Publications by authors named "Philipp Ströbel"

222 Publications

Challenges in lung and thoracic pathology.

Virchows Arch 2021 Mar 5. Epub 2021 Mar 5.

Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Str. 40, D-37075, Göttingen, Germany.

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http://dx.doi.org/10.1007/s00428-021-03067-9DOI Listing
March 2021

Molecular pathology of thymomas: implications for diagnosis and therapy.

Virchows Arch 2021 Mar 5. Epub 2021 Mar 5.

Institute of Pathology, University Medical Centre Mannheim and Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Thymomas exhibit a unique genomic landscape, comprising the lowest on average total mutational burden among adult human cancers; a unique point mutation in the GTF2I gene in WHO type A and AB thymomas (and rarely others); almost unique KMT2A-MAML2 translocations in rare WHO type B2 and B3 thymomas; a unique YAP1-MAML2 translocation in almost all metaplastic thymomas; and unique miRNA profiles in relation to GTF2I mutational status and WHO histotypes. While most thymomas can be diagnosed solely on the basis of morphological features, mutational analyses can solve challenging differential diagnostic problems. No molecular biomarkers have been identified that predict the response of unresectable thymomas to chemotherapy or agents with known molecular targets. Despite the common and strong expression of PDL1 in thymomas, immune checkpoint inhibitors are rarely applicable due to the poor predictability of common, life-threatening autoimmune side effects that are related to the unrivaled propensity of thymomas towards autoimmunity.
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http://dx.doi.org/10.1007/s00428-021-03068-8DOI Listing
March 2021

Identification of CD318, TSPAN8 and CD66c as target candidates for CAR T cell based immunotherapy of pancreatic adenocarcinoma.

Nat Commun 2021 Mar 5;12(1):1453. Epub 2021 Mar 5.

Miltenyi Biotec GmbH, R&D, Bergisch Gladbach, North Rhine-Westphalia, Germany.

A major roadblock prohibiting effective cellular immunotherapy of pancreatic ductal adenocarcinoma (PDAC) is the lack of suitable tumor-specific antigens. To address this challenge, here we combine flow cytometry screenings, bioinformatic expression analyses and a cyclic immunofluorescence platform. We identify CLA, CD66c, CD318 and TSPAN8 as target candidates among 371 antigens and generate 32 CARs specific for these molecules. CAR T cell activity is evaluated in vitro based on target cell lysis, T cell activation and cytokine release. Promising constructs are evaluated in vivo. CAR T cells specific for CD66c, CD318 and TSPAN8 demonstrate efficacies ranging from stabilized disease to complete tumor eradication with CD318 followed by TSPAN8 being the most promising candidates for clinical translation based on functionality and predicted safety profiles. This study reveals potential target candidates for CAR T cell based immunotherapy of PDAC together with a functional set of CAR constructs specific for these molecules.
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http://dx.doi.org/10.1038/s41467-021-21774-4DOI Listing
March 2021

Histopathological Findings Predict Renal Recovery in Severe ANCA-Associated Vasculitis Requiring Intensive Care Treatment.

Front Med (Lausanne) 2020 9;7:622028. Epub 2021 Feb 9.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Renal involvement is a common and severe complication of AAV as it can cause ESRD. Histopathological subgrouping and ARRS are helpful to predict long-term ESRD in patients with AAV. Because a subgroup of critically ill patients with severe AAV present with deterioration of kidney function requiring RRT at admission, we here aimed to evaluate histopathological findings and predictive value of Berden's histopathological subgrouping and ARRS for severity of AKI and requirement of RRT during the short-term clinical course in critically ill patients requiring intensive care treatment and predictors for short-term renal recovery in patients requiring RRT. A subgroup of 15/46 (32. 6%) AAV patients with biopsy-proven AAV required RRT during the short-term course of disease, associated with requirement of critical care treatment. While histopathological subgrouping and ARRS were associated with requirement of acute RRT, presence of global glomerular scarring was the strongest predictor of failure to recover from RRT after initiation of remission induction therapy. This new aspect requires further investigation in a prospective controlled setting for therapeutic decision making especially in this subgroup.
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http://dx.doi.org/10.3389/fmed.2020.622028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900153PMC
February 2021

Recent advances and conceptual changes in the classification of neuroendocrine tumors of the thymus.

Virchows Arch 2021 Feb 8. Epub 2021 Feb 8.

Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Str. 40, D-37075, Göttingen, Germany.

Neuroendocrine tumors of the thymus (TNET) are exceedingly rare neoplasms. Their histomorphology is identical to neuroendocrine tumors elsewhere in the body (in particular the lungs) and bears no similarity with thymomas and thymic carcinomas. Recent molecular findings have profoundly changed our perception of these tumors and may impact future histological classification systems.
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http://dx.doi.org/10.1007/s00428-021-03037-1DOI Listing
February 2021

Thymus and autoimmunity.

Semin Immunopathol 2021 Feb 3;43(1):45-64. Epub 2021 Feb 3.

Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

The thymus prevents autoimmune diseases through mechanisms that operate in the cortex and medulla, comprising positive and negative selection and the generation of regulatory T-cells (Tregs). Egress from the thymus through the perivascular space (PVS) to the blood is another possible checkpoint, as shown by some autoimmune/immunodeficiency syndromes. In polygenic autoimmune diseases, subtle thymic dysfunctions may compound genetic, hormonal and environmental cues. Here, we cover (a) tolerance-inducing cell types, whether thymic epithelial or tuft cells, or dendritic, B- or thymic myoid cells; (b) tolerance-inducing mechanisms and their failure in relation to thymic anatomic compartments, and with special emphasis on human monogenic and polygenic autoimmune diseases and the related thymic pathologies, if known; (c) polymorphisms and mutations of tolerance-related genes with an impact on positive selection (e.g. the gene encoding the thymoproteasome-specific subunit, PSMB11), promiscuous gene expression (e.g. AIRE, PRKDC, FEZF2, CHD4), Treg development (e.g. SATB1, FOXP3), T-cell migration (e.g. TAGAP) and egress from the thymus (e.g. MTS1, CORO1A); (d) myasthenia gravis as the prototypic outcome of an inflamed or disordered neoplastic 'sick thymus'.
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http://dx.doi.org/10.1007/s00281-021-00842-3DOI Listing
February 2021

Thymic Hyperplasia with Lymphoepithelial Sialadenitis (LESA)-Like Features: Strong Association with Lymphomas and Non-Myasthenic Autoimmune Diseases.

Cancers (Basel) 2021 Jan 16;13(2). Epub 2021 Jan 16.

Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.

Thymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of cases with LESA-like TH and/or thymic MALT-lymphoma. Among 36 patients (21 males) with LESA-like TH (age 52 years, 32-80; lesion diameter 7.0 cm, 1-14.5; median, range), five (14%) showed associated lymphomas, including four (11%) thymic MALT lymphomas and one (3%) diffuse large B-cell lymphoma. One additional case showed a clonal B-cell-receptor rearrangement without evidence of lymphoma. Twelve (33%) patients (7 women) suffered from partially overlapping autoimmune diseases: systemic lupus erythematosus ( = 4, 11%), rheumatoid arthritis ( = 3, 8%), myasthenia gravis ( = 2, 6%), asthma ( = 2, 6%), scleroderma, Sjögren syndrome, pure red cell aplasia, Grave's disease and anti-IgLON5 syndrome (each = 1, 3%). Among 11 primary thymic MALT lymphomas, remnants of LESA-like TH were found in two cases (18%). In summary, LESA-like TH shows a striking association with autoimmunity and predisposes to lymphomas. Thus, a hematologic and rheumatologic workup should become standard in patients diagnosed with LESA-like TH. Radiologists and clinicians should be aware of LESA-like TH as a differential diagnosis for mediastinal mass lesions in patients with autoimmune diseases.
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http://dx.doi.org/10.3390/cancers13020315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830871PMC
January 2021

STIM1 Mediates Calcium-dependent Epigenetic Reprogramming in Pancreatic Cancer.

Cancer Res 2021 Jan 12. Epub 2021 Jan 12.

Division of Gastroenterology and Hepatologyu, Mayo Clinic

Pancreatic Ductal Adenocarcinoma (PDAC) displays a dismal prognosis due to late diagnosis and high chemoresistance incidence. For advanced disease stages or patients with comorbidities, treatment options are limited to gemcitabine alone or in combination with other drugs. While gemcitabine resistance has been widely attributed to the levels of one of its targets, RRM1, the molecular consequences of gemcitabine resistance in PDAC remain largely elusive. Here we sought to identify genomic, epigenomic, and transcriptomic events associated with gemcitabine resistance in PDAC and their potential clinical relevance. We found that gemcitabine-resistant cells displayed a co-amplification of the adjacent RRM1 and STIM1 genes. Interestingly, RRM1, but not STIM1, was required for gemcitabine resistance, while high STIM1 levels caused an increase in cytosolic calcium concentration. Higher STIM1-dependent calcium influx led to an impaired ER stress response and a heightened NFAT activity. Importantly, these findings were confirmed in patient and patient-derived xenograft samples. Taken together, our study uncovers previously unknown biologically relevant molecular properties of gemcitabine-resistant tumors, revealing an undescribed function of STIM1 as a rheostat directing the effects of calcium signaling and controlling epigenetic cell fate determination. It further reveals the potential benefit of targeting STIM1-controlled calcium signaling and its downstream effectors in PDAC.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2874DOI Listing
January 2021

Quality of life in rectal cancer patients with or without oxaliplatin in the randomised CAO/ARO/AIO-04 phase 3 trial.

Eur J Cancer 2021 Feb 28;144:281-290. Epub 2020 Dec 28.

Department of Radiation Oncology, University Hospital Würzburg, Würzburg, Germany. Electronic address:

Background: The CAO/ARO/AIO trial has shown that oxaliplatin added to preoperative chemoradiotherapy and postoperative chemotherapy significantly improved disease-free survival in locally advanced rectal cancer (LARC). Here, we present a post-hoc analysis of quality of life (QoL) in disease-free patients.

Patients And Methods: Between 2006 and 2010, 1236 patients with LARC were randomly assigned either to preoperative chemoradiotherapy followed by total mesorectal excision and postoperative chemotherapy (N = 623) or combined with oxaliplatin (N = 613). QoL questionnaires (EORTC QLQ-C30, colorectal module CR38) were completed at baseline, after postoperative chemotherapy and during follow-up. Analysis was performed according intent-to-treat.

Results: Available questionnaires (baseline) were 82% (N = 512) in the control and 84% (N = 513) in the investigational group. Response rates were 49% (533 of 1086) at 1 year and 43% (403 of 928) at 3 years. Global health status (GHS) for disease-free patients was stable in both groups (range 0-100). At baseline: standard arm 62.0 (mean, SD 21.6; N = 491) versus oxaliplatin arm 63.2 (mean, SD 22; N = 503); at 3 years: 69.4 (SD 19.3; N = 187) versus 65.4 (SD 22.2; N = 202). After treatment and at 3 years, no significant differences (≥10 points) between groups were found in QoL subscales. Disease-free patients experiencing neurotoxic side-effects (grade 1-4) showed reduced GHS at 3 years versus patients without neurotoxicity (mean 59.2 versus 69.3; P < 0.001), while grade 3-4 rate was low.

Conclusion: The addition of oxaliplatin was not associated with worse overall QoL. This information is of interest to patients in many ongoing rectal cancer trials.

Trial Registration Information: NCT00349076.
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http://dx.doi.org/10.1016/j.ejca.2020.11.029DOI Listing
February 2021

Synthesis of Nitride Zeolites in a Hot Isostatic Press.

Angew Chem Int Ed Engl 2021 Feb 23;60(9):4470-4473. Epub 2020 Dec 23.

Department of Chemistry, University of Munich (LMU), Butenandtstr. 5-13, 81377, München, Germany.

The recently introduced nitridophosphate synthesis in a hot isostatic press (HIP) enabled simple access to large-scale product quantities starting from exclusively commercially available starting materials. Herein, we show that this method is suitable for the synthesis of highly condensed functional nitridophosphates, as well. Hence, the syntheses of the nitridophosphate zeolites Ba P N X (X=Cl, Br) are presented as proof of concept for this innovative access. Furthermore, samples of unprecedented Sr P N X (X=Cl, Br) were prepared and characterized to demonstrate the advantages of this synthetic approach over commonly used methods. Luminescence investigations on Eu -doped samples of AE P N X (AE=Sr, Ba; X=Cl, Br) were carried out and characteristics of observed emission bands are discussed.
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http://dx.doi.org/10.1002/anie.202012722DOI Listing
February 2021

KRAS mutation status concordance between the primary tumor and the corresponding metastasis in patients with rectal cancer.

PLoS One 2020 1;15(10):e0239806. Epub 2020 Oct 1.

Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany.

Introduction: Oncogenic mutation within the KRAS gene represents a negative predictor for treatment response to anti-epidermal growth factor receptor (EGFR) in patients with colorectal cancer. Recently, we have shown no relevant heterogeneity for KRAS mutation status within and between pre- and posttherapeutic samples from the primary tumor in patients with locally advanced rectal cancer. The aim of this study was to evaluate the intertumoral heterogeneity of KRAS mutation status between the primary tumor and the corresponding metastasis or local recurrence in the similar cohort and to evaluate the ideal representative tissue for KRAS mutation testing.

Materials And Methods: KRAS mutation status was analyzed from 47 patients with locally advanced rectal cancer, which were enrolled in the CAO/ARO/AIO-94 or CAO/ARO/AIO-04 trial. Mutations in KRAS codons 12, 13, and 61 were analyzed by using the KRAS RGQ PCR Kit (therascreen® KRAS test). Six patients needed to be excluded due to incomplete follow up data. 11 patients showed a relapse of the disease during the follow up presented by distant metastases or local recurrence. DNA from representative areas of metastatic tissue was obtained from formalin-fixed paraffin-embedded specimens.

Results: The mean patient age was 64.13 ± 10.64 years. In total, 19 patients showed a KRAS mutation (46.34%) in the primary tumor. Of the eleven patients with a metastatic disease or local recurrence, five patients showed a KRAS mutation whereas six patients had a KRAS wildtype status. Metastatic localizations included the liver (n = 2), lung (n = 4), local recurrence (n = 1), liver + lung (n = 3), lung + local recurrence (n = 1). For these eleven patients with paired data available for the primary tumor and metastatic tissue, a significant KRAS mutation status concordance was detected in 81.18% (9/11) of the patients (p = 0.03271). Only two patients showed intertumoral heterogeneity, which harbored in one patient a KRAS G12C mutation status in the primary tumor, but a G12V KRAS mutation status in the corresponding lung lesion, and in the other patient a G12A mutation in the primary lesion and a WT in the lung metastasis.

Conclusions: We show a significant concordance of the KRAS mutation status between tumor samples obtained from the primary tumor and the corresponding metastasis and/ or local recurrence in patients with rectal cancer indicating no relevant intertumoral heterogeneity. Our data suggest that sampling either the primary (pre- or posttherapeutical tumor tissue) or metastatic lesion may be valid for the initial evaluation of KRAS mutation status predicting the response to anti-EGFR treatment and guiding clinical decisions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239806PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529221PMC
November 2020

The detection of isochromosome i(12p) in malignant germ cell tumours and tumours with somatic malignant transformation by the use of quantitative real-time polymerase chain reaction.

Histopathology 2021 Mar 21;78(4):593-606. Epub 2020 Nov 21.

Institute of Pathology, University Medical Centre, Göttingen, Germany.

Aims: Malignant germ cell tumours (GCTs) of the testis are rare neoplasms, but the most common solid malignancies in young men. World Health Organization guidelines divide GCTs into five types, for which numerous immunohistochemical markers allow exact histological subtyping in the majority of cases. In contrast, a germ cell origin is often hard to prove in metastatic GCTs that have developed so-called somatic malignant transformation. A high percentage, up to 89%, of GCTs are characterised by the appearance of isochromosome 12p [i(12p)]. Fluorescence in-situ hybridisation has been the most common diagnostic method for the detection of i(12p) so far, but has the disadvantages of being time-consuming, demanding, and not being a stand-alone method. The aim of the present study was to establish a quantitative real-time polymerase chain reaction assay as an independent method for detecting i(12p) and regional amplifications of the short arm of chromosome 12 by using DNA extracted from formalin-fixed paraffin-embedded tissue.

Methods And Results: A cut-off value to distinguish between the presence and absence of i(12p) was established in a control set consisting of 36 tumour-free samples. In a training set of 149 GCT samples, i(12p) was detectable in 133 tumours (89%), but not in 16 tumours (11%). In a test set containing 27 primary and metastatic GCTs, all 16 tumours with metastatic spread and/or somatic malignant transformation were successfully identified by the detection of i(12p).

Conclusion: In summary, the qPCR assay presented here can help to identify, further characterise and assign a large proportion of histologically inconclusive malignancies to a GCT origin.
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http://dx.doi.org/10.1111/his.14258DOI Listing
March 2021

EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of .

Cancer Res 2020 11 9;80(21):4620-4632. Epub 2020 Sep 9.

Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Goettingen, Germany.

Recent studies have thoroughly described genome-wide expression patterns defining molecular subtypes of pancreatic ductal adenocarcinoma (PDAC), with different prognostic and predictive implications. Although the reversible nature of key regulatory transcription circuits defining the two extreme PDAC subtype lineages "classical" and "basal-like" suggests that subtype states are not permanently encoded but underlie a certain degree of plasticity, pharmacologically actionable drivers of PDAC subtype identity remain elusive. Here, we characterized the mechanistic and functional implications of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in controlling PDAC plasticity, dedifferentiation, and molecular subtype identity. Utilization of transgenic PDAC models and human PDAC samples linked EZH2 activity to PDAC dedifferentiation and tumor progression. Combined RNA- and chromatin immunoprecipitation sequencing studies identified EZH2 as a pivotal suppressor of differentiation programs in PDAC and revealed EZH2-dependent transcriptional repression of the classical subtype defining transcription factor Gata6 as a mechanistic basis for EZH2-dependent PDAC progression. Importantly, genetic or pharmacologic depletion of EZH2 sufficiently increased GATA6 expression, thus inducing a gene signature shift in favor of a less aggressive and more therapy-susceptible, classical PDAC subtype state. Consistently, abrogation of GATA6 expression in EZH2-deficient PDAC cells counteracted the acquisition of classical gene signatures and rescued their invasive capacities, suggesting that GATA6 derepression is critical to overcome PDAC progression in the context of EZH2 inhibition. Together, our findings link the EZH2-GATA6 axis to PDAC subtype identity and uncover EZH2 inhibition as an appealing strategy to induce subtype-switching in favor of a less aggressive PDAC phenotype. SIGNIFICANCE: This study highlights the role of EZH2 in PDAC progression and molecular subtype identity and suggests EZH2 inhibition as a strategy to recalibrate GATA6 expression in favor of a less aggressive disease. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/21/4620/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0672DOI Listing
November 2020

Characterization of PD-1 and PD-L1 Expression in Papillary Renal Cell Carcinoma: Results of a Large Multicenter Study.

Clin Genitourin Cancer 2021 Feb 9;19(1):53-59.e1. Epub 2020 Jul 9.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; Immune Cooperativ Oncology Group (ICOG) of the Comprehensive Cancer Center Lower-Saxoney (CCC-N), Hannover Medical School, Hannover, Germany.

Background: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) play a decisive role as prognostic markers in clear-cell renal cell carcinoma (RCC). To date, the role of PD-1/PD-L1 as a prognostic marker in papillary RCC (pRCC) remains scarce.

Patients And Methods: Patients' sample collection was a joint collaboration of the nationwide PANZAR consortium - a multicenter study. Medical history and tumor specimens were collected from 245 and 129 patients with pRCC types 1 and 2, respectively. Expression of PD-1 and PD-L1 was determined by immunohistochemistry in pRCC and tumor-infiltrating mononuclear cells.

Results: Of 374 pRCC specimens, 204 type 1 and 97 type 2 were evaluable for PD-1 and PD-L1 expression analysis. In total, PD-1 and PD-L1 expression were found in 8 (4.9%) of 162 and 12 (7.2%) of 166 evaluable pRCC type 1 specimens. Comparably, PD-1 and PD-L1 expression were found in 2 (2.4%) of 83 and 5 (6.2%) of 81 evaluable pRCC type 2 specimens. Hardly any clinically relevant associations between PD-1 and PD-L1 positivity and clinicopathologic or clinical courses were observed, neither in pRCC type 1 nor type 2.

Conclusion: The analysis of a large pRCC cohort from a multicenter consortium revealed no impact of PD-1/PD-L1 expression on prognosis in patients with pRCC with predominantly limited disease status, neither for type 1 nor type 2. However, the impact of PD-1 and PD-L1 in more advanced pRCC disease needs further elucidation.
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http://dx.doi.org/10.1016/j.clgc.2020.07.002DOI Listing
February 2021

HIP to be Square: Simplifying Nitridophosphate Synthesis in a Hot Isostatic Press.

Angew Chem Int Ed Engl 2020 Oct 17;59(41):18240-18243. Epub 2020 Aug 17.

Department of Chemistry, University of Munich (LMU), Butenandtstraße 5-13, 81377, München, Germany.

(Oxo)Nitridophosphates have recently been identified as a promising compound class for application in the field of solid-state lighting. Especially, the latest medium-pressure syntheses under ammonothermal conditions draw attention of the semiconductor and lighting industry on nitridophosphates. In this contribution, we introduce hot isostatic presses as a new type of medium-pressure synthetic tool, further simplifying nitridophosphate synthesis. In a second step, phosphorus nitride was replaced as starting material by red phosphorus, enabling the synthesis of Ca PN as model compound, starting only from readily available compounds. Moreover, first luminescence investigations on Eu -doped samples reveal Ca PN :Eu as a promising broad-band red-emitter (λ =650 nm; fwhm=1972 cm ). Besides simple handling, the presented synthetic method offers access to large sample volumes, and the underlying reaction conditions facilitate single-crystal growth, required for excellent optical properties.
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http://dx.doi.org/10.1002/anie.202008570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590079PMC
October 2020

Increased levels of VEGF-C and macrophage infiltration in lipedema patients without changes in lymphatic vascular morphology.

Sci Rep 2020 07 2;10(1):10947. Epub 2020 Jul 2.

Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.

Lipedema is a chronic adipose tissue disorder characterized by the disproportional subcutaneous deposition of fat and is commonly misdiagnosed as lymphedema or obesity. The molecular determinants of the lipedema remain largely unknown and only speculations exist regarding the lymphatic system involvement. The aim of the present study is to characterize the lymphatic vascular involvement in established lipedema. The histological and molecular characterization was conducted on anatomically-matched skin and fat biopsies as well as serum samples from eleven lipedema and ten BMI-matched healthy patients. Increased systemic levels of vascular endothelial growth factor (VEGF)-C (P = 0.02) were identified in the serum of lipedema patients. Surprisingly, despite the increased VEGF-C levels no morphological changes of the lymphatic vessels were observed. Importantly, expression analysis of lymphatic and blood vessel-related genes revealed a marked downregulation of Tie2 (P < 0.0001) and FLT4 (VEGFR-3) (P = 0.02) consistent with an increased macrophage infiltration (P = 0.009), without changes in the expression of other lymphatic markers. Interestingly, a distinct local cytokine milieu, with decreased VEGF-A (P = 0.04) and VEGF-D (P = 0.02) expression was identified. No apparent lymphatic anomaly underlies lipedema, providing evidence for the different disease nature in comparison to lymphedema. The changes in the lymphatic-related cytokine milieu might be related to a modified vascular permeability developed secondarily to lipedema progression.
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http://dx.doi.org/10.1038/s41598-020-67987-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331572PMC
July 2020

Minimal manifestation status and prednisone withdrawal in the MGTX trial.

Neurology 2020 08 1;95(6):e755-e766. Epub 2020 Jul 1.

From the Departments of Neurology (I.L.) and Biostatistics (H.-C.K., I.B.A., G.R.C., T.M., G.M.), University of Alabama at Birmingham; Department of Neurology (H.J.K.), George Washington University School of Medicine and Health Sciences, Washington, DC; Department of Neurology (J.S.), Greater Manchester Neuroscience Center, Salford, Greater Manchester, UK; Institute of Pathology (P.S.), University Medical Center Göttingen; Division of Neurology (J.O.), University of British Columbia, Vancouver, Canada; Department of Neurology (G.C.), University of Chile, Santiago; Division of Neurology (J.M.H.), Department of Medicine, University of Cape Town, South Africa; Department of Neurology (A.E.), Catholic University, Rome, Italy; Department of Neurology (W.N.), Johannes Gutenberg University, Mainz, Germany; Department of Neurology (E.C.), University of Rochester Medical Center, NY; Department of Neurosciences (G.A.), Mental Health and Sensory Organs, Sapienza University of Rome, Italy; Division of Neurology (R.W.), Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Department of Neurology (J.O.K.), Royal Melbourne Hospital, Victoria, Australia; Department of Neurology (S.R.B.), University of Southern California, Los Angeles; Department of Neurology (C.H.C.), McGill University, Montreal, Canada; Department of Neurology (A.C.B.), Medical College of Wisconsin, Milwaukee; Department of Neurology (A.A.A.), Harvard Medical School, Boston, MA; Nerve and Muscle Center of Texas (A.I.S.), Houston; Department of Neurology (B.K.), Case Western Reserve University, Cleveland, OH; Walton Centre for Neurology and Neurosurgery (B.R.F.L.), Liverpool; Nuffield Department of Clinical Neurosciences (C.B., A.V.), Oxford University, UK; Unit of Neurology (E.D.-T.), University of Brasilia, Brazil; Department of Neurology (H.Y.), Kanazawa University, Japan; Department of Neurology (M.W.-C.), Federal University, Rio de Janeiro, Brazil; Department of Neurology (M.T.P.), University of Florida, Jacksonville; Department of Neurology (M.H.R.), Augusta University, GA; Department of Neurology (A.K.-P.), Medical University of Warsaw, Poland; Department of Neurology (R.M.P.), Indiana School of Medicine, Indianapolis; Department of Neurology (C.E.J.), University of Texas Health Science Center, San Antonio; Department of Neurology (J.J.G.V.), Leiden University Medical Center, the Netherlands; Department of Neurology (J.M.M.), Duke University Medical Center, Durham, NC; Department of Neurology (J.T.K.), Ohio State University Wexner Medical Center, Columbus; Department of Neurology (L.C.W.), Universidade Federal do Parana, Curitiba, Brazil; Department of Neurology (M.B.), University of Miami, FL; Department of Neurology (R.J.B.), University of Kansas Medical Center, Kansas City; Department of Neurological Sciences (R.T.), University of Vermont College of Medicine, Burlington; Department of Neurology (T.M.), University of California Irvine Medical Center, Orange; Division of Extramural Research (R.C.), NIH, National Institute of Neurological Disorders and Stroke, Bethesda, MD; Section of General Thoracic Surgery (J.R.S.), Columbia University Medical Center, New York; and Department of Neurology (G.I.W.), University at Buffalo Jacobs School of Medicine and Biomedical Sciences, NY.

Objective: To examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG).

Methods: This study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups.

Results: Patients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone.

Conclusions: Thymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone.

Clinicaltrialsgov Identifier: NCT00294658.

Classification Of Evidence: This study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than those on prednisone alone.
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http://dx.doi.org/10.1212/WNL.0000000000010031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455358PMC
August 2020

Interobserver variation in the classification of thymic lesions including biopsies and resection specimens in an international digital microscopy panel.

Histopathology 2020 Nov 24;77(5):734-741. Epub 2020 Sep 24.

Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.

Aims: Thymic tumours are rare in routine pathology practice. Although the World Health Organization (WHO) classification describes a number of well-defined categories, the classification remains challenging. The aim of this study was to investigate the reproducibility of the WHO classification among a large group of international pathologists with expertise in thymic pathology and by using whole slide imaging to facilitate rapid diagnostic turnover.

Methods And Results: Three hundred and five tumours, consisting of 90 biopsies and 215 resection specimens, were reviewed with a panel-based virtual microscopy approach by a group of 13 pathologists with expertise in thymic tumours over a period of 6 years. The specimens were classified according to the WHO 2015 classification. The data were subjected to statistical analysis, and interobserver concordance (Fleiss kappa) was calculated. All cases were diagnosed within a time frame of 2 weeks. The overall level of agreement was substantial (κ = 0.6762), and differed slightly between resection specimens (κ = 0.7281) and biopsies (κ = 0.5955). When analysis was limited to thymomas only, and they were grouped according to the European Society for Medical Oncology Clinical Practice Guidelines into B2, B3 versus A, AB, B1 and B3 versus A, AB, B1, B2, the level of agreement decreased slightly (κ = 0.5506 and κ = 0.4929, respectively). Difficulties arose in distinguishing thymoma from thymic carcinoma. Within the thymoma subgroup, difficulties in distinction were seen within the B group.

Conclusions: Agreement in diagnosing thymic lesions is substantial when they are assessed by pathologists with experience of these rare tumours. Digital pathology decreases the turnaround time and facilitates access to what is essentially a multinational resource. This platform provides a template for dealing with rare tumours for which expertise is sparse.
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http://dx.doi.org/10.1111/his.14167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702114PMC
November 2020

Adipose Tissue Hypertrophy, An Aberrant Biochemical Profile and Distinct Gene Expression in Lipedema.

J Surg Res 2020 09 11;253:294-303. Epub 2020 May 11.

Division of Plastic Surgery, Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Göttingen, Georg-August-University, Göttingen, Germany; Clinic of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland. Electronic address:

Background: Lipedema is a common adipose tissue disorder affecting women, characterized by a symmetric subcutaneous adipose tissue deposition, particularly of the lower extremities. Lipedema is usually underdiagnosed, thus remaining an undertreated disease. Importantly, no histopathologic or molecular hallmarks exist to clearly diagnose the disease, which is often misinterpreted as obesity or lymphedema.

Materials And Methods: The aim of the present study is to characterize in detail morphologic and molecular alterations in the adipose tissue composition of lipedema patients compared with healthy controls. Detailed histopathologic and molecular characterization was performed using lipid and cytokine quantification as well as gene expression arrays. The analysis was conducted on anatomically matched skin and fat tissue biopsies as well as fasting serum probes obtained from 10 lipedema and 11 gender and body mass index-matched control patients.

Results: Histologic evaluation of the adipose tissue showed increased intercellular fibrosis and adipocyte hypertrophy. Serum analysis showed an aberrant lipid metabolism without changes in the circulating adipokines. In an adipogenesis gene array, a distinct gene expression profile associated with macrophages was observed. Histologic assessment of the immune cell infiltrate confirmed the increased presence of macrophages, without changes in the T-cell compartment.

Conclusions: Lipedema presents a distinguishable disease with typical tissue architecture and aberrant lipid metabolism, different to obesity or lymphedema. The differentially expressed genes and immune cell infiltration profile in lipedema patients further support these findings.
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http://dx.doi.org/10.1016/j.jss.2020.03.055DOI Listing
September 2020

Thymoma Associated Myasthenia Gravis (TAMG): Differential Expression of Functional Pathways in Relation to MG Status in Different Thymoma Histotypes.

Front Immunol 2020 16;11:664. Epub 2020 Apr 16.

Institute of Pathology, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany.

A unique feature of thymomas is their unrivaled frequency of associated myasthenia gravis (MG). Previous studies reported that MG+ thymomas contain a larger number of mature "pre-emigrant" CD4+ T cells than MG- thymomas and that most thymomas do not contain AIRE expressing cells irrespective of MG status. These findings suggest that CD4+ T cells that mature inside the abnormal microenvironment of thymomas and egress to the blood are critical to the development of thymoma-associated MG (TAMG) irrespective of thymoma histotype. However, underlying mechanisms have remained enigmatic. To get hints to mechanisms underlying TAMG, we pursue three hypotheses: (i) Functional pathways with metabolic and immunological relevance might be differentially expressed in TAMG(+) compared to TAMG(-) thymomas; (ii) differentially enriched pathways might be more evident in immature lymphocyte-poor (i.e., tumor cell/stroma-rich) thymoma subgroups; and (iii) mechanisms leading to TAMG might be different among thymoma histological subtypes. To test these hypotheses, we compared the expression of functional pathways with potential immunological relevance ( = 380) in relation to MG status separately in type AB and B2 thymomas and immature lymphocyte-rich and lymphocyte-poor subgroups of these thymoma types using the TCGA data set. We found that <10% of the investigated pathways were differentially upregulated or downregulated in MG+ compared to MG- thymomas with significant differences between AB and B2 thymomas. The differences were particularly evident, when epithelial cell/stroma-rich subsets of type AB and B2 thymomas were analyzed. Unexpectedly, some MG-associated pathways that were significantly upregulated in AB thymomas were significantly downregulated in B2 thymomas, as exemplified by the oxidative phosphorylation pathway. Conversely, the MG-associated pathway related to macrophage polarization was downregulated in MG+ AB thymoma and upregulated in MG+ B2 thymoma. We conclude that functional pathways are significantly associated with TAMG, and that some mechanisms leading to TAMG might be different among thymoma histological subtypes. Functions related to metabolisms, vascular and macrophage biology are promising new candidate mechanisms potentially involved in the pathogenesis of TAMG. More generally, the results imply that future studies addressing pathomechanisms of TAMG should take the histotype and abundance of tumor cells and non-neoplastic stromal components of thymomas into account.
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http://dx.doi.org/10.3389/fimmu.2020.00664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176899PMC
April 2020

Nitridophosphate-Based Ultra-Narrow-Band Blue-Emitters: Luminescence Properties of AEP N :Eu (AE=Ca, Sr, Ba).

Chemistry 2020 Jun 11;26(32):7292-7298. Epub 2020 May 11.

Department of Chemistry, University of Munich (LMU), Butenandtstr. 5-13, 81377, München, Germany.

The nitridophosphates AEP N (AE=Ca, Sr, Ba) were synthesized at 4-5 GPa and 1050-1150 °C applying a 1000 t press with multianvil apparatus, following the azide route. The crystal structures of CaP N and SrP N are isotypic. The space group Cmcm was confirmed by powder X-ray diffraction. The structure of BaP N (space group Amm2) was elucidated by a combination of transmission electron microscopy and diffraction of microfocused synchrotron radiation. Phase purity was confirmed by Rietveld refinement. IR spectra are consistent with the structure models and the chemical compositions were confirmed by X-ray spectroscopy. Luminescence properties of Eu -doped samples were investigated upon excitation with UV to blue light. CaP N (λ =470 nm; fwhm=1380 cm ) and SrP N (λ =440 nm; fwhm=1350 cm ) can be classified as the first ultra-narrow-band blue-emitting Eu -doped nitridophosphates. BaP N shows a notably broader blue emission (λ =417/457 nm; fwhm=2075/3550 cm ).
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http://dx.doi.org/10.1002/chem.202001129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318337PMC
June 2020

Fibroblast growth factor receptor 1 gene amplification and protein expression in human lung cancer.

Cancer Med 2020 05 24;9(10):3574-3583. Epub 2020 Mar 24.

Institute of Pathology, University Medical Center, Göttingen, Germany.

Background: Targeting fibroblast growth factor receptor 1 (FGFR1) is a potential treatment for squamous cell lung cancer (SQCLC). So far, treatment decision in clinical studies is based on gene amplification. However, only a minority of patients have shown durable response. Furthermore, former studies have revealed contrasting results regarding the impact of FGFR1 amplification and expression on patient's prognosis.

Aims: Here, we analyzed prevalence and correlation of FGFR1 gene amplification and protein expression in human lung cancer and their impact on overall survival. MATERIALS & METHODS: FGFR1 gene amplification and protein expression were analyzed by fluorescence in situ hybridization and immunohistochemistry (IHC) in 208 SQCLC and 45 small cell lung cancers (SCLC). Furthermore, FGFR1 protein expression was analyzed in 121 pulmonary adenocarcinomas (ACs). Amplification and expression were correlated to each other, clinicopathological characteristics, and overall survival.

Results: FGFR1 was amplified in 23% of SQCLC and 8% of SCLC. Amplification was correlated to males (P = .027) but not to overall survival. Specificity of immunostaining was verified by cellular CRISPR/Cas9 FGFR1 knockout. FGFR1 was strongly expressed in 9% of SQCLC, 35% of AC, and 4% of SCLC. Expression was correlated to females (P = .0187) and to the absence of lymph node metastasis in SQCLC (P = .018) with no significant correlation to overall survival. Interestingly, no significant correlation between amplification and expression was detected.

Discussion: FGFR1 gene amplification does not seem to correlate to protein expression.

Conclusion: We believe that patient selection for FGFR1 inhibitors in clinical studies should be reconsidered. Neither FGFR1 amplification nor expression influences patient's prognosis.
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http://dx.doi.org/10.1002/cam4.2994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288860PMC
May 2020

Sr P N : Complementary Approach by Ammonothermal and High-Pressure Syntheses.

Chemistry 2020 May 28;26(28):6257-6263. Epub 2020 Apr 28.

Department of Chemistry, University of Munich (LMU), Butenandtstraße 5-13 (D), 81377, Munich, Germany.

Nitridophosphates exhibit an intriguing structural diversity with different structural motifs, for example, chains, layers or frameworks. In this contribution the novel nitridophosphate Sr P N with unprecedented dreier double chains is presented. Crystalline powders were synthesized using the ammonothermal method, while single crystals were obtained by a high-pressure multianvil technique. The crystal structure of Sr P N was solved and refined from single-crystal X-ray diffraction and confirmed by powder X-ray methods. Sr P N crystallizes in monoclinic space group P2/c. Energy-dispersive X-ray and Fourier-transformed infrared spectroscopy were conducted to confirm the chemical composition, as well as the absence of NH functionality. The optical band gap was estimated to be 4.4 eV using diffuse reflectance UV/Vis spectroscopy. Upon doping with Eu , Sr P N shows a broad deep-red to infrared emission (λ =681 nm, fwhm≈3402 cm ) with an internal quantum efficiency of 42 %.
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http://dx.doi.org/10.1002/chem.202000297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318702PMC
May 2020

Intensified Histopathological Work-Up after Pancreatic Head Resection Reveals Relevant Prognostic Markers.

Digestion 2021 21;102(2):265-273. Epub 2020 Jan 21.

Department of General, Visceral, and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany,

Introduction: Local recurrence remains a major problem after pancreatic head resection. Intensified histopathological work-up of surgical specimens after pancreatic head resection has revealed an increased number of incomplete resections (R1) depending on tumor infiltration front at the resection margins (RMs). It remains unclear to which extent the increased R1 resection rate has a clinical relevance for the patients' prognosis.

Materials And Methods: Pancreatic head resections between 2006 and 2012 were histologically intensively worked-up by a previously described protocol. The distance between the tumor infiltration front and the resection planes or organ surfaces was documented. The impact of the size of the tumor and an additional portal vein resection was analyzed. The effect of a R1 resection status on development and type of recurrence was evaluated.

Results: A total of 203 pancreatic head resections were evaluated. Different definitions of R1 resection were applied. These led to significantly different prognosis for patients. A greater distance between the tumor infiltration front and the resection plane or organ surface was associated with a better outcome for the patients. For the ventral surface, the mesopancreas and the pancreatic body these differences were statistically significant comparing the different R1 definitions. For the dorsal surface, a significant difference in prognosis was found if the tumor was >2 mm away from the resection surface. A tumor size of 3 cm was identified to play a relevant role for the prognosis. Patients who had a portal vein resection without a histologically proven infiltration showed a statistically significant higher overall survival. Patients with R1 resection were at highest risk for developing local recurrence as well as distant metastasis.

Conclusion: Intensified histopathological work-up with an increased number of R1 resections has a clinical relevance for patients' prognosis. Tumors with a smaller size or with a greater distance to the organ surface or RM have a better outcome.
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http://dx.doi.org/10.1159/000504648DOI Listing
January 2020

Noninvasive assessment of liver fibrosis in a real-world cohort of patients with known or suspected chronic liver disease using 2D-shear wave elastography.

Eur J Gastroenterol Hepatol 2020 12;32(12):1559-1565

Department of Gastroenterology and Gastrointestinal Oncology.

Objectives: We aimed to investigate the diagnostic accuracy of liver stiffness measurement (LSM) by 2D-shear wave elastography (2D-SWE, GE, Logiq E9) in patients with known or suspected chronic liver disease and to define cutoff values for the different stages of fibrosis.

Methods: First, we retrospectively enrolled 21 patients in a pilot study and validated the results in a prospective cohort of 70 patients between May 2017 and February 2019. In all patients, LSM and liver biopsy were performed. We analyzed the diagnostic accuracy of LSM for the different fibrosis stages and examined the impact of additional clinical parameters on LSM.

Results: The success rate of LSM was 88.6%. In the prospective cohort, optimal cutoff values for F ≥ 1, F ≥ 2, F ≥ 3 and F = 4 were 6.24, 7.86, 8.05 and 10.74 kPa [area under the receiver operating characteristic curve (AUROC) 0.831, 0.913, 0.996 and 0.954]. In both cohorts and in the subgroup of patients with nonalcoholic fatty liver disease (NAFLD) (n = 35), a cutoff value of 8.05 kPa differentiates patients with advanced fibrosis (F ≥ 3) and patients with no or mild fibrosis (F0-F2) with high diagnostic accuracy (AUROC 0.995-1.000). Parameters such as age, sex, BMI, bilirubin- and alanine aminotransferase-level had no significant impact on LSM.

Conclusion: LSM by 2D-SWE is an excellent method to differentiate between patients with advanced fibrosis (F ≥ 3) and patients with no or mild fibrosis (F ≤ 2). We were able to show this also in a subgroup of patients with NAFLD.
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http://dx.doi.org/10.1097/MEG.0000000000001675DOI Listing
December 2020

Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer.

Cells 2019 Dec 24;9(1). Epub 2019 Dec 24.

Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, 37075 Göttingen, Germany.

The Kras;LSL-Trp53;Pdx-1-Cre (KPC) mouse model is frequently employed for preclinical therapeutic testing, in particular in regard to antistromal therapies. Here, we investigate the prognostic implications of histopathological features that may guide preclinical trial design. Pancreatic tumor tissue from n = 46 KPC mice was quantitatively analyzed using immunohistochemistry and co-immunofluorescence for proliferation (Ki67), mitotic rate (phospho-Histone 3, PHH3), apoptosis (cleaved caspase-3, CC3), collagen content, secreted protein acidic and rich in cysteine (SPARC), hyaluronic acid (HA), and α-smooth muscle actin (α-SMA). Furthermore, mean vessel density (MVD), mean lumen area (MLA), grading, activated stroma index (ASI), and fibroblast-proliferation rate (α-SMA/Ki67) were assessed. Univariate analysis using the Kaplan-Meier estimator and Cox regression model for continuous variables did not show association between survival and any of the analyzed parameters. Spearman correlation demonstrated that desmoplasia was inversely correlated with differentiated tumor grade (ρ = -0.84). Ki67 and PHH3 synergized as proliferation markers (ρ = 0.54), while SPARC expression was positively correlated with HA content (ρ = 0.37). MVD and MLA were correlated with each other (ρ = 0.31), while MLA positively correlated with CC3 (ρ = 0.45). Additionally, increased MVD was correlated with increased fibroblast proliferation rate (α-SMA + Ki67; ρ = 0.36). Our pilot study provides evidence that individual histopathological parameters of the primary tumor of KPC mice are not associated with survival, and may hint at the importance of systemic tumor-related effects such as cachexia.
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http://dx.doi.org/10.3390/cells9010058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017324PMC
December 2019

Enhancer of Zeste Homolog 2 in Colorectal Cancer Development and Progression.

Digestion 2021 6;102(2):227-235. Epub 2019 Nov 6.

Institute of Pathology, University Medical Center Goettingen, Georg-August-University, Goettingen, Germany.

Background: Colorectal cancer (CRC) is the leading gastrointestinal malignancy. The development from premalignant intraepithelial lesions leading to invasive cancer is paradigmatic for the stepwise carcinogenesis of epithelial cancers, but the knowledge of the underlying mechanism of carcinogenesis and progression of CRC is still incomplete. The understanding of epigenetic mechanisms of carcinogenesis has led to new therapeutic approaches during the last years. Enhancer of zeste homolog 2 (EZH2) is one central epigenetic silencer of the polycomb repressor complex 2 (PRC2) that is already in clinical use as a novel drug target and is associated with poorer prognosis in several cancer entities.

Patients And Methods: The protein expression of EZH2 and other members of the PRC2 as well as resulting posttranslational modifications were investigated by immunohistochemistry in 187 patients with CRC and in 94 patients with premalignant colorectal lesions and correlated with their clinical outcome. Furthermore, the corresponding mRNA expression levels were analyzed in 217 patients with rectal cancer that were enrolled in a prospective clinical trial.

Results: We found a weak expression of EZH2 in normal colon mucosa that increased in low grade, peaked in high grade intraepithelial neoplasia, and decreased again in invasive CRC. The posttranslational modification caused by EZH2 as a measure of EZH2 activity showed the same behavior. Strong protein and mRNA expression of EZH2 were significantly correlated with favorable prognosis in both investigated cohorts.

Conclusion: The expression and activity of EZH2 are associated with colorectal carcinogenesis and most expressed in intraepithelial high-grade lesions. Strong expression of EZH2 is associated with a significantly favorable prognosis in patients suffering from CRC.
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http://dx.doi.org/10.1159/000504093DOI Listing
November 2019

NO /RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer.

Int J Cancer 2020 06 19;146(11):3160-3169. Epub 2019 Nov 19.

Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, CCR, NCI, Bethesda, MD.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high- (>median, n = 31) and low-NOS2 (inducible nitric oxide synthase;
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http://dx.doi.org/10.1002/ijc.32733DOI Listing
June 2020

SPARC dependent collagen deposition and gemcitabine delivery in a genetically engineered mouse model of pancreas cancer.

EBioMedicine 2019 Oct 6;48:161-168. Epub 2019 Oct 6.

Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany. Electronic address:

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterised by extensive matrix deposition that has been implicated in impaired drug delivery and therapeutic resistance. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates collagen deposition and is highly upregulated in the activated stroma subtype with poor prognosis in PDAC patients.

Methods: Kras;p48-Cre;SPARC (KC-SPARC) and Kras;p48-Cre;SPARC (KC-SPARC) were generated and analysed at different stages of carcinogenesis by histological grading, immunohistochemistry for epithelial and stromal markers, survival and preclinical analysis. Pharmacokinetic and pharmacodynamic studies were conducted by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunohistochemistry following gemcitabine treatment (100 mg/kg) in vivo.

Findings: Global genetic ablation of SPARC in a Kras driven mouse model resulted in significantly reduced overall and mature collagen deposition around early and advanced pancreatic intraepithelial neoplasia (PanIN) lesions and in invasive PDAC (p < .001). However, detailed pathological scoring and molecular analysis showed no effects on PanIN to PDAC progression, vessel density (CD31), tumour incidence, grading or metastatic frequency. Despite comparable tumour kinetics, ablation of SPARC resulted in a significantly shortened survival in KC-SPARC mice (280 days versus 485 days, p < .03, log-rank-test). Using LC-MS/MS, we show that SPARC dependent collagen deposition does not affect intratumoural gemcitabine accumulation or immediate therapeutic response in tumour bearing KC-SPARC and KC-SPARCmice.

Interpretation: Global SPARC ablation reduces the collagen-rich microenvironment in murine PDAC. Moreover, global SPARC depletion did not affect tumour growth kinetics, grading or metastatic frequency. Notably, the dense-collagen matrix did not restrict access of gemcitabine to the tumour. These findings may have direct translational implications in clinical trial design.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838446PMC
October 2019

Proteomic Comparison of Malignant Human Germ Cell Tumor Cell Lines.

Dis Markers 2019 3;2019:8298524. Epub 2019 Sep 3.

Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.

Malignant germ cell tumors (GCT) are the most common malignant tumors in young men between 18 and 40 years. The correct identification of histological subtypes, in difficult cases supported by immunohistochemistry, is essential for therapeutic management. Furthermore, biomarkers may help to understand pathophysiological processes in these tumor types. Two GCT cell lines, TCam-2 with seminoma-like characteristics, and NTERA-2, an embryonal carcinoma-like cell line, were compared by a quantitative proteomic approach using high-resolution mass spectrometry (MS) in combination with stable isotope labelling by amino acid in cell culture (SILAC). We were able to identify 4856 proteins and quantify the expression of 3936. 347 were significantly differentially expressed between the two cell lines. For further validation, CD81, CBX-3, PHF6, and ENSA were analyzed by western blot analysis. The results confirmed the MS results. Immunohistochemical analysis on 59 formalin-fixed and paraffin-embedded (FFPE) normal and GCT tissue samples (normal testis, GCNIS, seminomas, and embryonal carcinomas) of these proteins demonstrated the ability to distinguish different GCT subtypes, especially seminomas and embryonal carcinomas. In addition, siRNA-mediated knockdown of these proteins resulted in an antiproliferative effect in TCam-2, NTERA-2, and an additional embryonal carcinoma-like cell line, NCCIT. In summary, this study represents a proteomic resource for the discrimination of malignant germ cell tumor subtypes and the observed antiproliferative effect after knockdown of selected proteins paves the way for the identification of new potential drug targets.
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http://dx.doi.org/10.1155/2019/8298524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745167PMC
February 2020