedrich, Corinna; Thieme, Anne; Keyl, Philipp; et al. (Nature Communications, 2022)
The diagnosis of sinonasal tumors is challenging due to a heterogeneous spectrum of various differential diagnoses as well as poorly defined, disputed entities such as sinonasal undifferentiated carcinomas (SNUCs). In this study, we apply a machine learning algorithm based on DNA methylation patterns to classify sinonasal tumors with clinical-grade reliability. We further show that sinonasal tumors with SNUC morphology are not as undifferentiated as their current terminology suggests but rather reassigned to four distinct molecular classes defined by epigenetic, mutational and proteomic profiles. This includes two classes with neuroendocrine differentiation, characterized by IDH2 or SMARCA4/ARID1A mutations with an overall favorable clinical course, one class composed of highly aggressive SMARCB1-deficient carcinomas and another class with tumors that represent potentially previously misclassified adenoid cystic carcinomas. Our findings can aid in improving the diagnostic classification of sinonasal tumors and could help to change the current perception of SNUCs.
CRIS-Team Scopus Importer:2022-12-09

Effect of low-thermal dissection device versus conventional electrocautery in mastectomy for female-to-male transgender patients - Schlosshauer, Torsten; Kiehlmann, Marcus; Riener, Marc-Oliver; Rothenberger, Jens; Sader, Robert; Rieger, Ulrich M. (International Wound Journal, 2020)
Subcutaneous mastectomy, the first step in sexual reassignment surgery of female-to-male transsexuals, is associated with high rates of complication and revision surgery. Also, conventional electrosurgery and the associated thermal tissue damage may compromise outcome. This retrospective randomised clinical study evaluated the effect of low-thermal plasma dissection device (PEAK PlasmaBlade, Medtronic, Minneapolis, Minnesota) in comparison with conventional electrosurgery. A total of 17 female-to-male transsexuals undergoing mastectomy were randomised to PEAK PlasmaBlade on one breast side and to monopolar electrosurgery on the other side of the same patient. Wounds of 17 patients were examined histologically for acute thermal injury. Significantly less total volume of drain output (58.8 ± 37.4 mL vs 98.5 ± 76.4 mL; P =.012) was found on the PEAK PlasmaBlade side compared with the electrosurgery side. Duration of drain was significantly shorter on the PEAK PlasmaBlade side (2.5 ± 0.7 days vs 3.2 ± 0.6 days; P =.010). Furthermore, the PEAK PlasmaBlade side showed fewer thermal damages (41.2% vs 82.4%; P =.039) and thermal injury depth from PEAK PlasmaBlade side was less (3170 vs 4060 μm). PEAK PlasmaBlade appears to be superior to monopolar electrosurgery for mastectomy in female-to-male transsexuals, because it demonstrated less thermal tissue damage, less total volume of drain output, and shorter duration of drain, resulting in faster wound healing.
CRIS-Team Scopus Importer:2020-06-02
Keywords: drain output; duration of drain; electrosurgery; mastectomy; PEAK PlasmaBlade; transsexuals

Genetic alterations driving metastatic colony formation are acquired outside of the primary tumour in melanoma - Werner-Klein, Melanie; Scheitler, Sebastian; Hoffmann, Martin; Hodak, Isabelle; Dietz, Klaus; Lehnert, Petra; Naimer, Veronika; Polzer, Bernhard; Treitschke, Steffi; Werno, Christian; Markiewicz, Aleksandra; Weidele, Kathrin; et al. (Nature Communications, 2018)
Mouse models indicate that metastatic dissemination occurs extremely early; however, the timing in human cancers is unknown. We therefore determined the time point of metastatic seeding relative to tumour thickness and genomic alterations in melanoma. Here, we find that lymphatic dissemination occurs shortly after dermal invasion of the primary lesion at a median thickness of 0.5 mm and that typical driver changes, including BRAF mutation and gained or lost regions comprising genes like MET or CDKNA2, are acquired within the lymph node at the time of colony formation. These changes define a colonisation signature that was linked to xenograft formation in immunodeficient mice and death from melanoma. Thus, melanoma cells leave primary tumours early and evolve at different sites in parallel. We propose a model of metastatic melanoma dormancy, evolution and colonisation that will inform direct monitoring of adjuvant therapy targets.
EVALuna2:35103

Histology and molecular pathology of salivary gland tumors - Schwarz-Furlan, Stephan (Der MKG-Chirurg, 2021)
Background Salivary gland tumors are rare but display great morphological heterogeneity with more than 30 entities. Recently, the different tumors have not only been better characterized using conventional histochemical and immunohistochemical methods, but also by molecular means. Hence, so-called driver mutations which play a role in the development of novel molecularly targeted therapies could be identified. Objective The article aims to show morphological criteria and immunohistochemical characteristics of different tumor entities. Additionally, an overview of tumor-specific genetic aberrations of the most common salivary gland tumors is given. Materials and methods Samples from daily routine practice are presented with histochemical and immunohistochemical staining. To compile recent molecular findings in salivary gland tumors, a literature review was performed. Results and conclusion For histopathological diagnosis of differentiated salivary gland tumors, immunohistochemical staining of basal/myoepithelial and luminal/epithelial cells is essential to assess cellular architecture and attribute proliferative activity. Based on correct tumor typing, various molecular parameters can be investigated in order to verify the diagnosis of highly differentiated nonmetastatic tumors. In the case of less differentiated, metastatic cancers, molecular pathology permits identification of potential therapeutic targets. Comprehensive genome profiling should nowadays be applied to highly aggressive salivary gland cancers.
CRIS-Team WoS Importer:2021-10-01

Neurotrophic tropomyosin receptor kinase (NTRK) and nerve growth factor (NGF) are not expressed in Caucasian patients with biliary tract cancers: pooled data from three independent cohorts - Westphalen, C. B.; Preinfalk, A.; Kruger, S.; Haas, M.; Renz, B. W.; Riener, M. O.; Weber, A.; Kirchner, T.; Werner, J.; Heinemann, V.; von Bergwelt-Baildon, M.; Baba, H. A.; et al. (Clinical & Translational Oncology, 2019)
Background: Neuronal signaling has been implicated in the pathophysiology of multiple malignancies. In biliary tract cancers (BTCs), tumor cell expression of nerve growth factor (NGF) and its receptor neurotrophic tropomyosin receptor kinase (NTRK) has been reported in Asian patients and linked to inferior clinical outcome. Furthermore, NTRK fusions have emerged as a promising target in various cancers. Expression patterns of these markers in Caucasian patients remain unknown. Methods: In this study, 106 patients with BTCs were included. Immunohistochemistry for pan-NTRK and NGF-beta was performed on > 90 samples of this cohort. Additionally, samples from two independent cohorts, incorporating 254 cases, were used to confirm the findings of the original cohort. Results: While expression of pan-NTRK and NGF-beta was readily detectable in peri-tumoral nerves, these markers were not detectable in malignant epithelial cells in our cohort. Conclusions: In a large cohort of Caucasian patients with BTC, NTRK and NGF-beta were not detectable, underscoring potential differences between Caucasian and Asian patient populations.
CRIS-Team Scopus Importer:2019-07-16
Keywords: Biliary tract cancer; Cholangiocarcinoma; Nerve growth factor; Neurotrophic tropomyosin receptor kinase

Quantitative Phase Imaging Using Digital Holographic Microscopy Reliably Assesses Morphology and Reflects Elastic Properties of Fibrotic Intestinal Tissue - Bokemeyer, Arne; Tepasse, Phil Robin; Quill, Lena; Lenz, Philipp; Rijcken, Emile; Vieth, Michael; Ding, Nik; Ketelhut, Steffi; Rieder, Florian; Kemper, Björn; Bettenworth, Dominik (Scientific Reports, 2019)
Intestinal strictures are a frequent complication in patients with Crohn’s Disease (CD) and the presence of fibrosis within strictures impacts the therapeutic treatment approach. Here, we evaluate quantitative phase imaging (QPI) using digital holographic microscopy (DHM) for the evaluation of fibrosis within CD strictures. 30 full thickness resection specimens were obtained from non-stenotic and stenotic tissue areas of 15 CD patients. Cryostat sections were analyzed by DHM to measure the spatial distribution of the refractive index (RI) to quantify tissue density. Complementary, histopathological evaluation of H&E staining and immunofluorescence (IF) targeting fibrosis markers served as the gold standard. Moreover, tissue stiffness was evaluated by elastography. RI values assessed by DHM were significantly higher in stenotic compared to non-stenotic tissue areas (p < 0.001). Histopathological analysis using H&E staining and IF confirmed the elevated expression of fibrosis markers in stenotic compared to non-stenotic tissue (all p < 0.001). The RI retrieved by DHM strongly correlated with the amount of fibrosis as determined by IF (p < 0.001; R2 = 0.48). Furthermore, elastography detected a significantly higher tissue stiffness in stenotic as compared to non-stenotic tissue sections (p < 0.001). In conclusion, QPI using DHM accurately assesses fibrotic properties of CD-associated strictures and may improve the characterization of CD strictures.
CRIS-Team Scopus Importer:2019-12-31

Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers V: Recommendations on the Use of Immunohistochemical and Molecular Biomarkers in Penile Cancer - Canete-Portillo, Sofía; Velazquez, Elsa F.; Kristiansen, Glen; Egevad, Lars; Grignon, David; Chaux, Alcides; Cubilla, Antonio L. (American Journal of Surgical Pathology, 2020)
Penile cancer and its precursor lesions are morphologically and clinically heterogenous and they can be further characterized by immunohistochemical (IHC) and molecular genetic analyses. According to the current World Health Organization (WHO) classification, penile intraepithelial neoplasia (PeIN) and invasive penile carcinomas can be grouped into human papillomavirus (HPV)-related and non-HPV-related neoplasms. This distinction is clinically relevant for etiological and prognostic reasons. To gain insight into the current use of molecular testing and IHC in their diagnostics, a survey was held among the membership of the International Society of Urological Pathology (ISUP). About 250 pathologists from 51 countries answered the survey on the practice and use of IHC/molecular technique as aids in the diagnosis of penile squamous neoplasia. More than half (60%) of the respondents worked at an academic hospital. The questions focused on condylomas, precancerous squamous lesions, and squamous cell carcinoma (SCC). About 35% to 45% of the pathologists considered the use of IHC or molecular tests of value in the pathologic evaluation of precancerous and invasive neoplasms. The vast majority of the respondents do not use IHC for the diagnosis and subtyping of condylomas. There is emerging evidence that some condylomas may participate in the penile carcinogenesis process, especially the high-risk HPV-related atypical condylomas. We recommend the use of p16 in such cases. For most PeIN cases, about half of the responding pathologists make the diagnosis on hematoxylin and eosin slides only. For their subtyping, 50% to 55% of the pathologists use IHC in warty or basaloid PeINs and 40% in differentiated PeIN. To separate HPV-related PeIN from non-HPV-related PeIN, 80% reported using p16 and 20% Ki-67. On the basis of literature review and our practice, the ISUP working group recommends the use of Ki-67 to separate non-HPV-differentiated PeIN from squamous hyperplasia and the use of p16 to distinguish the pleomorphic variant of differentiated PeIN from HPV-related PeIN. With respect to SCCs, according to the survey, immunostaining is only applied in 15% of conventional invasive SCCs, the majority being diagnosed by hematoxylin and eosin. To separate HPV and non-HPV tumors, most (80%) would use p16 and 25% would use p53. For subtype classification, they consider IHC necessary to identify verrucous, papillary, warty, warty-basaloid, and basaloid carcinomas. p16 is used as a surrogate of polymerase chain reaction for the identification of high-risk HPV. We recommend the use of p16 immunostain in cases where the tumoral histologic features of the SCCs are not classical for HPV-related neoplasms, especially in poorly differentiated tumors. Because the majority of these neoplasms harbor high-risk HPV (HPV16), identifying the presence of the virus is rather more important than documenting its specific genotype.
CRIS-Team Scopus Importer:2020-06-19

Report of the molecular pathology working group - Lassmann, S.; Haller, F.; Siebolts, U. (Pathologe, 2017)
EVALuna2:34926

Sonography of the renal allograft: Correlation between doppler sonographic resistance index (RI) and histopathology - Preuss, Stephanie; Rother, Charlotte; Renders, Lutz; Wagenpfeil, Stefan; Büttner-Herold, Maike; Slotta-Huspenina, Julia; Holtzmann, Christopher; Kuechle, Claudius; Heemann, Uwe; Stock, Konrad Friedrich (Clinical Hemorheology and Microcirculation, 2018)
INTRODUCTION: Allograft rejection (AR), chronic allograft injury (CAI) and acute tubular necrosis (ATN) can lead to renal allograft dysfunction after kidney transplantation. Interstitial fibrosis/tubular atrophy (Banff classification 2005) describes chronic allograft injury with no specific etiology, thus explaining the common final endpoint of various (immunologic and non immunologic) etiologies. The aim of this study was to evaluate correlations between the Doppler sonographic RI-values and histopathological changes of renal allografts biopsies during rejection, acute tubular necrosis and chronic allograft injury as well as the influence of donor and recipient features on the intrarenal RI-values.
CRIS-Team WoS Importer:2019-03-06

The gastric disease of Napoleon Bonaparte: brief report for the bicentenary of Napoleon’s death on St. Helena in 1821 - Lugli, Alessandro; Carneiro, Fatima; Dawson, Heather; Fléjou, Jean François; Kirsch, Richard; van der Post, Rachel S.; Vieth, Michael; Svrcek, Magali (Virchows Archiv, 2021)
After the defeat at the battle of Waterloo on June 18, 1815, Napoleon Bonaparte was sent into exile to the Island of St. Helena where he died 6 years later on May 5, 1821. One day after his death, Napoleon’s personal physician, Dr. Francesco Antommarchi, performed the autopsy in the presence of Napoleon’s exile companions and the British medical doctors. Two hundred years later, mysteries still surround the cause of his death and different hypotheses have been postulated in the medical and historical literature. The main reasons seem to be the presence of several autopsy reports, their interpretation and perhaps the greed for thrill and mystery. Therefore, for the bicentenary of Napoleon’s death, an international consortium of gastrointestinal pathologists assembled to analyse Napoleon’s autopsy reports based on the level of medical evidence and to investigate if the autopsy reports really do not allow a final statement.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Autopsy report; Bicentenary; Gastric cancer; Gastritis; Napoleon