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

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

Molecular profiling of single circulating tumor cells with diagnostic intention - Polzer, Bernhard; Medoro, Gianni; Pasch, Sophie; Fontana, Francesca; Zorzino, Laura; Pestka, Aurelia; Andergassen, Ulrich; Meier-Stiegen, Franziska; Czyz, Zbigniew T.; Alberter, Barbara; Treitschke, Steffi; Schamberger, Thomas; et al. (Embo Molecular Medicine, 2014)
Several hundred clinical trials currently explore the role of circulating tumor cell (CTC) analysis for therapy decisions, but assays are lacking for comprehensive molecular characterization of CTCs with diagnostic precision. We therefore combined a workflow for enrichment and isolation of pure CTCs with a non-random whole genome amplification method for single cells and applied it to 510 single CTCs and 189 leukocytes of 66 CTC-positive breast cancer patients. We defined a genome integrity index (GII) to identify single cells suited for molecular characterization by different molecular assays, such as diagnostic profiling of point mutations, gene amplifications and whole genomes of single cells. The reliability of > 90% for successful molecular analysis of high-quality clinical samples selected by the GII enabled assessing the molecular heterogeneity of single CTCs of metastatic breast cancer patients. We readily identified genomic disparity of potentially high relevance between primary tumors and CTCs. Microheterogeneity analysis among individual CTCs uncovered pre-existing cells resistant to ERBB2-targeted therapies suggesting ongoing microevolution at late-stage disease whose exploration may provide essential information for personalized treatment decisions and shed light into mechanisms of acquired drug resistance.
EVALuna2:6669

Molecular signature for lymphatic metastasis in colorectal carcinomas. - Croner, Roland S.; Förtsch, Thomas; Brueckl, Wolfgang M.; Roedel, Franz; Roedel, Claus; Papadopoulos, Thomas; Brabletz, Thomas; Kirchner, Thomas; Sachs, Martin; Behrens, Jürgen; Klein-Hitpass, Ludger; Stürzl, Michael; et al. (Annals of Surgery, 2008)
Fifty differently expressed genes between stage UICC I, II versus III CRC were identified respecting the selection criteria by allowing for multiple testing. The data validation by the independent clinical study confirmed our results. In comparison to MC, the genes were over- or underexpressed. They belong to various functional groups such as cellular adhesion, transporters, signaling, metabolism, protein synthesis, gene control, and immune system. Forty tumor samples of stage UICC I, II CRC, 40 samples of stage III CRC, and 25 biopsies of healthy mucosa (MC) were shock frozen in liquid nitrogen and underwent cryotomy after manual dissection for tumor tissue or MC enrichment. Isolated RNA was hybridized to GeneChips (HG-U133A, Affymetrix). Preprocessing of the microarray results was done by the robust multichip average method, and differentially expressed genes were selected by the maximum Wilcoxon statistic over 22,215 probe sets. The results were validated at an independent clinical study. Our large patient cohort and the data validation on an independent study identified 50 differentially expressed genes between CRC of different histopathologic stages. These findings indicate that molecular staging of CRC may be possible, which could help to guide individual CRC treatment before surgery. TNM-staging of colorectal carcinomas (CRC) relies on the histopathologic workup of the surgically removed specimen. If valid preoperative staging methods existed, patients could be selected for adequate individual therapy before surgery. Microarray techniques provide a promising tool to identify stage-specific molecular signatures on primary tumor biopsies. RESULTS MATERIAL AND METHODS CONCLUSION PURPOSE

Molecular staging of lymph node-negative colon carcinomas by one-step nucleic acid amplification (OSNA) results in upstaging of a quarter of patients in a prospective, European, multicentre study - Croner, R. S.; Geppert, Carol-Immanuel; Bader, F. G.; Nitsche, U.; Spaeth, C.; Rosenberg, R.; Zettl, A.; Matias-Guiu, Xavier; Tarragona, J.; Gueller, U.; Stürzl, Michael; Zuber, M. (British Journal of Cancer, 2014)
Background:Current histopathological staging procedures in colon carcinomas depend on midline division of the lymph nodes with one section of haematoxylin & eosin (H&E) staining only. By this method, tumour deposits outside this transection line may be missed and could lead to understaging of a high-risk group of stage UICC II cases, which recurs in 20% of cases. A new diagnostic semiautomated system, one-step nucleic acid amplification (OSNA), detects cytokeratin (CK) 19 mRNA in lymph node metastases and enables the investigation of the whole lymph node. The objective of this study was to assess whether histopathological pN0 patients can be upstaged to stage UICC III by OSNA.Methods:Lymph nodes from patients who were classified as lymph node negative after standard histopathology (single (H&E) slice) were subjected to OSNA. A result revealing a CK19 mRNA copy number >250, which makes sure to detect mainly macrometastases and not isolated tumour cells (ITC) or micrometastases only, was regarded as positive for lymph node metastases based on previous threshold investigations.Results:In total, 1594 pN0 lymph nodes from 103 colon carcinomas (median number of lymph nodes per patient: 14, range: 1-46) were analysed with OSNA. Out of 103 pN0 patients, 26 had OSNA-positive lymph nodes, resulting in an upstaging rate of 25.2%. Among these were 6/37 (16.2%) stage UICC I and 20/66 (30.3%) stage UICC II patients. Overall, 38 lymph nodes were OSNA positive: 19 patients had one, 3 had two, 3 had three, and 1 patient had four OSNA-positive lymph nodes.Conclusions:OSNA resulted in an upstaging of over 25% of initially histopathologically lymph node-negative patients. OSNA is a standardised, observer-independent technique, allowing the analysis of the whole lymph node. Therefore, sampling bias due to missing investigation of certain lymph node tissue can be avoided, which may lead to a more accurate staging.
EVALuna2:6584

Molecular Subtyping of Invasive Breast Cancer Using a PAM50-Based Multigene Expression Test-Comparison with Molecular-Like Subtyping by Tumor Grade/Immunohistochemistry and Influence on Oncologist's Decision on Systemic Therapy in a Real-World Setting - Erber, Ramona; Angeloni, Miriam; Stöhr, Robert; Lux, Michael P.; Ulbrich-Gebauer, Daniel; Pelz, Enrico; Bankfalvi, Agnes; Schmid, Kurt W.; Walter, Robert F. H.; Vetter, Martina; Thomssen, Christoph; Mayr, Doris; et al. (International Journal of Molecular Sciences, 2022)
In intermediate risk hormone receptor (HR) positive, HER2 negative breast cancer (BC), the decision regarding adjuvant chemotherapy might be facilitated by multigene expression tests. In all, 142 intermediate risk BCs were investigated using the PAM50-based multigene expression test Prosigna (R) in a prospective multicentric study. In 119/142 cases, Prosigna (R) molecular subtyping was compared with local and two central (C1 and C6) molecular-like subtypes relying on both immunohistochemistry (IHC; HRs, HER2, Ki-67) and IHC + tumor grade (IHC+G) subtyping. According to local IHC, 35.4% were Luminal A-like and 64.6% Luminal B-like subtypes (local IHC+G subtype: 31.9% Luminal A-like; 68.1% Luminal B-like). In contrast to local and C1 subtyping, C6 classified >2/3 of cases as Luminal A-like. Pairwise agreement between Prosigna (R) subtyping and molecular-like subtypes was fair to moderate depending on molecular-like subtyping method and center. The best agreement was observed between Prosigna (R) (53.8% Luminal A; 44.5% Luminal B) and C1 surrogate subtyping (Cohen's kappa = 0.455). Adjuvant chemotherapy was suggested to 44.2% and 88.6% of Prosigna (R) Luminal A and Luminal B cases, respectively. Out of all Luminal A-like cases (locally IHC/IHC+G subtyping), adjuvant chemotherapy was recommended if Prosigna (R) testing classified as Prosigna (R) Luminal A at high / intermediate risk or upgraded to Prosigna (R) Luminal B.
CRIS-Team WoS Importer:2022-08-26

Molekular definierte Nierenzellkarzinome 2025 - Stöhr, Christine; Fiegl, August; Bercebal, C.; Agaimy, Abbas; Hartmann, Arndt (Die Pathologie, 2025)
BACKGROUND: The latest edition of the WHO classification of urinary and male genital tumours was published in 2022. The revision was based on the newest scientific literature. This article summarizes the updated recommendations regarding the classification of molecularly defined tumours. RESULTS AND CONCLUSIONS: The current edition of the WHO classification of tumours introduced the new category of molecularly defined tumours. This category includes TFE3-rearranged RCC, TFEB-altered RCC, ELOC-mutated RCC, FH-deficient RCC, SDH-deficient RCC, ALK-rearranged RCC and SMARCB1-deficient RCC. The change reflects the importance of the respective alterations with regard to tumour biology and future treatment options. Simultaneously, the diagnosis of these tumours, which sometimes can show equivocal morphologies, is facilitated.
EVALuna2:585356

Molekulare Testung bei mesenchymalen Neoplasien: Was, wann und wie testen? Eine Übersicht mit besonderem Fokus auf den Stellenwert der Next-Generation-Immunhistochemie als Alternative für molekulare Testung - Agaimy, Abbas (Die Pathologie, 2024)
With the widespread use of diverse modern molecular testing tools, the last two decades have seen significant advances in the classification of soft tissue neoplasms. Specifically, numerous molecularly defined new entities have been introduced and many established older entities have received more insightful molecular studies that have developed their classification further. The discrepant therapeutic and prognostic implications of this evolving complexity of the nosology of neoplastic diseases make the precise subtyping of soft tissue neoplasms unavoidable. However, these rapid developments of the modern diagnostic molecular pathology did not only offer efficient solutions to many complex classification issues, but they were accompanied by similarly complex and diverse emerging problems. Most importantly, these advances have not only challenged the historical dogma of some phenotypes that were once considered specific, but they also have questioned the value of diagnostic immunohistochemistry compared to emerging modern diagnostic molecular tools. Moreover, the central question of when to test, what to test, and how to test became more confusing. This review addresses the major molecular categories in soft tissue neoplasms, their characteristics, and the criteria to be used for selecting the most appropriate molecular diagnostic tool to be used in individual cases with a special focus on the value of next generation immunohistochemistry as a substitute for molecular testing.
CRIS-Team Scopus Importer:2024-12-06
Keywords: Classification; High-precision medicine; Sarcoma; Targeted RNA sequencing; NGS; Targeted therapy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Multilocular cystic leiomyoma of the anterolateral abdominal wall: A case report and literature review - Yorita, Kenji; Tanaka, Yu; Hirano, Koki; Kuwahara, Michio; Nakatani, Kimiko; Fukunaga, Masaharu; Agaimy, Abbas (Medicine, 2017)
RATIONALE: Leiomyomas arising from the anterolateral abdominal wall are uncommon, and their pathogenesis remains unknown. We present the 15th case of such a tumor, having this unique tumor morphology, followed by a detailed discussion on disease pathogenesis. PATIENT CONCERNS: A 48-year-old, asymptomatic perimenopausal, multiparous Japanese woman presented with a left-sided pelvic mass. She had no history of previous surgeries or uterine leiomyomas. Although a transabdominal ultrasonogram raised suspicions of an ovarian tumor, a transvaginal ultrasonogram confirmed normal ovaries. Radiological images showed a multilocular cystic mass with enhanced solid lesions connected to the uterus. Retrospective radiological evaluation showed that the mass was largely connected to the peritoneum of the anterolateral abdominal wall. INTERVENTIONS: Intraoperatively, the mass appeared as a dome-like protrusion from the left lower quadrant of the abdominal wall, without connection to the uterus, ovaries, or the left round ligament. No other peritoneal masses were seen. The mass was easily enucleated from the abdominal wall. Pathology confirmed that the mass was a leiomyoma with hydropic and myxoid degeneration. No striated muscle tissues were noted between the tumor and resection margin, but a thin smooth muscle layer, positive for hormone receptors, was present at the periphery, suggesting the origin of the tumor. LESSONS: Benign leiomyomas of the anterolateral abdominal wall likely originate from Müllerian-like smooth muscle remnants in this region. They should be considered in the differential diagnosis of solid and cystic masses and be distinguished from uterine and ovarian masses on imaging to avoid unnecessary organ resection.
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Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden - Peneder, Peter; Stütz, Adrian M.; Surdez, Didier; Krumbholz, Manuela; Semper, Sabine; Chicard, Mathieu; Sheffield, Nathan C.; Pierron, Gaelle; Lapouble, Eve; Tötzl, Marcus; Ergüner, Bekir; Barreca, Daniele; et al. (Nature Communications, 2021)
Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.
CRIS-Team Scopus Importer:2021-06-11

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[New WHO classification 2022: urinary bladder cancer]. - Gaisa, Nadine Therese; Hartmann, Arndt; Knuechel-Clarke, Ruth (Die Pathologie, 2023)
The new World Health Organization (WHO) classification of urogenital tumors is still primarily based on anatomic location, but is also a hierarchical taxonomic classification without separate chapters for tumors of the upper urinary tract and the urethra. It clarifies aspects regarding grading and noninvasive entities. It consolidates the use of the Paris system for urinary cytology as well as various subtypes/special types of neoplasms, and incorporates general concepts of the 5th edition of the WHO blue book. In addition to mesenchymal tumors, well-differentiated neuroendocrine tumors and neuroendocrine carcinomas are addressed in separate chapters. Papillary non-invasive low- and high-grade carcinomas and carcinoma in situ remain, while dysplasia and urothelial proliferation of unknown malignant potential (UPUMP) are no longer treated as separate entities. Former variants of urothelial carcinoma are now called subtypes and aberrant differentiation and special types are more precisely defined.
EVALuna2:536073

NFATc1 Promotes Antitumoral Effector Functions and Memory CD8+ T-cell Differentiation during Non-Small Cell Lung Cancer Development - Heim, Lisanne; Friedrich, Juliane; Engelhardt, Marina; Trufa, Denis; Geppert, Carol-Immanuel; Rieker, Ralf; Sirbu, Horia; Finotto, Susetta (Cancer Research, 2018)
Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor activated by T-cell receptor (TCR) and Ca2+ signaling that affects T-cell activation and effector function. Upon tumor antigen challenge, TCR and calcium-release-activated channels are induced, promoting NFAT dephosphorylation and translocation into the nucleus. In this study, we report a progressive decrease of NFATc1 in lung tumor tissue and in tumor-infiltrating lymphocytes (TIL) of patients suffering from advanced-stage non-small cell lung cancer (NSCLC). Mice harboring conditionally inactivated NFATc1 in T cells (NFATc1ΔCD4) showed increased lung tumor growth associated with impaired T-cell activation and function. Furthermore, in the absence of NFATc1, reduced IL2 influenced the development of memory CD8+ T cells. We found a reduction of effector memory and CD103+ tissue-resident memory (TRM) T cells in the lung of tumor-bearing NFATc1ΔCD4 mice, underlining an impaired cytotoxic T-cell response and a reduced TRM tissue-homing capacity. In CD4+ICOS+ T cells, programmed cell death 1 (PD-1) was induced in the draining lymph nodes of these mice and associated with lung tumor cell growth. Targeting PD-1 resulted in NFATc1 induction in CD4+ and CD8+ T cells in tumor-bearing mice and was associated with increased antitumor cytotoxic functions. This study reveals a role of NFATc1 in the activation and cytotoxic functions of T cells, in the development of memory CD8+ T-cell subsets, and in the regulation of T-cell exhaustion. These data underline the indispensability of NFATc1 for successful antitumor immune responses in patients with NSCLC.Significance: The multifaceted role of NFATc1 in the activation and function of T cells during lung cancer development makes it a critical participant in antitumor immune responses in patients with NSCLC. Cancer Res; 78(13); 3619-33. ©2018 AACR.
EVALuna2:34901

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

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

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

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

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 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

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, 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 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

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.
EVALuna2:34302

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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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

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

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.
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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.
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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.
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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

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.
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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'.
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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

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 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)
EVALuna2:6877

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

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

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

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

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

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-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

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.
EVALuna2:52994

Perivascular hemosiderin deposits in human skeletal muscle tissue - Delbridge, Claire; Türk, Matthias; Agaimy, Abbas; Winterholler, Martin; Schröder, Rolf (Neuromuscular Disorders, 2018)
EVALuna2:34586

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

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

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

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

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

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 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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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

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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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 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

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

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.
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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.
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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.
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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

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 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.
EVALuna2:1971

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.
EVALuna2:6854

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.
EVALuna2:6892

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.
EVALuna2:6780

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