N-glycosylation Regulates Intrinsic IFN-γ Resistance in Colorectal Cancer: Implications for Immunotherapy - Krug, Julia; Rodrian, Gabriele; Petter, Katja; Yang, Hai; Khoziainova, Svetlana; Guo, Wei; Benard, Alan; Merkel, Susanne; Gellert, Susan; Maschauer, Simone; Spermann, Monika; Waldner, Maximilian; et al. (Gastroenterology, 2023)
Background & AIMS: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored. Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines. Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling. Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC.
CRIS-Team Scopus Importer:2023-02-10
Keywords: Colon Cancer; IFNGR1; Immune Evasion

Nierenbeteiligung bei Kollagenosen - Teil 1: Lupus-Nephritis - Oelzner, Peter; Amann, Kerstin Ute; Wolf, Gunter (Aktuelle Rheumatologie, 2020)
Lupus nephritis (LN) occurs dependent on ethnicity and gender in up to 50% of patients with systemic lupus erythematosus (SLE) and represents the prognostic most important organ manifestation in SLE. Pathogenetic important aspects of SLE are a multifactorial caused disturbance of the clearance of autoantigen released in the context of apoptosis and NETosis resulting in the development of autoimmune reaction, an amplification of the pathologic immune reaction by hyperactivation of type I-interferon signaling and cytokine imbalance. The pathogenetic process in the kidney results in immune complex glomerulonephritis. Early diagnosis and initiation of therapy are of critical importance for the prognosis of LN. The selection of therapy is based principally on the findings in renal biopsy. In the case of proliferative LN (class III or IV, also in combination with membranous LN) a remission induction with low-dose cyclophosphamide (CYC)-pulse therapy (6 x 500 mg) or with mycophenolatofetil (MMF) in combination with initial high dose glucocorticoids (GC) is followed by a maintenance therapy with azathioprine or MMF. In refractory situations a switch from CYC to MMF or conversely is indicated. Alternatively rituximab or calcineurin inhibitors can also be used. In other forms of LN the therapeutic procedure is essentially determinated by the course of renal function and the extent of proteinuria. In addition supportive procedures such as the general use of hydroxychloroquine, ACE inhibitors or angiotensin rezeptor blockers in dependence of the extent of proteinuria and of blood pressure and prophylactic measures to prevent thromboembolism, osteoporosis and infections come into use. Aims of therapy are a preferably complete renal remission, prevention of chronic damage and an effective reduction of GC dose. A complete remission which is defined by the preservation of normal renal function and a substantial reduction of proteinuria is achieved in approximately 50-60%. This underlines the effectiveness of the curent therapy on one hand but illuminates the need of new therapeutic strategies on the other, especially in view of the high rate of damage. New therapeutic approaches such multitarget therapy, new protocolls of B cell depletion and B cell neutralization and GC free treatment principles aim at a more effective and side effect poor therapy of LN.
CRIS-Team Scopus Importer:2020-04-21
Keywords: Lupus nephritis; pathogenesis; therapy

Nierenbeteiligung bei Kollagenosen – Teil 2: Antiphospholipid-Syndrom, primäres Sjögren-Syndrom, systemische Sklerose - Oelzner, Peter; Amann, Kerstin Ute; Wolf, Gunter (Aktuelle Rheumatologie, 2020)
Renal manifestations in antiphospholipid syndrome (APS), primary Sjögren?s syndrome (pSS) and systemic sclerosis (SSc) differ from each other substantially with respect to pathogenesis, histology, clinical picture, prognosis and therapeutic consequences. The frequency of APS-associated renal affections ranges from 10 to 40%. APS can affect the kidney in the form of renal hypertension, thrombosis or stenosis of the renal artery, renal infarction, thrombosis of the renal vein and intrarenal vasculopathy (APS nephropathy). Especially in the case of secondary APS, the differential diagnosis of lupus nephritis by renal biopsy is important because APS requires anticoagulation, but generally no immunosuppression. In pSS, too, renal affections are relatively common (20-40%). The characteristic and most frequent manifestation is interstitial nephritis with distal tubular acidosis type 1. Distal tubular acidosis is often asymptomatic, but can result in hypokalaemia and osteomalacia. Whereas interstitial nephritis and the less frequent glomerulonephritis generally respond well to immunosuppression, the response of distal tubular acidosis to immunosuppression is insufficient. Decrease of renal function and proteinuria as a sign of renal affection are observed in up to 36% of patients with SSc. This type of nephropathy, often multifactorial in origin, is characterised by sclerosed glomeruli, tubular atrophy and interstitial fibrosis, and has a good prognosis with respect to renal function. Scleroderma renal crisis, which is characterised by obstructive vasculopathy, accelerated arterial hypertension and progressive renal failure, is substantially less frequent (4-11%). Risk factors for renal crisis in SSc involve the presence of diffuse cutaneous SSc, older age, male gender, glucocorticoid use, pericardial effusion and the presence of anti-RNA polymerase III antibodies. Therapy of hypertensive renal crisis aims to reduce the systolic blood pressure by 10% per day to the normal range, preferably with ACE inhibitors, while avoiding prolonged periods of hypotension. In the case of insufficient reduction of blood pressure despite ACE inhibitor therapy, alpha-blockers, calcium channel blockers and/or minoxidil are used in addition. Intravenous administration of prostacycline to improve renal perfusion and the use of the endothelin receptor antagonist bosentan are also useful. The availability of ACE inhibitors has resulted in a significant reduction of mortality due to renal crisis; however, a progression to end-stage renal disease is to be expected in 40-50%.
CRIS-Team Scopus Importer:2020-04-24
Keywords: connective tissue diseases; pathogenesis; renal involvement; therapy

Nierenerkrankungen bei HIV‑Infektion - Bestandsaufnahme nach fast 40 Jahren Erfahrung mit HIV - Rieke, A.; Amann, Kerstin Ute; Lutz, J. (Nephrologe, 2020)
Human immunodeficiency virus (HIV) infections are nowadays a treatable chronic disease with a nearly normal life expectation. Kidney diseases play an increasingly important role in these patients due to the direct and indirect effects of HIV on the kidneys in the form of HIV-associated nephropathy (HIVAN), secondary glomerulonephritis, chronic inflammation and the increasing age with corresponding comorbidities. In patients with HIVAN and secondary glomerulonephritis an antiretroviral therapy (ART) should be quickly initiated; however, ART requires a continuous surveillance of the renal function as some medications can accumulate with decreasing renal function and can even have nephrotoxic effects themselves.
CRIS-Team Scopus Importer:2020-06-16
Keywords: AIDS-associated nephropathy; Antiretroviral therapy; Fanconi syndrome; Tubular transporters; Tubulopathy

Nivolumab Switch Maintenance Therapy After Tyrosine Kinase Inhibitor Induction in Metastatic Renal Cell Carcinoma: A Randomized Clinical Trial by the Interdisciplinary Working Group on Renal Tumors of the German Cancer Society (NIVOSWITCH; AIO-NZK-0116ass) - Grünwald, Viktor; Ivanyi, Philipp; Zschäbitz, Stefanie; Wirth, Manfred; Staib, Peter; Schostak, Martin; Dargatz, Philip; Müller, Lothar; Metz, Michael; Bergmann, Lothar; Steiner, Thomas; Welslau, Martin; et al. (European Urology, 2023)
Background: The role of immune checkpoint inhibitor (ICI) maintenance therapy in metastatic renal cell carcinoma (mRCC) is undefined. Objective: To determine whether switch maintenance therapy with nivolumab improves clinical outcomes in patients with mRCC with tyrosine kinase inhibitor (TKI) sensitivity. Design, setting, and participants: This open-label phase 2 trial randomized patients with a partial response or stable disease after 10–12-wk TKI induction therapy to either TKI or nivolumab maintenance. Key inclusion criteria were measurable disease, clear cell histology, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2, and adequate organ function. Intervention: Intravenous nivolumab 8 × 240 mg every 2 wk, followed by 480 mg every 4 wk or sunitinib 50 mg (4–2 regimen) or pazopanib 800 mg once daily orally. Outcome measurements and statistical analyses: The primary endpoint was overall survival (OS). Secondary endpoints were the objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival (PFS), safety (Common Terminology Criteria for Adverse Events v4.03), and patient-reported outcomes (Functional Assessment of Cancer Therapy Kidney Symptom Index). The Kaplan-Meier method, two-sided log-rank tests, and Cox regression models were used for statistical analysis. Results and limitations: Maintenance therapy was nivolumab for 25 patients (51.0%) and TKI for 24 (48.9%). The median age was 65 yr (range 35–79). Nine patients (18.4%) were female, 31 (63.3%) had ECOG PS of 0, and 15 (30.6%) had favorable risk. OS data are immature (17 deaths, 34.7%). The ORR was 20.0% (n = 5) for nivolumab and 52.2% (n = 12) for TKI. PFS was worse with nivolumab (hazard ratio 2.57, 95% confidence interval 1.36–4.89; p = 0.003). Grade ≥3 adverse events occurred in 14 patients (56.0%) with nivolumab and 17 (70.8%) with TKI. A major limitation is early termination of our study. Conclusions: TKI treatment achieved superior ORR and PFS in comparison to nivolumab maintenance therapy. Our data do not indicate a role for nivolumab switch maintenance in mRCC. Patient summary: Patients with metastatic kidney cancer who experienced a tumor response or disease stabilization after a short period of targeted treatment with a tyrosine kinase inhibitor did not benefit from a switch to the immunotherapy drug nivolumab. Patients who continued their original treatment achieved better responses and a longer time without disease progression. This trial is registered on EudraCT as 2016-002170-13 and on ClinicalTrials.gov as NCT02959554.
CRIS-Team Scopus Importer:2023-10-06
Keywords: Metastatic renal cell carcinoma; Nivolumab; Switch maintenance therapy; Tyrosine kinase inhibitor

NLRP3 Inhibition Leads to Impaired Mucosal Fibroblast Function in Patients with Inflammatory Bowel Diseases - Weber, Simone; Sitte, Selina; Vögele, Anna-Lena; Sologub, Ludmilla; Wilfer, Angelika; Rath, Timo; Nägel, Andreas; Zundler, Sebastian; Franchi, Luigi; Opipari, Anthony W.; Sonnewald, Sophia; Reid, Stephen; et al. (Journal of Crohns & Colitis, 2023)
Background and Aims: Inflammatory bowel diseases (IBD) are characterized by mucosal inflammation and sequential fibrosis formation, but the exact role of the hyperactive NLRP3 inflammasome in these processes is unclear. Thus, we studied the expression and function of the NLRP3 inflammasome in the context of inflammation and fibrosis in IBD. Methods: We analysed intestinal NLRP3 expression in mucosal immune cells and fibroblasts from IBD patients and NLRP3-associated gene expression via single-cell RNA sequencing and microarray analyses. Furthermore, cytokine secretion of NLRP3 inhibitor treated blood and mucosal cells, as well as proliferation, collagen production, and cell death of NLRP3 inhibitor treated intestinal fibroblasts from IBD patients were studied. Results: We found increased NLRP3 expression in the inflamed mucosa of IBD patients and NLRP3 inhibition led to reduced IL-1β and IL-18 production in blood cells and diminished the bioactive form of mucosal IL-1β. Single cell analysis identified overlapping expression patterns of NLRP3 and IL-1β in classically activated intestinal macrophages and we also detected NLRP3 expression in CD163+ macrophages. In addition, NLRP3 expression was also found in intestinal fibroblasts from IBD patients. Inhibition of NLRP3 led to reduced proliferation of intestinal fibroblasts, which was associated with a marked decrease in production of collagen type I and type VI in IBD patients. Moreover, NLRP3 inhibition in intestinal fibroblasts induced autophagy, a cellular process involved in collagen degradation. Conclusions: In the presented study, we demonstrate that inhibiting NLRP3 might pave the way for novel therapeutic approaches in IBD, especially to prevent the severe complication of intestinal fibrosis formation.
CRIS-Team Scopus Importer:2023-11-17
Keywords: fibroblasts; fibrosis; IL-18; IL-1β; Inflammatory bowel diseases; mucosal immune system; NLRP3 inflammasome; small molecule inhibitor

No benefit of HIF prolyl hydroxylase inhibition for hypertensive renal damage in renovascular hypertensive rats - Hartner, Andrea; Dambietz, Thomas; Cordasic, Nada; Willam, Carsten; Burzlaff, Nicolai; Brötsch, Martin; Daniel, Christoph; Schiffer, Mario; Amann, Kerstin Ute; Veelken, Roland; Schley, Gunnar; Hilgers, Karl Friedrich (Frontiers in Physiology, 2023)
Introduction: We previously reported that malignant hypertension is associated with impaired capillary density of target organs. Here, we tested the hypothesis that stabilization of hypoxia-inducible factor (HIF) in a modified “preconditioning” approach prevents the development of malignant hypertension. To stabilize HIF, we employed pharmacological inhibition of HIF prolyl hydroxylases (PHD), that profoundly affect HIF metabolism. Methods: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats; controls were sham operated. 2K1C rats received either intermittent injections of the PHD inhibitor ICA (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate) or placebo. Thirty-five days after clipping, the frequency of malignant hypertension was assessed (based on weight loss and the occurrence of characteristic vascular lesions). In addition, kidney injury was compared between all ICA treated versus all placebo treated 2K1C, regardless of the occurrence of malignant hypertension. HIF stabilization was evaluated by immunohistochemistry, and HIF target gene expression by RT-PCR. Results: Blood pressure was elevated to the same degree in ICA- and placebo-treated 2K1C compared to control rats. ICA treatment did not affect the frequency of malignant hypertension or the extent of kidney tissue fibrosis, inflammation, or capillary density. There was a trend towards higher mortality and worse kidney function in ICA-treated 2K1C rats. ICA increased the number of HIF-1α-positive renal tubular cell nuclei and induced several HIF-1 target genes. In contrast, expression of HIF-2α protein as well as HIF-2 target genes were markedly enhanced by 2K1C hypertension, irrespective of ICA treatment. Discussion: We conclude that intermittent PHD inhibition did not ameliorate severe renovascular hypertension in rats. We speculate that the unexpected strong renal accumulation of HIF-2α in renovascular hypertension, which could not be further augmented by ICA, may contribute to the lack of a benefit from PHD inhibition.
CRIS-Team Scopus Importer:2023-07-21
Keywords: capillarization; HIF stabilization; malignant hypertension; renovascular; vascular lesions

Nodular fasciitis: a case series unveiling novel and rare gene fusions, including two cases with aggressive clinical behavior - Saoud, Carla; Agaimy, Abbas; Stöhr, Robert; Michal, Michael; Wang, Scott Kuan Wen; Mandavilli, Srinivas; Charville, Gregory W.; Linos, Konstantinos (Virchows Archiv, 2025)
Nodular fasciitis is a benign myofibroblastic tumor characterized by rapid growth and spontaneous regression. While nodular fasciitis is typically an indolent process, rare cases with benign morphologic features have developed metastases. Conversely, nodular fasciitis with malignant histologic features and benign clinical course have also been reported. In this study, we present seven nodular fasciitis cases with novel USP6 gene fusion partners, in addition to two cases with rare fusions that displayed aggressive clinical behavior. The cohort comprised five females and four males with a median age of 36 years (range 13–59). Tumors were located in the forearm (n = 3), thigh (n = 2), and shoulder, abdominal wall, chest wall, and oral cavity (one each), ranging from 1.4 to 24.0 cm in size (median, 2.2 cm). Except for the clinically aggressive cases, patients presented with painless masses of varying onset from days to months. Of the clinically aggressive cases, one patient presented with a slowly growing subfascial thigh/hip mass over nine years, leading to erosion of the femur and pelvis; the other presented with a painful subfascial thigh mass of several months' duration. Histologically, all cases, including the clinically aggressive ones, showed conventional nodular fasciitis features without nuclear pleomorphism or atypical mitotic figures; one case with aggressive clinical behavior exhibited focal infarction-type necrosis. Break-apart FISH analysis using USP6 flanking probes failed to detect USP6 rearrangement in two cases (false negatives) and was inconclusive in one case. Next-generation RNA sequencing identified USP6 fusions in all cases. The clinically aggressive cases showed fusions with COL1A1 (exon 1) and PPP6R3 (exon 1), while novel fusions were identified in the remaining cases including EIF4A1 (exon 1), FILIP1L (exon 2), NF1 (exon 33), OMD (exon 1), PFN1 (exon 1), RLIM (exon 1), and SETD5 (exon 1). Six patients underwent surgical resection; three were managed conservatively, with two experiencing spontaneous tumor resolution. Of the clinically aggressive cases, one patient had progression of the tumor with erosion of the underlying bone, and the second patient developed local recurrence at 14 months and lung metastasis at 19 months, ultimately dying of disease at 22 months. The remaining patients showed no recurrence or metastasis. Our findings expand the spectrum of USP6 gene fusion partners in nodular fasciitis and, for the first time, report cases with conventional morphology exhibiting aggressive behavior, including death. These observations raise the question of whether a subset of deep lesions with conventional nodular fasciitis histology but unusual clinical features, such as large tumor size, represents malignant nodular fasciitis or alternatively a nodular fasciitis-like myofibroblastic sarcoma.
CRIS-Team Scopus Importer:2025-02-21
Keywords: Aggressive behavior; Nodular fasciitis; Novel gene fusions; Rare partners

Nodular tumour of the Vas deferens with epithelial structures - Wohlschlaeger, J.; Greimelmaier, K.; Ramankulov, A.; Feist, H.; Loch, T.; Hager, T.; Reis, Henning; Schmid, K. W.; Hartmann, Arndt; Agaimy, Abbas (Pathologe, 2021)
CRIS-Team WoS Importer:2021-10-15

No Evidence of Microsatellite Instability and Loss of Mismatch-Repair-Protein Expression in Squamous Cell Carcinoma of the Penis - Stoehr, Robert; Wendler, Olaf Dietrich; Giedl, Josef; Gaisa, Nadine T.; Richter, Georg; Campean, Valentina; Burger, Maximilian; Wullich, Bernd; Bertz, Simone; Hartmann, Arndt (Pathobiology, 2019)
Objective: Microsatellite instability (MSI) and a defective mismatch repair (MMR) system were described as beneficial tumor features for response to immune checkpoint therapy (PD-1 blockade). Meanwhile, the FDA approved PD-1/PD-L1 inhibition treatment for any solid tumor showing MSI and/or defects in the MMR system. For squamous cell carcinoma (SCC) of the penis, no data on the frequency of MSI and altered MMR protein expression are available to date. Therefore, we investigated the MSI status and the expression of MMR proteins in a large cohort of penile SCCs. Methods: The MSI status of 105 archival formalin-fixed, paraffin-embedded penile SCCs was analyzed using the 5 markers of the NCI consensus panel for MIS testing (BAT25, 26, D2S123, D17S250, and D5S346), or, in cases without representative nontumorous tissue using a validated panel of 5 quasimonomorphic mononucleotide repeat markers (BAT 25, 26 and NR21, 24, 27). The expression of the MMR proteins MLH1, MSH2, MSH6, and PMS2 was analyzed using immunohistochemistry and a tissue microarray of a subset of penile SCCs from our cohort (n = 75). Results: Overall, in 96/105 cases, at least 4 microsatellite markers gave interpretable results. None of the cases showed MSI. Immunohistochemistry for MMR proteins was analyzable in 70/75 cases. All cases showed a regular expression of the MMR proteins. Conclusion: MSI and defects in MMR protein expression are not regular features of penile SCC and might not act as biomarkers for PD-1/PD-L1 blockade therapy in penile carcinoma.
CRIS-Team Scopus Importer:2019-06-18
Keywords: Microsatellite instability; Mismatch-repair; Penile cancer; Squamous cell carcinoma; Tissue microarray

No evidence of pathogenic involvement of cathelicidins in patient cohorts and mouse models of lupus and arthritis - Kienhofer, D.; Hahn, Jonas; Schubert, I.; Reinwald, Christiane; Ipseiz, N.; Lang, Sabine; Borras, E. Bosch; Amann, Kerstin Ute; Sjowall, C.; Barron, A. E.; Hueber, Axel; Agerberth, B.; et al. (PLoS ONE, 2014)
Apart from their role in the immune defence against pathogens evidence of a role of antimicrobial peptides (AMPs) in autoimmune diseases has accumulated in the past years. The aim of this project was to examine the functional impact of the human cathelicidin LL-37 and the mouse cathelicidin-related AMP (CRAMP) on the pathogenesis of lupus and arthritis. Serum LL-37 and anti-LL-37 levels were measured by ELISA in healthy donors and patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA). Pristane-induced lupus was induced in female wild type (WT) and cathelicidin-deficient (CRAMP-/-) mice. Serum levels of anti-Sm/RNP, anti-dsDNA, and anti-histone were determined via ELISA, cytokines in sera and peritoneal lavages were measured via Multiplex. Expression of Interferon I stimulated genes (ISG) was determined by real-time PCR. Collagen-induced arthritis (CIA) was induced in male WT and CRAMP-/- mice and arthritis severity was visually scored and analysed histomorphometrically by OsteoMeasure software. Serum levels of anti-LL-37 were higher in SLE-patients compared to healthy donors or patients with RA. However, no correlation to markers of disease activity or organ involvement was observed. No significant differences of autoantibody or cytokine/chemokine levels, or of expression of ISGs were observed between WT and CRAMP-/- mice after pristane-injection. Furthermore, lung and kidney pathology did not differ in the absence of CRAMP. Incidence and severity of CIA and histological parameters (inflammation, cartilage degradation, and bone erosion) were not different in WT and CRAMP-/- mice. Although cathelicidins are upregulated in mouse models of lupus and arthritis, cathelicidin-deficiency did not persistently affect the diseases. Also in patients with SLE, autoantibodies against cathelicidins did not correlate with disease manifestation. Reactivity against cathelicidins in lupus and arthritis could thus be an epiphenomenon caused by extensive overexpression in blood and affected tissues. In addition, other cationic AMPs could functionally compensate for the deficiency of cathelicidins.
EVALuna2:12499

No juvenile arterial hypertension in sheep multiples despite reduced nephron numbers - Muehle, Anja; Mühle, Christiane; Amann, Kerstin Ute; Dötsch, Jörg; Nuesken, Kai-Dietrich; Boltze, Johannes; Schneider, Holm (Pediatric Nephrology, 2010)
Low birth weight is associated with an increased risk of metabolic dysfunction and arterial hypertension in later life. Because of their reduced birth weight twins have been used repeatedly as a natural model to investigate prenatal programming of hypertension. To reveal an early impact of lower nephron endowment on blood pressure, we performed a longitudinal study on lambs from single, twin and triplet pregnancies. The lambs were studied from birth until adulthood, including regular blood analyses, measurements of body weight and blood pressure and post-mortem estimation of glomerular numbers. Relative weight differences between multiples and singletons at birth were -28% for twins and -44% for triplets, respectively. Some lambs showed rapid catch-up growth. Total nephron number of twins and triplets was reduced by 21 and 37% with respect to that of singletons (p∈<∈0.01). However, multiples did not show increased blood pressure within the time frame of this study. No gender-specific effect was observed. Plasma concentrations of creatinine, urea, electrolytes or osmolality also did not differ. Our data indicate that the previously reported postnatal blood pressure differences between sheep multiples and singletons are a time-limited phenomenon. During infancy and adolescence, a reduced nephron number in sheep multiples is neither associated with increased blood pressure nor reflected by plasma parameters. © 2010 IPNA.
CRIS-Team Scopus Importer:2020-07-01
Keywords: Blood pressure; Nephron number; Prenatal programming

Non-Clear Cell Renal Cell Carcinoma - Pathology and Treatment Options - Ahrens, Marit; Scheich, Sebastian; Hartmann, Arndt; Bergmann, Lothar (Oncology Research and Treatment, 2019)
Non-clear cell renal cell carcinomas (nccRCC) are rare diseases with heterogeneous histopathologically and genetically defined entities. The clinical data on optimal systemic treatments of nccRCC is rather limited. In this review, the current World Health Organization (WHO) classification of nccRCC based on histopathologic and genetic findings is reported. Regarding systemic treatment options, the most commonly used agents are mTOR inhibitors like everolimus or temsirolimus, or tyrosine kinase inhibitors like sunitinib. 2 small randomized clinical trials with nccRCC comparing sunitinib with everolimus revealed a trend towards a better progression-free survival (PFS) and overall survival (OS) in favor of sunitinib. In RCC with predominant sarcomatoid features, both chemotherapy and targeted agents are reported without any preference for outcome. For subsequent lines of therapy, some case reports describe promising effects of PD-1 or PD-L1 inhibitors in nccRCC including sarcomatoid subtype and Bellini duct carcinoma. Currently, nccRCCs are treated similarly to clear cell RCC or, whenever possible, within clinical trials. Clinical trials with immune checkpoint inhibitors are ongoing. (c) 2019 S. Karger AG, Basel
CRIS-Team WoS Importer:2019-04-04

Nondysplastic Colon Crypts Intercalated in Tubular Adenomas Support Field Cancerization - Rubio, Carlos A.; Vieth, Michael; Lang-Schwarz, Corinna (Anticancer Research, 2024)
BACKGROUND/AIM: Tubular adenomas of the colon (TA) are neoplastic polyps composed of dysplastic tube-like crypts. Nondysplastic crypts, mostly in asymmetric branching have been previously reported, both beneath and bordering TA. In the present article, intercalated nondysplastic crypts (INDC) amidst dysplastic crypts in TA are showcased. PATIENTS AND METHODS: The occurrence of INDC was recorded in 139 TA. RESULTS: Out of the 139 TA, 31% exhibited INDC; of these, 58% were in asymmetric branching (INDCAB), 35% were single intercalated crypts without branching (INDSNB), and 7% were in symmetric branching (INDCSB). Luminal dysplasia occurred in 53% out of the 43 TA: in 37% TA with INDCAB, in 16% TA with INDSNB, but in none of the TA with INDCSB. Thus, INDCAB predominated. CONCLUSION: The finding of INDC in TA domain contrasts with the infrequency of INDCSB and with the absence of INDCAB in the normal colorectal mucosa. Hence, INDC emerge as integral components in TA. Since only 1 or 2 sections were available per TA, the total number of INDC in the entire TA is likely higher. INDC in TA may be remnants of acquired nondysplastic mucosal cores of abnormal cryptogenesis that were subsequently replaced by top-down growing dysplastic epithelium. The present and previous findings support the concept of field cancerization in the human colorectum.
CRIS-Team Scopus Importer:2024-10-11
Keywords: field cancerization; nondysplastic colon crypts; Tubular adenoma

Noninferiority of Artificial Intelligence-Assisted Analysis of Ki-67 and Estrogen/Progesterone Receptor in Breast Cancer Routine Diagnostics - Abele, Niklas; Tiemann, Katharina; Krech, Till; Wellmann, Axel; Schaaf, Christian; Länger, Florian; Peters, Anja; Donner, Andreas; Keil, Felix; Daifalla, Khalid; Mackens, Marina; Mamilos, Andreas; et al. (Modern Pathology, 2023)
Image analysis assistance with artificial intelligence (AI) has become one of the great promises over recent years in pathology, with many scientific studies being published each year. Nonetheless, and perhaps surprisingly, only few image AI systems are already in routine clinical use. A major reason for this is the missing validation of the robustness of many AI systems: beyond a narrow context, the large variability in digital images due to differences in preanalytical laboratory procedures, staining procedures, and scanners can be challenging for the subsequent image analysis. Resulting faulty AI analysis may bias the pathologist and contribute to incorrect diagnoses and, therefore, may lead to inappropriate therapy or prognosis. In this study, a pretrained AI assistance tool for the quantification of Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in breast cancer was evaluated within a realistic study set representative of clinical routine on a total of 204 slides (72 Ki-67, 66 ER, and 66 PR slides). This represents the cohort with the largest image variance for AI tool evaluation to date, including 3 staining systems, 5 whole-slide scanners, and 1 microscope camera. These routine cases were collected without manual preselection and analyzed by 10 participant pathologists from 8 sites. Agreement rates for individual pathologists were found to be 87.6% for Ki-67 and 89.4% for ER/PR, respectively, between scoring with and without the assistance of the AI tool regarding clinical categories. Individual AI analysis results were confirmed by the majority of pathologists in 95.8% of Ki-67 cases and 93.2% of ER/PR cases. The statistical analysis provides evidence for high interobserver variance between pathologists (Krippendorff's α, 0.69) in conventional immunohistochemical quantification. Pathologist agreement increased slightly when using AI support (Krippendorff α, 0.72). Agreement rates of pathologist scores with and without AI assistance provide evidence for the reliability of immunohistochemical scoring with the support of the investigated AI tool under a large number of environmental variables that influence the quality of the diagnosed tissue images.
CRIS-Team Scopus Importer:2023-03-31
Keywords: digital pathology; mammary carcinoma; surgical pathology

Non-Invasive Biomarkers for Diagnosis, Risk Prediction, and Therapy Guidance of Glomerular Kidney Diseases: A Comprehensive Review - Catanese, Lorenzo; Rupprecht, Harald; Huber, Tobias B.; Lindenmeyer, Maja T.; Hengel, Felicitas E.; Amann, Kerstin Ute; Wendt, Ralph; Siwy, Justyna; Mischak, Harald; Beige, Joachim (International Journal of Molecular Sciences, 2024)
Effective management of glomerular kidney disease, one of the main categories of chronic kidney disease (CKD), requires accurate diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for the assessment of specific aspects of glomerular diseases have been reported in the literature. Though, the vast majority of these have not been implemented in clinical practice or are not available on a global scale due to limited access, missing medical infrastructure, or economical as well as political reasons. The aim of this review is to compile all currently available information on the diagnostic, prognostic, and predictive biomarkers currently available for the management of glomerular diseases, and provide guidance on the application of these biomarkers. As a result of the compiled evidence for the different biomarkers available, we present a decision tree for a non-invasive, biomarker-guided diagnostic path. The data currently available demonstrate that for the large majority of patients with glomerular diseases, valid biomarkers are available. However, despite the obvious disadvantages of kidney biopsy, being invasive and not applicable for monitoring, especially in the context of rare CKD etiologies, kidney biopsy still cannot be replaced by non-invasive strategies.
CRIS-Team Scopus Importer:2024-04-05
Keywords: biomarker; CKD; diagnosis; glomerular diseases; kidney disease; prognosis; risk prediction

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): what do we need to know? - Coca-Pelaz, Andrés; Rodrigo, Juan P.; Agaimy, Abbas; Hartl, Dana M.; Stenman, Göran; Vander Poorten, Vincent; Mäkitie, Antti A.; Zafereo, Mark; Rao, Karthik N.; Randolph, Gregory W.; Rinaldo, Alessandra; Ferlito, Alfio (Virchows Archiv, 2024)
Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a recently defined thyroid nodule category characterized by follicular architecture with papillary nuclear features but lacking classical papillary carcinoma features like papillae or psammoma bodies. The diagnosis of NIFTP is based on histological examination and excludes cases with high-risk mutations like BRAFV600E. NIFTP carries a low risk of recurrence and distant metastasis, prompting a more conservative surgical approach compared to classical papillary thyroid carcinoma. The management of NIFTP typically involves lobectomy with postoperative monitoring of thyroglobulin levels and performing neck ultrasounds. While the identification of NIFTP represents a significant advancement in thyroid cancer diagnosis, challenges remain in refining preoperative diagnostic tools and establishing optimal long-term follow-up strategies. The objective of this review is to provide a comprehensive overview of NIFTP, including its histopathological characteristics, molecular profile, clinical presentation, diagnostic criteria, management strategies, and future research directions.
CRIS-Team Scopus Importer:2024-11-01
Keywords: Fine-needle aspiration cytology; Non-invasive follicular thyroid neoplasm with papillary-like nuclear features; Papillary thyroid carcinoma; Risk of malignancy; Thyroid

Non-professional phagocytosis: a general feature of normal tissue cells - Seeberg, Jacob; Loibl, Monika; Moser, Fabian; Schwegler, Manuela; Büttner-Herold, Maike; Daniel, Christoph; Engel, Felix; Hartmann, Arndt; Schlötzer-Schrehardt, Ursula; Goppelt-Strübe, Margarete; Schellerer, Vera; Naschberger, Elisabeth; et al. (Scientific Reports, 2019)
Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells.
CRIS-Team Scopus Importer:2019-08-27

Non-Professional Phagocytosis Increases in Melanoma Cells and Tissues with Increasing E-Cadherin Expression. - Unseld, Luzie Helene; Hildebrand, Laura; Putz, Florian; Büttner-Herold, Maike; Daniel, Christoph; Fietkau, Rainer; Distel, Luitpold (Current Oncology, 2023)
Non-professional phagocytosis in cancer has been increasingly studied in recent decades. In malignant melanoma metastasis, cell-in-cell structures have been described as a sign of cell cannibalism. To date, only low rates of cell-in-cell structures have been described in patients with malignant melanoma. To investigate these findings further, we examined twelve primary melanoma cell lines in both adherent and suspended co-incubation for evidence of engulfment. In addition, 88 malignant melanoma biopsies and 16 healthy tissue samples were evaluated. E-cadherin levels were determined in the cell lines and tissues. All primary melanoma cell lines were capable of phagocytosis, and phagocytosis increased when cells were in suspension during co-incubation. Cell-in-cell structures were also detected in most of the tissue samples. Early T stages and increasingly advanced N and M stages have correspondingly lower rates of cell-in-cell structures. Non-professional phagocytosis was also present in normal skin tissue. Non-professional phagocytosis appears to be a ubiquitous mechanism in malignant melanoma. The absence of phagocytosis in metastases may be one reason for the high rate of metastasis in malignant melanoma.
EVALuna2:539840

Nonsebaceous lymphadenoma of salivary glands: proposed development from intraparotid lymph nodes and risk of misdiagnosis - Weiler, Christoph; Agaimy, Abbas; Zengel, Pamela; Zenk, Johannes; Kirchner, Thomas; Ihrler, Stephan (Virchows Archiv, 2012)
Nonsebaceous lymphadenoma (NSLA) is a rare benign salivary gland tumor composed of lymphoid and epithelial components. By definition, the epithelial component lacks sebaceous differentiation and instead displays a wide range of histological differentiation. In this study, we have collected nine cases of NSLA to characterize their histological and immunohistochemical profiles. The samples were histologically reviewed and immunohistochemical stains for CK5/6, CK7, CK14, CK18, p63, and Ki67 performed. Patients were six males and three females (mean age, 50 years). All tumors were located in the parotid gland and showed intimate intermingling of lymphoid tissue with islands or strands of epithelium with a wide spectrum of histological differentiation. The immunohistochemical profiles mirrored the epithelial differentiation; hence, areas with basaloid or lymphoepithelial differentiation strongly expressed CK5/6, CK14, and p63, while areas with ductal differentiation showed strong positivity for CK18/CK7 and CK5/6/CK14/p63 in luminal and basal cell layers, respectively. A hilus structure with salivary inclusions or D2-40 (podoplanin)-positive marginal sinus was identifiable in four and nine of the cases, respectively, supporting origin within intra-/periparotid lymph nodes. Six cases were initially misdiagnosed as other benign (n = 4) or malignant tumors (n = 2). Our study on the second largest series of NSLA reported to date provides strong evidence that NSLA belongs to the group of salivary gland tumors that pathogenetically develop from embryonic salivary gland inclusions in intra-/periparotid lymph nodes. Knowledge of the wide histological spectrum of this rare and presumably underreported tumor is important in order to avoid misdiagnosis, particularly as malignant tumor.
EVALuna2:6440

Normal Variants in Magnetoencephalography - Rampp, Stefan; Kakisaka, Yosuke; Shibata, Sumiya; Wu, Xueqing; Rössler, Karl; Buchfelder, Michael; Burgess, Richard C. (Journal of Clinical Neurophysiology, 2020)
Normal variants, although not occurring frequently, may appear similar to epileptic activity. Misinterpretation may lead to false diagnoses. In the context of presurgical evaluation, normal variants may lead to mislocalizations with severe impact on the viability and success of surgical therapy. While the different variants are well known in EEG, little has been published in regard to their appearance in magnetoencephalography. Furthermore, there are some magnetoencephalography normal variants that have no counterparts in EEG. This article reviews benign epileptiform variants and provides examples in EEG and magnetoencephalography. In addition, the potential of oscillatory configurations in different frequency bands to appear as epileptic activity is discussed.
CRIS-Team Scopus Importer:2020-11-20

Novel criteria for intratumoral budding with prognostic relevance for colon cancer and its histological subtypes - Pour Farid, Pantea; Eckstein, Markus; Merkel, Susanne; Grützmann, Robert; Hartmann, Arndt; Bruns, Volker; Benz, Michaela; Schneider-Stock, Regine; Geppert, Carol-Immanuel (International Journal of Molecular Sciences, 2021)
Peritumoral budding and intratumoral budding (ITB) are important prognostic factors for colorectal cancer patients. Scientists worldwide have investigated the role of budding in tumor progression and its prognosis, but guidelines for reliably identifying tumor buds based on morphology are lacking. In this study, next-generation tissue microarray (ngTMA® ) construction was used for tumor bud evaluation, and highly detailed rule-out annotation was used for tumor definition in pancytokeratin-stained tissue sections. Initially, tissues of 245 colon cancer patients were evaluated with high interobserver reliability, and a concordance of 96% was achieved. It was shown that high ITB scores were associated with poor distant metastasis-free survival (p = 0.006 with a cut-off of ≥10 buds). This cut-off was defined as the best maximum value from one of two/three ngTMA® cores (0.6 mm diameter). ITB in 30 cases of mucinous, medullary, and signet ring cell carcinoma was analyzed for the subsequent determination of differences in tumor bud analyses between those subtypes. In conclusion, blinded randomized punched cores in the tumor center can be useful for ITB detection. It can be assumed that this method is suitable for its adoption in clinical routines.
CRIS-Team Scopus Importer:2021-12-17
Keywords: Histological subtypes; Immunohistochemistry; Medullary carcinoma; Metastasis; Mucinous carcinoma; Next-generation tissue microarray analysis; Prognostic biomarker; Signet ring cell carcinoma; Survival analysis; Tumor budding

Novel diagnostic and therapeutic techniques reveal changed metabolic profiles in recurrent focal segmental glomerulosclerosis - Müller-Deile, Janina; Sarau, George; Kotb, Ahmed M.; Jaremenko, Christian; Rolle-Kampczyk, Ulrike E.; Daniel, Christoph; Kalkhof, Stefan; Christiansen, Silke H.; Schiffer, Mario (Scientific Reports, 2021)
Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, which can lead to early recurrence of FSGS and kidney failure after kidney transplantation. In the past three decades, many research endeavors were undertaken to identify these unknown factors. Even though some potential candidates have been recently discussed in the literature, “the” actual factor remains elusive. Therefore, there is an increased demand in FSGS research for the use of novel technologies that allow us to study FSGS from a yet unexplored angle. Here, we report the successful treatment of recurrent FSGS in a patient after living-related kidney transplantation by removal of circulating factors with CytoSorb apheresis. Interestingly, the classical published circulating factors were all in normal range in this patient but early disease recurrence in the transplant kidney and immediate response to CytoSorb apheresis were still suggestive for pathogenic circulating factors. To proof the functional effects of the patient’s serum on podocytes and the glomerular filtration barrier we used a podocyte cell culture model and a proteinuria model in zebrafish to detect pathogenic effects on the podocytes actin cytoskeleton inducing a functional phenotype and podocyte effacement. We then performed Raman spectroscopy in the < 50 kDa serum fraction, on cultured podocytes treated with the FSGS serum and in kidney biopsies of the same patient at the time of transplantation and at the time of disease recurrence. The analysis revealed changes in podocyte metabolome induced by the FSGS serum as well as in focal glomerular and parietal epithelial cell regions in the FSGS biopsy. Several altered Raman spectra were identified in the fractionated serum and metabolome analysis by mass spectrometry detected lipid profiles in the FSGS serum, which were supported by disturbances in the Raman spectra. Our novel innovative analysis reveals changed lipid metabolome profiles associated with idiopathic FSGS that might reflect a new subtype of the disease.
CRIS-Team Scopus Importer:2021-03-19

Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia - Trpkov, Kiril; Williamson, Sean R.; Gill, Anthony J.; Adeniran, Adebowale J.; Agaimy, Abbas; Alaghehbandan, Reza; Amin, Mahul B.; Argani, Pedram; Chen, Ying-Bei; Cheng, Liang; Epstein, Jonathan; Cheville, John C.; et al. (Modern Pathology, 2021)
The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).
CRIS-Team WoS Importer:2021-02-19

Novel Heritable Human COSMC Mutation Results in a Multisystemic Chaperonopathy - Aryal, Rajindra P.; Erger, Florian; Reusch, Bjoern; Matsumoto, Yasuyuki; Meyer, Robert; Zeng, Junwei; Knopp, Cordula; Noel, Maxence; Wenzel, Andrea; Kohl, Stefan; Tschernoster, Nikolai; Rappl, Gunter; et al. (GLYCOBIOLOGY, 2022)
CRIS-Team WoS Importer:2022-12-02

Novel PGS/PCL electrospun fiber mats with patterned topographical features for cardiac patch applications - Tallawi, Marwa; Dippold, Dirk; Rai, Ranjana; D'Atri, D.; Roether, Judith; Schubert, Dirk W.; Rosellini, E.; Engel, Felix; Boccaccini, Aldo R. (Materials Science and Engineering C, 2016)
Nano- and micro-scale topographical features play a critical role in the induction and maintenance of various cellular properties and functions, including morphology, adhesion, gene regulation, and cell-to-cell communication. In addition, recent studies have indicated that the structure and function of heart tissue are also sensitive to mechanical cues at the nano- and micro-scale. Although fabrication methods exist for generating topographical features on polymeric scaffolds for cell culture, current techniques, especially those with nano-scale resolution, are typically complex, prohibitively expensive and not accessible to most biology laboratories. Here, we present a simple and tunable fabrication method for the production of patterned electrospun fibers that simulate the complex anisotropic and multi-scale architecture of cardiac tissue, to promote cardiac cell alignment. This method is based on the combination of electrospinning and soft lithography techniques, in which electrospun fibers, based on a blend of poly(glycerol sebacate) and poly(caprolactone), were collected on a patterned Teflon-coated silicon wafer with imprinted topographical features. Different surface topographies were investigated, such as squares and grooves, with constant or different interspatial distances. In vitro cell culture studies successfully demonstrated the alignment of both C2C12 myoblasts and neonatal rat cardiomyocytes on fabricated electrospun patterned surfaces. C2C12 cells were cultured over a period of 72h to study the effect of topographical cues on cell morphology. Cells attached within the first 8h after seeding and after 24h most of the cells started to align responding to the topographical cues. Similarly, cardiomyocytes responded to the topographical features by aligning themselves and by expressing Connexin 43 along cellular junctions. Summarizing, we have developed a new method with the potential to significantly promote cardiac tissue engineering by fabricating electrospun fibers with defined topographical features to guide and instruct donor and/or host cells.
EVALuna:34665

Novel Rearrangements in Salivary Gland Tumors Detected by Next Generation Sequencing Assay: Series of 104 Fusion Positive Cases - Skalova, Alena; Vanecek, Tomas; Martinek, Petr; Ptakova, Nikola; Agaimy, Abbas; Laco, Jan; Brcic, Luka; Baneckova, Martina; Koshyk, Olena; Michal, Michal (LABORATORY INVESTIGATION, 2020)
CRIS-Team WoS Importer:2020-03-24

Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart - Hausenloy, Derek J.; Garcia-Dorado, David; Botker, Hans Erik; Davidson, Sean M.; Downey, James; Engel, Felix; Jennings, Robert; Lecour, Sandrine; Leor, Jonathan; Madonna, Rosalinda; Ovize, Michel; Perrino, Cinzia; et al. (Cardiovascular Research, 2017)
Ischaemic heart disease and the heart failure that often results, remain the leading causes of death and disability in Europe and worldwide. As such, in order to prevent heart failure and improve clinical outcomes in patients presenting with an acute ST-segment elevation myocardial infarction and patients undergoing coronary artery bypass graft surgery, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury (IRI). During the last three decades, a wide variety of ischaemic conditioning strategies and pharmacological treatments have been tested in the clinic-however, their translation from experimental to clinical studies for improving patient outcomes has been both challenging and disappointing. Therefore, in this Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart, we critically analyse the current state of ischaemic conditioning in both the experimental and clinical settings, provide recommendations for improving its translation into the clinical setting, and highlight novel therapeutic targets and new treatment strategies for reducing acute myocardial IRI.
EVALuna2:25533

Novel T cell/organoid culture system allows ex vivo modeling of intestinal graft-versus-host disease - Matthe, Diana; Dinkel, Martin; Schmid, Benjamin; Vogler, Tina; Neurath, Markus; Poeck, Hendrik; Neufert, Clemens; Büttner-Herold, Maike; Hildner, Kai (Frontiers in Immunology, 2023)
Acute graft-versus-host disease (GvHD) remains the biggest clinical challenge and prognosis-determining complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Donor T cells are acceptedly key mediators of alloreactivity against host tissues and here especially the gut. In support of previous studies, we found that the intestinal intra-epithelial lymphocyte (IEL) compartment was dynamically regulated in the course of MHC class I full mismatch allo-HSCT. However, while intestinal epithelial cell (IEC) damage endangers the integrity of the intestinal barrier and is a core signature of intestinal GvHD, the question whether and to what degree IELs are contributing to IEC dysregulation is poorly understood. To study lymphoepithelial interaction, we employed a novel ex vivo T cell/organoid co-culture model system. Here, allogeneic intra-epithelial T cells were superior in inducing IEC death compared to syngeneic IEL and allogeneic non-IEL T cells. The ability to induce IEC death was predominately confined to TCRβ+ T cells and was executed in a largely IFNγ-dependent manner. Alloreactivity required a diverse T cell receptor (TCR) repertoire since IELs genetically modified to express a TCR restricted to a single, non-endogenous antigen failed to mediate IEC pathology. Interestingly, minor histocompatibility antigen (miHA) mismatch was sufficient to elicit IEL-driven IEC damage. Finally, advanced live cell imaging analyses uncovered that alloreactive IELs patrolled smaller areas within intestinal organoids compared to syngeneic controls, indicating their unique migratory properties within allogeneic IECs. Together, we provide here experimental evidence for the utility of a co-culture system to model the cellular and molecular characteristics of the crosstalk between IELs and IEC in an allogeneic setting ex vivo. In the light of the emerging concept of dysregulated immune-epithelial homeostasis as a core aspect of intestinal GvHD, this approach represents a novel experimental system to e.g. screen therapeutic strategies for their potential to normalize T cell/IEC- interaction. Hence, analyses in pre-clinical in vivo allo-HSCT model systems may be restricted to hereby positively selected, promising approaches.
CRIS-Team Scopus Importer:2023-09-22
Keywords: allogeneic hematopoietic stem cell transplantation; alloreactive T cell; epithelial cell death; ex vivo model; graft-versus-host disease; GvHD; intestinal organoids; intraepithelial lymphocytes

Novel therapeutic strategies for cardioprotection - Sluijter, Joost P. G.; Condorelli, Gianluigi; Davidson, Sean M.; Engel, Felix; Ferdinandy, Peter; Hausenloy, Derek J.; Lecour, Sandrine; Madonna, Rosalinda; Ovize, Michel; Ruiz-Meana, Marisol; Schulz, Rainer; Van Laake, Linda W. (Pharmacology & Therapeutics, 2014)
The morbidity and mortality from ischemic heart disease (IHD) remain significant worldwide. The treatment for acute myocardial infarction has improved over the past decades, including early reperfusion of occluded coronary arteries. Although it is essential to re-open the artery as soon as possible, paradoxically this leads to additional myocardial injury, called acute ischemia-reperfusion injury (IRI), for which currently no effective therapy is available. Therefore, novel therapeutic strategies are required to protect the heart from acute IRI in order to reduce myocardial infarction size, preserve cardiac function and improve clinical outcomes in patients with IHD. In this review article, we will first outline the pathophysiology of acute IRI and review promising therapeutic strategies for cardioprotection. These include novel aspects of mitochondrial function, epigenetics, circadian clocks, the immune system, microvesicles, growth factors, stem cell therapy and gene therapy. We discuss the therapeutic potential of these novel cardioprotective strategies in terms of pharmacological targeting and clinical application.
EVALuna2:25465

NR4A3 fusions characterize a distinctive peritoneal mesothelial neoplasm of uncertain biological potential with pure adenomatoid/microcystic morphology - Agaimy, Abbas; Brcic, Luka; Briski, Laurence M.; Hung, Yin P.; Michal, Michael; Michal, Michal; Nielsen, G. Petur; Stöhr, Robert; Rosenberg, Andrew E. (Genes Chromosomes & Cancer, 2022)
A focal adenomatoid-microcystic pattern is not uncommon in peritoneal mesothelioma, but tumors composed almost exclusively of this pattern are distinctly rare and have not been well characterized. A small subset of mesotheliomas (mostly in children and young adults) are characterized by gene fusions including EWSR1/FUS::ATF1, EWSR1::YY1, and NTRK and ALK rearrangements, and often have epithelioid morphology. Herein, we describe five peritoneal mesothelial neoplasms (identified via molecular screening of seven histologically similar tumors) that are pure adenomatoid/microcystic in morphology and unified by the presence of an NR4A3 fusion. Patients were three males and two females aged 31-70 years (median, 40 years). Three presented with multifocal/diffuse and two with a localized disease. The size of the individual lesions ranged from 1.5 to 8 cm (median, 4.7). The unifocal lesions originated in the small bowel mesentery and the mesosigmoid. Treatment included surgery, either alone (three) or combined with hyperthermic intraperitoneal chemotherapy (two), and neoadjuvant or adjuvant chemotherapy (one case each). At the last follow-up (6-13 months), all five patients were alive and disease-free. All tumors were morphologically similar, characterized by extensive sieve-like microcystic growth with bland-looking flattened cells lining variably sized microcystic spaces and lacked a conventional epithelioid or sarcomatoid component. Immunohistochemistry confirmed mesothelial differentiation, but most cases showed limited expression of D2-40 and calretinin. Targeted RNA sequencing revealed an NR4A3 fusion (fusion partners were EWSR1 in three cases and CITED2 and NIPBL in one case each). The nosology and behavior of this morphomolecularly defined novel peritoneal mesothelial neoplasm of uncertain biological potential and its distinction from adenomatoid variants of conventional mesothelioma merit further delineation as more cases become recognized.
CRIS-Team WoS Importer:2023-01-20

NSD3-NUTM1-rearranged carcinoma of the median neck/thyroid bed developing after recent thyroidectomy for sclerosing mucoepidermoid carcinoma with eosinophilia: report of an extraordinary case - Agaimy, Abbas; Tögel, Lars; Stöhr, Robert; Meidenbauer, Norbert; Semrau, Sabine; Hartmann, Arndt; Mantsopoulos, Konstantinos (Virchows Archiv, 2021)
Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is an exceedingly rare low-grade thyroid malignancy of unknown histogenesis. NUT carcinoma is another rare, highly aggressive neoplasm with predilection for the midline, defined by recurrent NUTM1 fusions. The bromodomain family genes (BRD4 or BRD3) and rarely NSD3, ZNF532, or others are known fusion partners. We describe an extraordinary case of a 42-year-old female with a thyroid SMECE treated by thyroidectomy and neck dissection. She presented 6 months later with extensive midline recurrence encasing/compressing the trachea. Biopsy revealed poorly differentiated carcinoma with abrupt squamous differentiation, suggestive of NUT carcinoma. Immunohistochemistry confirmed expression of monoclonal NUT antibody. Targeted RNA sequencing revealed the NSD3-NUTM1 fusion in the NUT carcinoma, but not in the SMECE. This unique case highlights unusual sequential origin of two exceptionally rare entities at same anatomic site and underlines the necessity of sampling unexpectedly aggressive recurrences of otherwise indolent malignancies.
CRIS-Team Scopus Importer:2021-05-07
Keywords: Head and neck; Midline carcinoma; NSD3; NUT carcinoma; NUTM1; Sclerosing mucoepidermoid carcinoma with eosinophilia; Thyroid gland

NTRK Testing Practice in German Pathologies - Weyerer, Veronika; Ortiz-Bruechle, Nadina; Demes, Melanie; Schildgen, Oliver; Haybaeck, Johannes; Westphal, Gabriela; Sander, Philip; Mairinger, Thomas; Goering, Wolfgang; Aigner, Thomas; Siebolts, Udo; Moske, Annika; et al. (MODERN PATHOLOGY, 2021)
CRIS-Team WoS Importer:2021-04-16

Nuclear NR4A2 (Nurr1) Immunostaining is a Novel Marker for Acinic Cell Carcinoma of the Salivary Glands Lacking the Classic NR4A3 (NOR-1) Upregulation - Haller, Florian; Moskalev, Evgeny; Kuck, Sarina; Bieg, Matthias; Winkelmann, Christa; Müller, Susanna; Ihrler, Stephan; Märkl, Bruno; Eils, Roland; Wiemann, Stefan; Iro, Heinrich; Hartmann, Arndt; et al. (American Journal of Surgical Pathology, 2020)
CRIS-Team Scopus Importer:2020-05-22

Nuclear NR4A3 Immunostaining Is a Specific and Sensitive Novel Marker for Acinic Cell Carcinoma of the Salivary Glands - Haller, Florian; Skálová, Alena; Ihrler, Stephan; Märkl, Bruno; Bieg, Matthias; Moskalev, Evgeny; Erber, Ramona; Blank, Susanne; Winkelmann, Christa; Hebele, Simone; Baněčková, Martina; Wiemann, Stefan; et al. (American Journal of Surgical Pathology, 2019)
Recently, we discovered the recurrent genomic rearrangement [t(4;9)(q13;q31)] enabling upregulation of the transcription factor Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) through enhancer hijacking as the oncogenic driver event in acinic cell carcinoma (AciCC) of the salivary glands. In the current study, we evaluated the usefulness of NR4A3 immunostaining and NR4A3 fluorescence in situ hybridization (FISH) in the differential diagnosis of AciCC, comparing a total of 64 AciCCs including 17% cases with high-grade transformation, 29 secretory (mammary analog) carcinomas (MASC), and 70 other salivary gland carcinomas. Nuclear NR4A3 immunostaining was a highly specific (100%) and sensitive (98%) marker for AciCC with only 1 negative case, whereas NR4A3 FISH was less sensitive (84%). None of the MASCs or other salivary gland carcinomas displayed any nuclear NR4A3 immunostaining. The recently described HTN3-MSANTD3 gene fusion was observed in 4 of 49 (8%) evaluable AciCCs, all with nuclear NR4A3 immunostaining. In summary, NR4A3 immunostaining is a highly specific and sensitive marker for AciCC, which may be especially valuable in cases with high-grade transformation and in "zymogen granule"-poor examples within the differential diagnostic spectrum of AciCC and MASC.
CRIS-Team Scopus Importer:2019-09-03
Keywords: acinic cell carcinoma; HTN3-MSANTD3; immunohistochemistry; NR4A3; salivary glands; translocation

NUT Carcinoma of the Salivary Glands: Clinicopathologic and Molecular Analysis of 3 Cases and a Survey of NUT Expression in Salivary Gland Carcinomas - Agaimy, Abbas; Fonseca, Isabel; Martins, Carmo; Thway, Khin; Barrette, Ryan; Harrington, Kevin J.; Hartmann, Arndt; French, Christopher A.; Fisher, Cyril (American Journal of Surgical Pathology, 2018)
NUT carcinoma (NC) represents a rare subset of highly aggressive poorly differentiated carcinomas characterized by rearrangement of the NUT (aka NUTM1, nuclear protein in testis) gene, most commonly fused to BRD4. Originally described as a mediastinal/thymic malignancy, NC has been reported at a variety of anatomic regions including the upper and lower aerodigestive tract. To date, only 7 NC cases of probable salivary gland origin have been reported. We herein describe 3 new cases (all affecting the parotid gland) in 2 women (39- and 55-y old) and 1 man (35-y old). Histologic examination showed poorly differentiated neoplasms composed of poorly cohesive small-sized to medium-sized cells with variable squamoid cell component that was focal and abrupt. Immunohistochemistry showed uniform expression of p63 and distinctive punctate expression of the NUT antigen in the tumor cell nuclei. Review of the reported salivary gland NC cases (total, 10) showed a male:female ratio of 1.5:1 and an age range of 12 to 55 years (median, 29 y). Site of the primary tumor was the parotid (7), sublingual (2), and submandibular (1) glands. All presented as rapidly growing masses treated by surgery followed by adjuvant radiotherapy/chemotherapy. Initial nodal status was positive in 8/10. At last follow-up (1 to 24 mo; median, 5 mo), 7/10 patients died of disease at a median of 5.5 months (1 to 24 mo) and only 2 were disease free at 7 and 14 months. Of 9 cases with genetic data, the fusion partner was BRD4 (n=7), non-BRD4/3 (n=1), or undetermined (n=1). None of 306 carcinomas spanning the spectrum of salivary carcinoma types screened by NUT immunohistochemistry was positive. This is the first small series on salivary NC highlighting the importance to include this rare disease in the differential diagnosis of poorly differentiated salivary gland carcinomas and in cases of presumable poorly differentiated carcinoma of unknown origin.
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Oat1/3 restoration protects against renal damage after ischemic AKI - Schneider, R.; Meusel, M.; Betz, B.; Held, C.; Moeller-Ehrlich, K.; Buettner-Herold, M.; Wanner, C.; Gekle, M.; Sauvant, C. (American Journal of Physiology-Renal Physiology, 2015)
Expression of proximal tubular organic anion transporters Oat1 and Oat3 is reduced by PGE2 after renal ischemia and reperfusion (I/R) injury. We hypothesized that impaired expression of Oat1/3 is decisively involved in the deterioration of renal function after I/R injury. Therefore, we administered probenecid, which blocks proximal tubular indomethacin uptake, to abolish the indomethacin-mediated restoration of Oat1/3 regulation and its effect on renal functional and morphological outcome. Ischemic acute kidney injury (iAKI) was induced in rats by bilateral clamping of renal arteries for 45 min with 24-h follow-up. Low-dose indomethacin (1 mg/kg) was given intraperitoneally (ip) at the end of ischemia. Probenecid (50 mg/kg) was administered ip 20 min later. Indomethacin restored the expression of Oat1/3, PAH net secretion, and PGE2 clearance. Additionally, indomethacin improved kidney function as measured by glomerular filtration rate (GFR), renal perfusion as determined by corrected PAH clearance, and morphology, whereas it reduced renal cortical apoptosis and nitric oxide production. Notably, indomethacin did not affect inflammation parameters in the kidneys (e.g., monocyte chemoattractant protein-1, ED1+ cells). On the other hand, probenecid blocked the indomethacin-induced restoration of Oat1/3 and moreover abrogated all beneficial effects. Our study indicates that the beneficial effect of low-dose indomethacin in iAKI is not due to its anti-inflammatory potency, but in contrast to its restoration of Oat1/3 expression and/or general renal function. Inhibition of proximal tubular indomethacin uptake abrogates the beneficial effect of indomethacin by resetting the PGE2-mediated Oat1/3 impairment, thus reestablishing renal damage. This provides evidence for a mechanistic effect of Oat1/3 in a new model of the induction of renal damage after iAKI.
EVALuna2:25476

Obligatory role for GPER in cardiovascular aging and disease - Meyer, Matthias R.; Fredette, Natalie C.; Daniel, Christoph; Sharma, Geetanjali; Amann, Kerstin Ute; Arterburn, Jeffrey B.; Barton, Matthias; Prossnitz, Eric R. (Science Signaling, 2016)
Pharmacological activation of the heptahelical G protein-coupled estrogen receptor (GPER) by selective ligands counteracts multiple aspects of cardiovascular disease. We thus expected that genetic deletion or pharmacological inhibition of GPER would further aggravate such disease states, particularly with age. To the contrary, we found that genetic ablation of Gper in mice prevented cardiovascular pathologies associated with aging by reducing superoxide (?O2(-)) formation by NADPH oxidase (Nox) specifically through reducing the expression of the Nox isoform Nox1 Blocking GPER activity pharmacologically with G36, a synthetic, small-molecule, GPER-selective blocker (GRB), decreased Nox1 abundance and ?O2(-) production to basal amounts in cells exposed to angiotensin II and in mice chronically infused with angiotensin II, reducing arterial hypertension. Thus, this study revealed a role for GPER activity in regulating Nox1 abundance and associated ?O2(-)-mediated structural and functional damage that contributes to disease pathology. Our results indicated that GRBs represent a new class of drugs that can reduce Nox abundance and activity and could be used for the treatment of chronic disease processes involving excessive ?O2(-) formation, including arterial hypertension and heart failure.
EVALuna2:25526

Occult metastasis is no burden factor in oral squamous cell carcinoma patients when adhering to a standardized approach in neck dissection - Struckmeier, Ann-Kristin; Buchbender, Mayte; Möst, Tobias; Lutz, Rainer; Agaimy, Abbas; Kesting, Marco Rainer (Clinical Oral Investigations, 2024)
Objectives: Management of the neck in patients with oral squamous cell carcinoma (OSCC) is pivotal to oncologic control and survival. However, there is controversy regarding necessity of neck dissection (ND) in patients with clinically node-negative neck. We aimed to assess risk factors for occult metastasis and to explore whether the presence of occult lymph node metastases (LNMs) has an impact on recurrence and survival. Material and methods: A retrospective cohort study was performed including patients with primary OSCC who underwent radical tumor resection and ND in a high-volume center adhering to the prevailing German guideline. The ND was performed according to a standardized approach. Results: Four hundred twenty-one patients with primary surgically treated OSCC were included. The incidence of occult metastasis was 14.49%. A pathological T stage > 1 (multivariate analysis, odds ratio (OR) 3.958, p = 0.042) and the presence of extranodal extension in LNMs (multivariate analysis, OR 0.287, p = 0.020) were identified as independent risk factors for occult metastasis. When comparing patients with and without occult metastasis, there were no significant differences in terms of progression-free survival (log-rank, p = 0.297) and overall survival (log-rank, p = 0.320). There were no cases of ipsilateral neck recurrence. One patient developed contralateral neck metastasis; however, he initially presented with a unilateral pT1 pN0 tumor. Conclusions: Overall, our findings suggest that conducting a standardized approach in ND should be applied in terms of management of the neck in order to maintain survival rates and to prevent neck recurrence in OSCC patients. Clinical relevance. None of the risk factors for occult metastasis can be reliably assessed preoperatively. Although elective ND does not guarantee the complete prevention of neck recurrence, it increases the likelihood of either timely removal of micrometastases or strengthens the justification for adjuvant therapy. Consequently, this approach leads to improvements in clinical outcomes.
CRIS-Team Scopus Importer:2024-02-02
Keywords: Lymph node metastasis; Neck dissection; Occult metastasis; Oral squamous cell carcinoma

One Step Nucleic Acid Amplification (OSNA) - a new method for lymph node staging in colorectal carcinomas - Croner, Roland S.; Schellerer, Vera; Demund, Helene; Schildberg, Claus; Papadopulos, Thomas; Naschberger, Elisabeth; Stürzl, Michael; Matzel, Klaus E.; Hohenberger, Werner; Schlabrakowski, Anne (Journal of Translational Medicine, 2010)
Background: Accurate histopathological evaluation of resected lymph nodes (LN) is essential for the reliable staging of colorectal carcinomas (CRC). With conventional sectioning and staining techniques usually only parts of the LN are examined which might lead to incorrect tumor staging. A molecular method called OSNA (One Step Nucleic Acid Amplification) may be suitable to determine the metastatic status of the complete LN and therefore improve staging.Methods: OSNA is based on a short homogenisation step and subsequent automated amplification of cytokeratin 19 (CK19) mRNA directly from the sample lysate, with result available in 30-40 minutes. In this study 184 frozen LN from 184 patients with CRC were investigated by both OSNA and histology (Haematoxylin & Eosin staining and CK19 immunohistochemistry), with half of the LN used for each method. Samples with discordant results were further analysed by RT-PCR for CK19 and carcinoembryonic antigen (CEA).Results: The concordance rate between histology and OSNA was 95.7%. Three LN were histology+/OSNA- and 5 LN histology-/OSNA+. RT-PCR supported the OSNA result in 3 discordant cases, suggesting that metastases were exclusively located in either the tissue analysed by OSNA or the tissue used for histology. If these samples were excluded the concordance was 97.2%, the sensitivity 94.9%, and the specificity 97.9%. Three patients (3%) staged as UICC I or II by routine histopathology were upstaged as LN positive by OSNA. One of these patients developed distant metastases (DMS) during follow up.Conclusion: OSNA is a new and reliable method for molecular staging of lymphatic metastases in CRC and enables the examination of whole LN. It can be applied as a rapid diagnostic tool to estimate tumour involvement in LN during the staging of CRC. © 2010 Croner et al; licensee BioMed Central Ltd.
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Onkozytäre Tumoren der Niere – neue Differenzialdiagnosen - Polifka, Iris; Ohashi, R.; Moch, H. (Pathologe, 2021)
Background: Recent developments in differential diagnosis have led to new knowledge about oncocytic renal neoplasms. Objectives: Overview of differential diagnosis of oncocytic tumours. Materials and methods: We performed a literature search on oncocytic renal tumours and mapped known tumour types. Possible differential diagnoses are discussed. Results: Besides the tumour types already acknowledged by the 2016 WHO classification, there is new evidence regarding the group of hard-to-classify oncocytic neoplasms. Findings point to immunohistochemical and molecular characteristics that may lead to the establishment of new entities in the future. In addition, important differential diagnosis can now be identified, facilitating specific therapies for oncocytic renal tumours. Conclusion: A correct diagnosis of oncocytic renal tumours not only improves prognostic assessment (and, if necessary, specific therapies) but is also clinically relevant regarding a possible association with hereditary tumour syndromes.
CRIS-Team Scopus Importer:2021-09-17
Keywords: Chromophobe renal cell carcinoma; ESC; MTOR; Oncocytoma; SDH

Only IF/TA in the Histological Evaluation of Post-Reperfusion Baseline Biopsies Correlates With Kidney Transplant Outcome. - Bachmann, Quirin; Torrez, Carlos; Büttner-Herold, Maike; Haller, Bernhard; Haberfellner, Flora; Hausinger, Renate; Assfalg, Volker; Renders, Lutz; Amann, Kerstin Ute; Heemann, Uwe; Schmaderer, Christoph; Kemmner, Stephan (Transplant International, 2025)
Here, we retrospectively evaluated the informational yield of 338 post-reperfusion kidney transplant biopsies (including 95 living donations) assessed according to BANFF for the histological characteristics interstitial fibrosis and tubular atrophy (IF/TA), glomerulosclerosis, arteriosclerosis, and acute tubular injury (ATI). Associations with delayed graft function (DGF) and death-censored graft survival were explored through Cox-regression analyses. The maximum follow-up time was 11.4 years, with DGF observed in 108 (32%) cases. After deceased donation there was no association between DGF and histologic parameters. Univariable Cox-regression unveiled an association of IF/TA and glomerulosclerosis with long-term death-censored graft survival (HR per 10% increase: IF/TA 1.63; 95% CI 1.17-2.28; p = 0.003; glomerulosclerosis 1.19; 95% CI 1.01-1.39; p = 0.031). In multivariable Cox regression analyses, adjusted for recognized clinical risk variables like expanded criteria donor-status, donor age, history of diabetes, and HLA-mismatches, only IF/TA maintained association over the total observation period in deceased donations and in the total cohort. Arteriosclerosis and ATI were not associated with clinical outcome after deceased donation. Especially ATI did not affect delayed graft function if only deceased donations were considered. Our data underlines the role of organ quality for transplant outcome prior to acute lesions such as ATI during the transplantation process.
EVALuna2:583979

On the representation of cells in bone marrow pathology by a scalar field: propagation through serial sections, co-localization and spatial interaction analysis - Weis, Cleo-Aron; Griessmann, Benedict Walter; Scharff, Christoph; Detzner, Caecilia; Pfister, Eva; Marx, Alexander; Zoellner, Frank Gerrit (Diagnostic Pathology, 2015)
Immunohistochemical analysis of cellular interactions in the bone marrow in situ is demanding, due to its heterogeneous cellular composition, the poor delineation and overlap of functional compartments and highly complex immunophenotypes of several cell populations (e.g. regulatory T-cells) that require immunohistochemical marker sets for unambiguous characterization. To overcome these difficulties, we herein present an approach to describe objects (e.g. cells, bone trabeculae) by a scalar field that can be propagated through registered images of serial histological sections.The transformation of objects within images (e.g. cells) to a scalar field was performed by convolution of the object's centroids with differently formed radial basis function (e.g. for direct or indirect spatial interaction). On the basis of such a scalar field, a summation field described distributed objects within an image.After image registration i) colocalization analysis could be performed on basis scalar field, which is propagated through registered images, and - due to the shape of the field - were barely prone to matching errors and morphological changes by different cutting levels; ii) furthermore, depending on the field shape the colocalization measurements could also quantify spatial interaction (e.g. direct or paracrine cellular contact); ii) the field-overlap, which represents the spatial distance, of different objects (e.g. two cells) could be calculated by the histogram intersection.The description of objects (e.g. cells, cell clusters, bone trabeculae etc.) as a field offers several possibilities: First, co-localization of different markers (e.g. by immunohistochemical staining) in serial sections can be performed in an automatic, objective and quantifiable way. In contrast to multicolour staining (e.g. 10-colour immunofluorescence) the financial and technical requirements are fairly minor. Second, the approach allows searching for different types of spatial interactions (e.g. direct and indirect cellular interaction) between objects by taking field shape into account (e.g. thin vs. broad). Third, by describing spatially distributed groups of objects as summation field, it gives cluster definition that relies rather on the bare object distance than on the modelled spatial cellular interaction.
EVALuna2:25518

On-treatment Modified Glasgow Prognostic Score Provides Predictive Information Complementary to Radiological Staging in Metastatic Urothelial Carcinoma on Immunotherapy. - Saal, Jonas; Grünwald, Viktor; Bald, Tobias; Ritter, Manuel; Brossart, Peter; Tomita, Yoshihiko; Hartmann, Arndt; Hölzel, Michael; Eckstein, Markus; Klümper, Niklas (European Urology Oncology, 2024)
In the immunotherapy era it is difficult to predict patient prognosis on the basis of radiological staging alone, especially for the subgroup with stable disease (SD), which encompasses a wide range of clinical outcomes. Thus, there is need for reliable and, ideally, cost-efficient biomarkers to improve the accuracy of outcome prediction. We evaluated the on-treatment modified Glasgow Prognostic Score (mGPS)-a known predictor of outcomes in several cancers that is based on serum C-reactive protein and albumin-in patients with metastatic urothelial carcinoma (mUC) treated with immune checkpoint inhibition (ICI) in the phase 2 IMvigor210 and phase 3 IMvigor211 trials. On-treatment mGPS provides valuable prognostic information complementary to radiological staging, particularly for patients with SD. In IMvigor210, on-treatment mGPS predicts outcomes as early as 6 wk after ICI initiation, considerably before the first routine staging typically performed after 10-12 wk. Our study suggests that on-treatment mGPS complements radiological imaging in predicting outcomes for patients with mUC undergoing ICI. PATIENT SUMMARY: For patients with metastatic bladder cancer receiving immunotherapy, it is difficult to predict treatment outcomes from imaging scans alone. Our study results suggest that a score called the modified Glasgow Prognostic Score based on just two proteins (C-reactive protein and albumin) measured in blood can accurately predict outcomes. Use of the mGPS along with imaging scans may be better in predicting the survival benefit from immunotherapy.
EVALuna2:548114

Optical Microscopy Systems for the Detection of Unlabeled Nanoparticles - Friedrich, Ralf P.; Kappes, Mona; Cicha, Iwona; Tietze, Rainer; Braun, Christian; Schneider-Stock, Regine; Nagy, Roland; Alexiou, Christoph; Janko, Christina (International Journal of Nanomedicine, 2022)
Label-free detection of nanoparticles is essential for a thorough evaluation of their cellular effects. In particular, nanoparticles intended for medical applications must be carefully analyzed in terms of their interactions with cells, tissues, and organs. Since the labeling causes a strong change in the physicochemical properties and thus also alters the interactions of the particles with the surrounding tissue, the use of fluorescently labeled particles is inadequate to characterize the effects of unlabeled particles. Further, labeling may affect cellular uptake and biocompatibility of nanoparticles. Thus, label-free techniques have been recently developed and implemented to ensure a reliable characterization of nanoparticles. This review provides an overview of frequently used label-free visualization techniques and highlights recent studies on the development and usage of microscopy systems based on reflectance, darkfield, differential interference contrast, optical coherence, photothermal, holographic, photoacoustic, total internal reflection, surface plasmon resonance, Rayleigh light scattering, hyperspectral and reflectance structured illumination imaging. Using these imaging modalities, there is a strong enhancement in the reliability of experiments concerning cellular uptake and biocompatibility of nanoparticles, which is crucial for preclinical evaluations and future medical application
Keywords: label free imaging; nanoparticle detection; non-fluorescent imaging; reflectance imaging; holotomography; scattering microscopy

Optimizing tissue stewardship in non-small cell lung cancer to support molecular characterization and treatment selection: statement from a working group of thoracic pathologists. - Kerr, Keith M.; Bubendorf, Lukas; Lopez-Rios, Fernando; Khalil, Farah; Roy-Chowdhuri, Sinchita; Joubert, Philippe; Hartmann, Arndt; Guerini-Rocco, Elena; Yatabe, Yasushi; Hofman, Paul; Cooper, Wendy A.; Dacic, Sanja (Histopathology, 2024)
Many patients with non-small cell lung cancer do not receive guideline-recommended, biomarker-directed therapy, despite the potential for improved clinical outcomes. Access to timely, accurate, and comprehensive molecular profiling, including targetable protein overexpression, is essential to allow fully informed treatment decisions to be taken. In turn, this requires optimal tissue management to protect and maximize the use of this precious finite resource. Here, a group of leading thoracic pathologists recommend factors to consider for optimal tissue management. Starting from when lung cancer is first suspected, keeping predictive biomarker testing in the front of the mind should drive the development of practices and procedures that conserve tissue appropriately to support molecular characterization and treatment selection.
EVALuna2:542959

Organ manifestations of COVID-19: what have we learned so far (not only) from autopsies? - Jonigk, Danny; Werlein, Christopher; Acker, Till; Aepfelbacher, Martin; Amann, Kerstin Ute; Baretton, Gustavo; Barth, Peter; Bohle, Rainer M.; Buettner, Andreas; Buettner, Reinhard; Dettmeyer, Reinhard; Eichhorn, Philip; et al. (Virchows Archiv, 2022)
The use of autopsies in medicine has been declining. The COVID-19 pandemic has documented and rejuvenated the importance of autopsies as a tool of modern medicine. In this review, we discuss the various autopsy techniques, the applicability of modern analytical methods to understand the pathophysiology of COVID-19, the major pathological organ findings, limitations or current studies, and open questions. This article summarizes published literature and the consented experience of the nationwide network of clinical, neuro-, and forensic pathologists from 27 German autopsy centers with more than 1200 COVID-19 autopsies. The autopsy tissues revealed that SARS-CoV-2 can be found in virtually all human organs and tissues, and the majority of cells. Autopsies have revealed the organ and tissue tropism of SARS-CoV-2, and the morphological features of COVID-19. This is characterized by diffuse alveolar damage, combined with angiocentric disease, which in turn is characterized by endothelial dysfunction, vascular inflammation, (micro-) thrombosis, vasoconstriction, and intussusceptive angiogenesis. These findings explained the increased pulmonary resistance in COVID-19 and supported the recommendations for antithrombotic treatment in COVID-19. In contrast, in extra-respiratory organs, pathological changes are often nonspecific and unclear to which extent these changes are due to direct infection vs. indirect/secondary mechanisms of organ injury, or a combination thereof. Ongoing research using autopsies aims at answering questions on disease mechanisms, e.g., focusing on variants of concern, and future challenges, such as post-COVID conditions. Autopsies are an invaluable tool in medicine and national and international interdisciplinary collaborative autopsy-based research initiatives are essential.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Acute kidney damage; Diffuse alveolar damage; Immune response; SARS-CoV-2

Osteoclastic expression of higher-level regulators NFATc1 and BCL6 in medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis - Wehrhan, Falk; Gross, Christian; Creutzburg, Kay; Amann, Kerstin Ute; Ries, Jutta; Kesting, Marco Rainer; Geppert, Carol-Immanuel; Weber, Manuel (Journal of Translational Medicine, 2019)
BackgroundWith an increasing indication spectrum of antiresorptive drugs, the medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy [MRONJ (BP)] is continuously gaining clinical relevance. Impaired osteoclast function, accompanied by altered cell morphology and expression of osteoclastic effector proteins, contributes to the pathogenesis of MRONJ (BP). However, the underlying regulatory mechanisms at a transcriptional level are unaddressed so far. These mechanisms are crucial to the development of disease-characteristic osteoclastic anomalies, that contribute to the pathogenesis of MRONJ (BP). NFATc1 is considered a master upstream osteoclastic activator, whereas BCL6 acts as osteoclastic suppressor. The present study aimed to elucidate the NFATc1 and BCL6 mediated osteoclastic regulation and activity in MRONJ (BP) compared to osteoradionecrosis (ORN) and osteomyelitis (OM) and normal jaw bone.MethodsFormalin-fixed jaw bone specimens from 70 patients [MRONJ (BP) n=30; OM: n=15, ORN: n=15, control: n=10] were analyzed retrospectively for osteoclast expression of NFATc1 and BCL6. The specimens were processed for H&E staining and immunohistochemistry. The histological sections were digitalized and analyzed by virtual microscopy.ResultsOsteoclastic expression of NFATc1 and BCL6 was significantly higher in MRONJ (BP) specimens compared to OM and control specimens. NFATc1 and BCL6 labeling indices revealed no significant differences between MRONJ (BP) and ORN. The ratio of nuclear BCL6+ osteoclasts to cytoplasmic BCL6+ osteoclasts revealed significantly higher values for MRONJ (BP) specimens compared to OM and controls.ConclusionThis study displays that osteoclasts in MRONJ (BP) tissues feature increased expression of the higher-level regulators, paradoxically of both NFATc1 and BCL6. These observations can help to explain the genesis of morphologically altered and resorptive inactive osteoclasts in MRONJ (BP) tissues by outlining the transcriptional regulation of the pathomechanically relevant osteoclastic effector proteins. Furthermore, they strengthen the etiological delineation of MRONJ (BP) from OM and extend the osteoclast profiles of MRONJ (BP), OM and ORN and thus could lead to a better histopathological differentiation that can improve treatment decision and motivate new therapeutic concepts.
CRIS-Team WoS Importer:2019-03-20

Osteoclast profile of medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis - Gross, Christian; Weber, Manuel; Creutzburg, Kay; Moebius, Patrick; Preidl, Raimund; Amann, Kerstin Ute; Wehrhan, Falk (Journal of Translational Medicine, 2017)
The medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy [MRONJ (BP)] is characterized by non-healing exposed bone in the maxillofacial region. The pathogenesis of MRONJ (BP) is not fully understood. Giant, hypernucleated, inactive osteoclasts were found in MRONJ (BP) tissues, which indicated that accelerated cell-cell fusion might play a role. Dendritic cell-specific transmembrane protein (DC-STAMP) is associated with the cell-cell fusion of osteoclasts and precursor cells. Tartrate-resistant acid phosphatase (TRAP) is essential for osteoclastic bone resorption. The cell-cell fusion, as part of the osteoclastogenesis, and the resorptive activity can determine the morphology of osteoclasts. This study analyzed jaw bone from patients with MRONJ (BP), osteomyelitis (OM) and osteoradionecrosis (ORN) because a comparison with the osteoclast profiles of OM and ORN is essential for characterizing the osteoclast profile of MRONJ (BP).Formalin-fixed routine jaw bone specimens from 70 patients [MRONJ (BP) n = 30; OM: n = 15, ORN: n = 15, control: n = 10] were analyzed retrospectively for osteoclast quantity, morphology and the expression of TRAP and DC-STAMP. The specimens were processed for hematoxylin and eosin staining (H&E), histochemistry (TRAP) and immunohistochemistry (anti-DC-STAMP) and were analyzed via virtual microscopy.The quantity, diameter and nuclearity of osteoclasts were significantly higher in MRONJ (BP) specimens than in OM, ORN and control specimens. Giant, hypernucleated osteoclasts were detected in MRONJ (BP) specimens only. Osteoclastic TRAP expression was lower in MRONJ (BP) and ORN specimens than in OM and control specimens. The DC-STAMP expression of osteoclasts and mononuclear cells was significantly higher in MRONJ (BP) and ORN specimens than in OM and control specimens.This study indicates that the osteoclast profile of MRONJ (BP) is characterized by osteoclast inactivation and a high cell-cell fusion rate; however, the presence of giant, hypernucleated osteoclasts cannot be attributed to increased DC-STAMP-triggered cell-cell fusion alone. The incidental characterization of the osteoclast profiles of OM and ORN revealed differences that might facilitate the histopathological differentiation of these diseases from MRONJ (BP), which is essential because their therapies are somewhat different.
EVALuna2:24432

Osteo-radio-necrosis (ORN) and bisphosphonate-related osteonecrosis of the jaws (BRONJ): the histopathological differences under the clinical similarities - Mitsimponas, Konstantinos; Moebius, Patrick; Amann, Kerstin Ute; Stockmann, Philipp; Schlegel, Karl-Andreas; Neukam, Friedrich Wilhelm; Wehrhan, Falk (International Journal of Clinical and Experimental Pathology, 2014)
Both Osteoradionecrosis (ORN) and Bisphosphonate associated osteonecrosis of the jaws (BRONJ) present clinically as regions of exposed necrotic bone. The study aimed to demonstrate the histopathological differences behind the observed clinical similarities.Ten ORN specimens and ten BRONJ specimens were used, as well as ten samples of normal mandibular bone as control. Two bone-specific stainings were used, i.e. Sirius Red for the study of the relative presence of collagen types I and III and toluidine blue for the study the osteon density.The Red Green Blue (RGB)-analysis of the specimens stained with Sirius Red identified significant differences between the chromatic patterns observed in bone preparations of patients suffering from ORN when compared to both BRONJ and control samples. Moreover, the osteon density of the BRONJ samples was significantly lower when compared to ORN and normal bone samples.The demonstrated differences in the bone architecture and in the bone collagen content between the two pathological conditions most likely reflect underlying pathophysiological differences.
EVALuna2:24379

Outcome and management of rare high-grade “salivary” adenocarcinoma: the important role of adjuvant (chemo)radiotherapy - Scherl, Claudia; Haderlein, Marlen; Agaimy, Abbas; Mantsopoulos, Konstantinos; Koch, Michael; Traxdorf, Maximilian; Fietkau, Rainer; Grundtner, Philipp; Iro, Heinrich (Strahlentherapie und Onkologie, 2019)
Purpose: To determine survival and management strategies for high-grade adenocarcinoma of salivary glands (ASG). Methods: A retrospective analysis of cases diagnosed between 1998 and 2015 from our single tertiary referral center was performed. Multivariable logistic regression was used to determine factors associated with survival. Results: Thirty-eight cases of high-grade ASG were identified. Most patients were men (68.4%) with a median age of 65.5 years (range 23–84 years). Most tumors were T3 and T4 (65.8%). Regional metastases were common (55.2%), and 42.1% developed distant metastases. The mean follow-up was 60.5 months. All patients received surgery as primary treatment, with 84.2% of patients receiving adjuvant radiation therapy or chemoradiotherapy ([C]RT). Cumulative overall survival was 89.1%, 50.9%, and 20.7% after 1, 5, and 10 years, respectively. Disease-specific survival was 94.4%, 69.8%, and 42.8%, and distant-metastases-free survival (DMFS) was 80.5%, 50.1%, and 40.1% after 1, 5, and 10 years. On multivariable analysis, advanced T status correlated with DMFS (hazard ratio 2.75, 95% CI 0.93–8.16). Postsurgical (C)RT reduced the locoregional recurrence rate by 23.9%, and it improved the locoregional-recurrence-free survival by 39% (p = 0.094). Conclusion: High-grade ASG is considered to have an unfavorable prognosis. Adjuvant (C)RT reduces the rate of locoregional recurrences. Distant metastases are common, and an advanced T stage has increased prognostic value for development of early distant lesions.
CRIS-Team Scopus Importer:2019-08-06
Keywords: Head and neck cancer; Salivary gland cancer; Salivary gland malignancy; Survival salivary gland cancer; Treatment salivary gland cancer

Outcome and prognostic factors in T4a oropharyngeal carcinoma, including the role of HPV infection - Psychogios, Georgios; Mantsopoulos, Konstantinos; Agaimy, Abbas; Brunner, Kathrin; Mangold, Elisabeth; Zenk, Johannes; Iro, Heinrich (BioMed Research International, 2014)
The prognosis of patients with advanced oropharyngeal carcinoma (OPSCC) is generally poor. The aim of this study is to investigate the different therapeutic approaches and identify prognostic factors associated with a worse outcome for patients treated for T4a OPSCC, in order to improve treatment selection for the individual.A retrospective study was conducted on 426 patients with T4a OPC treated between 1980 and 2010. Eleven prognostic factors including treatment modality, lymph node staging, and p16 status as a surrogate marker for human papillomavirus (HPV) infection were analyzed.Univariate analysis showed a significant difference in DSS between N0 and N+ (57.1% versus 26.9%, P < 0.001), primary surgical and primary nonsurgical treatment (52.7% versus 31.4%, P < 0.001), and perinodal invasion (51.7% versus 19.9%, P = 0.011). P16-negative patients tended towards a worse DSS than p16-positive patients (40.2% versus 64.6%, P = 0.126) but responded better to primary surgery than to nonsurgical treatment (71.4% versus 34.0%, P = 0.113). Multivariate analysis identified the N category as an independent prognostic factor for survival.The survival of p16-negative patients was worse than p16-positive patients, although they seem to respond better to primary surgery. The strongest independent prognostic factor for T4a carcinomas proved to be the presence of lymph node metastases.
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Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice - Mulay, Shrikant R.; Eberhard, Jonathan N.; Pfann, Victoria; Marschner, Julian A.; Darisipudi, Murthy N.; Daniel, Christoph; Romoli, Simone; Desai, Jyaysi; Grigorescu, Melissa; Kumar, Santhosh V.; Rathkolb, Birgit; Wolf, Eckhard; et al. (American Journal of Physiology-Renal Physiology, 2016)
Chronic kidney disease (CKD) research is limited by the lack of convenient inducible models mimicking human CKD and its complications in experimental animals. We demonstrate that a soluble oxalate-rich diet induces stable stages of CKD in male and female C57BL/6 mice. Renal histology is characterized by tubular damage, remnant atubular glomeruli, interstitial inflammation, and fibrosis, with the extent of tissue involvement depending on the duration of oxalate feeding. Expression profiling of markers and magnetic resonance imaging findings established to reflect inflammation and fibrosis parallel the histological changes. Within 3 wk, the mice reproducibly develop normochromic anemia, metabolic acidosis, hyperkalemia, FGF23 activation, hyperphosphatemia, and hyperparathyroidism. In addition, the model is characterized by profound arterial hypertension as well as cardiac fibrosis that persist following the switch to a control diet. Together, this new model of inducible CKD overcomes a number of previous experimental limitations and should serve useful in research related to CKD and its complications.
EVALuna2:3844

Oxidative DNA Damage in Kidneys and Heart of Hypertensive Mice Is Prevented by Blocking Angiotensin II and Aldosterone Receptors - Brand, Susanne; Amann, Kerstin Ute; Mandel, Philipp; Zimnol, Anna; Schupp, Nicole (PLoS ONE, 2014)
Recently, we could show that angiotensin II, the reactive peptide of the blood pressure-regulating renin-angiotensin-aldosterone-system, causes the formation of reactive oxygen species and DNA damage in kidneys and hearts of hypertensive mice. To further investigate on the one hand the mechanism of DNA damage caused by angiotensin II, and on the other hand possible intervention strategies against end-organ damage, the effects of substances interfering with the renin-angiotensin-aldosterone-system on angiotensin II-induced genomic damage were studied.In C57BL/6-mice, hypertension was induced by infusion of 600 ng/kg o min angiotensin II. The animals were additionally treated with the angiotensin II type 1 receptor blocker candesartan, the mineralocorticoid receptor blocker eplerenone and the antioxidant tempol. DNA damage and the activation of transcription factors were studied by immunohistochemistry and protein expression analysis.Administration of angiotensin II led to a significant increase of blood pressure, decreased only by candesartan. In kidneys and hearts of angiotensin II-treated animals, significant oxidative stress could be detected (1.5-fold over control). The redox-sensitive transcription factors Nrf2 and NF-?B were activated in the kidney by angiotensin II-treatment (4- and 3-fold over control, respectively) and reduced by all interventions. In kidneys and hearts an increase of DNA damage (3- and 2-fold over control, respectively) and of DNA repair (3-fold over control) was found. These effects were ameliorated by all interventions in both organs. Consistently, candesartan and tempol were more effective than eplerenone.Angiotensin II-induced DNA damage is caused by angiotensin II type 1 receptor-mediated formation of oxidative stress in vivo. The angiotensin II-mediated physiological increase of aldosterone adds to the DNA-damaging effects. Blocking angiotensin II and mineralocorticoid receptors therefore has beneficial effects on end-organ damage independent of blood pressure normalization.
EVALuna2:25417

P2Y1 gene deficiency protects from renal disease progression and capillary rarefaction during passive crescentic glomerulonephritis - Hohenstein, Bernd; Renk, Sindy; Lang, Kathrin; Daniel, Christoph; Freund, Monique; Léon, Catherine; Amann, Kerstin Ute; Gachet, Christian; Hugo, Christian (Journal of the American Society of Nephrology, 2007)
The metabotropic receptor P2Y1 is necessary for full ADP-induced platelet activation and is localized on various intrinsic renal cells, including mesangial cells, podocytes, and endothelial cells. To date, nothing is known about the role of the P2Y1 receptor during inflammatory renal disease. The role of the P2Y1 receptor was investigated using 22 P2Y1 gene-deficient (-/-) and 27 wild-type (wt) mice during the time course of passive crescentic nephrotoxic glomerulonephritis. Six P2Y1 -/- and six wt mice served as undiseased controls. Renal tissues were harvested on days 1, 10, and 28 after disease induction. No renal phenotype was found in P2Y1 -/- versus wt mice. In contrast, during crescentic glomerulonephritis, approximately 50% of all wt mice died, whereas all P2Y1 -/- mice survived. Renal function as assessed by creatinine clearance measurements, glomerulosclerosis, and tubulointerstitial injury indices as well as glomerular and interstitial matrix expansion were improved significantly in P2Y1 -/- compared with wt mice. These changes were preceded by reduced glomerular and peritubular capillary rarefaction indices in P2Y1 -/- compared with wt mice. The alteration of the rates of both peritubular apoptosis and endothelial cell proliferation suggests improved capillary preservation in P2Y1 -/- mice early in disease (day 10) and an additional enhanced repair reaction in P2Y1 -/- mice at the late time point (day 28), whereas injury on day 1 seemed to be equivalent in both groups. It is concluded that loss of P2Y1 receptor function safeguards against capillary loss, fibrosis, and death by renal failure during experimental crescentic glomerulonephritis. Copyright © 2007 by the American Society of Nephrology.
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P2Y2R and Cyst Growth in Polycystic Kidney Disease. - Kraus, Andre; Skoczynski, Kathrin; Brötsch, Martin; Burzlaff, Nicolai; Leipziger, Jens; Schiffer, Mario; Büttner-Herold, Maike; Buchholz, Björn (Journal of the American Society of Nephrology, 2024)
EVALuna2:569374

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study - Köbel, Martin; Kang, Eun-Young; Weir, Ashley; Rambau, Peter F.; Lee, Cheng-Han; Nelson, Gregg S.; Ghatage, Prafull; Meagher, Nicola S.; Riggan, Marjorie J.; Alsop, Jennifer; Anglesio, Michael S.; Beckmann, Matthias; et al. (Journal of Pathology: Clinical Research, 2023)
Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
EVALuna2:530730

P53 Codon 72 Polymorphism and Risk for Squamous Cell Carcinoma of the Penis: A Caucasian Case-Control Study - Stoehr, Robert; Weisser, Rebecca; Wendler, Olaf Dietrich; Giedl, Josef; Daifalla, Khalid; Gaisa, Nadine T.; Richter, Georg; Campean, Valentina; Burger, Maximilian; Wullich, Bernd; Hartmann, Arndt (Journal of Cancer, 2018)
Squamous cell carcinoma of the penis is a rare but often aggressive disease. A large proportion of penile cancers are associated with HPV infection, mainly with HPV high-risk subtypes 16 and 18. From other HPV-related malignancies a link between a functional SNP in the p53 gene (rs1042522, p.Arg72Pro) and a higher disease risk in the presence of HPV is documented. The p53 p.Arg72 variant was described as a risk factor for developing a malignancy in combination with the presence of HPV as the p.72Arg variant is more prone to HPV E6 protein-mediated degradation than the p.72Pro variant. For penile carcinoma there are only sparse data available on this topic. We therefore analyzed the distribution of this p53 codon 72 SNP in a cohort of 107 penile cancer patients and a healthy control group (n=194) using Restriction Fragment Length Polymorphism (RFLP) analysis. After DNA isolation a PCR amplicon including the variant nucleotide was generated. Based on the variant nucleotide this amplicon can be cleaved into two parts or remain unaffected by a restriction enzyme. Subsequent electrophoresis allowed the discrimination of SNP alleles in the investigated sample. Comparison of the allelic variants revealed no significant differences in the distribution of this SNP between cases and controls (p=0,622). There was also no difference in SNP distribution between cases with/without HPV infection (p=0,558) or histologic variants (p=0.339). In order to strengthen the impact of our data we performed a combined analysis of all published data on this topic with our results. This ended up in SNP distribution data from 177 cases and 1149 controls. Overall, there were also no significant differences in the allelic distribution of the p53 codon 72 SNP between either cases and controls (p=0,914) or HPV-positive and HPV-negative cases (p=0,486). From this most comprehensive data available to date we conclude that there is no influence of the p53 codon 72 SNP on the risk of development of penile carcinoma in Caucasians even in the presence of HPV.
EVALuna2:34861

Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern - Haller, Florian; Knopf, Jasmin; Ackermann, Andreas; Bieg, Matthias; Kleinheinz, Kortine; Schlesner, Matthias; Moskalev, Evgeny; Will, Rainer; Satir, Ali Abdel; Abdelmagid, Ibtihalat E.; Giedl, Josef; Carbon, Roman; et al. (Journal of Pathology, 2016)
Neoplasms with a myopericytomatous pattern represent a morphological spectrum of lesions encompassing myopericytoma of the skin and soft tissue, angioleiomyoma, myofibromatosis/infantile haemangiopericytoma and putative neoplasms reported as malignant myopericytoma. Lack of reproducible phenotypic and genetic features of malignant myopericytic neoplasms have prevented the establishment of myopericytic sarcoma as an acceptable diagnostic category. Following detection of a LMNA-NTRK1 gene fusion in an index case of paediatric haemangiopericytoma-like sarcoma by combined whole-genome and RNA sequencing, we identified three additional sarcomas harbouring NTRK1 gene fusions, termed 'spindle cell sarcoma, NOS with myo/haemangiopericytic growth pattern'. The patients were two children aged 11 months and 2 years and two adults aged 51 and 80 years. While the tumours of the adults were strikingly myopericytoma-like, but with clear-cut atypical features, the paediatric cases were more akin to infantile myofibromatosis/haemangiopericytoma. All cases contained numerous thick-walled dysplastic-like vessels with segmental or diffuse nodular myxohyaline myo-intimal proliferations of smooth muscle actin-positive cells, occasionally associated with thrombosis. Immunohistochemistry showed variable expression of smooth muscle actin and CD34, but other mesenchymal markers, including STAT6, were negative. This study showed a novel variant of myo/haemangiopericytic sarcoma with recurrent NTRK1 gene fusions. Given the recent introduction of a novel therapeutic approach targeting NTRK fusion-positive neoplasms, recognition of this rare but likely under-reported sarcoma variant is strongly encouraged.
EVALuna2:6792

Paediatric Peritoneal Mesothelioma - André, Nicolas; Agaimy, Abbas (Springer Science and Business Media Deutschland GmbH, 2022)
Malignant peritoneal mesothelioma is an aggressive and extremely rare paediatric tumour. To decide on the optimal treatment for individual patients and to try to increase our knowledge on this disease to understand its biological basis still represent great challenges for those involved with patient care, particularly paediatric oncologists. Treatment should rely on a multimodal approach. We suggest that advice should be taken from national rare tumour groups or international groups such as the EXPERT (European cooperative study group for paediatric rare tumour).
CRIS-Team Scopus Importer:2022-06-17
Keywords: Asbestos exposure; Epidermal growth factor receptor; Epidermal growth factor receptor mutation; Malignant mesothelioma; Serous carcinoma

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS - Southey, Melissa C.; Goldgar, David E.; Winqvist, Robert; Pylkas, Katri; Couch, Fergus; Tischkowitz, Marc; Foulkes, William D.; Dennis, Joe; Michailidou, Kyriaki; Van Rensburg, Elizabeth J.; Heikkinen, Tuomas; Nevanlinna, Heli; et al. (Journal of Medical Genetics, 2016)
The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10(-5)), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10(-8)) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p<=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
EVALuna2:6832

Pals1 Haploinsufficiency Results in Proteinuria and Cyst Formation - Weide, Thomas; Vollenbroeker, Beate; Schulze, Ulf; Djuric, Ivona; Edeling, Maria; Bonse, Jakob; Hochapfel, Florian; Panichkina, Olga; Wennmann, Dirk-Oliver; George, Britta; Kim, Seonhee; Daniel, Christoph; et al. (Journal of the American Society of Nephrology, 2017)
The nephron is the basic physiologic subunit of the mammalian kidney and is made up of several apicobasally polarized epithelial cell types. The process of apicobasal polarization in animal cells is controlled by the evolutionarily conserved Crumbs (CRB), Partitioning-defective, and Scribble protein complexes. Here, we investigated the role of protein associated with LIN-7 1 (Pals1, also known as Mpp5), a core component of the apical membrane-determining CRB complex in the nephron. Pals1 interacting proteins, including Crb3 and Wwtr1/Taz, have been linked to renal cyst formation in mice before. Immunohistologic analysis revealed Pals1 expression in renal tubular cells and podocytes of human kidneys. Mice lacking one Pals1 allele (functionally haploid for Pals1) in nephrons developed a fully penetrant phenotype, characterized by cyst formation and severe defects in renal barrier function, which led to death within 6-8 weeks. In Drosophila nephrocytes, deficiency of the Pals1 ortholog caused alterations in slit-diaphragm-like structures. Additional studies in epithelial cell culture models revealed that Pals1 functions as a dose-dependent upstream regulator of the crosstalk between Hippo- and TGF-?-mediated signaling. Furthermore, Pals1 haploinsufficiency in mouse kidneys associated with the upregulation of Hippo pathway target genes and marker genes of TGF-? signaling, including biomarkers of renal diseases. These findings support a link between apical polarity proteins and renal diseases, especially renal cyst diseases. Further investigation of the Pals1-linked networks is required to decipher the mechanisms underlying the pathogenesis of these diseases.
EVALuna2:25537

Pancreas transplantation—clinic, technique, and histological assessment Pankreastransplantation – Klinik, Technik und histologische Beurteilung - Büttner-Herold, Maike; Amann, Kerstin Ute; Pfister, Frederick; Tannapfel, Andrea; Maslova, Marina; Wunsch, Andreas; Pillokeit, Nina; Viebahn, Richard; Schenker, Peter (Pathologe, 2021)
Background: In Germany pancreas transplants are performed in only a few selected and specialized centres, usually combined with a kidney transplant. Knowlegde of the indications for and techniques of transplantation as well as of the histopathological assessment for rejection in pancreas and duodenal biopsies is not very widespread. Aim: To give an overview of the development and status quo in pancreas-kidney-transplantation in Germany summarizing the experience of the largest German pancreas transplant centre and to give a résumé of the results of histological diagnoses of biopsy specimens submitted between 06/2017 and 12/2020. Moreover, a detailed description and illustration of histological findings is included. Material and Methods: A thorough literature search for aspects of the history, technique and indication for pancreas transplantation was performed and discussed in the context of the local experience and technical particularities specific for the transplant centre in Bochum. The occurrence of complications was compared with international reports. Results of pancreas and duodenal biopsies submitted to Erlangen between 06/2017 and 12/2020 for histological evaluation, which were evaluated according to the Banff classification, were summarized. For a better understanding key histological findings of pancreas rejection and differential diagnoses were illustrated and discussed. Results: A total of 93 pancreas transplant specimens and 3 duodenal biopsies were included. 34.4% of pancreas specimens did not contain representative material for a diagnosis. In the remaining 61 biopsies 24.6% showed no rejection, 62.3% were diagnosed with acute T-cell mediated rejection (TCMR) and 8.2% with signs suspicious of antibody-mediated rejection (ABMR). Acute acinary epithelial injury was seen in 59%, pancreatitis in 8.2% and allograft fibrosis was reported in as many as 54.1%. Calcineurin-inhibitor toxicity was discussed in only 4.9%. Conclusion: Pancreas-kidney-transplantation and standardized histological assessment of the transplanted pancreas or rarely duodenum with reporting according to the updated Banff classification of pancreas transplants or previous reports of duodenal rejection are important mainstays in the management of patients with diabetes.
CRIS-Team Scopus Importer:2021-08-27
Keywords: Biopsy; Diabetes mellitus; Duodenum; Histology; Kidney transplantation

Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver–case report and review of literature - Zundler, Sebastian; Erber, Ramona; Agaimy, Abbas; Hartmann, Arndt; Kiesewetter, Franklin; Strobel, Deike; Neurath, Markus; Wildner, Dane (BMC Cancer, 2016)
Pancreatic panniculitis is a rare condition, which has only been described in relation with pancreatic diseases up to now. It is characterized by necrotizing subcutaneous inflammation and is thought to be triggered by adipocyte necrosis due to systemic release of pancreatic enzymes with consecutive infiltration of neutrophils. We present the first case of a patient with pancreatic panniculitis caused by pancreatic-type primary acinar cell carcinoma (ACC) of the liver and without underlying pancreatic disease.A 73-year old Caucasian female patient was referred to our department with painful cutaneous nodules persisting for eight weeks and with marked lipasemia ( 15000 U/l; normal range <60 U/l). Four weeks prior, several liver lesions had been detected. Empiric treatment with steroids did not show any effect. A biopsy of the skin nodules revealed "pancreatic" panniculitis, while abdominal imaging with ultrasound, computed tomography and magnetic resonance imaging detected no abnormal pancreatic findings. Ultrasound-guided biopsy of the liver lesions showed infiltrates of an ACC. The patient died soon thereafter. Autopsy failed to reveal any other primary for the ACC, so that a pancreatic-type ACC of the liver was diagnosed by exclusion. One hundred thirty cases of pancreatic panniculitis published within the last 20 years are reviewed. ACC of the pancreas is the most common underlying neoplastic condition. Patients with associated neoplasm are significantly older, take longer to be diagnosed and have higher lipase levels than patients with underlying pancreatitis. Extrapancreatic pancreatic-type ACC is very rare, but shows the same biological features as ACC of the pancreas. It is believed to develop from metaplastic or ectopic pancreatic tissue. Up to now, no pancreatic panniculitis in extrapancreatic ACC has been described.Pancreatic panniculitis should always be included in the differential diagnosis of lipolytic panniculitic lesions. It can be regarded as a facultative paraneoplastic phenomenon. When suspected, a thorough work-up for identification of the underlying disease is mandatory and extrapancreatic lesions (e.g. liver) should also be considered. While administration of octreotide or steroids can sometimes alleviate symptoms, immediate treatment of the associated condition is the only effective management option.
EVALuna2:2057

Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define two subtypes - Agaimy, Abbas; Haller, Florian; Frohnauer, Judith; Schaefer, Inga-Marie; Stroebel, Philipp; Hartmann, Arndt; Stoehr, Robert; Kloeppel, Guenter (Modern Pathology, 2015)
Pancreatic undifferentiated carcinoma is a heterogeneous group of neoplasms, including pleomorphic giant cell, sarcomatoid, round cell, and rhabdoid carcinomas, the molecular profiles of which have so far been insufficiently characterized. We studied 14 undifferentiated carcinomas with prominent rhabdoid cells, occurring as advanced tumors in seven females and seven males aged 44-96 years (mean: 65 years). Histologically, 10 tumors qualified as pleomorphic giant cell and 4 as monomorphic anaplastic carcinomas. A glandular component, either in the primary or in the metastases, was seen in 5 out of 14 tumors (4 out of 10 pleomorphic giant cell and 1 out of 4 monomorphic anaplastic subtypes, respectively). Osteoclast-like giant cells were absent. Immunohistochemistry revealed coexpression of cytokeratin and vimentin, and loss of membranous ?-catenin and E-cadherin staining in the majority of cases. Nuclear SMARCB1 (INI1) expression was lost in 4 out of 14 cases (28%), representing all 4 tumors of the monomorphic anaplastic subtype. FISH and mutation testing of KRAS revealed KRAS amplification in 5 out of 13 (38%) and exon 2 mutations in 6 out of 11 (54%) successfully analyzed cases. A strong correlation was found between KRAS alterations (mutation and/or copy number changes) and intact SMARCB1 expression (7 out of 8; 87%). On the other hand, loss of SMARCB1 expression correlated with the absence of KRAS alterations (3 out of 5 cases; 60%). The results suggest that rhabdoid phenotype in pancreatic undifferentiated rhabdoid carcinomas has a heterogeneous genetic background. SMARCB1 loss is restricted to the anaplastic monomorphic subtype and correlates with the absence of KRAS alterations, whereas the pleomorphic giant cell subtype is characterized by KRAS alterations and intact SMARCB1 expression. Recognition and appropriate subtyping of these rare variants might become necessary for future therapeutic strategies.
EVALuna2:6651

Papillary-cystic neoplasms of the middle ear are distinct from endolymphatic sac tumours - Taverna, Cecilia; Pollastri, Federica; Pecci, Rudi; Giannoni, Beatrice; Fattorini, Caterina; Santucci, Marco; Müller, Sarina Katrin; Stöhr, Robert; Franchi, Alessandro; Agaimy, Abbas (Histopathology, 2020)
Aims Papillary neoplasms of the middle and inner ear are rare and poorly characterised. The current World Health Organization classification divides them into two major subtypes: aggressive papillary tumours (APTs) and endolymphatic sac tumours (ELSTs). The aim of this article is to present two papillary neoplasms of the middle ear that do not fit into either the classic APT category or the classic ELST category, and compare them with three ELSTs.
CRIS-Team WoS Importer:2020-11-27

Papillary Neoplasms of the Salivary Duct System: A Review - Agaimy, Abbas (Surgical Pathology Clinics, 2020)
Papillary lesions of the salivary duct systems are uncommon. They encompass a heterogeneous group of benign, intermediate, and potentially aggressive neoplasms. With a few exceptions, historical descriptive terms such as papillary adenocarcinoma, papillary cystadenocarcinoma, and papillary adenoma are being replaced by defined entities, at same time acknowledging the papillary features as a histologic pattern. The evolving genetic landscape of these lesions increasingly permits their reproducible categorization. This article discusses those papillary proliferations encountered in the salivary glands with a focus on intraductal papillary mucinous neoplasms and cystadenomas. Intraductal carcinomas and sialadenoma papilliferum are addressed in separate articles in this issue.
CRIS-Team Scopus Importer:2020-12-25
Keywords: AKT1 mutations; Cystadenoma; Intraductal papillary mucinous neoplasm; Intraductal papilloma; IPMN; Mucinous; Papillary; Salivary glands

Papillary renal cell carcinoma with prominent spindle cell stroma - tumor mimicking mixed epithelial and stromal tumor of the kidney: Clinicopathologic, morphologic, immunohistochemical and molecular genetic analysis of 6 cases - Rogala, Joanna; Kojima, Fumiyoshi; Alaghehbandan, Reza; Agaimy, Abbas; Martinek, Petr; Ondic, Ondrej; Ulamec, Monika; Sperga, Maris; Michalova, Kvetoslava; Pivovarcikova, Kristyna; Pitra, Tomáš; Hora, Milan; et al. (Annals of Diagnostic Pathology, 2020)
Papillary renal cell carcinoma (PRCC) is currently a well-studied type of RCC. In addition to PRCC type 1, there are a number of other subtypes and variants of PRCCs which have been reported. We describe a series of 6 PRCCs with papillary, micropapillary and/or tubulopapillary architecture and prominent spindle cell stroma, resembling stroma in mixed epithelial and stromal tumor of the kidney (MESTK) or sarcomatoid RCC. Clinicopathologic, morphologic, immunohistochemical and molecular features were analyzed. All patients were males with an age range of 44–98 years (mean 65.3, median 65.5 years). Tumor size ranged from 2.4–11.4 cm (mean 5.8, median 4.5 cm). Follow-up data were available for 4 patients, ranging from 3 to 96 months (mean 42.75, median 36 months). Epithelial cells were mostly cylindrical with eosinophilic cytoplasm, showing nuclear grade 2 and 3 (ISUP/WHO). In all cases, loose to compact prominent stroma composed of spindle cells, without malignant mesenchymal heterologous elements was detected. No atypical mitoses were found, while typical mitoses were rare in both epithelial and stromal components. Epithelial cells were positive for CK7, AMACR, and vimentin in all cases, while negative for TFE3, HMB45, desmin, CD34, and actin. The stroma was positive for vimentin, actin and focally for CD34, while negative for CK7, AMACR, TFE3, HMB45, and desmin. Estrogen and progesterone receptors were completely negative. FH and SDHB expression was retained in all analyzable cases. Proliferative index was barely detectable in stromal component and low in epithelial component, ranging 0 to 5% positive stained cells/high power field. Copy number variation was variable with no distinct pattern. No mutations in CDKN2A, BAP1, MET were detected. PRCC with MESTK-like features is a distinct variant of PRCC mimicking MESTK. Our findings add to the body of literature on ever expanding variants of PRCCs. Both epithelial and stromal components lacked true Müllerian features, which was also proven by immunohistochemistry.
CRIS-Team Scopus Importer:2019-12-24
Keywords: Kidney; MESTK-like; Papillary renal cell carcinoma; Sarcomatoid-like

Paraneoplastic disorders associated with miscellaneous neoplasms with focus on selected soft tissue and Undifferentiated/ rhabdoid malignancies - Agaimy, Abbas (Seminars in Diagnostic Pathology, 2019)
A variety of soft tissue and visceral neoplasms have been associated with constitutional symptoms and signs including fever, fatigue, arthritis and laboratory abnormalities such as elevated erythrocyte sedimentation rate, leukocytosis with marked neutrophilia, anemia, thrombocytosis and others. This review addresses three main neoplastic categories that are associated with specific paraneoplastic phenomena: (1) neoplasms having in common the presence of diffuse mixed inflammatory infiltration (closely simulating an inflammatory pseudotumor) and frequently associated with constitutional symptoms; (2) neoplasms with undifferentiated, anaplastic or rhabdoid cell morphology (frequently SWI/SNF-deficient) associated with diverse paraneoplastic manifestations; and (3) paraneoplasia associated with neoplasms carrying specific gene fusions such as solitary fibrous tumor (STAT6-NAB2 gene fusions), infantile fibrosarcoma and congenital mesoblastic nephroma (ETV6-NTRK3 gene fusions), and angiomatoid fibrous histiocytoma (EWSR1-CREB1 & EWSR1-ATF1 fusions).
CRIS-Team Scopus Importer:2019-05-02
Keywords: Anaplastic carcinoma; Constitutional symptoms; Follicular dendritic cell tumor; Inflammatory myofibroblastic tumor; Inflammatory pseudotumor; Paraneoplastic syndromes; Rhabdoid; SWI/SNF; Undifferentiated

Paraneoplastic syndromes–“keys” to histopathological diagnoses and appropriate therapy - Agaimy, Abbas; Wick, Mark R. (Seminars in Diagnostic Pathology, 2019)
CRIS-Team Scopus Importer:2019-08-06

Paraproteinemia and renal involvement - Rupprecht, Harald; Amann, Kerstin Ute (Die Nephrologie, 2022)
Renal manifestations in patients with monoclonal paraproteinemia are frequent. Cast nephropathy is a disease that only occurs in manifest multiple myeloma with a high tumor burden. In contrast, monoclonal gammopathy of renal significance (MGRS) is defined as renal involvement due to a nephrotoxic clone that from a hematological standpoint would per se not require treatment. The diagnosis of MGRS can only be made by renal biopsy. Here monotypic immunoglobulin (Ig) deposits can be found in either organized (amyloidosis, fibrillary glomerulonephritis, GN, immunotactoid GN, cryoglobulinemic GN) or nonorganized forms (monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits). There are two forms of MGRS that can occur without the deposition of Ig, namely C3 glomerulopathy and thrombotic microangiopathy. For cast nephropathy there is always a fundamental indication for chemotherapy. The data on mechanical elimination of light chains by plasmapheresis or high cut-off dialysis are inconsistent. In patients with MGRS the indications for treatment must be made based on the renal prognosis in a cooperation between nephrologists and hematologists. Only a clone-directed treatment can lead to an improvement of renal function.
CRIS-Team WoS Importer:2022-12-16

Parotid pleomorphic adenomas: Factors influencing surgical techniques, morbidity, and long-term outcome relative to the new ESGS classification in a retrospective study - Schapher, Mirco; Koch, Michael; Agaimy, Abbas; Goncalves, Miguel; Mantsopoulos, Konstantinos; Iro, Heinrich (Journal of Cranio-Maxillofacial Surgery, 2019)
Purpose: To assess long-term results after treatment of parotid pleomorphic adenomas (PPAs) with different surgical techniques, standardized according to the European Salivary Gland Society (ESGS) classification system. Methods: We analyzed ESGS categories, occurrence of facial nerve paresis (FNP), Frey's syndrome, histopathology, and recurrences. Surgical modalities were compared, differentiating techniques with and without facial nerve dissection. A strict protocol ensured a postoperative follow-up-period of more than 7 years. Results: 205 patients were included. A complete follow-up was possible in 138 patients, 77 of whom underwent extracapsular dissection (ED) and 61 of whom had other surgical modalities (OSMs). ESGS categories correlated with the extent of surgery, significantly with the risk for FNP and Frey's syndrome, but not with recurrences. Recurrences did not differ significantly between ED and OSMs, whereas the risks for FNP (p < 0.001 each) and Frey's syndrome (p = 0.000) were significantly higher after OSMs in comparison with ED. Young women with a stroma-rich (myxoid) tumor subtype appear to have the greatest risk for recurrences. Conclusion: ED is the treatment of choice for PPAs, if possible, resulting in similar recurrence rates but significantly fewer comorbidities in comparison with more extensive surgery. After the treatment of PPAs, a long-term follow-up is needed, including imaging.
CRIS-Team Scopus Importer:2019-08-02
Keywords: Extracapsular dissection; Facial nerve paresis; Follow-up; Frey's syndrome; Pleomorphic adenoma; Recurrence

Pathogenetic aspects in precursor lesions of gastrointestinal tumors - Rau, Tilman (Pathologe, 2016)
The pathogenesis of precursor lesions of gastrointestinal tumors is manifested in many ways. In the esophagus an aberrant genetic expression of intestinal transcription factors, such as CDX2 is initiated by local environment factors. During the subsequent dysplasia to carcinoma sequence, chromosomal gain and loss of genes occurs. A 4-color fluorescence in situ hybridization (FISH) assay can be applied in dysplasia as well as in Barrett's adenocarcinoma to define prognostic marker combinations. In the gastric carcinogenesis sequence the gene expression of CDX1 is regulatively dependent on an interplay between inflammation and promotor methylation. In the colon sessile serrated adenomas show a sequence with initial BRAF mutation and late onset of MLH1 promotor hypermethylation with consecutive potential cancer progression. This event is accompanied by an increase of intraepithelial lymphocytes, which is an easy to use tool for routine diagnostics using H&E sections. Next generation sequencing (NGS) investigations of germline mutations in colorectal cancer revealed a spectrum of mutations with low penetration in the field of mismatch repair proteins as well as the APC gene. An individual risk stratification for penetration of these germline mutations is necessary. In conclusion, genetics, phenotypes and terminology of gastrointestinal precursor lesions are unified to a mutually influencing concept within medicine.
EVALuna2:6910

Pathogenetic Implications of BRAF Mutation Distribution in Stage IV Melanoma Patients - Baiter, Mirjam; Schuler, Gerold; Hartmann, Arndt; Schneider-Stock, Regine; Heinzerling, Lucie (Dermatology, 2015)
BRAF mutation frequencies in melanoma subtypes have clinical implications and offer pathogenetic clues.To characterize BRAF mutation status in melanoma of unknown primary (MUP) patients, in histological melanoma subtypes and by localization of primary tumors.In 179 patients with stage IV metastatic melanoma, BRAF mutation status, histological subtype and localization of primary (except for 29 MUP patients) were analyzed.BRAF mutations were found in 44.3%, of which 80.5% were BRAF V600E and 19.5% showed non-V600E BRAF mutations. BRAF mutation frequency depended on histological subtype (57.4% superficial spreading melanoma, 54.7% nodular melanoma, 11.1% mucosal melanoma, 28.6% acral lentiginous melanoma) and concerning non-V600E BRAF mutations on localization of primary. In MUP the BRAF mutation pattern resembled superficial spreading and nodular melanomas.BRAF mutation frequencies depend on histological subtype and localization of primary melanoma. Non-V600E BRAF mutations mostly occur in patients with primaries on 'head and neck' as well as 'trunk' but not on 'extremities'.
EVALuna2:6729

Pathological Diagnostic Testing and Biomarkers for Perioperative System Therapy Pathologische Diagnostik und Biomarker für die perioperative Systemtherapie - Erber, Ramona (Zentralblatt für Chirurgie, 2024)
Optimal personalized treatment planning for resectable lung cancer requires quality-assured, standardized and prompt processing of tissue samples in pathological laboratories, as well as the determination of relevant predictive and prognostic biomarkers. Pathological diagnostic testing includes histological tumor typing, staging and tumor grading, resection status and, if necessary, regression grading after neoadjuvant systemic therapy. Histopathological typing is performed according to the current WHO classification and includes adenocarcinomas, squamous cell carcinomas, other non-small cell lung carcinomas (NSCLCs), carcinoids, small cell and large cell neuroendocrine carcinomas. Standardized tumor grading currently plays an important role in invasive non-mucinous adenocarcinoma in particular and enables prognostic risk assessment. The R classification and regression grading are also prognostically relevant. In the early stages of NSCLC, molecular biomarkers such as EGFR, ALK and PD-L1, are relevant for decisions on individual treatment. Testing is performed on FFPE tissue samples and must be carried out in a quality-assured manner and in accordance with international standards.
CRIS-Team Scopus Importer:2024-08-23
Keywords: immune checkpoint inhibitor; lung cancer; NSCLC; pathology; predictive biomarker

Pathological findings in cardiac apex removed during implantation of left ventricular assist devices (LVAD) are non-specific: 13-year-experience at a German Heart Center - Strecker, Thomas; Roesch, Johannes; Weyand, Michael; Agaimy, Abbas (International Journal of Clinical and Experimental Pathology, 2014)
Ventricular assist devices (VAD) have become an established therapy for patients with end-stage heart failure. The two main reasons for this development are the shortage of appropriate donor organs and the increasing number of patients waiting for heart transplantation (HTX). Furthermore, the enormous advances in the technical equipment and the rising clinical experience have improved the implantation technique, the durability and the long-term patient outcomes.We reviewed all cases of left ventricular assist device (LVAD) implantation at our Erlangen Heart Center during January 2000-July 2013. The main aim of this study was to analyze the underlying pathology from the cardiac apex removed during the implantation. From all patients, we created a follow-up, analyzed the pathological features with the clinical diagnoses and described the overall outcome.VAD implantation was performed in 266 cases at our center in the last 13 years (2.2% of the total of 12254 cardiac surgical operations in that period). From these patients, 223 underwent LVAD or biventricular (BVAD) implantation; the remaining received a right (RVAD) implantation. The most frequent underlying clinical diagnoses were dilated (n = 84, 37.7%, DCM) or ischemic (n = 61, 27.4%, ICM) cardiomyopathy. The pathological findings in the apex biopsy were generally non-specific and showed variable interstitial myocardial fibrosis with evidence of fibre loss, fatty degeneration and variable irregular atrophy of muscle fibres, consistent with dilated and ischemic cardiomyopathies as the most frequent causes of heart failure in these patients. Only a few cases showed other specific features such as myocarditis and AL-amyloidosis.Pathological findings in cardiac apex removed during LVAD implantation are rather non-specific and they generally reflect the late stage or consequences of chronic myocardial damage in cases of dilated or ischemic cardiomyopathies. Variable patchy chronic inflammatory changes may be observed in cardiomyopathies as a non-specific reaction caused by myocardial fiber damage and should not lead to misinterpretation as evidence of myocarditis or revision of original diagnosis.
EVALuna2:6683

Pathological function of neutrophil extracellular traps in human colon cancer - Stehr, Antonia; Wang, Guangxia; Demmler, Richard; Stemmler, Marc; Tripal, Philipp; Geppert, Carol-Immanuel; Merkel, Susanne; Herrmann, Martin; Stürzl, Michael (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-12-16

Pathologically Tumor-free Resection Margin Distance as a Surrogate Parameter in Primary Vulvar Squamous Cell Cancer: Analysis of a Large Two-Center Patient Cohort - Balog, Eva; Stübs, Frederik; Berndt, Ronald; Dietl, Anna; Geppert, Carol-Immanuel; Hartmann, Arndt; Thunich, Oliver; Beckmann, Matthias; Koch, Martin C. (Geburtshilfe und Frauenheilkunde, 2025)
Background This study evaluated the role of tumor-free margin distances and other prognostic factors, including age, lymph-node metastases, lymphatic vessel invasion, and local recurrence, on the survival of patients with vulvar squamous cell carcinoma (VSCC) undergoing primary surgical treatment. Methods A retrospective analysis reviewed the records of 232 VSCC patients who had undergone primary radical local excision with R0 resection between 2009 and 2021 at ANregiomed Hospital Ansbach and Erlangen University Hospital (Germany). Patients, aged 18 and older with no distant metastases, were grouped by resection margin distances (1 to ≤Â 3Â mm, 3 to ≤Â 8Â mm, >Â 8Â mm) for survival analysis using the Kaplan-Meier and log-rank tests. A Cox proportional hazards regression model incorporating multiple covariates, selected using the best-subset selection method and guided by the Akaike information criterion (AIC), was used. In the next step, we conducted a separate analysis of the patients who experienced a local recurrence. Results The median age of the 232 patients analyzed was 69Â years, with a median follow-up period of 10.5Â years; 82 patients died. Survival varied significantly relative to resection margin distance (pÂ =Â 0.0022), with the highest rates in the 1 to ≤Â 3Â mm group and the lowest in the >Â 8Â mm group. Multivariate analysis revealed that age, lymphatic vessel invasion, and resection margin distance significantly influenced survival, with higher values associated with increased mortality. Out of 232 patients analyzed, 43 developed a local recurrence. In the group with resection margins of 1 to ≤Â 3Â mm, 37% of patients experienced a local recurrence. Among those with margins of 3 to ≤Â 8Â mm, 44% had a recurrence, while only 19% of patients with margins >Â 8Â mm showed a local recurrence. Conclusion The study underscored the significance of tumor-free margin distance as a surrogate marker for survival in VSCC patients. In addition to lymphatic vessel invasion as the most critical prognostic factor, tumor-free resection margin distance and age emerged as significant predictors of overall survival. The findings advocate for tailored, function-preserving surgical approaches to improve patient outcomes.
CRIS-Team Scopus Importer:2025-03-14
Keywords: resection margins; squamous cell cancer; vulvar cancer

Pathologic complete response after induction therapy and surgery is an independed long-term survival prognostic factor in locally advanced non-small cell lung cancer - Schreiner, Waldemar; Dudek, Wojciech; Lettmaier, S.; Rieker, Ralf; Fietkau, Rainer; Sirbu, Horia (2018)
EVALuna2:35736

Pathologic complete response after induction therapy-the role of surgery in stage IIIA/B locally advanced non-small cell lung cancer - Schreiner, Waldemar; Gavrychenkova, Sofiia; Dudek, Wojciech; Rieker, Ralf; Lettmaier, Sebastian; Fietkau, Rainer; Sirbu, Horia (Journal of Thoracic Disease, 2018)
Background: Pathologic complete response (pCR) is dominant prognostic factor determining favorable outcome in locally advanced non-small cell lung cancer (NSCLC) after induction therapy (IT). There is no non-operative diagnostics that adequately estimates the pCR. Aim of this retrospective study was to assess the correlation between clinical and pathological factors in patients with pCR. Methods: Twenty-five patients with pCR after curative lung resection following IT were assessed using univariate and multivariate Cox regression and descriptive analysis. The survival rate was estimated by Kaplan-Meier method. Results: The IT included chemoradiation with median doses of 50.4 Gy (range, 45-59.4 Gy) combined with platinum-based chemotherapy in 23 patients (92%) and induction platinum-based chemotherapy in 2 patients (8%). Clinical tumor stage before IT was IIIA in 21, IIIB in 4 patients. Mean interval between IT and surgery was 8.1±3.0 weeks. Perioperative morbidity and 30-day mortality was 32% and 4%, respectively. There was no significant correlation of pCR and different clinical and pathological factors. The estimated 5-year long-term survival (LTS) and progressive-free survival (PFS) was 57% and 54%, respectively. The median LTS and PFS was not reached. Conclusions: pCR in patients with locally advanced NSCLC following IT is an independent prognostic factor, without correlation with pathological and clinical factors. Non-operative accurate assessment of pCR is currently impossible. Surgical resection enables secure identification of pCR and might improve the patient stratification for additive therapy.
EVALuna2:35733

Pathologic response after induction chemo-immunotherapy with single or double immune checkpoint inhibition in locally advanced head and neck squamous cell carcinoma (HNSCC): Expansion cohorts of the CheckRad-CD8 trial. - Hecht, Markus; Eckstein, Markus; Kallies, Annett; Klautke, Gunther; Illmer, Thomas; von der Grün, Jens; Laban, Simon; Hautmann, Matthias; Tamaskovics, Bálint; Hinke, Axel; Brunner, Thomas; Frey, Benjamin; et al. (JOURNAL OF CLINICAL ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-11-04

Pathologie und Molekularpathologie des Peniskarzinoms - Fiegl, August; Hartmann, Arndt; Junker, Kerstin; Mink, Jan; Stöhr, Robert (Die Pathologie, 2025)
Penile carcinoma exhibits significant geographic variation in incidence, ranking 30th globally among newly diagnosed cancers with an annual rate of 0.84 cases per 100,000 men. Particularly high incidence rates of up to 2.2 are seen in Latin America, Asia, and Africa, largely due to a high prevalence of HPV, lower circumcision rates, and inadequate hygiene standards.The 2022 WHO classification of urogenital tumors continues to differentiate penile carcinomas based on their HPV status; however, the subdivision of numerous subtypes especially of the HPV(+) carcinomas was abandoned. This article aims to present current knowledge on the carcinogenesis of HPV(+) and HPV(-) penile carcinomas and their precursor lesions as well as updates from the latest WHO classification.Approximately 50% of penile carcinomas are caused by infection with high-risk HPV subtypes, with positive p16 immunohistochemistry serving as a good surrogate marker for HPV(+) tumors. HPV(-) carcinomas frequently show TP53 mutations and are associated with a poorer prognosis.While localized penile carcinomas have a relatively good prognosis, survival rates in metastatic cases remain poor. Neither microsatellite instability nor mismatch-repair deficiency appear to play a role, but up to 62.2% of tumors express PD-L1. Currently, immune checkpoint inhibitors such as Avelumab and Ipilimumab, along with antibody-drug conjugates targeting TROP2 and Nectin‑4, are being tested in clinical trials, potentially leading to the approval of targeted therapies for metastatic penile carcinoma in the future.
EVALuna2:578181

Pathologists - The watchpersons for hereditary tumor syndromes - Agaimy, Abbas; Wick, Mark R. (Seminars in Diagnostic Pathology, 2018)
EVALuna2:34877

Pathology and molecular pathology of renal cell cancer Pathologie und Molekularpathologie des Nierenzellkarzinoms - Erlmeier, Franziska; Agaimy, Abbas; Hartmann, Arndt; Stöhr, Christine G. (Onkologe, 2019)
Background: The latest edition of the WHO classification of urogenital tumors was published in January 2016. Numerous innovations have been included following the decisions of the consensus conference held in Zurich in March 2015. This review article presents the histopathology and molecular pathology of renal tumors defined in the 2016 WHO classification. Results and conclusions: In recent years knowledge about the morphology and the biological behavior of kidney tumors has steadily improved. In particular, the expanded molecular knowledge and improved data from clinicopathological studies of these tumors have led to the recognition of new entities by the WHO. These include, among others, succinate dehydrogenase B deficiency-associated renal cell carcinoma, hereditary leiomyomatosis-associated renal cell cancer, tubulocystic renal cell carcinoma and clear cell papillary renal cell carcinoma.
CRIS-Team Scopus Importer:2019-05-24
Keywords: Aberration; chromosomal; Mutation; Subtype; Urogenital tumors; WHO classification

Pathology and systemic therapy of non-clear cell renal cell carcinoma: an overview - Bergmann, Lothar; Weber, Sarah; Hartmann, Arndt; Ahrens, Marit (Expert Review of Anticancer Therapy, 2021)
Introduction: Non-clear cell renal cell carcinoma (nccRCC) represents a highly heterogenous group of kidney cancer entities. As most clinical trials predominantly include patients with clear cell RCC (ccRCC), nccRCC treatment guidelines are mainly extrapolated from recommendations in ccRCC. Here, we review and elucidate current data on the pathologic classification and treatment of nccRCC. Areas covered: This article gives an overview of the WHO classification of RCC, showing the histological diversity of nccRCC and focusing particularly on entities first characterized since 2016, their specific molecular behavior and their role as indicators for hereditary cancer syndromes. In this context, we discuss the available data on nccRCC treatment oprtions such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, cytotoxic chemotherapy, and immune checkpoint inhibitors. Expert opinion: Although nccRCCs are relatively uncommon, entities of this type account for a subgroup of up to 20-25% of all RCCs. Advances in histopathology and molecular genetics, together with evidence gained from retrospective and prospective clinical data, have improved understanding of these tumors in recent years. Nevertheless, selective trials of current and novel therapies including new targeted agents in patients with nccRCC are urgently needed to further improve treatment guidelines.
CRIS-Team WoS Importer:2021-08-20

Pathology of familial tumor syndromes - Hartmann, Arndt (Pathologe, 2017)
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Patient-derived zebrafish xenografts of uveal melanoma reveal ferroptosis as a drug target - Groenewoud, Arwin; Yin, Jie; Gelmi, Maria Chiara; Alsafadi, Samar; Nemati, Fariba; Decaudin, Didier; Roman-Roman, Sergio; Kalirai, Helen; Coupland, Sarah E.; Jochemsen, Aart G.; Jager, Martine J.; Engel, Felix; et al. (Cell Death Discovery, 2023)
Uveal melanoma (UM) has a high risk to progress to metastatic disease with a median survival of 3.9 months after metastases detection, as metastatic UM responds poorly to conventional and targeted chemotherapy and is largely refractory to immunotherapy. Here, we present a patient-derived zebrafish UM xenograft model mimicking metastatic UM. Cells isolated from Xmm66 spheroids derived from metastatic UM patient material were injected into 2 days-old zebrafish larvae resulting in micro-metastases in the liver and caudal hematopoietic tissue. Metastasis formation could be reduced by navitoclax and more efficiently by the combinations navitoclax/everolimus and flavopiridol/quisinostat. We obtained spheroid cultures from 14 metastatic and 10 primary UM tissues, which were used for xenografts with a success rate of 100%. Importantly, the ferroptosis-related genes GPX4 and SLC7A11 are negatively correlated with the survival of UM patients (TCGA: n = 80; Leiden University Medical Centre cohort: n = 64), ferroptosis susceptibility is correlated with loss of BAP1, one of the key prognosticators for metastatic UM, and ferroptosis induction greatly reduced metastasis formation in the UM xenograft model. Collectively, we have established a patient-derived animal model for metastatic UM and identified ferroptosis induction as a possible therapeutic strategy for the treatment of UM patients.
CRIS-Team Scopus Importer:2023-06-30

Patient's quality of life after surgery and radiotherapy for extremity soft tissue sarcoma-a retrospective single-center study over ten years - Götzl, Rebekka; Sterzinger, Sebastian; Semrau, Sabine; Vassos, Nikolaos; Hohenberger, Werner; Grützmann, Robert; Agaimy, Abbas; Arkudas, Andreas; Horch, Raymund E.; Beier, Justus (Health and Quality of Life Outcomes, 2019)
Background and objectives: The purpose of this study is to analyze major complication rates and different aspects of health-related quality of life (HRQoL) in extremity soft tissue sarcoma (STS) patients treated with or without radio (chemo) therapy and surgery. Methods: We performed a retrospective analysis of all patients who underwent Extremity STS excision from 2004 to 2014 (182 patients included). Patients' data were collected from patients' records. HRQoL was assessed by using EORTC QLQ-C30. Results: A total of 182 patients underwent sarcoma resection. After neoadjuvant radiochemotherapy (RCT), the major-complication rate amounted to 28% (vs. 7%, no radiotherapy, p < 0.001). Major-complication rates after adjuvant radiotherapy (RT) occurred in 8% (vs. 7%, no radiotherapy, p = 0.265). Comparison QoL scores between treating with neoadjuvant RCT or without RT revealed significant worse scores with neoadjuvant RCT. Further stratification of disease control of these patients showed significant reduced scores in the group of disease-free patients with neoadjuvant RCT compared to irradiated disease-free patients. Discussion: To date, there have only been a few investigations of QoL in STS. Retrospective study on quality of life have limitations, like a lack of baseline evaluation of QoL. Patient candidated to radiation therapy could have had worse QoL baseline due to more advanced disease. Disease status of the patients who answered the questionnaires could have been an influence of QoL and we could show reduced scores in the group of disease-free patients with neoadjuvant RCT, but not for the patients with recurrence or metastasis, so it is very hard to discriminate whether radiation therapy could really have an impact or not. Conclusion: This study might assist in further improving the understanding of QoL in STS patients and may animate for prospective studies examining the oncological therapies impact on HRQoL.
CRIS-Team Scopus Importer:2019-11-19
Keywords: Health related quality of life; QLQ-C30; Sarcoma major complication rates; Sarcoma radiotherapy; Soft tissue sarcoma

Patients with COVID-19: in the dark-NETs of neutrophils - Ackermann, Maximilian; Anders, Hans-Joachim; Bilyy, Rostyslav; Bowlin, Gary L.; Daniel, Christoph; De Lorenzo, Rebecca; Egeblad, Mikala; Henneck, Timo; Hidalgo, Andres; Hoffmann, Markus; Hohberger, Bettina; Kanthi, Yogendra; et al. (Cell Death and Differentiation, 2021)
SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.
CRIS-Team Scopus Importer:2021-06-04

Pattern of SMARCB1 (INI1) and SMARCA4 (BRG1) in poorly differentiated endometrioid adenocarcinoma of the uterus: analysis of a series with emphasis on a novel SMARCA4-deficient dedifferentiated rhabdoid variant - Strehl, Johanna D.; Wachter, David; Fiedler, Jutta; Heimerl, Engelbert; Beckmann, Matthias; Hartmann, Arndt; Agaimy, Abbas (Annals of Diagnostic Pathology, 2015)
The role of the switch/sucrose nonfermenting chromatin remodeling complex in the initiation and progression of cancer is emerging. In the female genital tract, only ovarian small cell carcinoma, hypercalcemic type harbors recurrent inactivating SMARCA4 mutations. Otherwise, only rare case reports documented SMARCB1 involvement in endometrial cancer. We analyzed 24 grade 3 uterine endometrioid adenocarcinomas and 2 undifferentiated carcinomas for immunohistochemical expression of SMARCB1 and SMARCA4. All tumors showed high-grade nuclear features with a predominance of solid growth pattern. All cases showed intact nuclear SMARCB1 expression in all tumor cells. However, 1 case of a 78-year-old woman showed complete loss of SMARCA4 in 90% of the tumor with retained expression in 10% of the tumor. The SMARCA4-intact component was a moderate-to-poorly differentiated endometrioid adenocarcinoma. The SMARCA4-deficient dominating component showed solid growth of highly anaplastic undifferentiated large cells with prominent rhabdoid features. None of the 25 SMARCA4-intact cases showed rhabdoid cell morphology. To our knowledge, this is the first systematic study of SMARCB1 and SMARCA4 expression in endometrioid adenocarcinoma of uterus and the first description of a novel SMARCA4-deficient variant of dedifferentiated/undifferentiated endometrial carcinoma. The presence of a differentiated SMARCA4-intact endometrioid component points to a novel pathway of dedifferentiation in endometrioid adenocarcinoma as a consequence of a "second hit." This case further underlines the close link between the "rhabdoid phenotype" and the SWI/SNF pathway.
EVALuna2:6700

Patterns of xanthogranulomatous reaction in salivary glands. Histomorphological spectrum and differential diagnosis - Agaimy, A.; Ihrler, S. (Pathologe, 2014)
Xanthogranulomatous inflammation is an uncommon subtype of chronic inflammatory processes that has been mainly reported in the kidneys, gallbladder and other less common sites. Due to the presence of tumefactive mixed inflammatory infiltrates with variable involvement of surrounding soft tissues, this benign condition is often mistaken for a malignancy on clinical examination. In the salivary glands xanthogranulomatous inflammation is rare and mainly represents reactive changes secondary to a preexisting lesion, in particular infarcted Warthin tumors as well as ruptured ductal cysts and other sialectatic ductal changes. A special type of xanthogranulomatous salivary gland disease is represented by the rare primary (idiopathic) xanthogranulomatous sialadenitis without identifiable predisposing parenchymal or ductal lesions. The histological differential diagnosis is mainly based on the dominant histological pattern and encompasses among others inflammatory pseudotumors of various etiologies (e.g. inflammatory myofibroblastic tumor, IgG4-related disease and sarcoidosis), neoplastic and paraneoplastic xanthogranulomatosis, malignant lymphoma and carcinoma with secondary xanthogranulomatous reactions. Thus, identification of the underlying lesion is necessary for correct classification and to avoid overlooking more serious neoplastic or autoimmune diseases.
EVALuna2:6581

Paul Hermanek 08.03.1924-17.09.2020 - Wittekind, Christian; Hofstaedter, Ferdinand; Hartmann, Arndt (Pathologe, 2020)
CRIS-Team WoS Importer:2020-12-25

PBRM1 but not BAP1 deficiency is a frequent feature of multifocal non-cystic low-grade clear cell renal cell carcinoma - Agaimy, Abbas; Trpkov, Kiril; Gao, Yuan; Hartmann, Arndt; Hes, Ondrej (MODERN PATHOLOGY, 2019)
CRIS-Team WoS Importer:2019-08-23

PD-1 and PD-L1 expression predict regression and prognosis following neoadjuvant radiochemotherapy of oesophageal adenocarcinoma - Göbel, Holger H.; Distel, Luitpold; Aigner, Thomas; Büttner-Herold, Maike; Grabenbauer, Gerhard G. (Clinical and Translational Radiation Oncology, 2022)
Background and purpose: PD-1 and PD-L1 are involved in anticancer immunosurveillance, and their expression may be predictive for therapeutic effectiveness of specific antibodies. Their influence on response to neoadjuvant radiochemotherapy (RCT) and prognosis in patients with oesophageal adenocarcinoma (OAC) remains to be defined. Materials and methods: Between 10/2004 and 06/2018, complete pre-RCT biopsy-specimens were available from 76 patients with locally advanced, non-metastatic OAC scheduled for trimodality therapy. We evaluated intra- and peritumoural expression of CD8, PD-1 and PD-L1 in pre-treatment specimens to determine their influence on tumour regression grade and survival. PD-1 and PD-L1 expression were considered positive (+) if ≥1% of all cells were stained positive, otherwise negative (-); densities of CD8+ cells were categorized as being high (Hi) or low (Lo) according to the median. Results: A negative PD-L1 expression in peritumoural cells predicted a poor tumour regression (RD 0.24 [95% CI 0.03–0.44], p = 0.023). A positive PD-1 expression in intra- as well as peritumoural cells was identified as an unfavourable prognostic factor (HR 0.52 [95% CI 0.29–0.93], p = 0.028; HR 0.50 [0.25–0.99], p = 0.047, respectively). With respect to CD8+ infiltration, positive PD-1 and PD-L1 expressions attenuated its favourable prognostic effect in intratumoural area (LoCD8/PD1 + vs. HiCD8/PD1-: HR 0.25 [0.09–0.69], p = 0.007; LoCD8/PDL1+ vs. HiCD8/PDL1-: HR 0.32 [0.12–0.89], p = 0.028) and were associated with negative outcome when seen in peritumoural area (HiCD8/PD1+ vs. LoCD8/PD1-: HR 0.29 [0.11–0.74], p = 0.010); HiCD8/PDL1+ vs. LoCD8/PDL1-: HR 0.33 [0.12–0.90], p = 0.031). Conclusions: PD-1 and PD-L1 expression were identified to be of predictive and prognostic value in patients with OAC, particularly when considering CD8+ infiltration. Further validation by a large size dataset is required.
CRIS-Team Scopus Importer:2022-04-15
Keywords: CD8+; Esophageal adenocarcinoma; PD-1; PD-L1; Radiochemotherapy

PD1 expression and correlation with its ligands in oral cancer specimens and peripheral blood - Wehrhan, Falk; Weber, Manuel; Baran, Christoph; Agaimy, Abbas; Büttner-Herold, Maike; Kesting, Marco Rainer; Ries, Jutta (Journal of Cranio-Maxillofacial Surgery, 2021)
Objectives: This study analyzed the expression of the PD1 receptor in tumor tissue and peripheral blood of oral squamous cell carcinoma (OSCC) patients, and correlated it with the PD1 ligands PD-L1 and PD-L2. The currently low response rates of checkpoint inhibitor treatment in OSCC could be increased by a better understanding of immune checkpoint biology. Despite evidence in the literature for upregulation of PD1 checkpoint ligands in OSCC tissue, there has been no correlation analysis of the PD1 receptor with its ligands in tissue specimens and peripheral blood of OSCC patients.
CRIS-Team WoS Importer:2021-03-05

Pd1/pd-l1 axis in uro-oncology - Junker, Kerstin; Eckstein, Markus; Fiorentino, Michelangelo; Montironi, Rodolfo (Current Drug Targets, 2020)
The immune system is important to control tumor development and progression in humans. However, tumor cells and cells of the tumor microenvironment can induce immune escape mecha-nisms including activation of immune checkpoints such as PD-1/PD-L1. Based on this knowledge, new immune therapies, including PD-1 and PD-L1 inhibition, have been developed and are already recommended as a standard treatment in metastatic bladder and kidney cancer patients. In addition to its role as a therapeutic target, PD-L1 seems to be a prognostic parameter although data are controversial. Only little is known about signaling pathways inducing PD-L1 expression in tumor cells on one hand and about its functional role for tumor cells itself. However, the understanding of the complex biological function of PD-L1 will improve therapeutic options in urological malignancies. This review is giving an overview of the current knowledge concerning the PD-1/PD-L1 axis in urological tumors including bladder, kidney, prostate, testicular and penile cancer.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Bladder cancer; Checkpoint inhibition; Kidney cancer; PD-L1; Penile cancer; Prostate cancer; Testicular germ cell tumors

PD-1/PD-L1 expression in chromophobe renal cell carcinoma: An immunological exception? - Erlmeier, Franziska; Hartmann, Arndt; Autenrieth, Michael; Wiedemann, Max; Ivanyi, Philipp; Steffens, Sandra; Weichert, Wilko (Medical Oncology, 2016)
Immune checkpoint inhibitors targeting the inhibitory cross talk between tumor and immune cells have been approved for therapy in renal cell carcinoma (RCC). In contrast to clear cell RCC, little is known on PD-1/PD-L1 expression patterns in rarer RCC subtypes. The aim of this study was to evaluate the prevalence, distribution and prognostic impact of PD-1 and PD-L1 expression in chromophobe (ch)RCC. Patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimen was analyzed for PD-1 and PD-L1 expression by immunohistochemistry. Expression data were correlated with clinic-pathological parameters including patient survival. Eighty-one chRCC patients were eligible for analysis, thereof 25 (30.9 %) and 11 (13.6 %) patients were positive for PD-1(+) tumor-infiltrating mononuclear cells (TIMCs) and tumoral PD-L1(+) expression, respectively. No significant associations were found for PD-1(+) TIMC or tumoral PD-L1(+) expression and clinical attributes. In addition, no differences in 5- and 10-year overall survival for PD-1(-) TIMC compared to PD-1(+) TIMC (90.5 and 72.2 vs. 100 and 75 %; p = 0.41) and for PD-L1(-) tumors compared to PD-L1(+) tumors (91.9 and 76.4 vs. 100 and 50 %; p = 0.48) were observed. In conclusion, to our knowledge this is the first study to evaluate the prognostic impact of PD-1 and PD-L1 in chRCC. PD-L1 does seem to be expressed in a minority of all chRCC, likewise only a minority of chRCC was infiltrated by PD-1-positive inflammatory cells. Neither PD-1(+) TIMC nor tumoral PD-L1(+) expression was associated with parameters of aggressiveness or survival.
EVALuna2:6819

PDE-5 inhibition impedes TSP-1 expression, TGF-β activation and matrix accumulation in experimental glomerulonephritis - Hohenstein, Bernd; Daniel, Christoph; Wittmann, Sabine; Hugo, Christian (Nephrology Dialysis Transplantation, 2008)
Background. Matrix expansion and mesangial proliferation are hallmarks of mesangial proliferative glomerulonephritis. Specific inhibition of PDE-5, an enzyme catalyzing the intracellular degradation of cyclic GMP, can be achieved by the inhibitor vardenafil. In this study, we investigated the effects of PDE-5 inhibition in the anti-Thy1 model in the rat in vivo. Methods. After disease induction, rats received 10 mg/kg bw vardenafil twice a day via gavage. On Days 2 and 6, renal biopsies, as well as glomerular isolates, urine and blood samples were taken to compare vardenafil- and placebo-treated groups during the course of disease. Results. Small amounts of PDE-5 were detected in healthy kidneys, but induced in a typical mesangial pattern during disease (by IHC and WB). Specific PDE-5 inhibition resulted in increased glomerular levels of cGMP. Treated animals demonstrated inhibition of MC proliferation and matrix accumulation while renal function and influx of inflammatory cells were not affected. Due to PDE-5 inhibition, the endogenous TGF-β-activating protein TSP-1 and the TGF-β-signalling protein p-smad-2/3 were decreased suggesting this as an antifibrotic mechanism of action of vardenafil in this model. Conclusion. Considering the availability and safety profile of vardenafil, the beneficial antiproliferative and antifibrotic effect in experimental glomerulonephritis may potentially be applicable to the treatment of mesangial proliferative glomerulonephritis in man. © The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
Created from Fastlane, Scopus look-up
Keywords: Anti-Thy1 model; Matrix expansion; PDE-5 inhibition; TGF-β; TSP-1

PD-L1 assessment in urothelial carcinoma: a practical approach - Eckstein, Markus; Cimadamore, Alessia; Hartmann, Arndt; Lopez-Beltran, Antonio; Cheng, Liang; Scarpelli, Marina; Montironi, Rodolfo; Gevaert, Thomas (Annals of Translational Medicine, 2019)
Five programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors are currently approved for treatment of locally advanced or metastatic urothelial carcinoma of the bladder and the upper urinary tract. Due to restrictions by the FDA and EMA first-line treatment with Atezolizumab and Pembrolizumab in platinum-ineligible patients requires immunohistochemical PD-L1 testing. In the second-line setting all drugs are approved without PD-L1 testing. Used PD-L1 assays in clinical trials include the 28-8 pharmDx (Nivolumab), the 22C3 pharmDx (Pembrolizumab), Ventana SP142 (Atezolizumab), and the Ventana PD-L1 SP263 assays (Durvalumab). Differences in antibodies, needed platforms and testing algorithms have raised questions about interchangeability and comparability among these assays and their diagnostic use. We provide a practical review about the current recommendations, used assays and algorithms of PD-L1 testing in urothelial carcinoma to help oncologists, urologists and pathologists to understand analytical features, differences in antibody assays, differences in scoring algorithms and comparability of various PD-L1 assays. We reviewed and summarized published studies from the last four years (2016-2019) on PD-L1 testing in bladder cancer and present a condensed practical guideline including pre-analytical, analytical and test-specific issues.
CRIS-Team WoS Importer:2019-12-20

PD-L1 Expression and Silva Invasion Pattern in Villoglandular Adenocarcinoma of the Uterine Cervix - Dietl, Anna; Beckmann, Matthias; Stübs, Frederik; Gaß, Paul; Emons, Julius; Hartmann, Arndt; Erber, Ramona (International Journal of Gynecological Pathology, 2024)
Villoglandular adenocarcinoma (VGA) of the uterine cervix is a rare subtype of endocervical adenocarcinoma in young women. Between 2007 and 2020, all women with endocervical adenocarcinoma were retrospectively reviewed to find patients with VGA. Eight patients in whom pure VGA had been diagnosed were included. The mean age at initial diagnosis was 36.3 years (range 24–46). After surgical treatment, patients were followed up for 59 months (range 16–150). To date, all patients are alive with no evidence of disease. Neither lymph node involvement nor lymphovascular invasion was found. Furthermore, we examined the samples with a focus on morphological invasion pattern (Silva), stromal tumor-infiltrating lymphocytes (sTILs), and immunohistochemical programmed death ligand-1 (PD-L1) expression. PD-L1 expression was observed in 7/8 using the combined positive score (cutoff ≥ 1%), 1/8 of VGAs using the tumor proportion score (cutoff ≥ 1%), and 7/8 using the immune cell (cutoff ≥ 1%). Using combined positive score and immune cell, PD-L1 expression was seen in 7/8 of pattern B and C tumors, with significantly higher expression in tumors with destructive-type patterns (Po0.05, A vs. B+C). Using tumor proportion score, no significant difference in PD-L1 expression was seen between VGAs with different invasion patterns. VGAs demonstrated twice higher sTILs in tumors with destructive-type invasion patterns. Our observations suggest that PD-L1 expression, tumor invasion patterns, and sTILs do not correlate with the excellent prognosis of pure VGA.
CRIS-Team Scopus Importer:2024-06-28
Keywords: Cervix; CPS; PD-L1; Silva pattern; TIL; Villoglandular adenocarcinoma

PD-L1-Expression in in primary and recurrent vulvar squamous cell cancer - Stübs, Frederik; Knöll, Antje; Hartmann, Arndt; Leikauf, Leah-Sophie; Matek, Christian; John, Nelson; Häberle, Lothar; Beckmann, Matthias; Geppert, Carol-Immanuel (Gynecologic Oncology, 2025)
Background: Squamous cell vulvar carcinoma is a rare malignant disease of women. In higher tumor stages survival rates are poor. Therapy options are limited. Immunoncology plays an increasing role in the treatment of gynecology cancers. Data on the expression of PD-L1 in vulvar cancer are rare and contradictory. We sought to describe the expression of PD-L1 in VSCC in respect to the clinicopathologic characteristics of the tumor. Study design: We conducted a retrospective analysis including women with primary and recurrent vulvar cancer between 2000 and 2021. A next generation tissue micro array (ngTMA) was constructed for the analysis of PD-L1 expression. Results: In total 238 women with primary VSCC and 66 cases of local or distant recurrent vulvar cancer were included. 80 women with primary VSCC (33.6 %) had tumors with common positive score (CPS) <1 and 63 women (26.5 %) had tumors with CPS 1- < 10 and 95 women with CPS ≥10 (39.9 %). In the PD-L1 positive group the rates of p53+, groin metastasis, lymphatic invasion and tumor infiltration lymphocytes were higher as compared to PD-L1 negative (CPS <1). There was no significant influence of CPS in overall survival in addition to other prognostic factors (P = 0.13, likelihood ratio test). Conclusion: PD-L1 expression in primary vulvar cancer is associated with poorer prognosis. Hence, PD-L1 is a possible target for immune checkpoint inhibitors and women might benefit from special treatment options.
CRIS-Team Scopus Importer:2025-01-31
Keywords: Checkpoint inhibitor; Immune oncology; PD-L1-expression; Tissue micro array; Tumor infiltrating lymphocytes; Vulvar cancer

PD-L1 expression in peripheral blood samples of patients with oral squamous cell carcinomas - Ries, Jutta; Weber, Manuel; Baran, Christoph; Agaimy, Abbas; Buettner-Herold, M.; Preidl, Raimund; Neukam, Friedrich Wilhelm; Wehrhan, Falk (2018)
EVALuna2:34230

PD-L1 expression in tumor tissue and peripheral blood of patients with oral squamous cell carcinoma - Weber, Manuel; Wehrhan, Falk; Baran, Christoph; Agaimy, Abbas; Büttner-Herold, Maike; Preidl, Raimund; Neukam, Friedrich Wilhelm; Ries, Jutta (Oncotarget, 2017)
Immune checkpoints like programmed cell death-1 (PD-1) and its ligand PD-L1 are involved in immune escape mechanisms of solid tumors including oral squamous cell carcinoma (OSCC). Inhibitors of the pathway are successfully used for treating especially advanced disease. However, the physiological relevance of PD-1/PD-L1-signaling in OSCC is insufficiently understood. The aim of the study was to analyze if PD-L1 expression in tumor tissue and peripheral blood samples of OSCC patients is associated with histomorphological tumor parameters and if PD-L1 expression in patients is different from controls.OSCC tumor specimens showed a significantly higher PD-L1 expression than oral mucosa controls (p < 0.001; upregulation more than 3-fold). Cross-tabulation revealed an association of increased expression of PD-L1 mRNA in tissue specimens with malignancy (p < 0.001).OSCC cases with higher tumor grade and cases with lymph node metastases (N+) were significantly (p < 0.05) associated with increased PD-L1 expression in peripheral blood. Cross-tabulation revealed an significant association with lymph node metastases (N+) (p <= 0.002).PD-L1 mRNA expression was analyzed in tumor specimens and corresponding samples of healthy oral mucosa and peripheral blood of 45 OSCC patients and 36 healthy control persons using RT-qPCR analysis. A Mann-Whitney U-test, a cut-off point analysis and a Chi-square test were carried out.PD-L1 expression in OSCC could contribute to the immunosuppressive local tumor microenvironment. Increased malignant behavior (higher tumor grade, positive nodal status) might be associated with PD-L1 mediated systemic immune tolerance. Thus, PD-L1 expression in peripheral blood might be an indicator of the existence of metastatic disease (N+) in OSCC.
EVALuna2:25563

PD-L1 is upregulated by radiochemotherapy in rectal adenocarcinoma patients and associated with a favourable prognosis - Hecht, Markus; Buettner-Herold, Maike; Erlenbach-Wuensch, Katharina; Haderlein, Marlen; Croner, Roland; Grützmann, Robert; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (European Journal of Cancer, 2016)
The influence of neoadjuvant radiochemotherapy (RCT) on programmed death-ligand 1 (PD-L1) expression, a predictive marker for programmed cell death protein 1 (PD-1) inhibitor therapy, was studied on tumour and inflammatory cells in rectal adenocarcinoma patients along with its prognostic value.PD-L1 immunohistochemistry was performed on tissue microarrays of 103 pre-RCT biopsies and 159 post-RCT surgical specimens (central tumour, invasive front and normal tissue) of 199 patients. In 63 patients, both samples were available. Proportion and maximum intensity of PD-L1-positive (PD-L1+) cells were evaluated.RCT increased the proportion of PD-L1-expressing cancer cells from 2.1% to 7.8% in the central tumour (p < 0.001) or 9.3% in the invasive front (p < 0.001). Cancer cell PD-L1 on its own could not predict prognosis. High PD-L1 expression on pre-RCT inflammatory cells (maximum intensity: p = 0.048) and post-RCT invasive front inflammatory cells (p = 0.010) correlated with improved no evidence of disease survival. In multivariate analysis, the combination of low PD-L1 in cancer and inflammatory cells was an independent negative prognostic marker for overall survival (OS) pre-RCT (Cox's proportional hazard ratio 0.438, p = 0.045) and in the invasive front post-RCT (Cox's proportional hazard ratio 0.257, p = 0.030).Neoadjuvant RCT is associated with an increased PD-L1 expression in rectal adenocarcinoma patients, which should prompt clinical trials combining radiotherapy and PD-1/PD-L1 pathway blockade. Combined low PD-L1 expression on tumour and inflammatory cells is an independent negative prognostic marker for OS in RCT of rectal adenocarcinoma.
EVALuna2:6814

PD-L1 Testing for Urothelial Carcinoma: Interchangeability, Reliability and Future Perspectives - Gevaert, Thomas; Cimadamore, Alessia; Montironi, Rodolfo; Eckstein, Markus (Current Drug Targets, 2021)
Five programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors are currently approved for the treatment of locally advanced or metastatic urothelial carcinoma of the bladder and the upper urinary tract. Following the FDA and EMA restrictions of first-line treatment with Atezolizumab and Pembrolizumab in platinum-ineligible patients, immunohistochemical PD-L1 testing is now required. Several emerging issues on antibodies, test platforms and scoring algorithms have raised concerns about the comparability and interchangeability between these assays. In this review, we have focused on the interchangeability of the used algorithms and assays for PD-L1 testing in urothelial carcinoma, on the predictive reliability of PD-L1 testing in urothelial carcinoma and the potential of other new and upcoming biomarkers.
CRIS-Team Scopus Importer:2021-03-19
Keywords: biomarker; immunohistochemistry; immunotherapy; interchangeability; PD-L1; urothelial carcinoma

PD-L2: A prognostic marker in chromophobe renal cell carcinoma? - Erlmeier, Franziska; Weichert, Wilko; Autenrieth, Michael; Wiedemann, Max; Schrader, Andres Jan; Hartmann, Arndt; Ivanyi, Philipp; Steffens, Sandra (Medical Oncology, 2017)
In the context of cancer immunotherapy, PD-1 as well as PD-L1 has been widely studied in renal cell carcinoma (RCC). PD-1 and PD-L1 play a significant role as prognostic markers in clear cell renal cell carcinoma. In contrast, little is known about PD-L2 expression patterns in RCC, especially in rarer subtypes. The aim of this study was to evaluate the prevalence, distribution and prognostic impact of PD-L2 expression in chromophobe (ch)RCC. Eighty-one patients who underwent renal surgery due to chRCC were retrospectively evaluated. Tumor specimens were analyzed for PD-L2 expression by immunohistochemistry. Expression data were associated with clinicopathological parameters and overall survival (OS). Twenty-three (28.4%) patients showed a PD-L2 > median (PD-L2 high) staining intensity. No significant association between clinicopathological parameters and PD-L2 expression was identified. A significant difference between 5- and 10-year OS in dependence of PD-L2 expression was found (PD-L2 low 96.4 and 87.7% vs. PD-L2 high 87.1 and 56%; log rank, p = 0.029). However, in multivariate analysis PD-L2 expression failed to be proofed as an independent prognostic factor. In conclusion, to our knowledge this is the first study evaluating the prognostic impact of PD-L2 in a considerably large cohort of chRCC. Our results showed a significant diminished OS in dependence of PD-L2 expression. This implicates that PD-L2 might play a role as prognostic marker in chRCC demanding further evaluation.
EVALuna2:6873

Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases - Argani, Pedram; Lian, Derrick W.Q.; Agaimy, Abbas; Metzler, Markus; Wobker, Sara E.; Matoso, Andres; Epstein, Jonathan I.; Sung, Yun Shao; Zhang, Lei; Antonescu, Cristina R. (American Journal of Surgical Pathology, 2021)
Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal serous carcinoma. The ALK genetic abnormalities were investigated by a combination of molecular methods. Archer FusionPlex was performed in 2 cases, showing fusions between ALK with either STRN or TPM1 genes, resulting in a transcript that retained the ALK kinase domain. One case was further studied by DNA targeted sequencing, but no additional genetic alterations were observed. In 1 case, cytogenetic analysis showed the presence of a t(2;15)(p23;q22) and fluorescence in situ hybridization confirmed the ALK gene break-apart. In the remaining 2 cases, ALK gene rearrangements were demonstrated by fluorescence in situ hybridization. Unlike adult mesotheliomas, which are tightly linked to asbestos exposure, often show loss of BAP1 expression and have complex karyotypes, ALK-rearranged mesothelioma appears to be similar to other fusion-positive mesotheliomas, such as those harboring EWSR1/FUS-ATF1 fusions, sharing significant morphologic overlap, occurring in young patients and displaying a simple, translocation-driven genetic profile.
CRIS-Team Scopus Importer:2021-04-23

Pediatric Pleural Mesothelioma - André, Nicolas; Kashanskiy, Sergey K.V.V.; Agaimy, Abbas (Springer Science and Business Media Deutschland GmbH, 2022)
Malignant mesothelioma is an aggressive tumor that originates from the lining cells (mesothelium) that cover the serosal surfaces of the pleural and peritoneal cavities, or more rarely the tunica vaginalis testis and the pericardium (Moore et al. 2008). Based on the stage of the disease at the time of diagnosis, mesothelioma may present as discrete multifocal nodules or as a diffuse confluent mass encasing the adjacent organs and/or obliterating the serosal cavity from which the tumor has originated.
CRIS-Team Scopus Importer:2022-06-17
Keywords: Asbestos exposure; Malignant mesothelioma; Malignant pleural mesothelioma; Peritoneal mesothelioma; Pleural thickening

Pediatric salivary gland tumors and tumor-like lesions - Agaimy, Abbas; Iro, Heinrich; Zenk, J. (Pathologe, 2017)
Salivary gland tumors and tumor-like lesions in the pediatric population are uncommon. They comprise a heterogeneous group of infectious/inflammatory and neoplastic conditions. Pediatric salivary neoplasms include benign tumors of mesenchymal or epithelial origin as well as malignancies of epithelial (carcinomas), mesenchymal (sarcoma) or hematolymphoid (lymphoma) derivation. Infectious/inflammatory conditions and hematolymphoid malignancies may represent either genuine parenchymal pathology or conditions involving intraglandular lymph nodes of the parotid glands (intraglandular lymphadenopathy and intraglandular nodal lymphomas). Pediatric sialadenitis may be of diverse etiologies including viral (mumps, CMV, HIV, etc.), bacterial, autoimmune (juvenile Sjögren syndrome) or idiopathic (chronic recurrent juvenile sialectatic sialadenitis). Angiomatous lesions (juvenile capillary hemangioma, lymphangioma and vascular malformation) and pleomorphic adenomas represent the most common pediatric benign mesenchymal and benign epithelial tumors, respectively. The vast majority of salivary gland carcinomas in children and adolescents represent low-grade mucoepidermoid carcinomas followed by acinic cell and adenoid cystic carcinomas (together >80% of carcinomas). Other malignant neoplasms include (rhabdomyo-) sarcomas, malignant lymphomas and very rarely sialoblastomas. This long differential diagnosis list of etiologically and biologically highly heterogeneous entities, their shared clinical presentation as "salivary gland enlargement" and the significant differences in their therapeutic strategies and prognosis underline the need for careful assessment to identify the correct diagnosis. Diagnosis is mainly based on a set of typical clinical and imaging features, serological/microbiological findings and, in selected cases, histomorphological characteristics in biopsy specimens.
EVALuna2:6863

PEG matrix enables cell-mediated local BMP-2 gene delivery and increased bone formation in a porcine critical size defect model of craniofacial bone regeneration - Wehrhan, Falk; Amann, Kerstin Ute; Molenberg, Aart; Lutz, Rainer; Neukam, Friedrich Wilhelm; Schlegel, Karl Andreas (Clinical Oral Implants Research, 2012)
Purpose: This study addressed the suitability of a polyethylene glycol (PEG) matrix as scaffold for cell-mediated local BMP-2 gene transfer in a calvarial critical size defect (CSD) model. Materials and methods: PEG matrix (degradation time 10 days) and PEG membrane (degradation time 120 days) were used in the pig calvarial model. Cylindrical (1 × 1 cm) CSD (9 per animal; 20 animals) were filled with: (i) HA/TCP, covered by PEG membrane (group 1); (ii) HA/TCP, mixed with PEG matrix (group 2); and (iii) HA/TCP mixed with BMP-2 transfected osteoblasts and PEG matrix (group 3). BMP-2/4 gene transfer: liposomal in vitro transfection of BMP-2/V5-tag fusion-protein. Quantitative histomorphometry (toluidine blue staining) after 2, 4 and 12 weeks assessed bone formation. Semiquantitative immunohistochemistry estimated the expression of BMP-2 and V5-tag. Results: Group 3 showed significantly higher new bone formation than groups 1, 2 at 4 (P < 0.05) and 12 (P < 0.02) weeks. BMP-2-V5-tag was detected for 4 weeks. BMP-2 expression in group 3 was higher compared to all other groups after 2 and 4 (P < 0.02) weeks. Conclusions: The PEG matrix serves as scaffold for cell-mediated BMP-2 gene delivery in guided bone regeneration facilitating cell survival and protein synthesis for at least 4 weeks. Local BMP-2 gene delivery by PEG matrix-embedded cells leads to increased bone formation during critical size defect regeneration. © 2011 John Wiley & Sons A/S.
CRIS-Team Scopus Importer:2024-05-13
Keywords: BMP-2; Bone regeneration; Critical size defect; Gene transfer; PEG

Pembrolizumab in combination with nab-paclitaxel for the treatment of patients with early-stage triple-negative breast cancer – A single-arm phase II trial (NeoImmunoboost, AGO-B-041) - Fasching, Peter; Hein, Alexander; Kolberg, Hans Christian; Häberle, Lothar; Uhrig, Sabrina; Rübner, Matthias; Belleville, Erik; Hack, Carolin; Fehm, Tanja N.; Janni, Wolfang; Hartmann, Arndt; Erber, Ramona; et al. (European Journal of Cancer, 2023)
Background: Pembrolizumab is approved for the neoadjuvant/adjuvant treatment of early triple-negative breast cancer (TNBC) patients in combination with chemotherapy. The Keynote-522 trial used platinum chemotherapy. As neoadjuvant nab-paclitaxel (nP) is also highly effective in triple-negative breast cancer patients, this study investigates the response to nP-containing neoadjuvant chemotherapy in combination with pembrolizumab. Patients and methods: NeoImmunoboost (AGO-B-041/NCT03289819) is a multicenter, prospective single-arm phase II trial. Patients were treated with 12 weekly cycles of nP followed by four three-weekly cycles of epirubicin/cyclophosphamide. Pembrolizumab was given three-weekly in combination with these chemotherapies. The study was planned for 50 patients. After 25 patients, the study was amended to include a pre-chemotherapy single application of pembrolizumab. The primary aim was pathological complete response (pCR), and the secondary aims were safety and quality of life. Results: Of 50 included patients, 33 (66.0%; 95%confidence interval: 51.2%–78.8%) had a (ypT0/is ypN0) pCR. The pCR rate in the per-protocol population (n = 39) was 71.8% (95%confidence interval: 55.1%–85.0%). The most common adverse events of any grade were fatigue (58.5%), peripheral sensory neuropathy (54.7%) and neutropenia (52.8%). The pCR rate in the cohort of 27 patients with a pre-chemotherapy pembrolizumab dose was 59.3%, and 73.9% in the 23 patients without pre-chemotherapy dose. Conclusions: pCR rates after NACT with nP and anthracycline combined with pembrolizumab are encouraging. With acceptable side-effect profiles, this treatment might be a reasonable alternative to platinum-containing chemotherapy in cases of contraindications. However, without data from randomised trials and long-term follow up, platinum/anthracycline/taxane-based chemotherapy remains the standard combination chemotherapy for pembrolizumab.
CRIS-Team Scopus Importer:2023-03-24
Keywords: Neoadjuvant chemotherapy; PD-L1; Pembrolizumab; Triple-negative

Percent mammographic density and dense area as risk factors for breast cancer - Rauh, C.; Hack, Caroline; Häberle, Lothar; Hein, Alexander; Engel, Anne; Schrauder, Michael G.; Fasching, Peter; Jud, Sebastian; Ekici, Arif Bülent; Loehberg, C. R.; Meier-Meitinger, Martina; Ozan-Mergner, Sevil Julia; et al. (Geburtshilfe und Frauenheilkunde, 2012)
Purpose: Mammographic characteristics are known to be correlated to breast cancer risk. Percent mammographic density (PMD), as assessed by computer-assisted methods, is an established risk factor for breast cancer. Along with this assessment the absolute dense area (DA) of the breast is reported as well. Aim of this study was to assess the predictive value of DA concerning breast cancer risk in addition to other risk factors and in addition to PMD. Methods: We conducted a case control study with hospital-based patients with a diagnosis of invasive breast cancer and healthy women as controls. A total of 561 patients and 376 controls with available mammographic density were included into this study. We describe the differences concerning the common risk factors BMI, parital status, use of hormone replacement therapy (HRT) and menopause between cases and controls and estimate the odds ratios for PMD and DA, adjusted for the mentioned risk factors. Furthermore we compare the prediction models with each other to find out whether the addition of DA improves the model. Results: Mammographic density and DA were highly correlated with each other. Both variables were as well correlated to the commonly known risk factors with an expected direction and strength, however PMD (ρ = 0.56) was stronger correlated to BMI than DA (ρ = 0.11). The group of women within the highest quartil of PMD had an OR of 2.12 (95 % CI: 1.25-3.62). This could not be seen for the fourth quartile concerning DA. However the assessment of breast cancer risk could be improved by including DA in a prediction model in addition to common risk factors and PMD. Conclusions: The inclusion of the parameter DA into a prediction model for breast cancer in addition to established risk factors and PMD could improve the breast cancer risk assessment. As DA is measured together with PMD in the process of computer-assisted assessment of PMD it might be considered to include it as one additional breast cancer risk factor that is obtained from breast imaging. © Georg Thieme Verlag KG Stuttgart · New York.
CRIS-Team Scopus Importer:2021-07-19
Keywords: breast cancer; mammographic density; risk

Perforations after routine biopsy in IBD patients, their management and potential risk reductions by microscopic imaging with endocytoscopy - Klenske, Entcho; Hartmann, Arndt; Atreya, Raja; Neurath, Markus; Rath, Timo (Journal of Gastrointestinal and Liver Diseases, 2020)
CRIS-Team Scopus Importer:2020-09-25

Performance of the Food and Drug Administration/EMA-approved programmed cell death ligand-1 assays in urothelial carcinoma with emphasis on therapy stratification for first-line use of atezolizumab and pembrolizumab - Eckstein, Markus; Erben, Philipp; Kriegmair, Maximilian C.; Worst, Thomas S.; Weiss, Cleo-Aron; Wirtz, Ralph M.; Wach, Sven; Stoehr, Robert; Sikic, Danijel; Geppert, Carol-Immanuel; Weyerer, Veronika; Bertz, Simone; et al. (European Journal of Cancer, 2019)
BACKGROUND: Recently, the Food and Drug Administration (FDA)/European Medicines Agency (EMA) restricted first-line use of atezolizumab and pembrolizumab in patients with metastasised urothelial carcinoma by defining distinct programmed cell death ligand-1 cut-offs. We analysed the diagnostic performance of all FDA/EMA-approved programmed cell death ligand-1 assays with emphasis on new restrictions for first-line treatment with atezolizumab and pembrolizumab. PATIENTS AND METHODS: Two hundred fifty-one urothelial carcinomas were analysed on tissue microarrays with four cores of each tumour. Stains were performed in certified laboratories on Ventana Benchmark Ultra and Dako Link 48 autostainers. Stains were read on an assay-by-assay basis by two trained pathologists. Overall percentage agreement (OPA) was calculated across the preset cut-offs. Positive percentage agreement (PPA) and negative percentage agreement (NPA) were calculated across different scoring algorithms. Venn diagrams were constructed to illustrate discordance according to the recent FDA/EMA guidelines. RESULTS: The Dako 28-8, 22c3 and the Ventana SP263 assays showed high interassay correlation (r-range 0.83-0.91). Interassay correlation between the Ventana SP142 and the three other assays was moderate (r-range 0.66-0.75). OPA of 93.3% was achieved between the Dako 28-8, 22c3 and Ventana SP263 assays. OPA including the SP142 was 84.1%. Pooled PPA and NPA of different scoring algorithms was 89.4% and 95.3% for the Dako 28-8, 22c3 and the SP263 assays, respectively. With the SP142 assay, pooled PPA was 59.1%. The SP142 assay identifies fewer eligible patients for first-line treatment with atezolizumab/pembrolizumab. CONCLUSION: Dako 28-8, 22c3 and SP263 assays show interchangeable performance. The SP142 assay shows divergent staining results. Interassay variability leads to different detection rates of eligible patients for first-line treatment with atezolizumab and pembrolizumab.
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Perivascular hemosiderin deposits in human skeletal muscle tissue - Delbridge, Claire; Türk, Matthias; Agaimy, Abbas; Winterholler, Martin; Schröder, Rolf (Neuromuscular Disorders, 2018)
EVALuna2:34586

Persistent scarring and dilated cardiomyopathy suggest incomplete regeneration of the apex resected neonatal mouse myocardium - A 180days follow up study - Andersen, Ditte Caroline; Jensen, Charlotte Harken; Baun, Christina; Hvidsten, Svend; Zebrowski, David; Engel, Felix; Sheikh, Soren Paludan (Journal of Molecular and Cellular Cardiology, 2016)
Heart damage in mammals is generally considered to result in scar formation, whereas zebrafish completely regenerate their hearts following an intermediate and reversible state of fibrosis after apex resection (AR). Recently, using the AR procedure, one-day-old mice were suggested to have full capacity for cardiac regeneration as well. In contrast, using the same mouse model others have shown that the regeneration process is incomplete and that scarring still remains 21days after AR. The present study tested the hypothesis that like in zebrafish, fibrosis in neonatal mammals could be an intermediate response before the onset of complete heart regeneration. Myocardial damage was performed by AR in postnatal day 1 C57BL/6 mice, and myocardial function and scarring assessed at day 180 using F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) and histology, respectively. AR mice exhibited decreased ejection fraction and wall motion with increased end-diastolic and systolic volumes compared to sham-operated mice. Scarring with collagen accumulation was still substantial, with increased heart size, while cardiomyocyte size was unaffected. In conclusion, these data thus show that apex resection in mice results in irreversible fibrosis and dilated cardiomyopathy suggesting that cardiac regeneration is limited in neonatal mammals and thus distinct from the regenerative capacity seen in zebrafish.
EVALuna2:25499

Personalized urooncology based on molecular uropathology: What is the future? Personalisierte Uroonkologie auf der Grundlage einer molekularen Uropathologie: Was ist die Zukunft? - Dahl, E.; Haller, Florian (Urologe, 2013)
Targeted therapies and biomarker validation are key drivers in the advancement of personalized oncology which is a growing topic in all clinical areas. Compared with other professions, such as pulmonology and gynecology, development in urology has so far been retarded but has recently gained increasing momentum. A basis for this is the currently growing and in future accelerated application of new knowledge derived from molecular biology in the field of uropathology. The rapid gain of knowledge is driven by a whole new class of analytical methods, such as massively parallel sequencing (deep sequencing or next generation sequencing), which enables analysis of virtually a new universe of potential biomarkers. This article describes the emerging paradigm shift in molecular pathological diagnostics of urological tumors using the example of prostate cancer. © 2013 Springer-Verlag Berlin Heidelberg.
CRIS-Team Scopus Importer:2025-03-24
Keywords: Biomarkers; Next generation sequencing; Personalized medicine; Prostate cancer; Urooncology

Perspectives, potentials and trends of ex vivo and in vivo optical molecular pathology - Krafft, Christoph; Von Eggeling, Ferdinand; Guntinas-Lichius, Orlando; Hartmann, Arndt; Waldner, Maximilian; Neurath, Markus; Popp, Juergen (Journal of Biophotonics, 2018)
It is pivotal for medical applications, such as noninvasive histopathologic characterization of tissue, to realize label-free and molecule-specific representation of morphologic and biochemical composition in real-time with subcellular spatial resolution. This unmet clinical need requires new approaches for rapid and reliable real-time assessment of pathologies to complement established diagnostic tools. Photonic imaging combined with digitalization offers the potential to provide the clinician the requested information both under in vivo and ex vivo conditions. This report summarizes photonic approaches and their use in combination with image processing, machine learning and augmented virtual reality that might solve current challenges in modern medicine. Details are given for pathology, intraoperative diagnosis in head and neck cancer and endoscopic diagnosis in gastroenterology.
EVALuna2:33796

PGAM5 acts as a key mediator of lung fibrosis by disrupting mitochondrial homeostasis - Ganzleben, Ingo; He, Gui-Wei; Günther, Claudia; Prigge, Elena-Sophie; Richter, Karsten; Rieker, Ralf; Mougiakakos, Dimitrios; Neurath, Markus; Becker, Christoph (EUROPEAN RESPIRATORY JOURNAL, 2019)
CRIS-Team WoS Importer:2020-02-04

PGAM5 is a key driver of mitochondrial dysfunction in experimental lung fibrosis - Ganzleben, Ingo; He, Gui Wei; Günther, Claudia; Prigge, Elena Sophie; Richter, Karsten; Rieker, Ralf; Mougiakakos, Dimitrios; Neurath, Markus; Becker, Christoph (Cellular and Molecular Life Sciences, 2019)
Rationale: Mitochondrial homeostasis has recently emerged as a focal point in the pathophysiology of idiopathic pulmonary fibrosis (IPF), but conflicting data have been reported regarding its regulation. We speculated that phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein at the intersection of multiple cell death and mitochondrial turnover pathways, might be involved in the pathogenesis of IPF. Methods: PGAM5-deficient mice and human pulmonary epithelial cells were analyzed comparatively with PGAM5-proficient controls in a bleomycin-based model of pulmonary fibrogenesis. Mitochondria were visualized by confocal and transmission electron microscopy. Mitochondrial homeostasis was assessed using JC1 (ΔΨ) and flow cytometry. Results: PGAM5 plays an important role in pulmonary fibrogenesis. Pgam5−/− mice displayed significantly attenuated lung fibrosis compared to controls. Complementary, in vitro studies demonstrated that PGAM5 impaired mitochondrial integrity on a functional and structural level independently of mtROS-production. On a molecular level, reduced mitophagy caused by PGAM5 deficiency improved mitochondrial homeostasis. Conclusions: Our study identifies PGAM5 as an important regulator of mitochondrial homeostasis in pulmonary fibrosis. Our data further indicate PGAM5-mediated mitophagy itself as a pivotal gateway event in the mediation of self-sustaining mitochondrial damage and membrane depolarization. Our work hereby highlights the importance of mitochondrial dynamics and identifies a potential therapeutic target that warrants further studies. Graphical abstract: Toxic agents lead to mitochondrial damage resulting in depolarization of the mitochondrial membrane potential (ΔΨ) which is a gateway event for the initiation of PGAM5-mediated mitophagy. PGAM5-mediated mitophagy in turn leads to a self-perpetuating escalation of ΔΨ depolarization. Loss of the mitophagy-based damage-enhancing loop under PGAM5-deficient conditions breaks this vicious cycle, leading to improved mitochondrial homeostasis.[Figure not available: see fulltext.].
CRIS-Team Scopus Importer:2019-06-21
Keywords: Bleomycin; IPF; Mitophagy

PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury - He, Gui-Wei; Günther, Claudia; Kremer, Andreas; Thonn, Veronika; Amann, Kerstin Ute; Poremba, Christopher; Neurath, Markus; Wirtz, Stefan; Becker, Christoph (Gut, 2016)
Autoimmune hepatitis (AIH) is a severe necroinflammatory liver disease associated with significant mortality. Although loss of hepatocytes is generally recognised as a key trigger of liver inflammation and liver failure, the regulation of hepatic cell death causing AIH remains poorly understood. The aim of this study was to identify molecular mechanisms that drive hepatocyte cell death in the pathogenesis of acute liver injury.Acute liver injury was modelled in mice by intravenous administration of concanavalin A (ConA). Liver injury was demonstrated by serum transaminases and histological assessment of liver sections. PGAM5-deficient mice (PGAM5-/-) were used to determine its role in experimental hepatitis. Mdivi-1 was used as an inhibitor of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Mitochondrial fission and the expression of PGAM5 were compared between liver biopsies derived from patients with AIH and control patients.PGAM5 was highly expressed in hepatocytes of patients with AIH and in mice with ConA-induced experimental hepatitis. Deficiency of PGAM5 protected mice from ConA-induced hepatocellular death and liver injury. PGAM5 regulated ConA-induced mitochondrial fission in hepatocytes. Administration of the Drp1-inhibitor Mdivi-1 blocked mitochondrial fission, diminished hepatocyte cell death and attenuated liver tissue damage induced by ConA.Our data demonstrate for the first time that PGAM5 plays an indispensable role in the pathogenesis of ConA-induced liver injury. Downstream of PGAM5, Drp1-mediated mitochondrial fission is an obligatory step that drives the execution of hepatic necrosis and tissue damage. Our data highlight the PGAM5-Drp1 axis as a potential therapeutic target for acute immune-mediated liver injury.
EVALuna2:2219

Phenotypical and molecular distinctness of sinonasal haemangiopericytoma compared to solitary fibrous tumour of the sinonasal tract - Agaimy, Abbas; Barthelmeß, Sarah; Geddert, Helene; Boltze, Carsten; Moskalev, Evgeny; Koch, Michael; Wiemann, Stefan; Hartmann, Arndt; Haller, Florian (Histopathology, 2014)
Sinonasal haemangiopericytoma (SN-HPC) is a rare sinonasal mesenchymal neoplasm of perivascular myoid cell origin. Solitary fibrous tumour (SFT) occurs only very rarely in the sinonasal tract. SFT and soft tissue HPC have been considered a single entity. Recently, recurrent gene fusions involving NAB2-STAT6 resulting in differential expression of STAT6 were characterized as central molecular events in SFT. However, no data exist for NAB2-STAT6 status or STAT6 expression in SN-HPC.We examined six SN-HPCs and two sinonasal SFTs by immunohistochemistry and RT-PCR for NAB2-STAT6 fusions. SN-HPC affected three females and three males (mean age: 72 years). They expressed smooth muscle actin, lacked strong CD34 reactivity and were negative for nuclear STAT6 expression. RT-PCR analysis confirmed the absence of NAB2-STAT6 fusions in all cases. Conversely, both sinonasal SFTs (in males aged 39 and 52 years) displayed classical features of pleuropulmonary and soft-tissue SFTs (uniformly CD34-positive with strong nuclear expression of STAT6). RT-PCR revealed NAB2-STAT6 fusions in both cases.These findings confirm the molecular and phenotypical distinctness of these two entities. While SN-HPC is a site-specific sinonasal neoplasm of as yet unknown molecular pathogenesis, sinonasal SFTs show phenotypical and molecular identity to their pleural/extrapleural counterparts.
EVALuna2:6649

[Philipp A. Schnabel : 24 May 1953-13 May 2021]. - Amann, Kerstin Ute (Pathologe, 2021)
EVALuna2:475671

Phosphaturic Mesenchymal Tumors: Clinicopathologic, Immunohistochemical and Molecular Analysis of 22 Cases Expanding their Morphologic and Immunophenotypic Spectrum - Agaimy, Abbas; Michal, Michael; Chiosea, Simion; Petersson, Fredrik; Hadravsky, Ladislav; Kristiansen, Glen; Horch, Raymund E.; Schmolders, Jan; Hartmann, Arndt; Haller, Florian; Michal, Michal (American Journal of Surgical Pathology, 2017)
Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm of uncertain histogenesis that has been linked to tumor-induced osteomalacia (TIO) since 1959. The neoplastic cells produce increased amount of FGF23 which results in TIO via uncontrolled renal loss of phosphate (phosphaturia), and consequently diminished bone mineralization. To date, 300 cases have been reported. Although there is increasing evidence that PMT can be diagnosed by reproducible histopathologic features, firm diagnosis has been often restricted to cases associated with TIO and, hence, diagnosis of "nonphosphaturic variants" remained challenging. Recently, FGFR1/FN1 gene fusions were detected in roughly half of cases. We herein reviewed the clinicopathologic features of 22 PMTs (15 cases not published before), stained them with an extended immunohistochemical marker panel and examined them by fluorescence in situ hybridization for FGFR1 gene fusions. Patients were 12 males and 9 females (one of unknown sex) aged 33 to 83 years (median: 52 y). Lesions affected the soft tissues (n=11), bones (n=6), sinonasal tract (n=4), and unspecified site (n=1). Most lesions originated in the extremities (9 in the lower and 4 in the upper extremities). Acral sites were involved in 10 patients (6 foot/heel, 3 fingers/hands, and 1 in unspecified digit). Phosphaturia and TIO were recorded in 10/11 and 9/14 patients with detailed clinical data, respectively. Limited follow-up (5 mo to 14 y; median: 16 mo) was available for 14 patients. Local recurrence was noted in one patient and metastasis in another patient. Histologically, 11 tumors were purely of conventional mixed connective tissue type, 3 were chondromyxoid fibroma-like, 2 were hemangio-/glomangiopericytoma-like with giant cells, and 1 case each angiomyolipoma-like and reparative giant cell granuloma-like. Four tumors contained admixture of patterns (predominantly cellular with variable conventional component). Immunohistochemistry showed consistent expression of CD56 (11/11; 100%), ERG (19/21; 90%), SATB2 (19/21; 90%), and somatostatin receptor 2A (15/19; 79%), while other markers tested negative: DOG1 (0/17), beta-catenin (0/14), S100 protein (0/14), and STAT6 (0/7). FGFR1 fluorescence in situ hybridization was positive in 8/17 (47%) evaluable cases. These results add to the phenotypic delineation of PMT reporting for the first time consistent expression of SATB2 and excluding any phenotypic overlap with solitary fibrous tumor or sinonasal glomangiopericytoma. The unifying immunophenotype of the neoplastic cells irrespective of the histologic pattern suggests a specific disease entity with diverse morphotypes/variants rather than different neoplasms unified by TIO.
EVALuna2:6834

Photonic imaging can reveal localization of bacteria during hematogenous osteomyelitis - Ebert, C.; Tannert, A.; Hoerr, V; Geppert, Carol-Immanuel; Poellath, C.; Tuchscherr, L.; Popp, Jürgen; Loeffler, B.; Neugebauer, U. (INFECTION, 2019)
CRIS-Team WoS Importer:2019-09-06

Pigmented villonodular synovitis. A rare differential diagnosis of synovial joint swelling - Jendrissek, Andreas; Hotfiel, Thilo; Swoboda, Bernd; Söder, Stephan; Janka, Rolf Matthias (Zeitschrift für Rheumatologie, 2016)
Pigmented villonodular synovitis (PVNS) describes a rare disease caused by an abnormal proliferation of the synovial membrane in large and small joints. In order to achieve an optimal result of treatment it is necessary to carry out specific diagnostics and a targeted therapy approach.This article gives a review of the epidemiology, etiopathogenesis and diagnostic management of PVNS as well as presenting the current therapy and treatment recommendations.A systematic search of the literature was performed in the databank of the National Center for Biotechnology Information ( http://www.ncbi.nlm.nih.gov/pubmed ). The search targeted randomized clinical and experimental studies, systematic and non-systematic review articles, expert opinions and case reports related to PVNS, independent of the level of evidence attained by each study.The differential diagnosis of PVNS should be considered in cases of recurrent hemorrhagic joint effusions. The cause of the disease has not yet been exactly clarified. The final diagnosis can ultimately only be confirmed by histological investigations. In order to obtain representative histological tissue samples for the diagnosis, magnetic resonance imaging (MRI) with the appropriate heme sequences should be carried out prior to taking samples. The management of PVNS is often difficult due to the high risk of recurrence depending on the various forms. In view of the high rate of recurrence, therapy should include a complete synovectomy.For the surgical approach arthroscopic and open procedures have been described, which are currently controversially discussed with respect to the complication and recurrence rates. Adjuvant interventional therapy forms, such as radiosynoviorthesis are recommended to reduce the recurrence rate.
EVALuna2:6817

PIK3CA mutation testing as a valuable molecular surrogate for lipomatosis of the median nerve: clinicopathological and molecular analysis of six cases - Osterloh, Justus; Agaimy, Abbas; Fried, Frederick; Stöhr, Robert; Janka, Rolf Matthias; Arkudas, Andreas; Horch, Raymund E. (Virchows Archiv, 2023)
Lipomatosis of peripheral nerves (LPN, also known as fibrolipomatous or lipofibromatous hamartoma of peripheral nerves) is a very rare, benign, intraneural, tumorous lesion that predominantly involves the median nerve but may rarely affect any peripheral nerve. Recently, PIK3CA mutations have been reported in macrodactyly, a rare condition related to LPN, and in other localized lipomatous overgrowth syndromes. In this retrospective study, we report 6 cases of FPN involving the median nerve (4 of them identified among 570 patients with carpal tunnel syndrome who underwent surgical decompression at our center from 2012 to 2022 and two seen in consultation by one of the authors). All cases were diagnosed via biopsy or resection supplemented by MRI. Patients were 4 males and 2 females aged 23 to 60 years (mean 38 years). One patient with bilateral lesions had in addition extensive angiomatosis of the paravertebral region. Histological examination showed an abnormal amount of mature fatty tissue containing disordered fibrous bands, entrapping normal-looking nerve fibers with prominent perineurial and endoneurial fibrosis. Genetic analysis using snapshot assay constructed to detect hotspots mutations in PIK3CA revealed similar PIK3CA mutations (p.H1047R; c.3140A>G) in 5/6 cases (83.3%). Our study represents a further contribution to the literature on LPN and highlights the diagnostic value of PIK3CA mutation testing as surrogate tool in equivocal cases and in those lesions without associated macrodactyly, especially as the biopsy findings of this lesion are essentially nonspecific.
CRIS-Team Scopus Importer:2023-04-28
Keywords: Everolimus; Lipomatosis; mTOR; Neuropathy; Peripheral nerves; Sequencing

PITX2 as a Sensitive and Specific Marker of Midgut Neuroendocrine Tumors: Results from a Cohort of 1157 Primary Neuroendocrine Neoplasms - Grass, Albert; Kasajima, Atsuko; Foersch, Sebastian; Kriegsmann, Mark; Brobeil, Alexander; Schmitt, Maxime; Wagner, Daniel; Poppinga, Jelte; Wiese, Dominik; Maurer, Elisabeth; Kirschbaum, Andreas; Muley, Thomas; et al. (Modern Pathology, 2024)
As neuroendocrine tumors (NETs) often present as metastatic lesions, immunohistochemical assignment to a site of origin is one of the most important tasks in their pathologic assessment. Because a fraction of NETs eludes the typical expression profiles of their primary localization, additional sensitive and specific markers are required to improve diagnostic certainty. We investigated the expression of the transcription factor Pituitary Homeobox 2 (PITX2) in a large-scale cohort of 909 NET and 248 neuroendocrine carcinomas (NEC) according to the immunoreactive score (IRS) and correlated PITX2 expression groups with general tumor groups and primary localization. PITX2 expression (all expression groups) was highly sensitive (98.1%) for midgut-derived NET, but not perfectly specific, as non–midgut NET (especially pulmonary/duodenal) were quite frequently weak or moderately positive. The specificity rose to 99.5% for a midgut origin of NET if only a strong PITX2 expression was considered, which was found in only 0.5% (one pancreatic/one pulmonary) of non–midgut NET. In metastases of midgut-derived NET, PITX2 was expressed in all cases (87.5% strong, 12.5% moderate), whereas CDX2 was negative or only weakly expressed in 31.3% of the metastases. In NEC, a fraction of cases (14%) showed a weak or moderate PITX2 expression, which was not associated with a specific tumor localization. Our study independently validates PITX2 as a very sensitive and specific immunohistochemical marker of midgut-derived NET in a very large collective of neuroendocrine neoplasms. Therefore, our data argue toward implementation into diagnostic panels applied for NET as a firstline midgut marker.
CRIS-Team Scopus Importer:2024-03-15
Keywords: midgut; neuroendocrine carcinoma; neuroendocrine neoplasms; neuroendocrine tumor; Pituitary Homeobox 2

Piwil 2 expression is correlated with disease-specific and progression-free survival of chemotherapy-treated bladder cancer patients - Taubert, Helge; Wach, Sven; Jung, Rudolf; Pugia, Michael; Keck, Bastian; Bertz, Simone; Nolte, Elke; Stoehr, Robert; Lehmann, Jan; Ohlmann, Carsten-H; Stöckle, Michael; Wullich, Bernd; et al. (Molecular Medicine, 2015)
Piwi-like 2 (Piwil 2) belongs to the family of Argonaute genes/proteins. The expression of Piwil 2 is associated with stem cells. A role in tumorigenesis and/or tumor progression is proposed for different cancers but not yet for bladder cancer (BCa). We investigated the Piwil 2 expression by immunohistochemistry in a cohort of 202 BCa patients treated by cystectomy and adjuvant chemotherapy. The association between Piwil 2 expression and disease-specific (DSS) or progression-free survival (PFS) was calculated using Kaplan Meier analyses and univariate/multivariate Cox's regression hazard models.In a multivariate Cox's regression, Piwil 2 expression, either in the cytoplasm or the nucleus, was significantly associated with DSS and PFS. A weak cytoplasmic staining pattern was associated with poor DSS and tumor progression (RR=2.7; P=0.004 and RR=2.4; P=0.027). Likewise,, absent nuclear Piwil 2 immunoreactivity was associated with poor DSS and tumor progression (RR=2.3; P=0.023 and RR=2.2; P=0.022). BCa patients whose tumors exhibited a combination of weak cytoplasmic and absent nuclear immunoreactivity had a 6-fold increased risk of tumor-related death (P=0.005) compared to patients with strong expression. Considering only patients with high grade G3 tumors, a 7.8-fold risk of tumor-associated death and a 3.6-fold risk of tumor progression were detected independently of the histologic tumor subtype or the chemotherapy regimen. In summary, a combination of weak cytoplasmic and absent nuclear expression of Piwil 2 is significantly associated with an increased risk of DSS and tumor progression. This implicates that Piwil 2 could be a valuable prognostic marker for high-risk BCa patients.
EVALuna2:6705

Piwi-like 1 and-2 protein expression levels are prognostic factors for muscle invasive urothelial bladder cancer patients - Eckstein, Markus; Jung, Rudolf; Weigelt, Katrin; Sikic, Danijel; Stoehr, Robert; Geppert, Carol-Immanuel; Agaimy, Abbas; Lieb, Verena; Hartmann, Arndt; Wullich, Bernd; Wach, Sven; Taubert, Helge (Scientific Reports, 2018)
Piwi-like proteins are essential for stem-cell maintenance and self-renewal in multicellular organisms. We analyzed the expression of Piwi-like 1 and Piwi-like 2 by immunohistochemistry (IHC) in 95 muscle invasive bladder cancer (MIBC) samples using tissue microarray. Application of an immunoreactive score (IRS) revealed 37 and 45 patients who were Piwi-like 1 and -2 positive (IRS > 2). IHC results were correlated with clinico-pathological and survival data. The expression of both proteins was positively correlated with each other, lymph node metastasis and expression of CK20 and GATA 3. A negative correlation for both proteins was detected for disease-specific survival (DSS), recurrence, Ki67/MIB1 proliferation index, and CK5 expression. Detection of Piwi-like 1 protein positivity was associated with poor DSS (P = 0.019; log rank test, Kaplan-Meier analysis), and in multivariate Cox's analysis (adjusted to tumor stage and tumor grade), it was an independent prognostic factor for DSS (RR = 2.16; P = 0.011). Piwi-like 2 positivity was associated with DSS (P = 0.008) and recurrence-free survival (RFS; P = 0.040), and in multivariate Cox's analysis, Piwi-like 2 positivity was an independent prognostic factor for DSS (RR = 2.46; P = 0.004) and RFS (RR = 3.0; P = 0.003). Most interestingly, in the basal type patient subgroup (CK5+/GATA3-), Piwi-like 2 positivity was associated with poorer DSS, OS and RFS (P < 0.001, P = 0.004 and P = 0.05; log rank test). In multivariate analysis, Piwi-like 2 positivity was an independent prognostic factor for DSS (RR = 12.70; P = 0.001), OS (RR = 6.62; = 0.008) and RFS (RR=13.0; P = 0.040). In summary, Piwi-like 1 and -2 positivity are associated with clinico-pathological factors and survival. Both Piwi-like proteins are suggested as biomarkers for MIBC patients.
EVALuna2:35874

Piwi-like 1 and 4 gene transcript levels are associated with clinicopathological parameters in renal cell carcinomas - Al-Janabi, Omar; Wach, Sven; Nolte, Elke; Weigelt, Katrin; Rau, Tilman; Stoehr, Christine; Legal, Wolfgang; Schick, Stefan; Greither, Thomas; Hartmann, Arndt; Wullich, Bernd; Taubert, Helge (Biochimica et Biophysica Acta - Molecular Basis of Disease, 2014)
Piwi-like gene family members (Piwil 1-4) are considered stem cell-associated genes/proteins. These are expressed predominantly in germline cells, but are re-expressed in different tumors. Piwil 1-4 gene expression has not previously been studied and correlated with clinicopathological parameters in renal cell carcinomas (RCC). The Piwil 1-4 transcript levels were analyzed by quantitative real-time PCR in 73 clear cell RCC (ccRCC) tissues and corresponding normal tissues. The transcript levels of Piwil 1, 2 and 4 were strongly and significantly correlated with each other, in both the tumor tissues and the normal tissues (P<0.001; Spearman's rank test). Piwil 4 gene expression was significantly higher in the ccRCC tissues than that in the corresponding normal renal tissues (P<0.001; Wilcoxon signed-rank test). When the ccRCC patient cohort was divided according to the median Piwil 1-4 expression into low- and high-expression groups and according to age into younger (<=64years) and older patient groups (>64years), the younger patients displayed significantly higher levels of Piwil 1 mRNA in comparison to the older patients (P=0.010; Fisher's exact test). Interestingly, Piwil 1 expression was left-right polarized in the normal tissues but not in the tumor tissues (P=0.004; Fisher's exact test). Altogether, associations were determined between the Piwi-like family member expression levels and clinicopathological parameters of ccRCC, suggesting a potential role for these genes/proteins in ccRCC diagnostics and tumorigenesis as well as in renal tissue embryology.
EVALuna2:6563

Piwi-like 1 and piwi-like 2 expression in breast cancer - Erber, Ramona; Meyer, Julia; Taubert, Helge; Fasching, Peter; Wach, Sven; Häberle, Lothar; Gaß, Paul; Schulz-Wendtland, Rüdiger; Landgraf, Laura; Olbricht, Sabrina; Jung, Rudolf; Beckmann, Matthias; et al. (Cancers, 2020)
PIWI-like 1 and PIWI-like 2 play a role in stem cell self-renewal, and enhanced expression has been reported for several tumor entities. However, few studies have investigated PIWI-like 1 and PIWI-like 2 expressions in breast cancer subtypes regarding prognosis. Therefore, we examined protein expression in a large consecutive cohort of breast cancer patients and correlated it to breast cancer subtypes and survival outcome. PIWI-like 1 and PIWI-like 2 expressions were evaluated using immunohistochemistry in a cohort of 894 breast cancer patients, of whom 363 were eligible for further analysis. Percentage and intensity of stained tumor cells were analyzed and an immunoreactive score (IRS) was calculated. The interaction of PIWI-like 1 and PIWI-like 2 showed a prognostic effect on survival. For the combination of high PIWI-like 1 and low PIWI-like 2 expressions, adjusted hazard ratios (HRs) were significantly higher with regard to overall survival (OS) (HR 2.92; 95% confidence interval (CI) 1.24, 6.90), disease-free survival (DFS) (HR 3.27; 95% CI 1.48, 7.20), and distant disease-free survival (DDFS) (HR 7.64; 95% CI 2.35, 24.82). Both proteins were significantly associated with molecular-like and PAM50 subgroups. Combining high PIWI-like 1 and low PIWI-like 2 expressions predicted poorer prognosis and both markers were associated with aggressive molecular subtypes.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Breast cancer; HER2; Luminal A; Luminal B; Molecular breast cancer subtypes; PIWI-like 1; PIWI-like 2; PIWIL1; PIWIL2; TNBC

Piwi-like 1 protein expression is a prognostic factor for renal cell carcinoma patients - Stoehr, Christine; Steffens, Sandra; Polifka, Iris; Jung, Rudolf; Kahlmeyer, Andreas; Ivanyi, Philipp; Weber, Florian; Hartmann, Arndt; Wullich, Bernd; Wach, Sven; Taubert, Helge (Scientific Reports, 2019)
The Piwi-like genes belong to the Argonaute gene family and are conserved in plants, animals and humans. In addition to their essential role in the germ line and as stem cell-associated genes, Piwi-like proteins play a role in different cancer types but have yet to be studied in renal cell carcinoma (RCC). We investigated tissue micro arrays (TMAs) with tumor samples of two independent cohorts of RCC patients (N = 265 and N = 345); we used immunohistochemistry to assess the protein expression of Piwi-like 1. Applying an immunoreactive score (IRS), we found Piwi-like 1 positivity (IRS > 0) in 28.3% and 14.8% of the tumors in cohorts 1 and 2, respectively. Piwi-like 1 positivity was correlated with Fuhrman grade, tumor stage and the presence of distant metastasis (P < 0.005). Moreover, in univariate and multivariate analyses (adjusted to Fuhrman grade and tumor stage), Piwi-like 1 positivity was associated with a shorter cancer-specific survival in the patients in the second cohort. In addition, Piwi-like 1 expression allowed to further distinguish the RCC patients with high Fuhrman grade, high tumor stage, distant metastasis or high pre-operative levels of C-reactive protein, as Piwi-like 1 positivity was associated with a shorter cancer-specific survival in both cohorts. Our data encourage further investigations to enlighten the role of Piwi-like 1 and its function as a marker of poor prognosis in RCC patients.
CRIS-Team WoS Importer:2019-02-22

PLA2R-positive (primary) membranous nephropathy in a child with IPEX syndrome - Chuva, Teresa; Pfister, Frederick; Beringer, Ortraud; Felgentreff, Kerstin; Buettner-Herold, Maike; Amann, Kerstin Ute (Pediatric Nephrology, 2017)
Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare primary immunodeficiency syndrome characterized by the development of multiple autoimmune disorders in affected individuals. Different forms of renal injury have been reported in IPEX syndrome, and membranous nephropathy (MN) is among the most common glomerulopathies found. However, the exact pathogenesis of MN in this setting has not been elucidated, and it is not clear whether it is part of the clinical spectrum of the disease or secondary to medications, infections or other concomitant insults.We describe a child diagnosed with IPEX syndrome shortly after birth who presented with nephrotic syndrome at the age of 11 weeks. Renal biopsy revealed a MN with enhanced immunohistochemical staining for phospholipase A2 receptor (PLA2R).This is the first report of a PLA2R-positive MN in a patient with IPEX syndrome. We suggest that, in this context, MN results from an autoimmune process against podocytic antigens, namely PLA2R.
EVALuna2:25544

PLAG1-Rearranged Uterine Sarcomas: A Study of 11 Cases Showing a Wide Phenotypical Spectrum Not Limited to Myxoid Leiomyosarcoma-like Morphology - Michal, Michael; Agaimy, Abbas; Croce, Sabrina; Mechtersheimer, Gunhild; Gross, John M.; Xing, Deyin; Bell, Debra A.; Gupta, Sounak; Mosaieby, Elaheh; Martínek, Petr; Klubíčková, Natálie; Michalová, Květoslava; et al. (Modern Pathology, 2024)
PLAG1 gene fusions were recently identified in a subset of uterine myxoid leiomyosarcomas (M-LMS). However, we have encountered cases of PLAG1-rearranged uterine sarcomas lacking M-LMS-like morphology and/or any expression of smooth muscle markers. To better characterize their clinicopathologic features, we performed a multiinstitutional search that yielded 11 cases. The patients ranged in age from 34 to 72 years (mean, 57 years). All tumors arose in the uterine corpus, ranging in size from 6.5 to 32 cm (mean, 15 cm). The most common stage at presentation was pT1b (n = 6), and 3 cases had stage pT1 (unspecified), and 1 case each presented in stages pT2a and pT3b. Most were treated only with hysterectomy and adnexectomy. The follow-up (range, 7-71 months; median, 39 months) was available for 7 patients. Three cases (7-21 months of follow-up) had no evidence of disease. Three of the 4 remaining patients died of disease within 55 to 71 months, while peritoneal spread developed in the last patient, and the patient was transferred for palliative care at 39 months. Morphologically, the tumors showed a high intertumoral and intratumoral heterogeneity. M-LMS-like and epithelioid leiomyosarcoma–like morphology were present in 3 and 5 primary tumors, respectively, the remaining mostly presented as nondescript ovoid or spindle cell sarcomas. Unusual morphologic findings included prominently hyalinized stroma (n = 3), adipocytic differentiation with areas mimicking myxoid liposarcoma (n = 2), osteosarcomatous differentiation (n = 1), and undifferentiated pleomorphic sarcoma–like areas (n = 1). The mitotic activity ranged from 3 to 24 mitoses per 10 high-power fields (mean, 9); 3 of 10 cases showed necrosis. In 3 of 11 cases, no expression of smooth muscle actin, h-caldesmon, or desmin was noted, whereas 5 of 5 cases expressed PLAG1. By RNA sequencing, the following fusion partners were identified: PUM1, CHCHD7 (each n = 2), C15orf29, CD44, MYOCD, FRMD6, PTK2, and TRPS1 (each n = 1). One case only showed PLAG1 gene break by fluorescence in situ hybridization. Our study documents a much broader morphologic spectrum of PLAG1-rearranged uterine sarcomas than previously reported, encompassing but not limited to M-LMS-like morphology with occasional heterologous (particularly adipocytic) differentiation. As it is currently difficult to precisely define their line of differentiation, for the time being, we suggest using a descriptive name “PLAG1-rearranged uterine sarcoma.”
CRIS-Team Scopus Importer:2024-07-19
Keywords: adipocytic differentiation; epithelioid; lipoleiomyosarcoma; myxoid leiomyosarcoma; PLAG1 fusion; uterine stromal sarcoma

Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome - Xiao, Mengyun; Bohnert, Bernhard N.; Aypek, Hande; Kretz, Oliver; Grahammer, Florian; Aukschun, Ute; Woern, Matthias; Janessa, Andrea; Essigke, Daniel; Daniel, Christoph; Amann, Kerstin Ute; Huber, Tobias B.; et al. (Acta Physiologica, 2020)
Aim: Sodium retention is the hallmark of nephrotic syndrome (NS) and mediated by the proteolytic activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases. Plasmin is highly abundant in nephrotic urine and has been proposed to be the principal serine protease responsible for ENaC activation in NS. However, a proof of the essential role of plasmin in experimental NS is lacking. Methods: We used a genetic mouse model of NS based on an inducible podocin knockout (Bl6-Nphs2tm3.1Antc*Tg(Nphs1-rtTA*3G)8Jhm*Tg(tetO-cre)1Jaw or nphs2Δipod). These mice were crossed with plasminogen deficient mice (Bl6-Plgtm1Jld or plg−/−) to generate double knockout mice (nphs2Δipod*plg−/−). NS was induced after oral doxycycline treatment for 14 days and mice were followed for subsequent 14 days. Results: Uninduced nphs2Δipod*plg−/− mice had normal kidney function and sodium handling. After induction, proteinuria increased similarly in both nphs2Δipod*plg+/+ and nphs2Δipod*plg−/− mice. Western blot revealed the urinary excretion of plasminogen and plasmin in nphs2Δipod*plg+/+ mice which were absent in nphs2Δipod*plg−/− mice. After the onset of proteinuria, amiloride-sensitive natriuresis was increased compared to the uninduced state in both genotypes. Subsequently, urinary sodium excretion dropped in both genotypes leading to an increase in body weight and development of ascites. Treatment with the serine protease inhibitor aprotinin prevented sodium retention in both genotypes. Conclusions: This study shows that mice lacking urinary plasminogen are not protected from ENaC-mediated sodium retention in experimental NS. This points to an essential role of other urinary serine proteases in the absence of plasminogen.
CRIS-Team Scopus Importer:2020-08-07
Keywords: epithelial sodium channel; nephrotic syndrome; plasminogen; proteasuria; sodium retention

Pleomorphic adenoma of the parotid gland and the parapharyngeal space: two diametrically opposing surgical philosophies for the same histopathologic entity? - Hornung, Benita; Constantinidis, Jannis; Thimsen, Vivian; Agaimy, Abbas; Koch, Michael; Gostian, Antoniu-Oreste; Sievert, Matti; Müller, Susanna; Iro, Heinrich; Mantsopoulos, Konstantinos (Journal of Clinical Medicine, 2022)
Background: The aim of this study was to investigate the histopathologic findings in parotid and parapharyngeal pleomorphic adenomas and draw conclusions concerning the surgical strategy. Methods: Retrospective study of medical charts of patients with resected pleomorphic adenomas (PA) between 2005 and 2020 at two tertiary medical referral centers. Histologic specimens were reexamined by an experienced head and neck pathologist. Patients with insufficient/incomplete data were excluded from our study sample. Results: A total of 844 patients formed our study sample (291 men, 553 women, average age 48.9 years); 786 cases had a PA in the parotid gland (PG) (93.1%), and the remaining 58 cases had a PA in the parapharyngeal space (PS) (6.9%). Recurrences were detected in 8/844 cases (7/786 in the PG, 1/58 in the PS, 0.94% in total) with a mean follow-up time of 86.7 months (10–189 months) with no statistically significant differences between the study groups (p = 0.527). Our analysis showed that parapharyngeal pleomorphic adenomas are characterized by a lower incidence of an intact anatomical capsule (71.4% vs. 82.6%, p = 0.035) and a remarkably more frequent occurrence of satellite nodules (20.7% vs. 7.5%, p < 0.001). Conclusions: The more challenging histopathologic profile of parapharyngeal pleomorphic adenomas points towards the fact that parapharyngeal surgery should remain in the hands of experienced surgeons at high-volume centers.
CRIS-Team Scopus Importer:2022-01-07
Keywords: Capsule; Parapharyngeal space; Parotid gland; Pleomorphic adenoma; Pseudopodium; Satellite

Pleomorphic adenoma of the parotid gland presenting as extensively ossified lesion with bone infiltration: a case report - Mayer, Marcel; Thoelken, Ruben; Jering, Monika; Märkl, Bruno; Agaimy, Abbas; Zenk, Johannes (Brazilian Journal of Otorhinolaryngology, 2021)
CRIS-Team Scopus Importer:2021-11-26

Pleomorphic (giant cell) carcinoma revisited: A historical perspective and conceptual reappraisal - Agaimy, Abbas (Seminars in Diagnostic Pathology, 2021)
The term pleomorphic "giant cell" carcinoma was coined by Sommers and Meissner in 1954 for a pancreatic carcinoma variant showing a "sarcoma-like transformation" and characterized by an admixture of undifferentiated cells with striking variation in size and shape. Based on the predominant cell type, four patterns were recognized: spindle cell (sarcomatoid), pleomorphic "giant cell", osteoclastic giant cell-rich, and anaplastic round cell. These four basic patterns frequently coexisted within same tumor, albeit to a significantly variable extent. Follow-up series further characterized the entity, expanded its topographic distribution to include almost all organ systems, and illustrated its morphological and phenotypic homology among different organs. Although resemblance of the neoplastic cells to rhabdomyoblasts was already pointed out by Stout in 1958, the term "rhabdoid" (introduced in 1978 for specific kidney tumors) was not used for carcinomas until 1993. Review of the old and recent literature indicates pleomorphic "giant cell" carcinoma is not an entity but a morphological pattern in the spectrum of undifferentiated (anaplastic) and sarcomatoid carcinoma that can originate in any organ, either in a pure form or as a dedifferentiated carcinoma component. These tumors fall into two major categories: a monomorphic (variable admixture of small or larger "gemistocyte-like" rhabdoid cells and epithelioid cells) and a pleomorphic (bizarre large polygonal, spindled, or multinucleated malignant cells) subtype. The few available genetic studies suggest close association of the monomorphic type with SWI/SNF pathway defects, while bizarre-looking pleomorphic tumors usually harbor complex and heterogeneous genetic alterations. Most tumors dominated by the pleomorphic "giant cell" pattern are extremely aggressive, resulting in death, soon after diagnosis, irrespective of treatment modalities. This review gives an historical account on the evolution of the pleomorphic "giant cell" carcinoma concept with special reference to their relationship to SWI/SNF complex alterations.
CRIS-Team Scopus Importer:2021-11-26
Keywords: Anaplastic carcinoma; Osteoclastic cells; Pleomorphic “giant cell” carcinoma; Rhabdoid carcinoma; Sarcomatoid carcinoma; SWI/SNF

Pleomorphic hyalinizing angiectatic tumor revisited: all tumors manifest typical morphologic features of myxoinflammatory fibroblastic sarcoma, further suggesting 2 morphologic variants of a single entity. - Michal, Michael; Kazakov, Dmitry V.; Hadravsky, Ladislav; Agaimy, Abbas; Svajdler, Marian; Kuroda, Naoto; Michal, Michal (Annals of Diagnostic Pathology, 2016)
We describe 9 cases of pleomorphic hyalinizing angiectatic tumor (PHAT). Recently described TGFBR3 and MGEA5 gene rearrangements in these tumors have confirmed the long-hypothesized link between PHAT and another soft tissue entity, the myxoinflammatory fibroblastic sarcoma (MIFS). Myxoinflammatory fibroblastic sarcoma and PHAT share the same translocation and in addition have a very similar clinical presentation. However, to our best knowledge, no study has ever addressed the striking morphologic similarities between MIFS and PHAT. Our findings based on histological criteria suggest that most, if not all, tumors diagnosed as PHAT might, in fact, represent examples of MIFS that, in addition to a conventional MIFS morphology, manifest aberrant angiectatic hyalinized vessels.
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Pleomorphic liposarcoma of the head and neck: Presentation of two cases and literature review - Agarwal, Jay; Kadakia, Sameep; Agaimy, Abbas; Ogadzanov, Anna; Khorsandi, Azita; Chai, Raymond L. (American Journal of Otolaryngology, 2017)
Pleomorphic liposarcoma (PL) is an exceedingly rare tumor of the head and neck. This aggressive liposarcoma variant portends a poorer prognosis compared to more typical sarcomatous tumors.Multi-institutional study including two cases of PL, the first case occurring in the post-auricular region and the second in the cheek with later recurrence within the parotid bed.Both patients were treated surgically with wide local excision. One patient required reoperation to obtain negative margins. The other patient underwent a total parotidectomy with neck dissection for recurrent intraparotid nodal disease. Both patients underwent adjuvant radiotherapy. No patient had evidence of recurrent disease with minimum one year follow-up.Although the literature is sparse on this disease, wide surgical extirpation with negative margins and adjuvant radiation is recommended. Increased reports of this pathology can be helpful in providing practitioners with experienced-based information that can aid in early detection and treatment. We present the first case series of PL of the head and neck in the literature.
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PML-nuclear bodies decrease with age and their stress response is impaired in aged individuals - Wenger, Barbara; Schwegler, Manuela; Brunner, Michaela; Daniel, Christoph; Schmidt, Manfred; Fietkau, Rainer; Distel, Luitpold (BMC Geriatrics, 2014)
Promyelocytic leukemia nuclear bodies (PML-NBs) have been depicted as structures which are involved in processing cell damages and DNA double-strand break repairs. The study was designed to evaluate differences in patients' PML-NBs response to stress factors like a cancerous disease and ionizing radiation exposure dependent on age.In order to clarify the role of PML-NBs in the aging process, we examined peripheral blood monocytes of 134 cancer patients and 41 healthy individuals between 22 and 92 years of age, both before and after in vitro irradiation. Additionally, we analyzed the samples of the cancer patients after in vivo irradiation. Cells were immunostained and about 1600 cells per individual were analyzed for the presence of PML- and ?H2AX foci.The number of existing PML-NBs per nucleus declined with age, while the number of ?H2AX foci increased with age. There was a non-significant trend that in vivo irradiation increased the number of PML-NBs in cells of young study participants, while in older individuals PML-NBs tended to decrease. It can be assumed that PML-NBs decrease in number during the process of aging.The findings suggest that there is a dysfunctional PML-NBs stress response in aged cells.
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PODOCYTE AND GLOMERULAR ENDOTHELIAL CELL DERIVED MICRORNAS REGULATE PODOCYTE NEPHRONECTIN IN MEMBRANOUS GLOMERULONEPHRITIS - Müller-Deile, Janina; Sopel, Nina; Ohs, Alexandra; Kotb, Ahmed; Gröner, Marwin; Daniel, Christoph; Amann, Kerstin Ute; Schiffer, Mario (NEPHROLOGY DIALYSIS TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-12-03

POFUT1 mRNA expression as an independent prognostic parameter in muscle-invasive bladder cancer - Wahby, Sarah; Jarczyk, Jonas; Fierek, Alexander; Heinkele, Jakob; Weis, Cleo Aron; Eckstein, Markus; Martini, Thomas; Porubsky, Stefan; Hafner, Mathias; Erben, Philipp (Translational Oncology, 2021)
Muscle-invasive bladder cancer (MIBC) is characterized by high recurrence and rapid progression. Progression is linked to changes in glycan structures and altered levels of glycosyltransferases. The relationship of mRNA expression by glycosyltransferase genes B4GALT1, EXT1, MGAT5B, and POFUT1 to the probability of surviving MIBC after radical cystectomy has not yet been investigated. mRNA expression was analyzed using qRT-PCR in formalin-fixed and paraffin-embedded tumor samples (n = 105; 74% male patients and 26% female patients; median age = 72 years), correlated with histopathological variables, and evaluated by means of multivariable Cox regression analysis regarding to overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). Multivariable Cox regression analysis identified POFUT1 mRNA expression as superior prognostic marker, compared with currently used histological tumor stage methods, for CSS by MIBC patients following radical cystectomy. Thus, the patients with low POFUT1 mRNA were at a 4.9-fold greater risk for cancer-specific death according to the multivariable analysis (p = 0.0001). Low mRNA levels predicted poor survival according to the Kaplan-Meier analysis ((POFUT1:OS p = 0.0014; CSS p = 0.0007; DFS p = 0.0088); (EXT1:OS p = 0.0150; CSS p = 0.0130; DFS p = 0.0286); (B4GALT1:CSS p = 0.0134; DFS p = 0.0493)). A subgroup analysis of patients without lymph node metastasis (pN−; n = 73) indicated that low expression of POFUT1 predicted reduced OS (p = 0.0073), CSS (p = 0.0058,) and DSS (p = 0.0079). Low levels of POFUT1 mRNA are an independent prognostic indicator for OS and CSS in MIBC patients following radical cystectomy. This finding demonstrates the importance of altered glycosylation for the progress of MIBC.
CRIS-Team Scopus Importer:2020-10-30
Keywords: FFPE tumor samples; Glycosyltransferases; mRNA expression; Muscle-invasive bladder cancer; Prognostic marker; qRT-PCR

Poly(Glycerol Sebacate)/Poly(Butylene Succinate-Butylene Dilinoleate) Fibrous Scaffolds for Cardiac Tissue Engineering - Tallawi, Marwa; Zebrowski, David; Rai, Ranjana; Roether, Judith; Schubert, Dirk W.; El Fray, Miroslawa; Engel, Felix; Aifantis, Katerina E.; Boccaccini, Aldo R. (Tissue Engineering - Part C: Methods, 2015)
The present article investigates the use of a novel electrospun fibrous blend of poly(glycerol sebacate) (PGS) and poly(butylene succinate-butylene dilinoleate) (PBS-DLA) as a candidate for cardiac tissue engineering. Random electrospun fibers with various PGS/PBS-DLA compositions (70/30, 60/40, 50/50, and 0/100) were fabricated. To examine the suitability of these fiber blends for heart patches, their morphology, as well as their physical, chemical, and mechanical properties were measured before examining their biocompatibility through cell adhesion. The fabricated fibers were bead-free and exhibited a relatively narrow diameter distribution. The addition of PBS-DLA to PGS resulted in an increase of the average fiber diameter, whereas increasing the amount of PBS-DLA decreased the hydrophilicity and the water uptake of the nanofibrous scaffolds to values that approached those of neat PBS-DLA nanofibers. Moreover, the addition of PBS-DLA significantly increased the elastic modulus. Initial toxicity studies with C2C12 myoblast cells up to 72 h confirmed nontoxic behavior of the blends. Immunofluorescence analyses and scanning electron microscopy analyses confirmed that C2C12 cells showed better cell attachment and proliferation on electrospun mats with higher PBS-DLA content. However, immunofluorescence analyses of the 3-day-old rat cardiomyocytes cultured for 2 and 5 days demonstrated better attachment on the 70/30 fibers containing well-aligned sarcomeres and expressing high amounts of connexin 43 in cellular junctions indicating efficient cell-to-cell communication. It can be concluded, therefore, that fibrous PGS/PBS-DLA scaffolds exhibit promising characteristics as a biomaterial for cardiac patch applications.

Polymorphisms in the RANK/RANKL genes and their effect on bone specific prognosis in breast cancer patients - Hein, Alexander; Bayer, Christian M.; Schrauder, Michael G.; Haeberle, Lothar; Heusinger, Katharina; Strick, Reiner; Ruebner, Matthias; Lux, Michael P.; Renner, Stefan; Schulz-Wendtland, Rüdiger; Ekici, Arif Bülent; Hartmann, Arndt; et al. (BioMed Research International, 2014)
The receptor activator of NF-?B (RANK) pathway is involved in bone health as well as breast cancer (BC) pathogenesis and progression. Whereas the therapeutic implication of this pathway is established for the treatment of osteoporosis and bone metastases, the application in adjuvant BC is currently investigated. As genetic variants in this pathway have been described to influence bone health, aim of this study was the prognostic relevance of genetic variants in RANK and RANKL. Single nucleotide polymorphisms in RANK(L) (rs1054016/rs1805034/rs35211496) were genotyped and analyzed with regard to bone metastasis-free survival (BMFS), disease-free survival, and overall survival for a retrospective cohort of 1251 patients. Cox proportional hazard models were built to examine the prognostic influence in addition to commonly established prognostic factors. The SNP rs1054016 seems to influence BMFS. Patients with two minor alleles had a more favorable prognosis than patients with at least one common allele (HR 0.37 (95% CI: 0.17, 0.84)), whereas other outcome parameters remained unaffected. rs1805034 and rs35211496 had no prognostic relevance. The effect of rs1054016(RANKL) adds to the evidence that the RANK pathway plays a role in BC pathogenesis and progression with respect to BMFS, emphasizing the connection between BC and bone health.
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Polypoid Undifferentiated Rhabdoid Carcinoma in the Intestine: A Distinctive Presentation of Metastatic -Mostly Occult -Undifferentiated Non-small Cell Lung Carcinoma Illustrated in a Series of 12 Cases - Agaimy, Abbas; Daum, Ondrej; Michal, Michal; Hartmann, Arndt; Lauwers, Gregory (MODERN PATHOLOGY, 2020)
CRIS-Team WoS Importer:2020-03-24

Pooled analysis of the prognostic relevance of progesterone receptor status in five German cohort studies - Salmen, Jessica; Neugebauer, Julia; Fasching, Peter; Häberle, Lothar; Huober, Jens; Woeckel, Achim; Rauh, Claudia; Schuetz, Florian; Weissenbacher, Tobias; Kost, Bernd; Stickeler, Elmar; Klar, Maximilian; et al. (Breast Cancer Research and Treatment, 2014)
The progesterone receptor (PR) has been increasingly well described as an important mediator of the pathogenesis and progression of breast cancer. The aim of this study was to assess the role of PR status as a prognostic factor in addition to other well-established prognostic factors. Data from five independent German breast cancer centers were pooled. A total of 7,965 breast cancer patients were included for whom information about their PR status was known, as well as other patient and tumor characteristics commonly used as prognostic factors. Cox proportional hazards models were built to compare the predictive value of PR status in addition to age at diagnosis, tumor size, nodal status, grading, and estrogen receptor (ER) status. PR status significantly increased the accuracy of prognostic predictions with regard to overall survival, distant disease-free survival, and local recurrence-free survival. There were differences with regard to its prognostic value relative to subgroups such as nodal status, ER status, and grading. The prognostic value of PR status was greatest in patients with a positive nodal status, negative ER status, and low grading. The PR-status adds prognostic value in addition to ER status and should not be omitted from clinical routine testing. The significantly greater prognostic value in node-positive and high-grade tumors suggests a greater role in the progression of advanced and aggressive tumors.
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Poorly differentiated sinonasal tract malignancies: A review focusing on recently described entities - Agaimy, Abbas (Cesko-Slovenska Patologie a Soudni Lekarstvi, 2016)
Sinonasal tract malignancies are uncommon, representing no more than 5% of all head and neck neoplasms. However, in contrast to other head and neck sites, a significant proportion of sinonasal neoplasms tend to display a poorly/ undifferentiated significantly overlapping morphology and a highly aggressive clinical course, despite being of diverse histogenetic and molecular pathogenesis. The wide spectrum of poorly differentiated sinonasal epithelial neoplasms with small "basaloid" blue cell morphology includes basaloid squamous cell carcinoma (both HPV+ and HPV-unrelated), nasopharyngeal-type lymphoepithelial carcinoma (EBV+), small/large cell neuroendocrine carcinoma, esthesioneuroblastoma, poorly differentiated carcinoma of salivary type (myoepithelial carcinoma and solid adenoid cystic carcinoma), NUT midline carcinoma, the recently described SMARCB1-deficient sinonasal carcinoma, sinonasal teratocarcinosarcoma and, as a diagnosis of exclusion, sinonasal undifferentiated carcinoma (SNUC). On the other hand, a variety of sarcomas, melanoma and haematolymphoid malignancies have a predilection for the sinonasal cavities, and they occasionally display aberrant cytokeratin expression and show small round cell morphology thus closely mimicking poorly differentiated carcinomas. This review summarizes the clinicopathological features of the most recently described entities and discuss their differential diagnosis with emphasis on those aspects that represent pitfalls.
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Poorly differentiated thyroid carcinomas: conceptual controversy and clinical impact - Coca-Pelaz, Andrés; Rodrigo, Juan P.; Agaimy, Abbas; Williams, Michelle D.; Saba, Nabil F.; Nuyts, Sandra; Randolph, Gregory W.; López, Fernando; Vander Poorten, Vincent; Kowalski, Luiz P.; Civantos, Francisco J.; Zafereo, Mark E.; et al. (Virchows Archiv, 2024)
Poorly differentiated thyroid carcinomas (PDTC) are rare diseases; nevertheless, they account for the majority of deaths from non-anaplastic follicular cell-derived thyroid carcinomas. Establishing the diagnosis and treatment of PDTC is challenging given the low incidence and the lack of standardization of diagnostic criteria. These limitations hamper the ability to compare therapeutic modalities and outcomes between recent and older studies. Recently, the 5th edition of the classification of endocrine tumors has been published, which includes changes in nomenclature and the addition of the disease entity of “differentiated high-grade follicular cell-derived carcinomas”. On the other hand, the recently witnessed advances in molecular diagnostics have enriched therapeutic options and improved prognosis for patients. We herein review the various historical variations and evolution in the diagnostic criteria for PDTC. This systematic review attempts to clarify the evolution of the histological and molecular characteristics of this disease, its prognosis, as well as its treatment options.
CRIS-Team Scopus Importer:2024-03-08
Keywords: High-grade follicular derived thyroid carcinoma; Outcome; Poorly differentiated thyroid cancer; Radioiodine; Treatment

Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure - Madonna, Rosalinda; Van Laake, Lindaw.; Davidson, Sean M.; Engel, Felix; Hausenloy, Derek J.; Lecour, Sandrine; Leor, Jonathan; Perrino, Cinzia; Schulz, Rainer; Ytrehus, Kirsti; Landmesser, Ulf; Mummery, Christine L.; et al. (European Heart Journal, 2016)
Despite improvements in modern cardiovascular therapy, the morbidity and mortality of ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and worldwide. Patients with IHD may benefit from therapies that would accelerate natural processes of postnatal collateral vessel formation and/or muscle regeneration. Here, we discuss the use of cells in the context of heart repair, and the most relevant results and current limitations from clinical trials using cell-based therapies to treat IHD and HF. We identify and discuss promising potential new therapeutic strategies that include ex vivo cell-mediated gene therapy, the use of biomaterials and cell-free therapies aimed at increasing the success rates of therapy for IHD and HF. The overall aim of this Position Paper of the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to improve the therapeutic application of cell-based therapies for cardiac regeneration and repair.
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Positive factors on survival of head and neck cancer of unknown primary: what the clinician can do - Khalil, Firas; Koch, Michael; Iro, Heinrich; Sievert, Matti; Haderlein, Marlen; Semrau, Sabine; Fietkau, Rainer; Agaimy, Abbas; Scherl, Claudia (Acta Oto-Laryngologica, 2023)
Background: Management of patients with head and neck cancer of unknown primary (HNCUP) is challenging. Aims/Objectives: To provide a long-term analysis focusing on protective survival factors for clinical decision-making. Furthermore, the prognostic value of the current N classification system was evaluated. Material and methods: We retrospectively analyzed patients with HNCUP between 2003 and 2016. Univariate and multivariate analyses were used to investigate predictors of overall survival (OS). Results: A primary tumor was found in 67 of 290 patients with suspected HNCUP, leaving after exclusion 141 HNCUP cases for analysis, who received multi-step therapy (MST) (n = 108) or single therapy (n = 28). Chemotherapy (CT) (n = 101), curative MST, ≤3 positive lymph nodes (LN) (n = 33), squamous cell carcinoma (SCC) (n = 123), HPV+ (n = 21), M0 (n = 70) increased OS by 21.8%, 24.4%, 12.7%, 6.8%, 18.7%, 29.6%, respectively. 5- and 10-year OS was 78.1%/66.6%. The number of metastatic LNs predicted OS is better than N classification. Conclusion and significance: Aspects for clinical decision-making: Curative MST and SCC histology were the most significant predictors for improved OS. Categorizing LN into 1, 2-3, and >3 LNs was more significant than the traditional N classification. The addition of CT to curative MST has a stronger impact on survival than HPV and N classifications.
CRIS-Team Scopus Importer:2023-10-27
Keywords: cancer; cancer of unknown primary; CUP; head and neck; hNCUP; hNSCC; squamous cell carcinoma; survival

Positive fibroblast growth factor receptor 3 immunoreactivity is associated with low-grade non-invasive urothelial bladder cancer - Poyet, Cedric; Hermanns, Thomas; Zhong, Qing; Drescher, Eva; Eberli, Daniel; Burger, Maximilian; Hofstaedter, Ferdinand; Hartmann, Arndt; Stoehr, Robert; Zwarthoff, Ellen C.; Sulser, Tullio; Wild, Peter J. (Oncology Letters, 2015)
In addition to conventional clinicopathological parameters, molecular markers are also required in order to predict the course of disease in patients with urothelial bladder cancer (BC). Little is known about fibroblast growth factor receptor 3 (FGFR3) immunoreactivity and the clinical significance it may possess with regard to BC. The present study aimed to investigate the immunoreactivity of FGFR3 in primary urothelial bladder tumours, with regard to clinicopathological features and FGFR3 mutation status. Tissue microarrays were used to immunohistochemically analyse FGFR3 expression in 255 primary, unselected patients with BC. FGFR3 mutations were detected using SNaPshot analysis. Positive FGFR3 immunoreactivity was identified in 113/207 analysable cases (54.6%), and was significantly associated with FGFR3 mutation (P<0.001), low tumour stage (P<0.001), low histological grade (P<0.001) and a papillary growth pattern (P<0.001). Positive FGFR3 immunostaining (P=0.002) and FGFR3 mutation (P=0.002) were found to be significantly associated with increased disease-specific survival following univariate analysis, demonstrating a median follow-up period of 75 months. Using multivariate analyses, FGFR3 immunoreactivity was found not to be independent of classical pathological parameters. Immunohistochemical expression of FGFR3 is an early occurrence during the carcinogenesis of papillary non-invasive BC. The presence of FGFR3 immunoreactivity in non-invasive papillary urothelial carcinomas may be utilised as an indicator of tumours possessing low-grade features and good prognosis.
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Possible links between groundwater geochemistry and chronic kidney disease of unknown etiology (CKDu): an investigation from the Ginnoruwa region in Sri Lanka - Balasooriya, Shyamalie; Munasinghe, Harshaka; Herath, A. T.; Diyabalanage, Saranga; Ileperuma, O. A.; Manthrithilake, Herath; Daniel, Christoph; Amann, Kerstin Ute; Zwiener, Christian; Barth, Johannes; Chandrajith, Rohana (Exposure and Health, 2019)
Since at least two decades, Chronic Kidney Disease of Uncertain Etiology (CKDu) has become an increasingly discussed health issue in Sri Lanka and as well as in other tropical regions. Areas that are particularly affected with the disease are mostly located in the dry zone of Sri Lanka. The disease is more prominent among communities that consume groundwater as their main source of drinking water. Hydrogeochemical investigations were carried out in the Ginnoruwa area, a known hotspot of CKDu. It revealed possible links between drinking water chemistry and the spreading of the disease. This work compares hydrogeochemical data of drinking water sources of wells whose consumers are affected by CKDu and other nearby wells whose consumers were not affected by the disease. A total of 63 groundwater samples were collected from selected wells. About one-third of these samples (i.e., 19) were collected from wells used by CKDu patients. Significantly higher values of pH, total hardness, electrical conductivity, Ca2+, Mg2+, F−, Cl−, PO4 3−, and SO4 2− were found in wells that were used by CKDu patients. Mean contents of Na+, Ca2+, and Mg2+ in CKDu affected wells were 33.8 mg/L, 30.1 mg/L, and 14.9 mg/L, respectively, compared to 23.1 mg/L, 26.7 mg/L, and 9.65 mg/L in non-CKDu wells. Differences in major ion geochemistry in groundwaters are possibly governed by variable time periods of water storage in fractured hard rock aquifers in this region. Hydrogeochemical parameters were statistically compared by a Mann–Whitney U test and indicated significant differences in total dissolved solids (TDS) (p = 0.016), SO4 2− (p = 0.005), PO4 3− (p = 0.030), F− (p = 0.048), Na+ (p = 0.008), and Mg2+(p = 0.008) between non-CKDu and CKDu wells at p = 0.050 level. Other suspected solutes such as nephrotoxic trace elements including As, Cd, and Pb were similar in both types of wells. They were also lower than the accepted guideline limits of the World Health Organization (WHO). Results of this study suggest that fluoride in drinking water in combination with water hardness may be one of the responsible factors for kidney damage and progression of the disease. This may be particularly the case when elevated amounts of Mg2+ are present in hard groundwater.
CRIS-Team Scopus Importer:2019-12-31
Keywords: Fluoride; Girandurukotte; Kidney damage; Magnesium; Mann–Whitney U test; Water hardness

Postinflammatory Medial Meatal Fibrosis: Histopathologic Features and Outcomes of Surgical Management - Mantsopoulos, Konstantinos; Thimsen, Vivian; Müller-Hübner, Sarina Katrin Ursel; Sievert, Matti; Goncalves, Miguel; Iro, Heinrich; Agaimy, Abbas; Hornung, Joachim (Ent-Ear Nose & Throat Journal, 2021)
Objectives: The aims of our study were to investigate the clinical and audiometric outcome of the surgical treatment of postinflammatory medial meatal fibrosis (PIMMF) and to review the histopathologic changes in the specimens of the fibrotic plug, in order to try to shed light on the pathogenesis of the disease. Materials and Methods: The clinical records and the histopathologic specimens of all patients who underwent tympanomeatoplasty for PIMMF at the ENT Clinic of the University of Erlangen between 2006 and 2020 were evaluated retrospectively. Results: Thirty-four patients (41 primary surgical procedures) made up our study cohort. Of this, 28 cases were managed by means of meatoplasty and 13 cases with tympanomeatoplasty. The mean preoperative air–bone gap (ABG) was 27.8 dB (10-44 dB). Postoperative ABG was significantly improved compared to preoperative values at both short- and long-term follow-ups (P <.001 for both). No significant difference was noted between short-term and long-term ABG (P =.240). An ABG ≤20 dB was achieved in 65.8% of patients (short term) and 50% (long term). The overall rate of revision surgery for restenosis was 29.3% (12/41). Histopathologic reevaluation of the fibrotic plugs revealed a mosaic of patterns with frequent occurrence of secondary cholesteatoma-like lesions and keloid-like tissue changes. Lichenoid submucosal inflammation and increased ectopic ceruminous gland lobules were seen less frequently. Discussion: The moderate long-term outcome of surgical management and the identification of histologic changes with therapeutic implications might pave the way for alternative nonsurgical treatment options.
CRIS-Team Scopus Importer:2021-04-19
Keywords: air–bone gap; cholesteatoma; keloid; lichen; postinflammatory medial meatal fibrosis

Postlaryngectomy sinonasal squamous cell carcinoma: Case report and review of the literature - Mantsopoulos, Konstantinos; Agaimy, Abbas; Iro, Heinrich; Taha, Lava (Clinical Case Reports, 2020)
Postlaryngectomy sinonasal squamous cell carcinoma, being theoretically associated with exposure to the same risk factors or development of precancerous lesions due to altered nasal physiology, should warrant a thorough head and neck examination.
CRIS-Team WoS Importer:2020-01-21

Post-Transcriptional Regulation of Rab7a in Lysosomal Positioning and Drug Resistance in Nutrient-Limited Cancer Cells - Güleç Taşkıran, Aliye Ezgi; Hüsnügil, Hepşen H.; Soltani, Zahra E.; Oral, Göksu; Menemenli, Nazlı S.; Hampel, Chuanpit; Hübner, Kerstin; Erlenbach-Wünsch, Katharina; Sheraj, Ilir; Schneider-Stock, Regine; Akyol, Aytekin; Liv, Nalan; et al. (Traffic (Copenhagen, Denmark), 2024)
Limited nutrient availability in the tumor microenvironment can cause the rewiring of signaling and metabolic networks to confer cancer cells with survival advantages. We show here that the limitation of glucose, glutamine and serum from the culture medium resulted in the survival of a population of cancer cells with high viability and capacity to form tumors in vivo. These cells also displayed a remarkable increase in the abundance and size of lysosomes. Moreover, lysosomes were located mainly in the perinuclear region in nutrient-limited cells; this translocation was mediated by a rapid post-transcriptional increase in the key endolysosomal trafficking protein Rab7a. The acidic lysosomes in nutrient-limited cells could trap weakly basic drugs such as doxorubicin, mediating resistance of the cells to the drug, which could be partially reversed with the lysosomal inhibitor bafilomycin A1. An in vivo chorioallantoic membrane (CAM) assay indicated a remarkable decrease in microtumor volume when nutrient-limited cells were treated with 5-Fluorouracil (5-FU) and bafilomycin A1 compared to cells treated with either agent alone. Overall, our data indicate the activation of complementary pathways with nutrient limitation that can enable cancer cells to survive, proliferate and acquire drug resistance.
CRIS-Team Scopus Importer:2024-10-04
Keywords: chemoresponse; drug trapping; lysosome; nutrient limitation; Rab7a

Potential and Uncertainties of RejectClass in Acute Kidney Graft Dysfunction: An Independent Validation Study. - Von Samson-Himmelstjerna, Friedrich A.; Kakavand, Nassim; Gleske, Charlotte; Schraml, Florian; Basta, Agathe A.; Braunisch, Matthias C.; Bräsen, Jan H.; Schmitz, Jessica; Kraus, Daniel; Weinmann-Menke, Julia; Zacharias, Helena U.; Vaulet, Thibaut; et al. (Transplantation, 2024)
BACKGROUND: Kidney graft rejections are classified based on the Banff classification. The RejectClass algorithm, initially derived from a cohort comprising mostly protocol biopsies, identifies data-driven phenotypes of acute rejection and chronic pathology using Banff lesion scores. It also provides composite scores for inflammation activity and chronicity. This study independently evaluates the performance of RejectClass in a cohort consisting entirely of indication biopsies. METHODS: We retrospectively applied RejectClass to 441 patients from the German TRABIO (TRAnsplant BIOpsies) cohort who had received indication biopsies. The primary endpoint was death-censored graft failure during 2 y of follow-up. RESULTS: The application of RejectClass to our cohort demonstrated moderately comparable phenotypic features with the derivation cohort, and most clusters indicated an elevated risk of graft loss. However, the reproduction of all phenotypes and the associated risks of graft failure, as depicted in the original studies, was not fully accomplished. In contrast, adjusted Cox proportional hazards analyses substantiated that both the inflammation score and the chronicity score are independently associated with graft loss, exhibiting hazard ratios of 1.7 (95% confidence interval, 1.2-2.3; P = 0.002) and 2.2 (95% confidence interval, 1.8-2.6; P < 0.001), respectively, per 0.25-point increment (scale: 0.0-1.0). CONCLUSIONS: The composite inflammation and chronicity scores may already have direct utility in quantitatively assessing the disease stage. Further refinement and validation of RejectClass clusters are necessary to achieve more reliable and accurate phenotyping of rejection.
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Potential biomarkers correlated with poor survival rate of melanoma patients - Morais, Alice S.; Monteiro, Ana C.; Andrade, Fernando; Goedert, Lucas; Espreafico, Enilza; Schneider-Stock, Regine; Fujiota, Andre; Jasiulionis, Miriam G. (CANCER RESEARCH, 2018)
CRIS-Team WoS Importer:2019-06-18

Potential of graphene-based nanomaterials for cardiac tissue engineering - Edrisi, Fatemeh; Baheiraei, Nafiseh; Razavi, Mehdi; Roshanbinfar, Kaveh; Imani, Rana; Jalilinejad, Negin (Journal of Materials Chemistry B, 2023)
Cardiovascular diseases are the primary cause of death worldwide. Despite significant advances in pharmacological treatments and surgical interventions to restore heart function after myocardial infarction, it can progress to heart failure due to the restricted inherent potential of adult cardiomyocytes to self-regenerate. Hence, the evolution of new therapeutic methods is critical. Nowadays, novel approaches in tissue engineering have assisted in restoring biological and physical specifications of the injured myocardium and, hence, cardiac function. The incorporation of a supporting matrix that could mechanically and electronically support the heart tissue and stimulate the cells to proliferate and regenerate will be advantageous. Electroconductive nanomaterials can facilitate intracellular communication and aid synchronous contraction via electroactive substrate creation, preventing the issue of arrhythmia in the heart. Among a wide range of electroconductive materials, graphene-based nanomaterials (GBNs) are promising for cardiac tissue engineering (CTE) due to their outstanding features including high mechanical strength, angiogenesis, antibacterial and antioxidant properties, low cost, and scalable fabrication. In the present review, we discuss the effect of applying GBNs on angiogenesis, proliferation, and differentiation of implanted stem cells, their antibacterial and antioxidant properties, and their role in improving the electrical and mechanical properties of the scaffolds for CTE. Also, we summarize the recent research that has applied GBNs in CTE. Finally, we present a concise discussion on the challenges and prospects.
CRIS-Team Scopus Importer:2023-08-18

Potential Use of Gluconate in Cancer Therapy - Mycielska, Maria E.; Mohr, Markus T. J.; Schmidt, Katherina; Drexler, Konstantin; Ruemmele, Petra; Haferkamp, Sebastian; Schlitt, Hans J.; Gaumann, Andreas; Adamski, Jerzy; Geissler, Edward K. (Frontiers in Oncology, 2019)
We have recently discovered that cancer cells take up extracellular citrate through plasma membrane citrate transporter (pmCiC) and advantageously use citrate for their metabolism. Citrate uptake can be blocked with gluconate and this results in decreased tumor growth and altered metabolic characteristics of tumor tissue. Interestingly, gluconate, considered to be physiologically neutral, is incidentally used in medicine as a cation carrier, but not as a therapeutically active substance. In this review we discuss the results of our recent research with available literature and suggest that gluconate may be useful in the treatment of cancer.
CRIS-Team WoS Importer:2019-07-09

PPARβ/δ: Linking Metabolism to Regeneration - Magadum, Ajit; Engel, Felix (International Journal of Molecular Sciences, 2018)
In contrast to the general belief that regeneration is a rare event, mainly occurring in simple organisms, the ability of regeneration is widely distributed in the animal kingdom. Yet, the efficiency and extent of regeneration varies greatly. Humans can recover from blood loss as well as damage to tissues like bone and liver. Yet damage to the heart and brain cannot be reversed, resulting in scaring. Thus, there is a great interest in understanding the molecular mechanisms of naturally occurring regeneration and to apply this knowledge to repair human organs. During regeneration, injury-activated immune cells induce wound healing, extracellular matrix remodeling, migration, dedifferentiation and/or proliferation with subsequent differentiation of somatic or stem cells. An anti-inflammatory response stops the regenerative process, which ends with tissue remodeling to achieve the original functional state. Notably, many of these processes are associated with enhanced glycolysis. Therefore, peroxisome proliferator-activated receptor (PPAR) β/δ—which is known to be involved for example in lipid catabolism, glucose homeostasis, inflammation, survival, proliferation, differentiation, as well as mammalian regeneration of the skin, bone and liver—appears to be a promising target to promote mammalian regeneration. This review summarizes our current knowledge of PPARβ/δ in processes associated with wound healing and regeneration.
EVALuna2:34819
Keywords: PPAR beta/delta; regeneration; proliferation; differentiation; metabolism; Wnt signaling; PDK1; Akt; glycolysis

Praktische Aspekte von COVID-19-Obduktionen - Boor, Peter; Eichhorn, Philip; Hartmann, Arndt; Lax, Sigurd F.; Märkl, Bruno; Menter, Thomas; Skok, Kristijan; Slotta-Huspenina, Julia; von Stillfried, Saskia; Tzankov, Alexandar; Weirich, Gregor (Pathologe, 2021)
Background: The COVID-19 pandemic represents a so far unknown challenge for the medical community. Autopsies are important for studying this disease, but their safety was challenged at the beginning of the pandemic. Objectives: To determine whether COVID-19 autopsies can be performed under existing legal conditions and which safety standards are required. Materials and methods: The autopsy procedure undertaken in five institutions in Germany, Austria, and Switzerland is detailed with respect to legal and safety standards. Results: In all institutions the autopsies were performed in technically feasible rooms. The personal equipment consisted of functional clothing including a disposable gown and apron, a surgical cap, eye protection, FFP‑3 masks, and two pairs of gloves. In four institutions, complete autopsies were performed; in one institution the ultrasound-guided biopsy within the postmortal imaging and biopsy program. The latter does not allow the appreciation of gross organ pathology; however, it is able to retrieve standardized biopsies for diagnostic and research purposes. Several scientific articles in highly ranked journals resulted from these autopsies and allowed deep insights into organ damage and conclusions to better understand the pathomechanisms. Viral RNA was frequently detectable in the COVID-19 deceased, but the issue of infectivity remains unresolved and it is questionable if Ct values are greater than 30. Conclusions: With appropriate safeguards, autopsies of people who have died from COVID-19 can be performed safely and are highly relevant to medical research.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Biomedical research; Reference standards; Safety management; SARS-CoV‑2; Ultrasonography

Preclinical evidence for the use of anti-Trop-2 antibody-drug conjugate Sacituzumab govitecan in cerebral metastasized castration-resistant prostate cancer - Weiten, Richard; Niemann, Max; Below, Eduard; Friker, Lea L.; Ralser, Damian J.; Toma, Marieta; Kristiansen, Glen; Hahn, Oliver; Zechel, Sabrina; Grünwald, Viktor; Bald, Tobias; Siewert, Johannes; et al. (Cancer Medicine, 2024)
Purpose: Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC). Methods: Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) in vitro. Results: Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180–280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels in vitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG. Conclusion: The substantial expression of Trop-2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases.
CRIS-Team Scopus Importer:2024-06-28
Keywords: antibody-drug conjugates; cerebral metastasized CRPC; prostate cancer; Sacituzumab govitecan; Trop-2

Predicting Triple-Negative Breast Cancer Subtype Using Multiple Single Nucleotide Polymorphisms for Breast Cancer Risk and Several Variable Selection Methods - Häberle, Lothar; Hein, Alexander; Rübner, Matthias; Schneider, Michael; Ekici, Arif Bülent; Gaß, Paul; Hartmann, Arndt; Schulz-Wendtland, Rüdiger; Beckmann, Matthias; Lo, Wing-Yee; Schroth, Werner; Brauch, Hiltrud; et al. (Geburtshilfe und Frauenheilkunde, 2017)
Studies of triple-negative breast cancer have recently been extending the inclusion criteria and incorporating additional molecular markers into the selection criteria, opening up scope for targeted therapies. The screening phases required for studies of this type are often prolonged, since the process of determining the molecular subtype and carrying out additional biomarker assessment is time-consuming. Parameters such as germline genotypes capable of predicting the molecular subtype before it becomes available from pathology might be helpful for treatment planning and optimizing the timing and cost of screening phases. This appears to be feasible, as rapid and low-cost genotyping methods are becoming increasingly available. The aim of this study was to identify single nucleotide polymorphisms (SNPs) for breast cancer risk capable of predicting triple negativity, in addition to clinical predictors, in breast cancer patients.This cross-sectional observational study included 1271 women with invasive breast cancer who were treated at a university hospital. A total of 76 validated breast cancer risk SNPs were successfully genotyped. Univariate associations between each SNP and triple negativity were explored using logistic regression analyses. Several variable selection and regression techniques were applied to identify a set of SNPs that together improve the prediction of triple negativity in addition to the clinical predictors of age at diagnosis and body mass index (BMI). The most accurate prediction method was determined by cross-validation.The SNP rs10069690 (TERT, CLPTM1L) was the only significant SNP (corrected p = 0.02) after correction of p values for multiple testing in the univariate analyses. This SNP and three additional SNPs from the genes RAD51B, CCND1, and FGFR2 were selected for prediction of triple negativity. The addition of these SNPs to clinical predictors increased the cross-validated area under the curve (AUC) from 0.618 to 0.625. Age at diagnosis was the strongest predictor, stronger than any genetic characteristics.Prediction of triple-negative breast cancer can be improved if SNPs associated with breast cancer risk are added to a prediction rule based on age at diagnosis and BMI. This finding could be used for prescreening purposes in complex molecular therapy studies for triple-negative breast cancer.
EVALuna2:6850

Prediction of pathological complete response after neoadjuvant chemotherapy for HER2-negative breast cancer patients with routine immunohistochemical markers. - Häberle, Lothar; Erber, Ramona; Gaß, Paul; Hein, Alexander; Niklos, Melitta; Volz, Bernhard; Hack, Carolin; Schulz-Wendtland, Rüdiger; Hübner, Hanna; Goossens, Chloe; Christgen, Matthias; Dörk, Thilo; et al. (Breast Cancer Research, 2025)
BACKGROUND: Pathological complete response (pCR) is an established surrogate marker for prognosis in patients with breast cancer (BC) after neoadjuvant chemotherapy. Individualized pCR prediction based on clinical information available at biopsy, particularly immunohistochemical (IHC) markers, may help identify patients who could benefit from preoperative chemotherapy. METHODS: Data from patients with HER2-negative BC who underwent neoadjuvant chemotherapy from 2002 to 2020 (n = 1166) were used to develop multivariable prediction models to estimate the probability of pCR (pCR-prob). The most precise model identified using cross-validation was implemented in an online calculator and a nomogram. Associations among pCR-prob, prognostic IHC3 distant recurrence and disease-free survival were studied using Cox regression and Kaplan-Meier analyses. The model's utility was further evaluated in independent external validation cohorts. RESULTS: 273 patients (23.4%) achieved a pCR. The most precise model had across-validated area under the curve (AUC) of 0.84, sensitivity of 0.82, and specificity of 0.71. External validation yielded AUCs between 0.75 (95% CI, 0.70-0.81) and 0.83 (95% CI, 0.78-0.87). The higher the pCR-prob, the greater the prognostic impact of pCR status (presence/absence): hazard ratios decreased from 0.55 (95% central range, 0.07-1.77) at 0% to 0.20 (0.11-0.31) at 50% pCR-prob. Combining pCR-prob and IHC3 score further improved the precision of disease-free survival prognosis. CONCLUSIONS: A pCR prediction model for neoadjuvant therapy decision-making was established. Combining pCR and recurrence prediction allows identification of not only patients who benefit most from neoadjuvant chemotherapy, but also patients with a very unfavorable prognosis for whom alternative treatment strategies should be considered.
EVALuna2:585357

Prediction of pathological complete response and prognosis in patients with neoadjuvant treatment for triple-negative breast cancer - Gaß, Paul; Lux, Michael P.; Rauh, Claudia; Hein, Alexander; Bani, Mayada; Fießler, Cornelia; Hartmann, Arndt; Häberle, Lothar; Pretscher, Jutta; Erber, Ramona; Wachter, David; Schulz-Wendtland, Rüdiger; et al. (BMC Cancer, 2018)
BACKGROUND: It has been reported that pathological complete response is an important surrogate marker for disease-free survival and overall survival in patients with triple-negative breast cancer. This study investigates predictors of the response to neoadjuvant platinum-based or anthracycline-based treatment, and of the prognosis, in patients with triple-negative breast cancer. METHODS: A total of 121 patients with triple-negative breast cancer received neoadjuvant treatment with either platinum or anthracycline between 2008 and 2013. Pathological complete response was assessed relative to different treatments using logistic regression models with age, clinical tumor stage, grading, and Ki-67 as predictors and interaction terms, to obtain adjusted and subgroup-specific results. The impact of the pathological complete response rate on disease-free survival and overall survival was also analyzed. RESULTS: The pathological complete response rate was higher after platinum/taxane treatment compared with anthracycline/taxane (50.0% vs. 41.8%), but this was not significant in the adjusted analysis (OR 1.44; 95% CI, 0.68 to 3.09). A high histological grade (G3) was a predictor for higher pathological complete response in platinum-based therapy (OR 2.27; 95% CI, 1.00 to 5.30). The effect of neoadjuvant chemotherapy on pathological complete response was significantly different for G1-2 vs. G3 (Pinteraction = 0.013), and additional subgroup-specific differences were noted. Pathological complete response was a predictor for improved disease-free survival and overall survival in both treatment groups, with and without platinum chemotherapy. CONCLUSIONS: This retrospective study of patients with triple-negative breast cancer adds to the evidence that the treatment effect of platinum may be greatest particularly in G3 tumors. In addition, the effect of pathological complete response on the prognosis does not depend on the treatment used.
EVALuna2:34850

Predictive biomarkers for immunotherapy in the treatment of advanced urothelial carcinoma: Where we stand and where we go - Gevaert, Thomas; Cimadamore, Alessia; Eckstein, Markus; Scarpelli, Marina; Lopez-Beltran, Antonio; Cheng, Liang; Montironi, Rodolfo (Future Oncology, 2019)
CRIS-Team Scopus Importer:2019-08-02
Keywords: atezolizumab; basal-type; genitourinary tumors; immunotherapy; luminal-type; lymphocytes; microbiome; PD-L1; urothelial carcinoma

Predictive role of HER2/neu, topoisomerase-II-alpha, and tissue inhibitor of metalloproteinases (TIMP-1) for response to adjuvant taxane-based chemotherapy in patients with intermediate-risk breast cancer: results from the WSG-AGO EC-Doc trial - Erber, Ramona; Gluz, Oleg; Brünner, Nils; Kreipe, Hans Heinrich; Pelz, Enrico; Kates, Ronald; Bartels, Annette; Huober, Jens; Mohrmann, Svjetlana; Moustafa, Zehra; Liedtke, Cornelia; Möbus, Volker; et al. (Breast Cancer Research and Treatment, 2015)
Taxane-anthracycline-based adjuvant chemotherapy is standard of care in patients with node-positive breast cancer (BC) but is also associated with severe side effects and significant costs. It is yet unclear, which biomarkers would predict benefit from taxanes and/or general chemoresistance. In this study, we investigate a large cohort of patients with intermediate-risk BC treated within the WSG EC-DOC Trial for the predictive impact of topoisomerase-II-alpha, HER2/neu, and TIMP-1. Tumor tissue was available in a representative cohort of 772 cases of the WSG EC-DOC Trial collective which compared 4xEC-4xDoc versus 6xCEF/CMF. In addition to hormone receptor status and Ki-67, HER2/neu+ and topoisomerase-II-alpha status using fluorescence in situ hybridisation (FISH) and immunohistochemistry, TIMP-1 using immunohistochemistry, and aneuploidy of chromosome 17 using FISH were evaluated and correlated with outcome and taxane benefit. There was significant superiority of EC-Doc over CEF regarding 5-year DFS (90 vs. 80 %, respectively, p = 0.006) particularly in patient subgroups defined by HR+, HER2/neu+, high proliferation (i.e., Ki-67 >= 20 %), patient age >50 years old and normal chromosome 17 status, high TIMP-1 and low topoisomerase-II-alpha protein expression. Significant prognostic factors in multivariate analysis were EC-Doc therapy (HR = 0.61; 95 %CI 0.38-0.986), age <50 years old (HR = 1.682; 95 %CI 1.025-2.579), centrally assessed grade 3 (HR = 4.657; 95 %CI 1.809-11.989), and high Ki-67 (HR = 2.232; 95 %CI 1.209-4.121). Interestingly, we observed a significant interaction between treatment arm (EC-Doc vs. CEF) and high topoisomerase-II-alpha protein expression (HR = 0.427; 95 %CI 0.203-0.900) in multivariate interaction analysis. Despite of univariate predictive effect of HER2/neu status among other factors only topoisomerase-II-alpha protein expression was associated with significant benefit from EC-Doc compared to CEF by multivariate interaction analysis.
EVALuna2:6702

Predictive value of FHIT, p27, and pERK1/ERK2 in salivary gland carcinomas: a retrospective study - Fiedler, Mathias; Renner, Patty; Schubert, Juergen; Weber, Florian; Hartmann, Arndt; Iro, Heinrich; Vielsmeier, Veronika; Bohr, Christopher; Gerken, Michael; Reichert, Torsten E.; Ettl, Tobias (Clinical Oral Investigations, 2019)
Objectives: The aim of this study was to investigate the predictive value of the biomarkers FHIT, p27, and pERK1/ERK2 in salivary gland carcinomas. Material and methods: Immunohistochemical staining of FHIT, p27, and pERK1/ERK2 of 265 patients with salivary gland carcinomas was conducted, and associations with clinico-histopathological data, overall survival, and disease-specific survival were examined. Results: Expression of FHIT (quick score 98.7 vs. 206.4) and p27 (QS 187.3 vs. 244.8) was significantly lower in carcinomas compared to non-tumor control tissue. Loss of FHIT frequently occurred in ACC (55.2%), SDC (68.2%), and SCC (100%). In the totality of tumors, loss of FHIT expression was found in 46.7% (106/227) and was significantly associated with advanced T stage and UICC stage, high-grade histology, loss of p27, PI3K, and survivin. FHIT positivity went along with significantly better overall and disease-specific survival. Negativity of p27 occurred in 28.7% (70/244) of tumors, particularly in SDC (54.4%) and SCC (50%). In the totality of tumors, p27 was associated with advanced patient age, high-grade histology, PI3K, survivin as well as better overall and disease-specific survival (p < 0.05). Positive pERK1/ERK2 expression correlated with positive survivin expression but did not affect overall survival in the totality of tumors. In mucoepidermoid carcinomas, pERK1/ERK2 expression was associated with low-grade malignancy, positive nuclear survivin, and better disease-specific survival. Conclusions: Loss of FHIT and p27 characterizes aggressive tumor growth and unfavorable prognosis in salivary gland cancer. Clinical relevance: The results may help to stratify patient-specific therapies according to individual tumor characteristics.
CRIS-Team Scopus Importer:2019-10-25
Keywords: FHIT; p27; pERK1/ERK2; Salivary gland carcinoma

Predictive value of fibroblast growth factor receptor (FGFR) alterations on anti-PD-(L)1 treatment outcomes in patients (Pts) with advanced urothelial cancer (UC): Pooled analysis of real-world data - Kim, William Y.; Rose, Tracy; Roghmann, Florian; Eckstein, Markus; Jarczyk, Jonas; Zengerling, Friedemann; Sikic, Danijel; Breyer, Johannes; Bolenz, Christian; Hartmann, Arndt; Mayhew, Gregory; Shibata, Yoichiro; et al. (JOURNAL OF CLINICAL ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-05-22

Predictive value of molecular subtyping in NMIBC by RT-qPCR of ERBB2, ESR1, PGR and MKI67 from formalin fixed TUR biopsies - Breyer, Johannes; Wirtz, Ralph Markus; Otto, Wolfgang; Laible, Mark; Schlombs, Kornelia; Erben, Philipp; Kriegmair, Maximilian Christian; Stoehr, Robert; Eidt, Sebastian; Denzinger, Stefan; Burger, Maximilian; Hartmann, Arndt (Oncotarget, 2017)
Expression of ESR1, PGR, HER2 and Ki67 is important for risk stratification and therapy in breast cancer. Hormone receptor expression can also be found in MIBC, reflecting luminal and basal subtypes of breast cancer. Thus the purpose was to investigate on the mRNA expression of the aforementioned markers and their prognostic value in pT1 bladder cancer. Retrospective analysis of clinical data and Formalin-Fixed Paraffin-Embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder was performed. mRNA expression was measured by single step RT-qPCR. Relative gene expression was determined by normalization to two housekeeping genes (CALM2, B2M) using the 40-??CT method. Correlation of mRNA expression with outcome was assessed using Kaplan-Meier analysis and multivariate Cox regression analysis. From overall 302 patients, 255 samples could be analyzed with valid measurements. Subtype distribution was Luminal-A in 11.4%, Luminal-B in 38.8%, triple negative in 36.9% and ERBB2 in 12.9%, respectively. Kaplan-Meier analysis revealed molecular subtyping being statistical significant for RFS (p=0.0408) and PFS (p=0.0039). Luminal-A patients did have the best RFS and PFS. Multivariate analysis revealed molecular subtyping to be significant for PFS (L-R Chi(2) of 11.89, p=0.0078). Elevated expression of HER2 was statistically significant for PFS (p=0.0025) and discriminated among G3 tumors a high risk group (60% PFS) from a low risk risk group (90% PFS) after 5 year follow-up (p<0.001). Expression of ESR1, PGR and HER2 has predictive value in stage pT1 NMIBC and reveals potential therapeutic targets.
EVALuna2:6903

Predictive Value of Multiparametric MRI for Response to Single-Cycle Induction Chemo-Immunotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma - Hellwig, Konstantin; Ellmann, Stephan; Eckstein, Markus; Wiesmüller, Marco; Rutzner, Sandra; Semrau, Sabine; Frey, Benjamin; Gaipl, Udo; Hartmann, Arndt; Iro, Heinrich; Fietkau, Rainer; Uder, Michael; et al. (Frontiers in Oncology, 2021)
Objectives
CRIS-Team WoS Importer:2021-11-19

Predictive value of tumor budding in head and neck squamous cell carcinoma: an update - Chiesa-Estomba, Carlos M.; Thompson, Lester; Agaimy, Abbas; Zidar, Nina; Simpson, Roderick H.W.; Franchi, Alessandro; Rodrigo, Juan P.; Mäkitie, Antti A.; Almangush, Alhadi; Leivo, Ilmo; Ferlito, Alfio (Virchows Archiv, 2023)
Head and neck squamous cell carcinoma forms an anatomically and functionally complex group of malignancies. The significant local aggressiveness and frequent regional relapses motivate ongoing research to identify more reliable and sensitive prognostic and predictive biomarkers. One emerging area of cancer biology is the evaluation of tumor budding at the advancing invasive front of various types of epithelial cancers. Recent studies suggest that tumor budding is a relatively common phenomenon in cancer progression and that it may have important prognostic implications for patients due to its potential to provide valuable insights into the biology and clinical behavior of head and neck cancer. In this review, we aim to provide information about tumor budding in head and neck squamous cell carcinoma. Thus, we hope to shed light on the complex biology of these malignancies, as well as aiding diagnostic, classification, and better characterization and thereby, looking for new avenues for improving patient outcomes.
CRIS-Team Scopus Importer:2023-09-08
Keywords: Budding; Cancer; Head; Neck; Tumor

Predictors of cervical lymph node metastasis in salivary gland cancer - Ettl, Tobias; Gosau, Martin; Brockhoff, Gero; Schwarz-Furlan, Stephan; Agaimy, Abbas; Reichert, Torsten E.; Rohrmeier, Christian; Zenk, Johannes; Iro, Heinrich (Head and Neck-Journal For the Sciences and Specialties of the Head and Neck, 2014)
This study compares clinicopathological parameters with novel molecular markers for predicting cervical lymph node metastasis in salivary gland cancer.Three hundred sixteen salivary gland carcinomas were included in this study. Genomic epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and hepatocyte growth factor receptor (MET) was determined by fluorescence in situ hybridization (FISH). Chi-square tests, multivariate regression, and Kaplan-Meier survival analysis were used for statistics.Nodal staging determines long-term survival. Clinicopathological parameters associated with positive neck nodes are advanced age (p = .006), T3/T4 classification, histological high-grade malignancy, and diagnosis of salivary duct carcinoma (p < .001 each). Neck node metastases also correlate with copy number gain of EGFR (p = .004) and HER2, aberration of MET, and deletion of PTEN (p < .001 each). Multivariate analysis showed SDC (p = .002) to be the strongest predictor of lymph node metastasis, followed by MET aberration (p = .009), T3/T4 classification (p = .017), PTEN deletion (p = .042), and adenocarcinoma not otherwise specified (NOS; p = .047).The histological subtype is crucial for decisions regarding neck dissection. New molecular parameters may also indicate elective treatment of the neck.
EVALuna2:6596

Preliminary observations on whole-ovary xenotransplantation as an experimental model for fertility preservation - Nichols-Burns, Stephanie M.; Lotz, Laura; Schneider, Heike; Adamek, Edyta; Daniel, Christoph; Stief, Andrea; Grigo, Christina; Klump, Dorothee; Hoffmann, Inge; Beckmann, Matthias; Dittrich, Ralf (Reproductive Biomedicine Online, 2014)
Ovarian tissue preservation and retransplantation is a promising strategy to restore fertility in cancer survivors. Ischaemia accompanying ovarian tissue grafting, however, can lead to significant follicle loss. Transplantation of the whole ovary by vascular anastomosis has been considered as an alternative to prevent widespread ischaemic damage. In this study, the feasibility and function of transplanting whole ovary with intact vasculature were evaluated, with the goal of developing a xenograft model for studies using donated human ovaries. Whole-swine ovaries with vascular pedicles were perfused and transplanted as intact ovaries by anastomosis into irradiated ovariectomized nude rats (n = 10). The observation period was between 1 and 4 weeks. Fresh swine ovaries served as controls (n = 10). Ovarian stroma and follicle populations were assessed through histological examination in both transplanted and control ovaries. Most of the transplanted whole ovaries (n = 6) maintained stromal quality and all preantral follicle classes were represented, although follicle numbers decreased compared with fresh control. Four transplanted ovaries were fibrotic after 1-4 weeks within the nude rat. Our results demonstrate transplantation of whole-pig ovary into nude rats is possible and support development of this xenograft model system for human studies.
EVALuna2:15573

Pre-treatment metastatic biopsy: a step towards precision oncology for urothelial cancer - Klümper, Niklas; Cox, Alexander; Sjödahl, Gottfrid; Roghmann, Florian; Bolenz, Christian; Hartmann, Arndt; Grünwald, Viktor; Faltas, Bishoy M.; Hölzel, Michael; Eckstein, Markus (NAT REV UROL, 2024)
Early metastatic spread and clonal expansion of individual mutations result in a heterogeneous tumour landscape in metastatic urothelial cancer (mUC). Substantial molecular heterogeneity of common drug targets, such as membranous NECTIN4, FGFR3 mutations, PDL1 or immune phenotypes, has been documented between primary and metastatic tumours. However, translational and clinical studies frequently do not account for such heterogeneity and often investigate primary tumour samples that might not be representative in patients with mUC. We propose this as a potential factor for why many biomarkers for mUC have failed to be integrated into clinical practice. Fresh pre-treatment metastatic biopsies enable the capturing of prevailing tumour biology in real time. The characterization of metastatic tumour samples can improve response prediction to immunotherapy, the anti-NECTIN4 antibody–drug conjugate enfortumab vedotin and the FGFR inhibitor erdafitinib. Routine metastatic biopsy can thus improve the precision of identifying driver druggable alterations, thus improving treatment selection for patients with mUC.
CRIS-Team Scopus Importer:2024-11-08

Prevalence and implications of bilateral and solely contralateral lymph node metastases in oral squamous cell carcinoma - Struckmeier, Ann-Kristin; Buchbender, Mayte; Agaimy, Abbas; Kesting, Marco Rainer (Clinical Oral Investigations, 2024)
Objectives: Effective management of neck in oral squamous cell carcinoma (OSCC) is pivotal for oncological outcomes. Although consensus exists for ipsilateral neck dissection (ND), the necessity for contralateral ND remains controversial. This study aimed to assess the prevalence and implications of bilateral/solely contralateral (B/SC) lymph node metastases (LNMs) to determine the need for contralateral elective ND. Additionally, it examined the prevalence and implications of occult B/SC metastases. Materials and methods: In a retrospective cohort study, 420 OSCC patients underwent primary surgical treatment following German guidelines at a tertiary center. Preoperative contrast-enhanced computed tomography was conducted, and ND adhered to a standardized approach. Results: Solely contralateral metastases occurred in 0.95% of patients, with bilateral metastases observed in 7.13%. Occult B/SC metastases occurred in 3.81% of the cases. Correlation analysis revealed a statistically significant association between B/SC metastases and higher tumor stages, tumor localization at the upper jaw or floor of the mouth, proximity to the midline, ipsilateral LNMs, and lymphatic invasion (all p < 0.05). Patients with B/SC metastases showed poorer disease-free survival, with statistical significance reached in the bilateral LNMs group (p = 0.010). Similarly, a significant difference was noted in overall survival between patients with bilateral and solely ipsilateral metastases (p = 0.044). Conclusions: B/SC LNMs are rare in patients with OSCC, especially in those who present with clinico-radiologically negative ipsilateral necks. Higher rates of B/SC metastases occur in case of advanced tumors and those localized at the upper jaw or floor of the mouth. Ipsilateral LNMs significantly elevate the risk of contralateral LNMs, tripling the associated risk. Clinical relevance: These findings provide valuable insights for surgeons considering contralateral ND or extended adjuvant treatment for OSCC patients. However, the absence of high-level evidence from randomized controlled trials impedes the establishment of a definitive standard of care.
CRIS-Team Scopus Importer:2024-05-03
Keywords: Bilateral metastases; Contralateral metastases; Lymph node metastasis; Neck dissection; Oral squamous cell carcinoma

Prevalence of an association between coeliac disease and vitiligo - Henker, J.; Hartmann, Arndt (Hautarzt, 2019)
Coeliac disease and vitiligo are immune-mediated disorders that are often associated with other immune-mediated disorders. In a prospective study we included 174 patients with vitiligo between the ages of 3 and 79 years (mean 38.2 years) to investigate whether there is an increased risk for coeliac disease in patients with vitiligo. We determined immunoglobulin A and IgA- and IgG-antibodies against tissue transglutaminase, while also optionally measuring blood count, ferritin, and endomysial-IgA-antibodies. In 3 of 174 (1.7%) vitiligo patients, coeliac disease was diagnosed serologically and by duodenal biopsy. Assuming a coeliac disease prevalence of less than 0.0033%, the incidence is statistically significant. In two other patients with vitiligo, coeliac disease was already known and confirmed with biopsy. If these two patients are included in the calculation, 2.8% (5 von 176) of vitiligo patients have coeliac disease. This value is statistically significant even with a higher coeliac disease prevalence of 0.01. Thus, it is recommended that celiac-disease-specific antibodies also be determined during routine blood workup in vitiligo patients. In case of positive results, a gastroduodenoscopy with biopsy of the small intestine is recommended for diagnosis confirmation. If celiac disease is unlikely, a trial of gluten-free diet for a specific time should nevertheless be discussed with individuals affected by vitiligo because repigmentation appears possible.
CRIS-Team WoS Importer:2019-10-18

Prevalence of SARS-CoV-2 in Pregnant Women Assessed by RT-PCR in Franconia, Germany: First Results of the SCENARIO Study (SARS-CoV-2 prEvalence in pregNAncy and at biRth In FrancOnia) - Hein, Alexander; Kehl, Sven; Häberle, Lothar; Tiemann, Carsten; Peuker, Rebecca; Mereutanu, Denise; Stumpfe, Florian; Faschingbauer, Florian; Meyer-Schlinkmann, Kirstin; Koch, Martin C.; Kainer, Franz; Dammer, Ulf; et al. (Geburtshilfe und Frauenheilkunde, 2022)
Purpose Detection of SARS-CoV-2-infected pregnant women admitted to maternity units during a pandemic is crucial. In addition to the fact that pregnancy is a risk factor for severe COVID-19 and that medical surveillance has to be adjusted in infected women and their offspring, knowledge about infection status can provide the opportunity to protect other patients and healthcare workers against virus transmission. The aim of this prospective observational study was to determine the prevalence of SARS-CoV-2 infection among pregnant women in the hospital setting. Material and Methods All eligible pregnant women admitted to the nine participating hospitals in Franconia, Germany, from 2 June 2020 to 24 January 2021 were included. COVID-19-related symptoms, secondary diseases and pregnancy abnormalities were documented. SARS-CoV-2 RNA was detected by RT-PCR from nasopharyngeal swabs. The prevalence of acute SARS-CoV-2 infection was estimated by correcting the positive rate using the Rogan-Gladen method. The risk of infection for healthcare workers during delivery was estimated using a risk calculator. Results Of 2414 recruited pregnant women, six were newly diagnosed RT-PCR positive for SARS-CoV-2, which yielded a prevalence of SARS-CoV-2 infection of 0.26% (95% CI, 0.10-0.57%). Combining active room ventilation and wearing FFP2 masks showed an estimated reduction of risk of infection for healthcare workers in the delivery room to < 1%. Conclusions The prevalence of newly diagnosed SARS-CoV-2 infection during pregnancy in this study is low. Nevertheless, a systematic screening in maternity units during pandemic situations is important to adjust hygienic and medical management. An adequate hygienic setting can minimise the calculated infection risk for medical healthcare workers during patients' labour.
CRIS-Team Scopus Importer:2022-02-25
Keywords: COVID-19; infection; pregnancy; prevalence; SARS-CoV-2

Primary and Secondary/ Metastatic Salivary Duct Carcinoma Presenting within the Sinonasal Tract - Agaimy, Abbas; Müller, Sarina Katrin; Bishop, Justin A.; Chiosea, Simion I. (Head and Neck Pathology, 2021)
Traditionally, sinonasal adenocarcinomas have been subdivided into intestinal (ITAC) and non-intestinal (non-ITAC) categories. The latter encompasses salivary-type adenocarcinomas originating from the seromucinous glands of the sinonasal mucosa and non-salivary adenocarcinomas. The non-salivary adenocarcinoma category is further subdivided into low-and high-grade variants. Among salivary-type sinonasal adenocarcinomas, tumors recapitulating salivary duct carcinoma (SDC) are exceedingly rare, but some might have been lumped into the high-grade non-ITAC category. To date, only three primary SDCs originating in the sinonasal tract have been reported. We herein describe 7 cases of SDC including one previously reported case (4 primary sinonasal, 3 metastatic/ extension from parotid gland SDC). The primary tumors affected 3 males and one female aged 60 – 75. Different sites were involved by the primary tumors while the secondary tumors affected the sphenoidal (2) and the frontal + maxillary (1) sinuses. Three primary tumors were de novo high-grade SDC and one was confined to contours of a pre-existing pleomorphic adenoma. All 3 secondary tumors were SDC ex pleomorphic adenoma of the parotid with a long history of recurrences, ultimately involving the sinonasal tract. Androgen receptor was positive in 7/7 cases. Four of 6 cases were strongly HER2/neu + (either score 3 + or with verified amplification). This small case series adds to the delineation of primary sinonasal SDC highlighting that almost half of invasive SDC presenting within sinonasal tract indeed represents extension or metastasis from a parotid gland primary. There is a tendency towards overrepresentation of HER2/neu-positive cases in both categories (primary and metastatic), but this needs clarification in larger studies.
CRIS-Team Scopus Importer:2021-01-22
Keywords: Carcinoma ex pleomorphic adenoma; Ductal adenocarcinoma; HER2/neu; Non-intestinal adenocarcinoma; Salivary duct carcinoma; Sinonasal tract

Primary glomerulonephritides - Floege, Juergen; Amann, Kerstin Ute (Lancet, 2016)
Most glomerulonephritides, even the more common types, are rare diseases. They are nevertheless important since they frequently affect young people, often cannot be cured, and can lead to chronic kidney disease, including end-stage renal failure, with associated morbidity and cost. For example, in young adults, IgA nephropathy is the most common cause of end-stage renal disease. In this Seminar, we summarise existing knowledge of clinical signs, pathogenesis, prognosis, and treatment of glomerulonephritides, with a particular focus on data published between 2008 and 2015, and the most common European glomerulonephritis types, namely IgA nephropathy, membranous glomerulonephritis, minimal change disease, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and the rare complement-associated glomerulonephritides such as dense deposit disease and C3 glomerulonephritis.
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Primary high-grade myoepithelial carcinoma of the lung: A study of three cases illustrating frequent SMARCB1-deficiency and review of the literature - Agaimy, Abbas; Naroditsky, Inna; Ben-Izhak, Ofer (Annals of Diagnostic Pathology, 2021)
Primary myoepithelial carcinoma of the lung is exceptionally rare and, hence, remained poorly characterized. We present 3 tumors affecting 2 males and 1 female aged 60 to 84 years. Tumor size ranged from 4 to 10 cm. All presented as well circumscribed non-encapsulated peripheral solitary masses. One patient died postoperatively. The other two were lost to follow-up. Histologically, all tumors were high-grade with predominance of myxoid/chordoid (2) and rhabdoid (1) pattern. Immunohistochemistry (IHC) showed reactivity with vimentin, pankeratin, EMA and smooth muscle actin. Two tumors were SMARCB1-deficient (one with additional loss of SMARCA2 and PBRM1). RNA sequencing revealed no gene fusions. Review of reported cases (total: 16) showed that pulmonary myoepithelial carcinoma affects both sexes equally at a median age of 60 years (24–84), presents predominantly as peripheral masses (69%) in the lower lobes (66%) of smokers (70%) with a median size of 6 cm (1.5–13), and originates as high-grade de novo carcinoma. Forty percent of patients died of disease at a median of 12.5 months (0 to 62). Only 40% of patients were disease free at last follow-up (median, 9.5 months). Prominent lobulation and myxoid stroma were frequent histological features. Most tumors displayed variable combinations of epithelioid, spindle, plasmacytoid, clear, ovoid or round cells. Three of 6 tumors subjected to different RNA panels showed EWSR1 rearrangements (fused to PBX1, ZNF444 or to unknown partner). Two of 3 tumors lacking gene fusions were SMARCB1-deficient (both showed secondary EWSR1 FISH abnormalities due to 22q deletion). Primary pulmonary myoepithelial carcinoma is a rare aggressive malignancy that recapitulates its soft tissue and salivary counterpart. Exclusion of metastasis from other primaries is mandatory and can only be achieved by detailed clinical history and imaging.
CRIS-Team Scopus Importer:2021-06-18
Keywords: EWSR1; Lung; Myoepithelial carcinoma; Primary; SMARCB1; SWI/SNF

Primary lung carcinoma in children and adolescents – Clinical characteristics and outcome of 12 cases from the German registry for rare paediatric tumours (STEP) - Voggel, Sarah; Abele, Michael; Seitz, Christian; Agaimy, Abbas; Vokuhl, Christian; Dirksen, Uta; Bier, Andrea; Flaadt, Tim; Classen, Carl F.; Claviez, Alexander; Schneider, Dominik T.; Brecht, Ines B. (Lung Cancer, 2021)
Objectives: Primary lung carcinomas are very rare paediatric tumours with an incidence of < 2/1.000.000 per year. They are clinically and histologically heterogeneous, and there are no therapeutic guidelines for this age group. Therefore, they represent a challenge for treating physicians. This analysis was performed to expand knowledge on characteristics, treatment and prognosis of primary lung carcinoma in paediatric patients. Material and methods: Between 2009 and 2019, twelve children and adolescents with lung carcinoma were identified in the prospective German registry for rare paediatric tumours (STEP). Data were analysed for histopathological entities, symptoms, diagnostics, therapy, clinical course and outcome. Results: Mucoepidermoid carcinoma (MEC) was the most frequent entity (n = 7), followed by adenocarcinoma (n = 2), squamous cell carcinoma (SCC; n = 2) and adenosquamous carcinoma (n = 1). Patients presented with non-specific symptoms and often, they were initially mistreated for airway infections. Patients with MEC showed no metastases and were successfully treated with complete resection. Patients with adenocarcinoma and SCC were older than 16 years of age at diagnosis. While patients with SCC presented with distant metastases and died within one year after diagnosis, those with adenocarcinoma and adenosquamous carcinoma achieved complete remission after multimodal treatment. Conclusions: Presenting symptoms of lung carcinomas are unspecific and therefore, diagnostic evaluation and treatment are difficult. In the absence of carcinogen exposure, etiology seems to differ from adult lung carcinoma. Children diagnosed with MEC face a favourable outcome. In contrast, patients with prognostically unfavourable adenocarcinoma and SCC might benefit from molecular profiling and targeted therapies. International collaboration for the establishment of treatment protocols adjusted for distinct features of primary lung carcinoma in childhood is essential.
CRIS-Team Scopus Importer:2021-08-27
Keywords: Adenocarcinoma; German Registry for Rare Pediatric Tumors (STEP); Lung carcinoma; Mucoepidermoid carcinoma; Pediatric oncology; Squamous cell carcinoma

Primary Manifestation of Inflammatory Bowel Disease Following Subcutaneous Autovaccination - Raithel, Martin; Weidenhiller, Michael; Hahn, Markus; Hagel, Alexander; Bechthold, Caroline; Neurath, Markus; Rieker, Ralf J.; Stein, Juergen (Journal of Crohns & Colitis, 2015)
Onset of inflammatory bowel disease [IBD] is nowadays seen as an interplay or a combination of genetic susceptibility, disturbed intestinal immunity, and environmental factors including gut microbiome. However, the initiation of inflammation and progression to IBD pathogenesis in a given individual is poorly understood. In this case report we describe the clinical course of a 17-year-old female patient developing symptoms suggestive of IBD after 'autovaccine therapy', in which sterilised samples of the patient's own stool were injected subcutaneously for improvement of her general immunity. The patient presented with a severe onset of disease, which was first suspected to be ulcerative colitis on outpatient examination and was later corrected to IBD with Crohn's-like features due to high systemic inflammation, mixed lymphocytic-granulocytic infiltrates in gastric biopsies, and further characteristics suggestive of Crohn's disease. A prolonged and complicated course was seen with intermittent steroid dependency in the long term. Numerous publications postulate that [auto-]immune reactions against resident bacterial stool flora may play a role in IBD. It is possible that in this patient tolerance to endogenous bacteria was disrupted by systemic pro-inflammatory mechanisms induced by autovaccination.
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Primary mixed adeno-neuroendocrine carcinoma (MANEC) of the urinary bladder: a rare entity - Eckstein, Markus; Rasper, Bernd; Busche, Joerg; Stachetzki, Ulf; Wistuba, D. E.; Agaimy, Abbas; Hartmann, Arndt; Bertz, Simone (Aktuelle Urologie, 2017)
A 67-year-old male patient underwent transurethral resection for a bladder tumour at the lower posterior wall found incidentally on imaging for an unrelated disease. The initial histomorphological examination suggested an adenocarcinoma with partial neuroendocrine differentiation. Imaging of the thorax and the abdomen, showed no evidence of another primary tumour. Due to the unusual diagnosis, the case was sent to our department of pathology for expert consultation, which confirmed the diagnosis of a primary mixed adeno-neuroendocrine carcinoma of the bladder (MANEC). Mixed adeno-neuroendocrine carcinomas are rare tumours that mostly occur in the colorectum. To our knowledge, this case is the fifth case report of a MANEC primarily arising in the urinary bladder.
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Primary Pleomorphic Lipoma of the Parotid Gland with Prominent Myxoid Change: Report of a Rare Case Mimicking Carcinoma Ex Pleomorphic Adenoma on Fine Needle Aspiration Cytology - Goh, Giap Hean; Putti, Thomas Choudary; Ngo, Raymond; Agaimy, Abbas; Petersson, Fredrik (Head and Neck Pathology, 2019)
We present a case of a primary 2.5 cm pleomorphic lipoma of the right parotid gland with prominent myxoid change which on FNA displayed features that mimicked a carcinoma or sarcoma ex pleomorphic adenoma. The patient was a 79 year old man with no oncological history or tumor elsewhere. On immunohistochemistry the neoplastic cells strongly expressed CD34. There was no expression of retinoblastoma protein, smooth muscle actin, S100-protein or cytokeratins (AE1/3 and CAM5.2). The Ki-67 proliferation index was low (< 2%). Fluorescence in situ hybridization was negative for MDM2 gene amplification.
CRIS-Team Scopus Importer:2019-08-20
Keywords: Carcinoma ex pleomorphic adenoma; Carcinosarcoma ex pleomorphic adenoma; Fine needle aspiration cytology; Parotid gland; Pleomorphic lipoma

Primary pseudomyogenic haemangioendothelioma of the testis with a novel POTEI::FOSB gene fusion - Gersmann, Ann Kathrin; Haller, Florian; Behnert, Nina; Richter, Annika; Stöhr, Robert; Hartmann, Arndt; Ströbel, Philipp; Bremmer, Felix (Histopathology, 2022)
CRIS-Team Scopus Importer:2022-06-03
Keywords: POTEI::FOSB; pseudomyogenic haemangioendothelioma; testis

Primary renal synovial sarcoma; a clinicopathological study of 19 cases comparing diagnostic utility of SS18-SSX-specific antibody with TLE1 - Din, N. Ud; Fatima, S.; Hartmann, Arndt; Agaimy, Abbas (HISTOPATHOLOGY, 2021)
CRIS-Team WoS Importer:2021-10-08

Primary renal well-differentiated neuroendocrine tumour (carcinoid): next-generation sequencing study of 11 cases - Pivovarcikova, Kristyna; Agaimy, Abbas; Martinek, Petr; Alaghehbandan, Reza; Perez-Montiel, Delia; Alvarado-Cabrero, Isabel; Rogala, Joanna; Kuroda, Naoto; Rychly, Boris; Gasparov, Slavko; Michalova, Kvetoslava; Michal, Michal; et al. (Histopathology, 2019)
Aims: Primary renal well-differentiated neuroendocrine tumour (NET) (hereafter referred to as renal NET) is rare, with 100 cases having been reported in the literature. There are also limited data on the molecular–genetic background of primary renal NETs. Methods and results: We analysed 11 renal NETs by using next-generation sequencing (NGS) to identify characteristic genetic aberrations. All tumours were positive for synaptophysin, and also expressed insulinoma-associated protein 1 (10/11), chromogranin-A (8/11), and CD56 (3/11). Cytoplasmic positivity of CD99 was present in eight of 11 cases, and strong nuclear expression of α-thalassaemia/mental retardation syndrome X-linked (ATRX) was retained in all 11 cases. Molecular–genetic analysis of aberration of VHL gave negative results in all cases. Loss of heterozygosity on chromosome 3p21 was found in three of nine analysable cases. NGS was successful in nine cases, showing a total of 56 variants being left after the updated filtering process, representing an average of five variants per sample. All analysable cases were negative for ATRX and DAXX (death-domain associated protein X) mutations. The most frequently mutated genes were CDH1 and TET2, with three mutations in two cases. Mutations in AKT3, ROS1, PIK3R2, BCR and MYC were found in two cases. The remaining 41 genes were found to be mutated only in individual cases. In four cases, the mutations affected a subset of genes related to angiogenesis. Conclusions: Overall, the mutation profile of primary renal NETs is variable, and none of the studied genes or affected pathways seems to be specific for renal NET.
CRIS-Team Scopus Importer:2019-07-02
Keywords: carcinoid; kidney; next-generation sequencing; primary; well-differentiated neuroendocrine tumour

Primary results of the phase II CheckRad-CD8 trial: First-line treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) with double checkpoint blockade and radiotherapy dependent on intratumoral CD8+T-cell infiltration. - Hecht, Markus; Eckstein, Markus; Rutzner, Sandra; von der Grün, Jens; Illmer, Thomas; Klautke, Gunther; Laban, Simon; Hautmann, Matthias G.; Brunner, Thomas; Tamaskovics, Bálint; Hinke, Axel; Frey, Benjamin; et al. (ASCO 2021 Annual Meeting, 2021)
CRIS-Team WoS Importer:2021-11-26

Primary Results of the phase II CheckRad-CD8 Trial: First-Line Treatment of locally advanced Head and Neck Tumors with double Checkpoint Blockade and Radiotherapy dependent on intratumoral CD8+T-Cell Infiltration - Hecht, Markus; Eckstein, Markus; Rutzner, Sandra; Von Der Gruen, J.; Illmer, T.; Klautke, G.; Laban, S.; Hautmann, M.; Brunner, T.; Tamaskovics, B.; Hinke, A.; Frey, Benjamin; et al. (STRAHLENTHERAPIE UND ONKOLOGIE, 2021)
CRIS-Team WoS Importer:2021-07-16

Primary signet ring stromal tumor of the testis: a study of 13 cases indicating their phenotypic and genotypic analogy to pancreatic solid pseudopapillary neoplasm - Michalova, Kvetoslava; Michal, Michael; Kazakov, Dmitry V.; Sedivcova, Monika; Hes, Ondrej; Hadravsky, Ladislav; Agaimy, Abbas; Tretiakova, Maria; Bacchi, Carlos; Hartmann, Arndt; Kuroda, Naoto; Bulimbasic, Stela; et al. (Human Pathology, 2017)
Primary signet ring stromal tumor of the testis (PSRSTT) is an extremely rare tumor described only twice in the literature. Pancreatic-analogue solid pseudopapillary neoplasm (SPN) of the testis is a recently reported entity with morphological overlap with PSRSTT. We reviewed our files to find all cases of PSRSTT to better characterize this entity. We studied 13 cases of PSRSTTs using histological, immunohistochemical (IHC), and molecular genetic methods and compared the results with pancreatic SPN. Grossly, the size of PSRSTTs ranged from 0.5 to 2 cm (mean 1.1). Microscopically, PSRSTTs predominantly showed a proliferation of low-grade epithelioid cells containing characteristic cytoplasmic vacuole dislodging the nucleus (signet ring cells) separated by fibrous septa into trabeculae and nests. The immunoprofile was characterized by immunoreactivity for ?-catenin, cyclin D1 (nuclear positivity for both antibodies), CD10, vimentin, galectin-3, claudin 7, ?-1-antitrypsin, CD56, and neuron-specific enolase and negativity for chromogranin, inhibin, calretinin, SF-1, NANOG, OCT3/4, and SALL4. In some cases, the IHC panel was restricted because of a limited amount of tissue. Molecular genetic analysis revealed mutations within exon 3 of the CTNNB1 encoding ?-catenin in all analyzable cases. Based on histological similarities between pancreatic SPN and PSRSTT and their identical IHC and molecular genetic features, we assume that both neoplasms share the same pathogenesis, and thus, PSRSTT can be considered as a testicular analogue of pancreatic SPN.
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Proceedings of the North American Society of Head and Neck Pathology, Los Angeles, CA, March 20, 2022: SWI/SNF-deficient Sinonasal Neoplasms: An Overview - Agaimy, Abbas (Head and Neck Pathology, 2022)
The pathology of poorly differentiated sinonasal malignancies has been the subject of extensive studies during the last decade, which resulted into significant developments in the definitions and histo-/pathogenetic classification of several entities included in the historical spectrum of “sinonasal undifferentiated carcinomas (SNUC)” and poorly differentiated unclassified carcinomas. In particular, genetic defects leading to inactivation of different protein subunits in the SWI/SNF chromatin remodeling complex have continuously emerged as the major (frequently the only) genetic player driving different types of sinonasal carcinomas. The latter display distinctive demographic, phenotypic and genotypic characteristics. To date, four different SWI/SNF-driven sinonasal tumor types have been recognized: SMARCB1(INI1)-deficient carcinoma (showing frequently non-descript basaloid, and less frequently eosinophilic, oncocytoid or rhabdoid undifferentiated morphology), SMARCB1-deficient adenocarcinomas (showing variable gland formation or yolk sac-like morphology), SMARCA4-deficient carcinoma (lacking any differentiation markers and variably overlapping with large cell neuroendocrine carcinoma and SNUC), and lastly, SMARCA4-deficient sinonasal teratocarcinosarcoma. These different tumor types display highly variable immunophenotypes with SMARCB1-deficient carcinomas showing variable squamous immunophenotype, while their SMARCA4-related counterparts lack such features altogether. While sharing same genetic defect, convincing evidence is still lacking that SMARCA4-deficient carcinoma and SMARCA4-deficient teratocracinosarcoma might belong to the spectrum of same entity. Available molecular studies revealed no additional drivers in these entities, confirming the central role of SWI/SNF deficiency as the sole driver genetic event in these aggressive malignancies. Notably, all studied cases lacked oncogenic IDH2 mutations characteristic of genuine SNUC. Identification and precise classification of these entities and separating them from SNUC, NUT carcinoma and other poorly differentiated neoplasms of epithelial melanocytic, hematolymphoid or mesenchymal origin is mandatory for appropriate prognostication and tailored therapies. Moreover, drugs targeting the SWI/SNF vulnerabilities are emerging in clinical trials.
CRIS-Team Scopus Importer:2022-03-25
Keywords: Epithelioid sarcoma; Head and neck; Rhabdoid tumor; SMARCB1; SWI/SNF complex; Teratocarcinosarcoma

Proficiency testing of PIK3CA mutations in HR+/HER2-breast cancer on liquid biopsy and tissue - Vollbrecht, Claudia; Hoffmann, Inga; Lehmann, Annika; Merkelbach-Bruse, Sabine; Fassunke, Jana; Wagener-Ryczek, Svenja; Ball, Markus; Dimitrova, Lora; Hartmann, Arndt; Stöhr, Robert; Erber, Ramona; Weichert, Wilko; et al. (Virchows Archiv, 2022)
Precision oncology based on specific molecular alterations requires precise and reliable detection of therapeutic targets in order to initiate the optimal treatment. In many European countries—including Germany—assays employed for this purpose are highly diverse and not prescribed by authorities, making inter-laboratory comparison difficult. To ensure reproducible molecular diagnostic results across many laboratories and different assays, ring trials are essential and a well-established tool. Here, we describe the design and results of the ring trial for the detection of therapeutically relevant PIK3CA hotspot mutations in HR+/HER2-breast cancer tissue and liquid biopsy (LB). For PIK3CA mutation detection in tissue samples, 43 of the 54 participants (80%) provided results compliant with the reference values. Participants using NGS-based assays showed higher success rate (82%) than those employing Sanger sequencing (57%). LB testing was performed with two reference materials differing in the length of the mutated DNA fragments. Most participants used NGS-based or commercial real-time PCR assays (70%). The 167 bp fragments led to a successful PIK3CA mutation detection by only 31% of participants whereas longer fragments of 490 bp were detectable even by non-optimal assays (83%). In conclusion, the first ring trial for PIK3CA mutation detection in Germany showed that PIK3CA mutation analysis is broadly established for tissue samples and that NGS-based tests seem to be more suitable than Sanger sequencing. PIK3CA mutation detection in LB should be carried out with assays specifically designed for this purpose in order to avoid false-negative results.
CRIS-Team Scopus Importer:2022-11-25
Keywords: Alpelisib; Breast cancer; Liquid biopsy; PIK3CA; Proficiency testing

Proficiency Test PD-L1 Expression in Squamous Cell Carcinomas of the Head and Neck (HNSCC) - Joehrens, Korinna; Baretton, Gustavo; Schildhaus, Hans-Ulrich; Agaimy, Abbas; Scheel, Andreas; Schwammborn, Kristina; Laenger, Florian; Tiemann, Markus; Dietel, Manfred (Pathologe, 2021)
CRIS-Team WoS Importer:2021-05-21

Profiling intratumoral heterogeneity of bladder cancer subtypes at the single-cell level using machine-learning assisted histopathology. - van Rhijn, Bas W. G.; Mertens, Laura; Mayr, Roman; Bostrom, Peter; Marques, Mirari; Van Leenders, Geert; Gotz, Stefanie; Van Der Heijden, Michiel; Jewett, Michael; Real, Francisco; Stöhr, Robert; Zlotta, Alexandre; et al. (CLINICAL CANCER RESEARCH, 2020)
CRIS-Team WoS Importer:2020-08-28

Prognosis of patients with colonic carcinoma before, during and after implementation of complete mesocolic excision - Merkel, Susanne; Weber, K.; Matzel, Klaus; Agaimy, Abbas; Göhl, Jonas; Hohenberger, Werner (British Journal of Surgery, 2016)
The implementation of complete mesocolic excision (CME) for colonic cancer was accompanied by other important changes, including more patients with early diagnosis by screening and the introduction of adjuvant chemotherapy in patients with stage III disease. The contribution of CME remains unclear.In this observational study, data from patients with stage I-III colonic carcinoma were analysed by comparing five time intervals: 1978-1984 (pre-CME), 1985-1994 (CME development), 1995-2002 (CME implementation), 2003-2009 (CME) and 2010-2014 (CME), with a special focus on indicators of process and outcome quality.During the observed periods, the median age of patients increased (from 65 to 67 years), there were more right-sided carcinomas (from 17·0 to 32·4 per cent), more stage I disease (from 14·0 to 27·7 per cent) and fewer patients with regional lymph node metastases (from 42·7 to 32·0 per cent). The proportion of patients with pN0 disease and at least 12 examined regional lymph nodes increased (from 84·8 to 100 per cent) as did the R0 resection rate (from 97·0 to 100 per cent). Overall morbidity increased, whereas the in-hospital mortality rate was stable (range 1·8-3·7 per cent). Use of adjuvant chemotherapy in stage III colonic carcinoma increased from 0 to 79 per cent. The improvement in outcome quality was more evident in stage III than in stage I-II tumours. In stage III, the 5-year locoregional recurrence rate decreased from 14·8 to 4·1 per cent (P = 0·046) and the 5-year cancer-related survival rate increased from 61·7 to 80·9 per cent (P = 0·010).With CME, the quality indicators of process and outcome quality improved, especially in stage III colonic carcinoma. Adjuvant chemotherapy in stage III and multidisciplinary approaches in patients with metachronous distant metastases contributed to further outcome improvement.
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Prognosis prediction with the IHC3 score in patients with node-negative, hormone receptor-positive, HER2-negative early breast cancer - Seitz, Katharina; Goossens, Chloe; Hübner, Hannah; Gaß, Paul; Uhrig, Sabrina; Heindl, Felix; Emons, Julius; Rübner, Matthias; Anetsberger, Daniel; Hartmann, Arndt; Beckmann, Matthias; Erber, Ramona; et al. (ESMO Open, 2024)
Background: Prognostication has been used to identify patient populations that could potentially benefit from treatment de-escalation. In patients with hormone receptor-positive (HRpos), human epidermal growth factor receptor 2-negative (HER2neg) early breast cancer (eBC), treatment de-escalation classically involved omitting chemotherapy. With recently developed specialized therapies that require hands-on side-effect management, the therapeutic landscape is changing and therapy decisions are no longer based only on prognosis, but also consider potential side-effects. Therefore, identification of patient groups based on prognostication has gained importance. Materials and methods: In this retrospective analysis, a population of 2359 node-negative HRpos/HER2neg eBC patients was selected from all patients treated at the University Breast Center of Franconia, Germany between 2002 and 2021. The prognostic value of the IHC3 score (incorporating immunohistochemical measurements of the estrogen and progesterone receptor status and Ki-67) with clinical parameters (lymph node status, tumor stage, grading) regarding invasive disease-free survival (iDFS) and overall survival (OS) was assessed. Results: IHC3 positively correlated with Ki-67 expression and inversely correlated with hormone receptor expression. IHC3 categorized into quartiles identified patients with a more unfavorable prognosis: 5-year and 10-year iDFS rates for patients in the highest versus the lowest quartile were 84% versus 95% and 70% versus 88%, respectively. A sensitivity analysis of distant disease-free survival showed similar results to those of iDFS. Five-year and 10-year OS rates for patients in the highest versus the lowest quartile were, respectively, 92% versus 97% and 81% versus 92%. Conclusions: IHC3 is able to define prognostic groups in patients with node-negative, HRpos/HER2neg eBC. Node-negative patients with a high IHC3 score had the worst prognosis, which was comparable to that of node-positive patients described in recent trials. This simple and cost-effective tool could thus potentially aid in identifying patient groups for innovative therapeutic approaches.
CRIS-Team Scopus Importer:2024-11-01
Keywords: early breast cancer; hormone receptor-positive; IHC3; molecular marker; prognosis

Prognostic and predictive molecular markers for urologic cancers - Hartmann, Arndt; Schlomm, T.; Bertz, Simone; Heinzelmann, J.; Hoelters, S.; Simon, R.; Stoehr, R.; Junker, K. (Urologe, 2014)
Molecular prognostic factors and genetic alterations as predictive markers for cancer-specific targeted therapies are used today in the clinic for many malignancies. In recent years, many molecular markers for urogenital cancers have also been identified. However, these markers are not clinically used yet. In prostate cancer, novel next-generation sequencing methods revealed a detailed picture of the molecular changes. There is growing evidence that a combination of classical histopathological and validated molecular markers could lead to a more precise estimation of prognosis, thus, resulting in an increasing number of patients with active surveillance as a possible treatment option. In patients with urothelial carcinoma, histopathological factors but also the proliferation of the tumor, mutations in oncogenes leading to an increasing proliferation rate and changes in genes responsible for invasion and metastasis are important. In addition, gene expression profiles which could distinguish aggressive tumors with high risk of metastasis from nonmetastasizing tumors have been recently identified. In the future, this could potentially allow better selection of patients needing systemic perioperative treatment. In renal cell carcinoma, many molecular markers that are associated with metastasis and survival have been identified. Some of these markers were also validated as independent prognostic markers. Selection of patients with primarily organ-confined tumors and increased risk of metastasis for adjuvant systemic therapy could be clinically relevant in the future.
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