Publications by authors named "Vera Genitsch"

22 Publications

  • Page 1 of 1

Patient-derived xenografts and organoids model therapy response in prostate cancer.

Nat Commun 2021 02 18;12(1):1117. Epub 2021 Feb 18.

Department for BioMedical Research, Urology Research Laboratory, University of Bern, Bern, Switzerland.

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.
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http://dx.doi.org/10.1038/s41467-021-21300-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892572PMC
February 2021

Kissed by MDA-5: lobular panniculitis of the cheek as an initial symptom of dermatomyositis.

Rheumatology (Oxford) 2019 Nov 29. Epub 2019 Nov 29.

Department of Rheumatology, Immunology, and Allergology, Inselspital, University Hospital and University of Bern.

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http://dx.doi.org/10.1093/rheumatology/kez567DOI Listing
November 2019

Morphologic and genomic characterization of urothelial to sarcomatoid transition in muscle-invasive bladder cancer.

Urol Oncol 2019 11 1;37(11):826-836. Epub 2019 Oct 1.

Department of Urology, Inselspital, Bern University Hospital, University of Bern, Switzerland. Electronic address:

Introduction: The sarcomatoid morphology of muscle-invasive bladder cancer (MIBC) is associated with unfavorable prognosis. However, the genomic, transcriptomic, and proteomic relationship between conventional urothelial and synchronous sarcomatoid morphology is poorly defined.

Methods: We compiled a cohort of 21 MIBC patients with components of conventional urothelial and adjacent sarcomatoid morphology within the same tumor focus. We performed comprehensive pathologic and immunohistochemical characterization and in 4 selected cases, subjected both morphologic components to targeted DNA sequencing and whole transcriptome analysis.

Results: Synchronous sarcomatoid and urothelial morphology from the same MIBC foci shared truncal somatic mutations, indicating a common ancestral clone. However, additional mutations or copy number alterations restricted to the either component suggested divergent evolution at the genomic level. This was confirmed at the transcriptome level since while the urothelial component exhibited a basal-like subtype (TCGA2014: cluster III, LundTax: basal/squamous-like), the sarcomatoid morphology was predominantly cluster IV (claudin-low). Protein expression was consistent with a basal-like phenotype in both morphologies in 18/21 of cases. However, most cases had evidence of active epithelial-to-mesenchymal transition (E-Cad ↓ and Zeb1 or TWIST1 ↑) from urothelial toward the sarcomatoid morphology. Drug response signatures nominated different targets for each morphology and proposed agents under clinical investigation in liposarcoma or other sarcoma. PD-L1 expression was higher in the sarcomatoid than the urothelial component.

Conclusions: Conventional urothelial and adjacent sarcomatoid morphologies of MIBC arise from the same common ancestor and share a basal-like phenotype. However, divergence between the morphologies at the genome, transcriptome, and proteome level suggests differential sensitivity to therapy.
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http://dx.doi.org/10.1016/j.urolonc.2019.09.025DOI Listing
November 2019

Multicenter Validation of Histopathologic Tumor Regression Grade After Neoadjuvant Chemotherapy in Muscle-invasive Bladder Carcinoma.

Am J Surg Pathol 2019 12;43(12):1600-1610

Department of Urology, University of Bern, Bern.

Response classification after neoadjuvant chemotherapy in muscle-invasive bladder carcinoma is based on the TNM stage at radical cystectomy. We recently showed that histopathologic tumor regression grades (TRGs) add prognostic information to TNM. Our aim was to validate the prognostic significance of TRG in muscle-invasive bladder cancer in a multicenter setting. We enrolled 389 patients who underwent cisplatin-based chemotherapy before radical cystectomy in 8 centers between 2010 and 2016. Median follow-up was 2.2 years. TRG was determined in radical cystectomy specimens by local pathologists. Central pathology review was conducted in 20% of cases, which were randomly selected. The major response was defined as ≤pT1N0. The remaining patients were grouped into partial responders (≥ypT2N0-3 and TRG 2) and nonresponders (≥ypT2N0-3 and TRG 3). TRG was successfully determined in all cases, and interobserver agreement in central pathology review was high (κ=0.83). After combining TRG and TNM, 47%, 15%, and 38% of patients were major, partial, and nonresponders, respectively. Combination of TRG and TNM showed significant prognostic discrimination of overall survival (major responder: reference; partial responder: hazard ratio 3.5 [95% confidence interval: 1.8-6.8]; nonresponder: hazard ratio 6.1 [95% confidence interval: 3.6-10.3]). This discrimination was superior compared with TNM staging alone, supported by 2 goodness-of-fit criteria (P=0.041). TRG is a simple, reproducible histopathologic measurement of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. Integrating TRG with TNM staging resulted in significantly better prognostic stratification than TNM staging alone.
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http://dx.doi.org/10.1097/PAS.0000000000001371DOI Listing
December 2019

Morphologic and genomic characterization of urothelial to sarcomatoid transition in muscle-invasive bladder cancer.

Urol Oncol 2019 09 26;37(9):573.e19-573.e29. Epub 2019 Jul 26.

Department of Urology, Inselspital, Bern University Hospital, University of Bern, Switzerland. Electronic address:

Introduction: The sarcomatoid morphology of muscle-invasive bladder cancer (MIBC) is associated with unfavorable prognosis. However, the genomic, transcriptomic, and proteomic relationship between conventional urothelial and synchronous sarcomatoid morphology is poorly defined.

Methods: We compiled a cohort of 21 MIBC patients with components of conventional urothelial and adjacent sarcomatoid morphology within the same tumor focus. We performed comprehensive pathologic and immunohistochemical characterization and in 4 selected cases, subjected both morphologic components to targeted DNA sequencing and whole transcriptome analysis.

Results: Synchronous sarcomatoid and urothelial morphology from the same MIBC foci shared truncal somatic mutations, indicating a common ancestral clone. However, additional mutations or copy number alterations restricted to the either component suggested divergent evolution at the genomic level. This was confirmed at the transcriptome level since while the urothelial component exhibited a basal-like subtype (TCGA2014: cluster III, LundTax: basal/squamous-like), the sarcomatoid morphology was predominantly cluster IV (claudin-low). Protein expression was consistent with a basal-like phenotype in both morphologies in 18/21 of cases. However, most cases had evidence of active epithelial-to-mesenchymal transition (E-Cad ↓ and Zeb1 or TWIST1 ↑) from urothelial toward the sarcomatoid morphology. Drug response signatures nominated different targets for each morphology and proposed agents under clinical investigation in liposarcoma or other sarcoma. PD-L1 expression was higher in the sarcomatoid than the urothelial component.

Conclusions: Conventional urothelial and adjacent sarcomatoid morphologies of MIBC arise from the same common ancestor and share a basal-like phenotype. However, divergence between the morphologies at the genome, transcriptome, and proteome level suggests differential sensitivity to therapy.
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http://dx.doi.org/10.1016/j.urolonc.2019.06.021DOI Listing
September 2019

Peripheral and central nervous system involvement in a patient with primary Sjögren's syndrome: a case report.

J Med Case Rep 2019 May 25;13(1):165. Epub 2019 May 25.

University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, Freiburgstrasse 4, 3010, Bern, Switzerland.

Background: Primary Sjögren's syndrome is the second most common rheumatological disorder after rheumatoid arthritis. It typically presents as xerophthalmia and xerostomia in postmenopausal women. Involvement of the central nervous system has been recognized, although its pathogenesis and characteristics are poorly understood. Central nervous system complications are a diagnostic challenge and emphasize the need for systematic screening of patients with new peripheral and central neurological symptoms.

Case Report: We report a case of a 58-year-old Swiss woman presenting with rapidly progressive sensorimotor distal polyneuropathy together with new-onset generalized seizures. Initial magnetic resonance imaging (MRI) of the brain performed after the first seizure showed multiple, bihemispheric, confluent white matter hyperintensities with contrast enhancement. Follow-up imaging 3 days after the initial magnetic resonance imaging demonstrated a fulminant disease progression associated with the serious clinical deterioration of the patient. In light of the results of a minor salivary gland biopsy, autoantibody testing, nerve conduction studies, and cranial magnetic resonance imaging, primary Sjögren's syndrome with cryoglobulinemia type II was diagnosed. Response to plasmapheresis and subsequent administration of cyclophosphamide was favorable.

Conclusion: Even though exocrinopathy is the hallmark of Sjögren's syndrome, systemic symptoms are observed in one-third of patients. There is an urgent need to better characterize the mechanisms underlying different disease phenotypes and to perform randomized controlled trials in order to provide tailored and evidence-based treatment for primary Sjögren's syndrome.
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http://dx.doi.org/10.1186/s13256-019-2086-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534842PMC
May 2019

Relationship between renal CD68 infiltrates and the Oxford Classification of IgA nephropathy.

Histopathology 2019 Mar 15;74(4):629-637. Epub 2019 Jan 15.

Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Aims: The Oxford Classification E score (endocapillary hypercellularity) predicts renal functional decline in IgA nephropathy (IgAN) patients free from steroid/immunosuppressive (IS) therapy, but is poorly reproducible. We hypothesise that endocapillary hypercellularity reflects glomerular inflammation and that the presence of CD68-positive cells is a more robust marker of E score.

Methods And Results: CD68-positive cells were quantified in glomeruli and tubulointerstitium in biopsies from 118 IgAN patients, and cell counts were correlated with the criteria of the Oxford Classification, assigned on PAS-stained serial sections. There was a strong correlation between median glomerular CD68 count and the percentage of glomeruli showing endocapillary hypercellularity (r = 0.67; P < 0.001; r  = 0.45), while there was no correlation between CD68-positive cells and mesangial hypercellularity, % segmental sclerosis, % of crescents and % tubular atrophy/interstitial fibrosis (TA/IF). ROC curve analysis demonstrated that a maximum glomerular CD68 count of 6 is the best cut-off for distinguishing E0 from E1 (sensitivity 94.1%, specificity 71%, area under the curve = 89%). Identification of biopsies with a maximum glomerular CD68-count >6 was reproducible (kappa score 0.8), and there was a strong correlation between glomerular CD68 counts obtained by conventional light microscopy and by image analysis (r = 0.80, r  = 0.64, P < 0.0001). Digital image analysis revealed that tubulointerstitial CD68-positive cells correlated moderately with % TA/IF (r = 0.59, r  = 0.35, P < 0.001) and GFR at the time of biopsy (r = 0.54, r  = 0.29, P < 0.0001), but not with mesangial and endocapillary hypercellularity.

Conclusions: While glomerular CD68-positive cells emerge as markers of endocapillary hypercellularity, their tubulointerstitial counterparts are associated with chronic damage.
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http://dx.doi.org/10.1111/his.13768DOI Listing
March 2019

Long-term Outcomes of Kidney Transplantation in Fabry Disease.

Transplantation 2018 Nov;102(11):1924-1933

Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene that obliterate or markedly reduce α-galactosidase A activity. This results in the systemic accumulation of its glycosphingolipid substrates in body fluids and organs, including the kidney. Fabry nephropathy can lead to end-stage renal disease requiring kidney transplantation. Little is known about its long-term outcomes and the overall patient survival after kidney transplantation.

Methods: Here, we report 17 Fabry patients (15 male and 2 female subjects) who received kidney transplants and their long-term treatment and follow-up at 4 specialized Fabry centers.

Results: The posttransplant follow-up ranged to 25 years, with a median of 11.5 (range, 0.8-25.5] years. Graft survival was similar, and death-censored graft survival was superior to matched controls. Fabry patients died with functioning kidneys, mostly from cardiac causes. In 2 male subjects 14 and 23 years posttransplant, the grafts had a few typical FD lamellar inclusions, presumably originating from invading host macrophages and vascular endothelial cells.

Conclusions: We conclude that kidney transplantation has an excellent long-term outcome in FD.
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http://dx.doi.org/10.1097/TP.0000000000002252DOI Listing
November 2018

Loss of BID Delays FASL-Induced Cell Death of Mouse Neutrophils and Aggravates DSS-Induced Weight Loss.

Int J Mol Sci 2018 Feb 28;19(3). Epub 2018 Feb 28.

Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.

Neutrophils are key players in the early defense against invading pathogens. Due to their potent effector functions, programmed cell death of activated neutrophils has to be tightly controlled; however, its underlying mechanisms remain unclear. Fas ligand (FASL/CD95L) has been shown to induce neutrophil apoptosis, which is accelerated by the processing of the BH3-only protein BH3 interacting domain death agonist (BID) to trigger mitochondrial apoptotic events, and been attributed a regulatory role during viral and bacterial infections. Here, we show that, in accordance with previous works, mouse neutrophils underwent caspase-dependent apoptosis in response to FASL, and that this cell death was significantly delayed upon loss of BID. However, pan-caspase inhibition failed to protect mouse neutrophils from FASL-induced apoptosis and caused a switch to RIPK3-dependent necroptotic cell death. Intriguingly, such a switch was less evident in the absence of BID, particularly under inflammatory conditions. Delayed neutrophil apoptosis has been implicated in several auto-inflammatory diseases, including inflammatory bowel disease. We show that neutrophil and macrophage driven acute dextran sulfate sodium (DSS) induced colitis was slightly more aggravated in BID-deficient mice, based on significantly increased weight loss compared to wild-type controls. Taken together, our data support a central role for FASL > FAS and BID in mouse neutrophil cell death and further underline the anti-inflammatory role of BID.
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http://dx.doi.org/10.3390/ijms19030684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877545PMC
February 2018

Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation.

Front Immunol 2018 24;9:23. Epub 2018 Jan 24.

Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.

Aberrant interferon gamma (IFNγ) expression is associated with the pathogenesis of numerous autoimmune- and inflammatory disorders, including inflammatory bowel diseases (IBD). However, the requirement of IFNγ for the pathogenesis of chronic intestinal inflammation remains controversial. The aim of this study was thus to investigate the role of IFNγ in experimental mouse models of innate and adaptive immune cell-mediated intestinal inflammation using genetically and microbiota-stabilized hosts. While we find that IFNγ drives acute intestinal inflammation in the anti-CD40 colitis model in an innate lymphoid cell (ILC)-dependent manner, IFNγ secreted by both transferred CD4 T cells and/or cells of the lymphopenic recipient mice was dispensable for CD4 T cell-mediated colitis. In the absence of IFNγ, intestinal inflammation in CD4 T cell recipient mice was associated with enhanced IL17 responses; consequently, targeting IL17 signaling in IFNγ-deficient mice reduced T cell-mediated colitis. Intriguingly, in contrast to the anti-CD40 model of colitis, depletion of ILC in the recipients of colitogenic CD4 T cells did not prevent induction of colonic inflammation. Together, our findings demonstrate that IFNγ represents an essential, or a redundant, pro-inflammatory cytokine for the induction of intestinal inflammation, depending on the experimental mouse model used and on the nature of the critical disease inducing immune cell populations involved.
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http://dx.doi.org/10.3389/fimmu.2018.00023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787534PMC
February 2019

The ESRP1-GPR137 axis contributes to intestinal pathogenesis.

Elife 2017 10 4;6. Epub 2017 Oct 4.

Institute of Pathology, University of Bern, Bern, Switzerland.

Aberrant alternative pre-mRNA splicing (AS) events have been associated with several disorders. However, it is unclear whether deregulated AS directly contributes to disease. Here, we reveal a critical role of the AS regulator epithelial splicing regulator protein 1 (ESRP1) for intestinal homeostasis and pathogenesis. In mice, reduced ESRP1 function leads to impaired intestinal barrier integrity, increased susceptibility to colitis and altered colorectal cancer (CRC) development. Mechanistically, these defects are produced in part by modified expression of ESRP1-specific isoforms differently activating the Wnt pathway. In humans, is downregulated in inflamed biopsies from inflammatory bowel disease patients. ESRP1 loss is an adverse prognostic factor in CRC. Furthermore, generation of dependent isoforms is altered in CRC and expression of a specific isoform predicts CRC patient survival. These findings indicate a central role of ESRP1-regulated AS for intestinal barrier integrity. Alterations in ESRP1 function or expression contribute to intestinal pathology.
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http://dx.doi.org/10.7554/eLife.28366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665647PMC
October 2017

Neuroendocrine Differentiation in Metastatic Conventional Prostate Cancer Is Significantly Increased in Lymph Node Metastases Compared to the Primary Tumors.

Int J Mol Sci 2017 Jul 28;18(8). Epub 2017 Jul 28.

Institute of Pathology, University of Bern, Bern 3008, Switzerland.

Neuroendocrine serum markers released from prostate cancers have been proposed for monitoring disease and predicting survival. However, neuroendocrine differentiation (NED) in various tissue compartments of metastatic prostate cancer is poorly described and its correlation with specific tumor features is unclear. NED was determined by Chromogranin A expression on immunostains from a tissue microarray of 119 nodal positive, hormone treatment-naïve prostate cancer patients who underwent radical prostatectomy and extended lymphadenectomy. NED in the primary cancer and in the metastases was correlated with tumor features and survival. The mean percentage of NED cells increased significantly ( < 0.001) from normal prostate glands (0.4%), to primary prostate cancer (1.0%) and nodal metastases (2.6%). In primary tumors and nodal metastases, tumor areas with higher Gleason patterns tended to display a higher NED, although no significance was reached. The same was observed in patients with a larger primary tumor volume and higher total size and number of metastases. NED neither in the primary tumors nor in the metastases predicted outcome significantly. Our data suggest that (a) increasing levels of neuroendocrine serum markers in the course of prostate cancer might primarily derive from a poorly differentiated metastatic tumor component; and (b) NED in conventional hormone-naïve prostate cancers is not significantly linked to adverse tumor features.
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http://dx.doi.org/10.3390/ijms18081640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578030PMC
July 2017

Successful Treatment of Pituitary Germinoma with Etoposide, Cisplatin, Vincristine, Methotrexate and Bleomycin Chemotherapy Without Radiotherapy.

Anticancer Res 2017 06;37(6):3111-3115

Department of Medical Oncology, University Hospital Bern, Bern, Switzerland

We report on the case of a 25-year-old man with pituitary germinoma. The patient had noticed polydipsia, reduced sexual function, and loss of body hair. Laboratory investigations confirmed panhypopituitarism including diabetes insipidus. Magnetic resonance imaging of the brain showed a 14×8.4 mm enhancing lesion of the pituitary stalk and histopathology of the neurosurgical biopsy confirmed pituitary germinoma. The patient was treated with 3 cycles of chemotherapy, consisting of 150 mg/m etoposide and 75 mg/m cisplatin, with the administration of intrathecal 12.5 mg methotrexate, on day one, alternating every 10 to 11 days with 1 mg/m vincristine, 1,000 mg/m methotrexate on day 1 and 30 mg/m bleomycin on day 2. MRI scans showed lasting complete remission more than a year after completion of chemotherapy. Intracranial germinomas are exquisitely sensitive to radiation. However, due to concerns of side-effects (radiation-associated tumour, relapse outside the radiation field, mental and pituitary hormonal dysfunction), and after discussing both approaches carefully with the patient, the decision was made to treat his pituitary germinoma with chemotherapy alone. Further studies should address the question as to whether a modulated approach, using radiotherapy only as a salvage in patients with relapse, might result in a better overall outcome, given the potentially harmful long-term side-effects of radiotherapy to the brain.
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http://dx.doi.org/10.21873/anticanres.11668DOI Listing
June 2017

Her2 alterations in muscle-invasive bladder cancer: Patient selection beyond protein expression for targeted therapy.

Sci Rep 2017 02 16;7:42713. Epub 2017 Feb 16.

Department of Urology, University of Bern, Bern, Switzerland.

Although the introduction of novel targeted agents has improved patient outcomes in several human cancers, no such advance has been achieved in muscle-invasive bladder cancer (MIBC). However, recent sequencing efforts have begun to dissect the complex genomic landscape of MIBC, revealing distinct molecular subtypes and offering hope for implementation of targeted therapies. Her2 (ERBB2) is one of the most established therapeutic targets in breast and gastric cancer but agents targeting Her2 have not yet demonstrated anti-tumor activity in MIBC. Through an integrated analysis of 127 patients from three centers, we identified alterations of Her2 at the DNA, RNA and protein level, and demonstrate that Her2 relevance as a tumor driver likely may vary even within ERBB2 amplified cases. Importantly, tumors with a luminal molecular subtype have a significantly higher rate of Her2 alterations than those of the basal subtype, suggesting that Her2 activity is also associated with subtype status. Although some of our findings present rare events in bladder cancer, our study suggests that comprehensively assessing Her2 status in the context of tumor molecular subtype may help select MIBC patients most likely to respond to Her2 targeted therapy.
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http://dx.doi.org/10.1038/srep42713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5311866PMC
February 2017

Importance and outcome relevance of central pathology review in prostatectomy specimens: data from the SAKK 09/10 randomized trial on prostate cancer.

BJU Int 2017 11 19;120(5B):E45-E51. Epub 2017 Jan 19.

Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland.

Objective: To conduct a central pathology review within a randomized clinical trial on salvage radiation therapy (RT) in the presence of biochemical recurrence after prostatectomy to assess whether this results in changes in histopathological prognostic factors, such as Gleason score.

Patients And Methods: A total of 350 patients were randomized and specimens from 279 patients (80%) were centrally reviewed by a dedicated genitourinary pathologist. Gleason score, tumour classification and resection margin status were reassessed and compared with the results of local pathology review. Agreement was assessed using contingency tables and Cohen's kappa coefficient. The association between other histopathological features (e.g. largest diameter of carcinoma) and rapid biochemical progression (up to 6 months after salvage RT) was also investigated.

Results: There was good concordance between central and local pathology review for seminal vesicle invasion (pT3b: 91%; κ = 0.95 [95% confidence interval {CI} 0.89, 1.00]), extraprostatic extension (pT3a/b: 94%; κ = 0.82 [95% CI 0.75, 0.89]) and positive surgical margin (PSM) status (87%; κ = 0.7 [95% CI 0.62, 0.79]). The rate of agreement was lower for Gleason score (78%; κ = 0.61 [95% CI 0.52, 0.70]). The median (range) largest diameter of carcinoma was 16 (3-38) mm. A total of 49 patients (18%) experienced rapid biochemical progression after salvage RT. Largest diameter of carcinoma (odds ratio [OR] 2.04 [95% CI 1.30, 3.20]; P = 0.002), resection margin status (OR 0.36 [95% CI 0.18, 0.72]; P = 0.004) and Gleason score (OR 1.55 [95% CI 1.00, 2.42]; P = 0.05) remained associated with rapid progression after salvage RT after backward selection.

Conclusion: The results of the central pathology analyses showed concordance between central and local pathology review with regard to seminal vesicle invasion, extraprostatic extension and PSM status, but a lower rate of agreement for Gleason score. Largest diameter of carcinoma was found to be a potential prognostic factor for rapid biochemical progression after salvage RT.
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http://dx.doi.org/10.1111/bju.13742DOI Listing
November 2017

The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice.

Oncoimmunology 2016;5(1):e1062966. Epub 2015 Jun 26.

Institute of Pathology, University of Bern , Bern, Switzerland.

Colorectal cancer (CRC) develops through a multistep process and is modulated by inflammation. However, the inflammatory pathways that support intestinal tumors at different stages remain incompletely understood. Interleukin (IL)-33 signaling plays a role in intestinal inflammation, yet its contribution to the pathogenesis of CRC is unknown. Using immunohistochemistry on 713 resected human CRC specimens, we show here that IL-33 and its receptor ST2 are expressed in low-grade and early-stage human CRCs, and to a lesser extent in higher-grade and more advanced-stage tumors. In a mouse model of CRC, ST2-deficiency protects from tumor development. Moreover, bone marrow (BM) chimera studies indicate that engagement of the IL-33/ST2 pathway on both the radio-resistant and radio-sensitive compartment is essential for CRC development. Mechanistically, activation of IL-33/ST2 signaling compromises the integrity of the intestinal barrier and triggers the production of pro-tumorigenic IL-6 by immune cells. Together, this data reveals a tumor-promoting role of IL-33/ST2 signaling in CRC.
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http://dx.doi.org/10.1080/2162402X.2015.1062966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760343PMC
June 2015

A Specific Mapping Study Using Fluorescence Sentinel Lymph Node Detection in Patients with Intermediate- and High-risk Prostate Cancer Undergoing Extended Pelvic Lymph Node Dissection.

Eur Urol 2016 11 5;70(5):734-737. Epub 2016 Feb 5.

Department of Urology, Bern University Hospital, Bern, Switzerland. Electronic address:

Sentinel lymph node (SLN) detection techniques have the potential to change the standard of surgical care for patients with prostate cancer. We performed a lymphatic mapping study and determined the value of fluorescence SLN detection with indocyanine green (ICG) for the detection of lymph node metastases in intermediate- and high-risk patients undergoing radical prostatectomy and extended pelvic lymph node dissection. A total of 42 patients received systematic or specific ICG injections into the prostate base, the midportion, the apex, the left lobe, or the right lobe. We found (1) that external and internal iliac regions encompass the majority of SLNs, (2) that common iliac regions contain up to 22% of all SLNs, (3) that a prostatic lobe can drain into the contralateral group of pelvic lymph nodes, and (4) that the fossa of Marcille also receives significant drainage. Among the 12 patients who received systematic ICG injections, 5 (42%) had a total of 29 lymph node metastases. Of these, 16 nodes were ICG positive, yielding 55% sensitivity. The complex drainage pattern of the prostate and the low sensitivity of ICG for the detection of lymph node metastases reported in our study highlight the difficulties related to the implementation of SNL techniques in prostate cancer.

Patient Summary: There is controversy about how extensive lymph node dissection (LND) should be during prostatectomy. We investigated the lymphatic drainage of the prostate and whether sentinel node fluorescence techniques would be useful to detect node metastases. We found that the drainage pattern is complex and that the sentinel node technique is not able to replace extended pelvic LND.
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http://dx.doi.org/10.1016/j.eururo.2016.01.034DOI Listing
November 2016

Epstein-barr virus in gastro-esophageal adenocarcinomas - single center experiences in the context of current literature.

Front Oncol 2015 26;5:73. Epub 2015 Mar 26.

Institute of Pathology, University of Bern , Bern , Switzerland.

Epstein-Barr virus (EBV)-associated gastric carcinomas (GC) represent a distinct and well-recognized subtype of gastric cancer with a prevalence of around 10% of all GC. In contrast, EBV has not been reported to play a major role in esophageal adenocarcinomas (EAC) and adenocarcinomas of the gastro-esophageal junction (GEJ). We report our experiences on EBV in collections of gastro-esophageal adenocarcinomas from two surgical centers and discuss the current state of research in this field. Tumor samples from 465 primary resected gastro-esophageal adenocarcinomas (118 EAC, 73 GEJ, and 274 GC) were investigated. Presence of EBV was determined by EBV-encoded small RNAs (EBER) in situ hybridization. Results were correlated with pathologic parameters (UICC pTNM category, Her2 status, tumor grading) and survival. EBER positivity was observed in 14 cases. None of the EAC were positive for EBER. In contrast, we observed EBER positivity in 2/73 adenocarcinomas of the GEJ (2.7%) and 12/274 GC (4.4%). These were of intestinal type (seven cases) or unclassifiable (six cases), while only one case was of diffuse type according to the Lauren classification. No association between EBV and pT, pN, or tumor grading was found, neither was there a correlation with clinical outcome. None of the EBER positive cases were Her2 positive. In conclusion, EBV does not seem to play a role in the carcinogenesis of EAC. Moreover, adenocarcinomas of the GEJ show lower rates of EBV positivity compared to GC. Our data only partially correlate with previous reports from the literature. This highlights the need for further research on this distinct entity. Recent reports, however, have identified specific epigenetic and genetic alterations in EBV-associated GC, which might lead to a distinct treatment approach for this specific subtype of GC in the future.
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http://dx.doi.org/10.3389/fonc.2015.00073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374449PMC
April 2015

Prevalence and prognostic significance of TMPRSS2-ERG gene fusion in lymph node positive prostate cancers.

Prostate 2014 Dec 22;74(16):1647-54. Epub 2014 Sep 22.

Institute of Pathology, University of Bern, Switzerland.

Background: TMPRSS2-ERG gene fusion is the most frequent genetic alteration in prostate cancer. However, information about its distribution in lymph node positive prostate cancers and the prognostic significance in these advanced tumors is unknown.

Methods: Gene fusion status was determined by fluorescence in situ hybridization on a tissue-microarray constructed from 119 hormone-naïve nodal positive, surgically treated prostate cancers containing samples from the primary tumors and corresponding lymph node metastases. Data were correlated with various tumor features (Gleason score, stage, cancer volume, nodal tumor burden) and biochemical recurrence-free, disease-specific, and overall survival.

Results: TMPRSS2-ERG fusion was detected in 43.5% of the primary tumors. Conversely, only 29.9% of the metastasizing components showed the fusion. Concordance in TMPRSS2-ERG status between primary tumors and metastases was 70.9% (Kappa 0.39); 20.9% and 8.1% of the patients showed the mutation solely in their primary tumors and metastases, respectively. TMPRSS2-ERG fusion was not correlated with specific histopathological tumor features but predicted favorable biochemical recurrence-free, disease-specific and overall survival independently when present in the primary tumor (P < 0.05 each).

Conclusion: TMPRSS2-ERG fusion is more frequent in primary prostate cancer than in corresponding metastases suggesting no selection of fusion-positive cells in the metastatic process. The gene fusion in primary tumors independently predicts favorable outcome.
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http://dx.doi.org/10.1002/pros.22882DOI Listing
December 2014

TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance.

PLoS Pathog 2014 Jan 16;10(1):e1003900. Epub 2014 Jan 16.

Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory innate immune reactions. While TREM-1-amplified responses likely aid an improved detection and elimination of pathogens, excessive production of cytokines and oxygen radicals can also severely harm the host. Studies addressing the pathogenic role of TREM-1 during endotoxin-induced shock or microbial sepsis have so far mostly relied on the administration of TREM-1 fusion proteins or peptides representing part of the extracellular domain of TREM-1. However, binding of these agents to the yet unidentified TREM-1 ligand could also impact signaling through alternative receptors. More importantly, controversial results have been obtained regarding the requirement of TREM-1 for microbial control. To unambiguously investigate the role of TREM-1 in homeostasis and disease, we have generated mice deficient in Trem1. Trem1(-/-) mice are viable, fertile and show no altered hematopoietic compartment. In CD4(+) T cell- and dextran sodium sulfate-induced models of colitis, Trem1(-/-) mice displayed significantly attenuated disease that was associated with reduced inflammatory infiltrates and diminished expression of pro-inflammatory cytokines. Trem1(-/-) mice also exhibited reduced neutrophilic infiltration and decreased lesion size upon infection with Leishmania major. Furthermore, reduced morbidity was observed for influenza virus-infected Trem1(-/-) mice. Importantly, while immune-associated pathologies were significantly reduced, Trem1(-/-) mice were equally capable of controlling infections with L. major, influenza virus, but also Legionella pneumophila as Trem1(+/+) controls. Our results not only demonstrate an unanticipated pathogenic impact of TREM-1 during a viral and parasitic infection, but also indicate that therapeutic blocking of TREM-1 in distinct inflammatory disorders holds considerable promise by blunting excessive inflammation while preserving the capacity for microbial control.
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http://dx.doi.org/10.1371/journal.ppat.1003900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894224PMC
January 2014

Fatal pulmonary embolism in a premature neonate after twin-to-twin transfusion syndrome.

Pediatrics 2010 Aug 5;126(2):e483-7. Epub 2010 Jul 5.

Department of Pediatrics, University of Bern, Bern, Switzerland.

Thrombotic events are being increasingly recognized during the neonatal period. An infant girl was born at 29 weeks' gestation after a pregnancy complicated by twin-to-twin transfusion syndrome. After an initial uncomplicated clinical course, her oxygen requirement increased, which was interpreted as an early sign of bronchopulmonary dysplasia. At 3 weeks of age, she suddenly collapsed and died of severe pulmonary hypertension. At autopsy, multiple pulmonary artery emboli and several older renal vein thromboses were found. Results of genetic analyses of the infant and her family were negative for thrombophilia. Although embolism represents a frequent emergency in adults, fatal pulmonary embolism has never, to our knowledge, been described for premature infants. This case suggests that thrombotic events are underdiagnosed and that additional studies are needed to define infants at risk and optimal treatment strategies.
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http://dx.doi.org/10.1542/peds.2009-3490DOI Listing
August 2010