119 results on '"Ferlicot, Sophie"'
Search Results
2. Geographic variation of mutagenic exposures in kidney cancer genomes.
- Author
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Senkin S, Moody S, Díaz-Gay M, Abedi-Ardekani B, Cattiaux T, Ferreiro-Iglesias A, Wang J, Fitzgerald S, Kazachkova M, Vangara R, Le AP, Bergstrom EN, Khandekar A, Otlu B, Cheema S, Latimer C, Thomas E, Atkins JR, Smith-Byrne K, Cortez Cardoso Penha R, Carreira C, Chopard P, Gaborieau V, Keski-Rahkonen P, Jones D, Teague JW, Ferlicot S, Asgari M, Sangkhathat S, Attawettayanon W, Świątkowska B, Jarmalaite S, Sabaliauskaite R, Shibata T, Fukagawa A, Mates D, Jinga V, Rascu S, Mijuskovic M, Savic S, Milosavljevic S, Bartlett JMS, Albert M, Phouthavongsy L, Ashton-Prolla P, Botton MR, Silva Neto B, Bezerra SM, Curado MP, Zequi SC, Reis RM, Faria EF, de Menezes NS, Ferrari RS, Banks RE, Vasudev NS, Zaridze D, Mukeriya A, Shangina O, Matveev V, Foretova L, Navratilova M, Holcatova I, Hornakova A, Janout V, Purdue MP, Rothman N, Chanock SJ, Ueland PM, Johansson M, McKay J, Scelo G, Chanudet E, Humphreys L, de Carvalho AC, Perdomo S, Alexandrov LB, Stratton MR, and Brennan P
- Subjects
- Female, Humans, Male, Aristolochic Acids adverse effects, Genome, Human genetics, Genomics, Hypertension epidemiology, Incidence, Japan epidemiology, Obesity epidemiology, Risk Factors, Romania epidemiology, Serbia epidemiology, Thailand epidemiology, Tobacco Smoking adverse effects, Tobacco Smoking genetics, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell epidemiology, Carcinoma, Renal Cell chemically induced, Environmental Exposure adverse effects, Environmental Exposure analysis, Geography, Kidney Neoplasms genetics, Kidney Neoplasms epidemiology, Kidney Neoplasms chemically induced, Mutagens adverse effects, Mutation
- Abstract
International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden
1 . In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2 . Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics., (© 2024. The Author(s).)- Published
- 2024
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3. DCLRE1B/Apollo germline mutations associated with renal cell carcinoma impair telomere protection.
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Bories C, Lejour T, Adolphe F, Kermasson L, Couvé S, Tanguy L, Luszczewska G, Watzky M, Poillerat V, Garnier P, Groisman R, Ferlicot S, Richard S, Saparbaev M, Revy P, Gad S, and Renaud F
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- Humans, Germ-Line Mutation, Telomere genetics, DNA Damage, DNA Repair genetics, Exodeoxyribonucleases genetics, Carcinoma, Renal Cell genetics
- Abstract
Hereditary renal cell carcinoma (RCC) is caused by germline mutations in a subset of genes, including VHL, MET, FLCN, and FH. However, many familial RCC cases do not harbor mutations in the known predisposition genes. Using Whole Exome Sequencing, we identified two germline missense variants in the DCLRE1B/Apollo gene (Apollo
N246I and ApolloY273H ) in two unrelated families with several RCC cases. Apollo encodes an exonuclease involved in DNA Damage Response and Repair (DDRR) and telomere integrity. We characterized these two functions in the human renal epithelial cell line HKC8. The decrease or inhibition of Apollo expression sensitizes these cells to DNA interstrand crosslink damage (ICLs). HKC8 Apollo-/- cells appear defective in the DDRR and present an accumulation of telomere damage. Wild-type and mutated Apollo forms could interact with TRF2, a shelterin protein involved in telomere protection. However, only ApolloWT can rescue the telomere damage in HKC8 Apollo-/- cells. Our results strongly suggest that ApolloN246I and ApolloY273H are loss-of-function mutants that cause impaired telomere integrity and could lead to genomic instability. Altogether, our results suggest that mutations in Apollo could induce renal oncogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024. Published by Elsevier B.V.)- Published
- 2024
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4. Bone Marrow Oxalosis.
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d'Izarny-Gargas T, Dang J, Grünenwald A, Mechref Z, Besson FL, Ferlicot S, and Zaidan M
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- 2024
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5. Immune checkpoints are predominantly co-expressed by clonally expanded CD4 + FoxP3 + intratumoral T-cells in primary human cancers.
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Bredel D, Tihic E, Mouraud S, Danlos FX, Susini S, Aglave M, Alfaro A, Mohamed-Djalim C, Rouanne M, Halse H, Bigorgne A, Tselikas L, Dalle S, Hartl DM, Baudin E, Guettier C, Vibert E, Rosmorduc O, Robert C, Ferlicot S, Parier B, Albiges L, de Montpreville VT, Besse B, Mercier O, Even C, Breuskin I, Classe M, Radulescu C, Lebret T, Pautier P, Gouy S, Scoazec JY, Zitvogel L, Marabelle A, and Bonvalet M
- Subjects
- Humans, T-Lymphocyte Subsets, Receptors, Antigen, T-Cell, CD8-Positive T-Lymphocytes, Neoplasms genetics, Neoplasms metabolism
- Abstract
Background: In addition to anti-PD(L)1, anti-CTLA-4 and anti-LAG-3, novel immune checkpoint proteins (ICP)-targeted antibodies have recently failed to demonstrate significant efficacy in clinical trials. In these trials, patients were enrolled without screening for drug target expression. Although these novel ICP-targeted antibodies were expected to stimulate anti-tumor CD8 + T-cells, the rationale for their target expression in human tumors relied on pre-clinical IHC stainings and transcriptomic data, which are poorly sensitive and specific techniques for assessing membrane protein expression on immune cell subsets. Our aim was to describe ICP expression on intratumoral T-cells from primary solid tumors to better design upcoming neoadjuvant cancer immunotherapy trials., Methods: We prospectively performed multiparameter flow cytometry and single-cell RNA sequencing (scRNA-Seq) paired with TCR sequencing on freshly resected human primary tumors of various histological types to precisely determine ICP expression levels within T-cell subsets., Results: Within a given tumor type, we found high inter-individual variability for tumor infiltrating CD45 + cells and for T-cells subsets. The proportions of CD8
+ T-cells (~ 40%), CD4+ FoxP3- T-cells (~ 40%) and CD4+ FoxP3+ T-cells (~ 10%) were consistent across patients and indications. Intriguingly, both stimulatory (CD25, CD28, 4-1BB, ICOS, OX40) and inhibitory (PD-1, CTLA-4, PD-L1, CD39 and TIGIT) checkpoint proteins were predominantly co-expressed by intratumoral CD4+ FoxP3+ T-cells. ScRNA-Seq paired with TCR sequencing revealed that T-cells with high clonality and high ICP expressions comprised over 80% of FoxP3+ cells among CD4+ T-cells. Unsupervised clustering of flow cytometry and scRNAseq data identified subsets of CD8+ T-cells and of CD4+ FoxP3- T-cells expressing certain checkpoints, though these expressions were generally lower than in CD4+ FoxP3+ T-cell subsets, both in terms of proportions among total T-cells and ICP expression levels., Conclusions: Tumor histology alone does not reveal the complete picture of the tumor immune contexture. In clinical trials, assumptions regarding target expression should rely on more sensitive and specific techniques than conventional IHC or transcriptomics. Flow cytometry and scRNAseq accurately characterize ICP expression within immune cell subsets. Much like in hematology, flow cytometry can better describe the immune contexture of solid tumors, offering the opportunity to guide patient treatment according to drug target expression rather than tumor histological type., (© 2023. The Author(s).)- Published
- 2023
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6. Prognostic value of programmed death ligand-1 and programmed death-1 expression in patients with upper tract urothelial carcinoma.
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Campedel L, Compérat E, Cancel-Tassin G, Varinot J, Pfister C, Delcourt C, Gobet F, Roumiguié M, Patard PM, Daniel G, Bigot P, Carrouget J, Eymerit C, Larré S, Léon P, Durlach A, Ruffion A, de Mazancourt ES, Decaussin-Petrucci M, Bessède T, Lebacle C, Ferlicot S, Robert G, Vuong NS, Philip M, Crouzet S, Matillon X, Mège-Lechevallier F, Lang H, Mouracade P, Lindner V, Gougis P, Cussenot O, Rouprêt M, and Seisen T
- Abstract
Objective: To evaluate the prognostic value of programmed death ligand-1 (PD-L1) and programmed death-1 (PD-1) expression in patients with upper tract urothelial carcinoma (UTUC)., Patients and Methods: A retrospective multicentre study was conducted in 283 patients with UTUC treated with radical nephroureterectomy (RNU) between 2000 and 2015 at 10 French hospitals. Immunohistochemistry analyses were performed using 2 mm-core tissue microarrays with NAT105® and 28.8® antibodies at a 5% cut-off for positivity on tumour cells and tumour-infiltrating lymphocytes to evaluate PD-L1 and PD-1 expression, respectively. Multivariable Cox regression models were used to determine the independent predictors of recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS)., Results: Overall, 63 (22.3%) and 220 (77.7%) patients with UTUC had PD-L1-positive and -negative disease, respectively, while 91 (32.2%) and 192 (67.8%) had PD-1-positive and -negative disease, respectively. Patients who expressed PD-L1 or PD-1 were more likely to have pathological tumour stage ≥pT2 (68.3% vs 49.5%, P = 0.009; and 69.2% vs 46.4%, P < 0.001, respectively) and high-grade (90.5% vs 70.0%, P = 0.001; and 91.2% vs 66.7%, P < 0.001, respectively) disease with lymphovascular invasion (52.4% vs 17.3%, P < 0.001; and 39.6% vs 18.2%, P < 0.001, respectively) as compared to those who did not. In multivariable Cox regression analysis adjusting for each other, PD-L1 and PD-1 expression were significantly associated with decreased RFS (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.09-3.08, P = 0.023; and HR 1.59, 95% CI 1.01-2.54, P = 0.049; respectively), CSS (HR 2.73, 95% CI 1.48-5.04, P = 0.001; and HR 1.96, 95% CI 1.12-3.45, P = 0.019; respectively) and OS (HR 2.08, 95% CI 1.23-3.53, P = 0.006; and HR 1.71, 95% CI 1.05-2.78, P = 0.031; respectively). In addition, multivariable Cox regression analyses evaluating the four-tier combination of PD-L1 and PD-1 expression showed that only PD-L1/PD-1-positive patients (n = 38 [13.4%]) had significantly decreased RFS (HR 3.07, 95% CI 1.70-5.52; P < 0.001), CSS (HR 5.23, 95% CI 2.62-10.43; P < 0.001) and OS (HR 3.82, 95% CI 2.13-6.85; P < 0.001) as compared to those with PD-L1/PD-1-negative disease (n = 167 [59.0%])., Conclusions: We observed that PD-L1 and PD-1 expression were both associated with adverse pathological features that translated into an independent and cumulative adverse prognostic value in UTUC patients treated with RNU., (© 2023 BJU International.)
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- 2023
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7. C3 Glomerulopathy With Concurrent Thrombotic Microangiopathy: Clinical and Immunological Features.
- Author
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Chabannes M, Rabant M, El Sissy C, Dragon-Durey MA, Vieira Martins P, Meuleman MS, Karras A, Buob D, Bridoux F, Daugas E, Audard V, Caillard S, Olagne J, Kandel C, Ferlicot S, Philipponnet C, Crepin T, Thervet E, Ducloux D, Frémeaux-Bacchi V, and Chauvet S
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- Humans, Female, Child, Adolescent, Young Adult, Adult, Middle Aged, Aged, Male, Retrospective Studies, Kidney, Atypical Hemolytic Uremic Syndrome drug therapy, Thrombotic Microangiopathies therapy, Thrombotic Microangiopathies complications, Paraproteinemias complications
- Abstract
Rationale & Objective: C3 glomerulopathy (C3GN) and atypical hemolytic uremic syndrome (aHUS) are 2 distinct rare kidney diseases caused by dysregulation of the alternative complement pathway. Patients with C3GN and concurrent kidney lesions of thrombotic microangiopathy (TMA) have been rarely reported. We characterized the clinical features and underlying immunological abnormalities in these patients., Study Design: Case series., Setting & Participants: Patients with C3GN and concomitant TMA lesions on biopsy registered from 2009 to 2019 in the French National Registry of C3GN., Findings: Among 278 registered patients with C3GN, 16 (6%) had biopsy-proven glomerular and/or vascular TMA lesions. Their median age at diagnosis was 39 years (range, 7-76), and 59% were female. Fourteen of the 16 patients (88%) had an estimated glomerular filtration rate of<30mL/min/1.73m
2 and 3 of 16 (19%) required dialysis. Twelve of the 14 evaluated patients (86%) showed evidence of mechanical hemolysis. Fifty percent of the patients had low C3 levels. Six of the 14 evaluated patients had a rare variant in complement genes, and 4 of the 16 patients (25%) had monoclonal gammopathy. Among the 16 patients, 10 (63%) received eculizumab, 5 (31%) received immunosuppressive therapy, and 4 (25%) received clone-targeted chemotherapy. Median kidney survival was 49 months., Limitations: Small retrospective case series with a limited number of biopsies including electron microscopy., Conclusions: Concomitant C3GN and TMA is extremely rare and is associated with poor kidney outcomes. Genetic or acquired abnormalities of the alternative complement pathway are common as is the presence of monoclonal gammopathy, which may inform the selection of treatment approaches., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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8. Pathological spectrum of hereditary transthyretin renal amyloidosis and clinicopathologic correlation: a French observational study.
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Dang J, Ferlicot S, Misrahi M, Mussini C, Kounis I, Rémy P, Samuel D, Planté-Bordeneuve V, Adams D, Funalot B, Snanoudj R, Damy T, Moktefi A, Audard V, and Zaidan M
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- Humans, Retrospective Studies, Prealbumin genetics, Plaque, Amyloid pathology, Kidney, Proteinuria pathology, Amyloid Neuropathies, Familial pathology, Kidney Diseases pathology, Immunoglobulin Light-chain Amyloidosis
- Abstract
Background: Cardiac and neurological involvements are the main clinical features of hereditary transthyretin (ATTRv) amyloidosis. Few data are available about ATTRv amyloid nephropathy (ATTRvN)., Methods: We retrospectively included 30 patients with biopsy-proven ATTRvN [V30M (26/30) including two domino liver recipients, S77Y (2/30), V122I (1/30) and S50R (1/30) variants] from two French reference centers. We described the pathological features by comparing amyloid deposits distribution to patients with AL or AA amyloidosis, and sought to determine clinicopathological correlation with known disease-modifying factors such as TTR variant, gender and age at diagnosis., Results: In comparison with AL and AA amyloidosis, ATTRv patients had similar glomerular, arteriolar and arterial amyloid deposits, but more cortical and medullary tubulointerstitial (33%, 44%, 77%, P = .03) involvement. While the presence of glomerular deposits is associated with the range of proteinuria, some patients with abundant glomerular ATTRv amyloidosis had no significant proteinuria. V30M patients had more glomerular (100% and 25%, odds ratio = 114, 95% confidence interval 3.85-3395.00, P = .001) deposits, and higher estimated glomerular filtration rate [50 (interquartile range 44-82) and 27 (interquartile range 6-31) mL/min/1.73 m², P = .004] than non-V30M patients. We did not find difference in amyloid deposition according to gender or age at diagnosis., Conclusion: ATTRvN affects all kidney compartments, but compared with AL/AA amyloidosis, ATTRvN seems to involve more frequently tubulointerstitial areas. V30M patients represents the dominant face of the disease with a higher risk of glomerular/arteriolar involvement. ATTRvN should thus be considered in patients, and potential relatives, with ATTRv amyloidosis and kidney dysfunction, regardless of proteinuria level., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)
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- 2023
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9. Clinical and Prognostic Factors in Patients with IgG4-Related Kidney Disease.
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Chaba A, Devresse A, Audard V, Boffa JJ, Karras A, Cartery C, Deltombe C, Chemouny J, Contamin C, Courivaud C, Duquennoy S, Garcia H, Joly D, Goumri N, Hanouna G, Halimi JM, Plaisier E, Hamidou M, Landron C, Launay D, Lebas C, Legendre M, Masseau A, Mathian A, Mercadal L, Morel N, Mutinelli-Szymanski P, Palat S, Pennaforte JL, Peraldi MN, Pozdzik A, Schleinitz N, Thaunat O, Titeca-Beauport D, Mussini C, Touati S, Prinz E, Faller AL, Richter S, Vilaine E, Ferlicot S, Von-Kotze C, Belliere J, Olagne J, Mesbah R, Snanoudj R, Nouvier M, Ebbo M, and Zaidan M
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- Adult, Middle Aged, Humans, Male, Aged, Female, Rituximab adverse effects, Cohort Studies, Prognosis, Kidney pathology, Immunoglobulin G, Recurrence, Retrospective Studies, Immunoglobulin G4-Related Disease complications, Immunoglobulin G4-Related Disease diagnosis, Immunoglobulin G4-Related Disease drug therapy, Nephritis, Interstitial pathology
- Abstract
Background: IgG4-related kidney disease is a major manifestation of IgG4-related disease, a systemic fibroinflammatory disorder. However, the clinical and prognostic kidney-related factors in patients with IgG4-related kidney disease are insufficiently defined., Methods: We conducted an observational cohort study using data from 35 sites in two European countries. Clinical, biologic, imaging, and histopathologic data; treatment modalities; and outcomes were collected from medical records. Logistic regression was performed to identify the possible factors related to an eGFR ≤30 ml/min per 1.73 m 2 at the last follow-up. Cox proportional hazards model was performed to assess the factors associated with the risk of relapse., Results: We studied 101 adult patients with IgG4-related disease with a median follow-up of 24 (11-58) months. Of these, 87 (86%) patients were male, and the median age was 68 (57-76) years. Eighty-three (82%) patients had IgG4-related kidney disease confirmed by kidney biopsy, with all biopsies showing tubulointerstitial involvement and 16 showing glomerular lesions. Ninety (89%) patients were treated with corticosteroids, and 18 (18%) patients received rituximab as first-line therapy. At the last follow-up, the eGFR was below 30 ml/min per 1.73 m 2 in 32% of patients; 34 (34%) patients experienced a relapse, while 12 (13%) patients had died. By Cox survival analysis, the number of organs involved (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.55) and low C3 and C4 concentrations (HR, 2.31; 95% CI, 1.10 to 4.85) were independently associated with a higher risk of relapse, whereas first-line therapy with rituximab was protective (HR, 0.22; 95% CI, 0.06 to 0.78). At their last follow-up, 19 (19%) patients had an eGFR ≤30 ml/min per 1.73 m 2 . Age (odd ratio [OR], 1.11; 95% CI, 1.03 to 1.20), peak serum creatinine (OR, 2.74; 95% CI, 1.71 to 5.47), and serum IgG4 level ≥5 g/L (OR, 4.46; 95% CI, 1.23 to 19.40) were independently predictive for severe CKD., Conclusions: IgG4-related kidney disease predominantly affected middle-aged men and manifested as tubulointerstitial nephritis with potential glomerular involvement. Complement consumption and the number of organs involved were associated with a higher relapse rate, whereas first-line therapy with rituximab was associated with lower relapse rate. Patients with high serum IgG4 concentrations (≥5 g/L) had more severe kidney disease., (Copyright © 2023 by the American Society of Nephrology.)
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- 2023
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10. Urinary biomarkers for bladder cancer diagnosis and NMIBC follow-up: a systematic review.
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Soorojebally Y, Neuzillet Y, Roumiguié M, Lamy PJ, Allory Y, Descotes F, Ferlicot S, Kassab-Chahmi D, Oudard S, Rébillard X, Roy C, Lebret T, Rouprêt M, and Audenet F
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- Humans, Biomarkers, Tumor urine, Cystoscopy methods, Cytodiagnosis, Neoplasm Recurrence, Local pathology, Urinary Bladder pathology, Urinary Bladder Neoplasms pathology
- Abstract
Background: Bladder cancer detection and follow-up is based on cystoscopy and/or cytology, but it remains imperfect and invasive. Current research focuses on diagnostic biomarkers that could improve bladder cancer detection and follow-up by discriminating patients at risk of aggressive cancer who need confirmatory TURBT (Transurethral Resection of Bladder Tumour) from patients at no risk of aggressive cancer who could be spared from useless explorations., Objective: To perform a systematic review of data on the clinical validity and clinical utility of eleven urinary biomarkers (VisioCyt
® , Xpert® Bladder, BTA stat® , BTA TRAK™, NMP22 BC® , NMP22® BladderChek® Test, ImmunoCyt™/uCyt1+™, UroVysion Bladder Cancer Kit® , Cxbladder, ADXBLADDER, Urodiag® ) for bladder cancer diagnosis and for non-muscle invasive bladder cancer (NMIBC) follow-up., Methods: All available studies on the 11 biomarkers published between May 2010 and March 2021 and present in MEDLINE® were reviewed. The main endpoints were clinical performance for bladder cancer detection, recurrence or progression during NMIBC monitoring, and additional value compared to cytology and/or cystoscopy., Results: Most studies on urinary biomarkers had a prospective design and high level of evidence. However, their results should be interpreted with caution given the heterogeneity among studies. Most of the biomarkers under study displayed higher detection sensitivity compared with cytology, but lower specificity. Some biomarkers may have clinical utility for NMIBC surveillance in patients with negative or equivocal cystoscopy or negative or atypical urinary cytology findings, and also for recurrence prediction., Conclusion: Urinary biomarkers might have a complementary place in bladder cancer diagnosis and NMIBC surveillance. However, their clinical benefit remains to be confirmed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2023
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11. Cryptic splice site poisoning and meiotic arrest caused by a homozygous frameshift mutation in RBMXL2: A case report.
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Ghieh F, Izard V, Poulain M, Fortemps J, Kazdar N, Mandon-Pepin B, Ferlicot S, Ayoubi JM, and Vialard F
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- Humans, Mice, Animals, Male, RNA Splice Sites genetics, Frameshift Mutation, Meiosis genetics, Spermatogenesis genetics, Testis metabolism, RNA-Binding Proteins genetics, Mutation, Mammals genetics, Mammals metabolism, Azoospermia chemically induced, Azoospermia genetics, Azoospermia metabolism, Infertility, Male genetics, Infertility, Male metabolism
- Abstract
Gene expression in meiotic cells in the testis is characterized by intense transcriptional activity and alternative splicing. These processes are mainly controlled by RNA-binding proteins expressed strongly in germ cells. Functional impairments in any of these proteins' functions can lead to defects in meiosis and thus severe male infertility. Here, we have identified a homozygous frameshift mutation (NM_014469.4:c.301dup; p.Ser101LysfsTer29) in the RNA-binding motif protein, X-linked like 2 (RBMXL2) gene in a man with an azoospermia due to meiotic arrest. As RBMXL2 is known to be crucial for safeguarding the meiotic transcriptome in mice testes, we hypothesized that this variant leads to cryptic splice site poisoning. To determine the variant's impact on spermatogenesis, we confirmed the absence of RBMXL2 protein in the patient's testis tissue and then evidenced abnormal expression of several spermatogenesis proteins (e.g. meiosis-specific with coiled-coil domain) known to be altered in rbmxl2 knock-out mice with meiotic arrest. Our results indicate that RBMXL2's function in spermatogenesis is conserved in mammals. We hypothesize that deleterious variant in the RBMXL2 gene can result in male infertility and complete meiotic arrest, due to the disruption of gene expression by cryptic splice site poisoning., (© 2022 Wiley-VCH GmbH.)
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- 2022
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12. Renal involvement of lymphomas proven by kidney biopsy: report of 10 cases from a tertiary care center and comparison with the literature.
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Urbain F, Ferlicot S, Rocher L, Besson FL, Gomez L, Michot JM, Lazure T, Mariette X, Nocturne G, Lambotte O, Zaidan M, and Noel N
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- Humans, Tertiary Care Centers, Kidney pathology, Biopsy, Lymphoma, B-Cell, Marginal Zone pathology, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Lymphomas localized in the kidney are a rare entity that may be challenging to diagnose. We analyzed data from 10 patients with renal involvement of lymphoma diagnosed between 2009 and 2019 on fine needle biopsy from our tertiary center, and compared these with findings of 160 cases reported in the literature. Diffuse large B-cell lymphoma was the main histology subtype (40 and 38% in our sample and in the literature, respectively), followed by low-grade B-cell lymphomas, mostly from the marginal zone (MZ). Altogether, 106 patients had urological inaugural symptoms and 64 had general symptoms. Patients with urological presentation more often had renal masses than diffuse infiltration (p < 0.001), unilateral tumors (p = 0.0036) and low-grade B-cell lymphomas (17 vs 6%, p = 0.043). In both groups, nearly one-fourth of patients had diffuse (stage IV) lymphomas. Overall survival did not differ by the presence of urological/systemic symptoms, stage or aggressive lymphoma status. Notably, 3 of 10 patients from our series had MZ lymphomas associated with primary Sjögren syndrome revealed by acute kidney injury, including one where the autoimmune disease was detected. Lymphoproliferative disorders localized in the kidney are a challenging condition that can lead to detection of aggressive or diffuse lymphomas., (© 2022. Japanese Society of Hematology.)
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- 2022
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13. Ultrasound and Magnetic Resonance Imaging of Burned-Out Testicular Tumours: The Diagnostic Keys Based on 48 Cases.
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Desmousseaux T, Arama E, Maxwell F, Ferlicot S, Hani C, Fizazi K, Lebacle C, Loriot Y, Boumerzoug M, Cohen J, Garrouche N, and Rocher L
- Abstract
The spontaneous regression of testicular germ-cell tumours is a rare event whose mechanisms have yet to be elucidated. In the majority of published cases, tumour regression is concomitant with the metastatic development of the disease. Residual lesions, often referred to as burned-out testicular tumours (BOTTs), are difficult to diagnose due to the paucity of published data, especially in the field of imaging. The aim of this article is to describe the radiological signs of BOTTs on multimodal ultrasound and multiparametric MRI from a series of 48 patients whose diagnosis was confirmed histologically. The demographic, clinical and laboratory characteristics of the patients are studied, as well as the data of the imaging examinations, including conventional scrotal ultrasound, shear-wave elastography, contrast-enhanced ultrasound (CEUS) and multiparametric MRI. A total of 27 out of 48 patients were referred for investigation of primary testicular lesion following the discovery of retroperitoneal metastases, 18/48 patients were referred because of lesions suspected on an ultrasound that was performed for an infertility work-up, and 3/48 were referred because of scrotal clinical signs. Of these last 21 patients (infertility work-up/scrotal clinical sign), 6 were found to be metastatic on the extension work-up. Of the 48 orchiectomy specimens, tumour involution was complete in 41 cases, and a small active contingent remained in 7 cases, with 6 suspected upon advanced US and MRI. Typically, BOTTs appear on a conventional ultrasound as ill-delineated, hypoechoic and hypovascular nodular areas. Clustered microliths (60.4%) and macrocalcifications (35.4%) were frequent. Shear-wave elastography showed areas of focal induration (13.5 ± 8.4 vs. 2.7 ± 1.2 kPa for normal parenchyma, p < 0.01) in 92.5% of the patients for whom it was performed, and contrast ultrasonography demonstrated hypoperfusion of these lesions. Of the 42 MRIs performed, BOTTs corresponded to nodules on T2-weighted sequences (hyposignal) with significantly increased ADC values compared with healthy parenchyma (2 ± 0.3 versus 1.3 ± 0.3 × 10−3 mm2/s, p < 0.01) and an enhancement defect after injection. This enhancement defect overlapped the lesions visible on T2-weighted sequences in most cases. In the case of predominant partial regression, an enhanced portion after contrast injection was visible on MRI in all seven patients of our series, and in six of them a focal diffusion restriction zone was also present. Spontaneously involuted testicular germ-cell tumours have specific radiological signs, and all of the mentioned examinations contribute to this difficult diagnosis, even histologically, because there is no tumour cell left. These signs are similar whether the patient is initially symptomatic metastatic or whether the discovery is fortuitous on the occasion of an infertility work-up, and whatever the seminomatous or non-seminomatous nature of the germ-cell tumour, when this can be determined. The appearance of regressed germ-cell tumours is often trivialized, which can lead to the wrong diagnosis of an extra gonadal germ-cell tumour (in metastatic patients) or of scarring from an acute event such as trauma or infection, which is not recognized or forgotten. In our series, two patients had an unrecognized diagnosis in their history, with local and/or distant recurrence. An improvement in diagnosing burned-out tumours, combining advanced US and MRI, is necessary in order to optimize patient management, with special attention paid to asymptomatic patients, to prompt extension screening and orchiectomy with analysis of the whole testis. This may reveal a persistent viable tumour or lesions of germinal neoplasia in situ, which are precursors of testicular germ-cell tumours.
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- 2022
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14. Testicular Lesions in Infertile Men.
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Dupeux M, Maxwell F, Rocher L, Izard V, Guettier C, and Ferlicot S
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- Humans, Male, Retrospective Studies, Infertility complications, Leydig Cell Tumor complications, Leydig Cell Tumor diagnosis, Leydig Cell Tumor pathology, Seminoma complications, Seminoma diagnosis, Seminoma pathology, Testicular Neoplasms pathology
- Abstract
Objectives: An increasing number of incidental testicular tumors are diagnosed in patients during infertility workup. The aim of this study was to evaluate the accuracy of frozen section examination (FSE) for the management of these tumors., Methods: We retrospectively studied a series of 46 testicular tumors diagnosed during exploration for infertility from 2000 to 2019 and submitted for FSE., Results: A diagnosis of malignancy was made in 23 cases on both gross examination (yellow-white or cream-colored nodules for seminomas) and FSE, then confirmed on final diagnosis in 22 of the cases. One seminoma reported on FSE was revised as being a Leydig cell tumor. The 23 other lesions were diagnosed as benign on FSE, including 11 Leydig cell tumors (yellow-brown nodules), 2 Leydig cell hyperplasias, and 10 whitish fibrous lesions. All Leydig cell lesions were confirmed except 1, which was reclassified as a Sertoli cell tumor. Of the 10 cases of fibrous lesions, 6 were associated with malignancy., Conclusions: The high incidence of Leydig cell tumors and the accuracy of FSE for these lesions demonstrate the interest in FSE. In contrast, FSE is not reliable for fibrous lesions, and surgeons should be aware that a fibrosis result often corresponds with regressed tumors., (© The Author(s) 2021. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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15. Editor's Note: ITPR1 Protects Renal Cancer Cells against Natural Killer Cells by Inducing Autophagy.
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Messai Y, Noman MZ, Hasmim M, Janji B, Tittarelli A, Boutet M, Baud V, Viry E, Billot K, Nanbakhsh A, Ben Safta T, Richon C, Ferlicot S, Donnadieu E, Couve S, Gardie B, Orlanducci F, Albiges L, Thiery J, Olive D, Escudier B, and Chouaib S
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- 2022
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16. Poussée lupique sévère chez un homme de 76 ans suivi pour un syndrome de Gougerot-Sjögren primaire dans les suites d’une infection à COVID-19.
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Roger G, Pavot A, Bonnet I, Ferlicot S, and Mariette X
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- 2022
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17. The Clinicopathological Spectrum of Kidney Lesions in Chikungunya Fever: A Report of 5 Cases With Kidney Biopsy.
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Aurore AC, Couderc T, Dueymes JM, Deligny C, Lecuit M, Molinié V, and Ferlicot S
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- Animals, Biopsy, Humans, Kidney, Acute Kidney Injury diagnosis, Acute Kidney Injury epidemiology, Acute Kidney Injury etiology, Chikungunya Fever complications, Chikungunya Fever diagnosis, Chikungunya Fever epidemiology, Nephritis, Interstitial
- Abstract
Chikungunya nephropathy is an uncommon etiology of acute kidney injury, associated with the mosquito-borne chikungunya arbovirus (CHIKV). The very limited number of pathologic reports to date have only involved postmortem analyses. We here report 5 cases of acute kidney injury for which kidney biopsies were performed in patients with confirmed acute CHIKV infection, during the recent outbreak of chikungunya disease in the French West Indies. The patients ranged from 42 to 76 years of age. All of the patients developed kidney injury, 3 of whom required short-term dialysis and underwent a kidney biopsy. Analysis of kidney biopsies revealed 2 main histopathologic patterns: acute interstitial nephritis with predominant lymphoid inflammation and acute tubular injury. Epithelioid granulomas were observed in 2 cases. There were no glomerular lesions, except in biopsies from 2 patients, including 1 with a previous known primary focal segmental glomerulosclerosis. CHIKV antigen immunofluorescence microscopy revealed staining in tubular cells. In all of the cases, the short-term outcome was favorable, with recovery of kidney function., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)
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- 2021
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18. Involvement of PBRM1 in VHL disease-associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway.
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Gad S, Le Teuff G, Nguyen B, Verkarre V, Duchatelle V, Molinie V, Posseme K, Grandon B, Da Costa M, Job B, Meurice G, Droin N, Mejean A, Couve S, Renaud F, Gardie B, Teh BT, Richard S, and Ferlicot S
- Abstract
Von Hippel-Lindau (VHL) disease is the main cause of inherited clear-cell renal cell carcinoma (ccRCC) and is caused by germline mutations in the VHL tumor suppressor gene. Bi-allelic VHL alterations lead to inactivation of pVHL, which plays a major role by downstream activation of the hypoxia inducible factor (HIF) pathway. Somatic VHL mutations occur in 80% of sporadic ccRCC cases and the second most frequently mutated gene is polybromo 1 ( PBRM1 ). As there is currently no data regarding PBRM1 involvement in VHL disease-associated ccRCC, the aim of the present study was to assess the PBRM1 mutational status, and PBRM1 and HIF expression in VHL disease-associated ccRCC series compared with a sporadic series. PBRM1 gene was screened by Sanger sequencing for 23 VHL-disease-associated ccRCC and 22 sporadic ccRCC cases. Immunohistochemical studies were performed to detect the expression of PBRM1, HIF1 and HIF2 for all cases. In VHL-associated tumors, 13.0% (n=3/23) had PBRM1 somatic mutations and 17.4% (n=4/23) had a loss of PBRM1 nuclear expression. In sporadic cases, 27.3% (n=6/22) showed PBRM1 somatic mutations and 45.5% (n=10/22) had a loss of PBRM1 nuclear expression. Loss of PBRM1 was associated with an advanced tumor stage. HIF1-positive tumors were observed more frequently in the VHL-associated ccRCC than in the sporadic series. Furthermore, in the VHL cohort, PBRM1 expression appeared to be associated more with HIF1 than with HIF2. Given that hereditary tumors tend to be less aggressive, these results would suggest that co-expression of PBRM1 and HIF1 may have a less oncogenic role in VHL-associated ccRCC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Gad et al.)
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- 2021
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19. Phenotypic switch from non-active primary Sjögren's syndrome to severe systemic Lupus erythematosus after COVID-19 infection in an elderly man.
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Roger G, Pavot A, Bonnet I, Ferlicot S, and Mariette X
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- Aged, Humans, Male, SARS-CoV-2, COVID-19, Lupus Erythematosus, Systemic complications, Lupus Erythematosus, Systemic diagnosis, Sjogren's Syndrome complications, Sjogren's Syndrome diagnosis
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- 2021
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20. Clear cell and papillary renal cell carcinomas in hereditary papillary renal cell carcinoma (HPRCC) syndrome: a case report.
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Ferlicot S, Just PA, Compérat E, Rouleau E, Tissier F, Vaessen C, and Richard S
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- Biomarkers, Tumor analysis, Carcinoma, Renal Cell chemistry, Carcinoma, Renal Cell secondary, Carcinoma, Renal Cell therapy, DNA Mutational Analysis, Genetic Predisposition to Disease, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Kidney Neoplasms chemistry, Kidney Neoplasms pathology, Kidney Neoplasms therapy, Male, Middle Aged, Neoplastic Syndromes, Hereditary metabolism, Neoplastic Syndromes, Hereditary pathology, Neoplastic Syndromes, Hereditary therapy, Phenotype, Biomarkers, Tumor genetics, Carcinoma, Renal Cell genetics, Germ-Line Mutation, Kidney Neoplasms genetics, Neoplastic Syndromes, Hereditary genetics, Proto-Oncogene Proteins c-met genetics, Von Hippel-Lindau Tumor Suppressor Protein genetics
- Abstract
Background: Hereditary papillary renal cell carcinoma (HPRCC) is a rare autosomal dominant disease characterized by the development of multiple and bilateral papillary type I renal cell carcinomas (RCC) and papillary adenomas caused by activating mutations in the MET proto-oncogene. Classically, distinctive histological features of RCC are described according to the familial renal cell carcinoma syndrome. To date, no clear cell RCC has been reported in HPRCC syndrome., Case Presentation: We describe the case of a 51-year-old man with a germline MET mutation detected on peripheral blood testing, and no germline VHL mutation, who developed numerous papillary tumors but also unexpectedly clear cell renal cell carcinomas. During the follow-up, an adrenal metastasis was observed 7 years after the initial diagnosis corresponding to a clear cell RCC metastasis. By immunohistochemistry, clear cell tumors showed focal cytokeratin 7, moderate racemase, and diffuse and membranous CAIX expression, while papillary tumors expressed strong diffuse cytokeratin 7 and racemase without CAIX positivity. Using FISH, VHL deletion was observed in one of the clear cell tumors, and the metastatic clear cell tumor presented a trisomy of chromosomes 7 and 17. These last genomic alterations are usually detected in papillary RCC, highlighting the potential link between both histological subtypes of tumors and the HPRCC syndrome., Conclusions: The pathologist must be aware that the presence of a non-papillary RCC associated with numerous papillary tumors should not exclude the diagnostic suspicion of HPRCC and thus to perform a thorough genomic study., (© 2021. The Author(s).)
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- 2021
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21. Azoospermia and reciprocal translocations: should whole-exome sequencing be recommended?
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Ghieh F, Barbotin AL, Prasivoravong J, Ferlicot S, Mandon-Pepin B, Fortemps J, Garchon HJ, Serazin V, Leroy C, Marcelli F, and Vialard F
- Abstract
Background: Although chromosome rearrangements are responsible for spermatogenesis failure, their impact depends greatly on the chromosomes involved. At present, karyotyping and Y chromosome microdeletion screening are the first-line genetic tests for patients with non-obstructive azoospermia. Although it is generally acknowledged that X or Y chromosome rearrangements lead to meiotic arrest and thus rule out any chance of sperm retrieval after a testicular biopsy, we currently lack markers for the likelihood of testicular sperm extraction (TESE) in patients with other chromosome rearrangements., Results: We investigated the use of a single nucleotide polymorphism comparative genome hybridization array (SNP-CGH) and whole-exome sequencing (WES) for two patients with non-obstructive azoospermia and testicular meiotic arrest, a reciprocal translocation: t(X;21) and t(20;22), and an unsuccessful TESE. No additional gene defects were identified for the t(X;21) carrier - suggesting that t(X;21) alone damages spermatogenesis. In contrast, the highly consanguineous t(20;22) carrier had two deleterious homozygous variants in the TMPRSS9 gene; these might have contributed to testicular meiotic arrest. Genetic defect was confirmed with Sanger sequencing and immunohistochemical assessments on testicular tissue sections., Conclusions: Firstly, TMPRSS9 gene defects might impact spermatogenesis. Secondly, as a function of the chromosome breakpoints for azoospermic patients with chromosome rearrangements, provision of the best possible genetic counselling means that genetic testing should not be limited to karyotyping. Given the risks associated with TESE, it is essential to perform WES - especially for consanguineous patients., (© 2021. The Author(s).)
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- 2021
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22. Germline mutation in the NBR1 gene involved in autophagy detected in a family with renal tumors.
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Adolphe F, Ferlicot S, Verkarre V, Posseme K, Couvé S, Garnier P, Droin N, Deloger M, Job B, Giraud S, Paillerets BB, Gardie B, Richard S, Renaud F, and Gad S
- Subjects
- Adult, Aged, Carcinoma, Renal Cell genetics, Female, Follow-Up Studies, Humans, Kidney Neoplasms genetics, Male, Middle Aged, Pedigree, Prognosis, Autophagy, Carcinoma, Renal Cell pathology, Genetic Predisposition to Disease, Germ-Line Mutation, Intracellular Signaling Peptides and Proteins genetics, Kidney Neoplasms pathology
- Abstract
Hereditary Renal Cell Carcinomas (RCC) are caused by mutations in predisposing genes, the major ones including VHL, FLCN, FH and MET. However, many families with inherited RCC have no germline mutation in these genes. Using Whole Exome Sequencing on germline DNA from a family presenting three different histological renal tumors (an angiomyolipoma, a clear-cell RCC and an oncocytic papillary RCC), we identified a frameshift mutation in the Neighbor of BRCA1 gene 1 (NBR1), segregating with the tumors. NBR1 encodes a cargo receptor protein involved in autophagy. Genetic and functional analyses suggested a pathogenic impact of the mutation. Indeed, functional study performed in renal cell lines showed that the mutation alters NBR1 interactions with some of its partners (such as p62/SQSTM1), leading to a dominant negative effect. This results in an altered autophagic process and an increased proliferative capacity in renal cell lines. Our study suggests that NBR1 may be a new predisposing gene for RCC, however its characterization needs to be further investigated in order to confirm its role in renal carcinogenesis., Competing Interests: Declarations of Competing Interest none, (Copyright © 2021. Published by Elsevier Inc.)
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- 2021
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23. IL-15 Prevents Renal Fibrosis by Inhibiting Collagen Synthesis: A New Pathway in Chronic Kidney Disease?
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Devocelle A, Lecru L, Ferlicot S, Bessede T, Candelier JJ, Giron-Michel J, and François H
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- Animals, Chemokine CCL2 metabolism, Collagen biosynthesis, Disease Models, Animal, Drug Evaluation, Preclinical, Humans, Interleukin-15 metabolism, Interleukin-15 pharmacology, Interleukin-15 Receptor alpha Subunit metabolism, Kidney pathology, Mice, Inbred C57BL, Myofibroblasts drug effects, Myofibroblasts metabolism, Renal Insufficiency, Chronic metabolism, Ureteral Obstruction, Mice, Interleukin-15 therapeutic use, Interleukin-15 Receptor alpha Subunit therapeutic use, Kidney metabolism, Nephrosclerosis prevention & control, Renal Insufficiency, Chronic drug therapy
- Abstract
Chronic kidney disease (CKD), secondary to renal fibrogenesis, is a public health burden. The activation of interstitial myofibroblasts and excessive production of extracellular matrix (ECM) proteins are major events leading to end-stage kidney disease. Recently, interleukin-15 (IL-15) has been implicated in fibrosis protection in several organs, with little evidence in the kidney. Since endogenous IL-15 expression decreased in nephrectomized human allografts evolving toward fibrosis and kidneys in the unilateral ureteral obstruction (UUO) model, we explored IL-15's renoprotective role by pharmologically delivering IL-15 coupled or not with its soluble receptor IL-15Rα. Despite the lack of effects on myofibroblast accumulation, both IL-15 treatments prevented tubulointerstitial fibrosis (TIF) in UUO as characterized by reduced collagen and fibronectin deposition. Moreover, IL-15 treatments inhibited collagen and fibronectin secretion by transforming growth factor-β (TGF-β)-treated primary myofibroblast cultures, demonstrating that the antifibrotic effect of IL-15 in UUO acts, in part, through a direct inhibition of ECM synthesis by myofibroblasts. In addition, IL-15 treatments resulted in decreased expression of monocyte chemoattractant protein 1 (MCP-1) and subsequent macrophage infiltration in UUO. Taken together, our study highlights a major role of IL-15 on myofibroblasts and macrophages, two main effector cells in renal fibrosis, demonstrating that IL-15 may represent a new therapeutic option for CKD.
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- 2021
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24. Technical feasibility and correlations between shear-wave elastography and histology in kidney fibrosis in children.
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Desvignes C, Dabadie A, Aschero A, Ruocco A, Garaix F, Daniel L, Ferlicot S, Villes V, Loundou AD, Gorincour G, and Petit P
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- Adolescent, Child, Feasibility Studies, Fibrosis, Humans, Kidney diagnostic imaging, Kidney pathology, Reproducibility of Results, Elasticity Imaging Techniques, Kidney Diseases diagnostic imaging, Kidney Diseases pathology
- Abstract
Background: Ultrasound elastography has been suggested for assessing organ fibrosis., Objective: To study the feasibility of shear-wave elastography in children with kidney disease and the correlation between elasticity and kidney fibrosis in order to reduce the indications for kidney biopsy and its complications., Materials and Methods: Four operators measured kidney elasticity in children with kidney diseases or transplants, all of whom also had a renal biopsy. We assessed the feasibility and the intraobserver variability of the elasticity measurements for each probe used and each kidney explored. Then we tested the correlation between elasticity measurements and the presence of fibrosis., Results: Overall, we analyzed 95 children and adolescents, 31 of whom had renal transplant. Measurements with the convex probe were possible in 100% of cases. Linear probe analysis was only possible for 20% of native kidneys and 50% of transplants. Intraobserver variabilities ranged from moderate to high, depending on the probe and kidney studied. Elasticity was higher with the linear probe than with the convex probe (P<0.001 for left kidney and P=0.03 for right kidney). Measurements did not differ from one kidney to another in the same child. Elasticity and fibrosis were both higher in transplant patients (P=0.02 with convex probe; P=0.01 with linear probe; P=0.04 overall). There was no correlation between elasticity and fibrosis., Conclusion: Of the devices used in this work, kidney elastography was more accurately analyzed with a convex probe. Our study did not identify any correlation between elasticity and kidney fibrosis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2021
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25. Transplantation Outcome in Recipients Engrafted With Organs Recovered From the First French Deceased Donor With a SARS-COV-2 Vaccine-induced Thrombotic Thrombocytopenia.
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Jamme M, Elalamy I, d'Izarny Gargas T, Pettenati C, Desire E, Tissot A, Rabant M, Lefebvre M, Soorojebally Y, Vourc'h M, Conti F, Ferlicot S, Delahousse M, Sartorius-Brodin A, and Hertig A
- Subjects
- Aged, COVID-19 immunology, COVID-19 virology, COVID-19 Vaccines administration & dosage, ChAdOx1 nCoV-19, Donor Selection, Fatal Outcome, Female, Humans, Male, Middle Aged, Risk Assessment, Risk Factors, Treatment Outcome, Vaccination adverse effects, COVID-19 prevention & control, COVID-19 Vaccines adverse effects, Organ Transplantation adverse effects, Purpura, Thrombotic Thrombocytopenic etiology, SARS-CoV-2 immunology, Tissue Donors
- Abstract
Competing Interests: The authors declare no funding or conflicts of interest.
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- 2021
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26. Long-term exposure to monoclonal anti-TNF is associated with an increased risk of lymphoma in BAFF-transgenic mice.
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Nocturne G, Ly B, Paoletti A, Pascaud J, Seror R, Nicco C, Mackay F, Vincent FB, Lazure T, Ferlicot S, Stimmer L, Pascal Q, Roulland S, Krzysiek R, Hacein-Bey S, Batteux F, and Mariette X
- Subjects
- Animals, Autoimmune Diseases immunology, Autoimmunity immunology, B-Lymphocytes immunology, Cell Line, Mice, Mice, Inbred C57BL, Spleen immunology, Antibodies, Monoclonal immunology, Arthritis, Rheumatoid immunology, B-Cell Activating Factor immunology, Lymphoma immunology, Mice, Transgenic immunology, Tumor Necrosis Factor Inhibitors immunology, Tumor Necrosis Factor-alpha immunology
- Abstract
The impact of treatment on the risk of lymphoma in patients with rheumatoid arthritis (RA) is unclear. Here, we aimed to assess if the risk of lymphoma differs according to the type of tumor necrosis factor inhibitor (TNFi), comparing monoclonal anti-TNF antibodies to the soluble TNF receptor. We used B cell activating factor belonging to the TNF family (BAFF)-transgenic (Tg) mice as a model of autoimmunity-associated lymphoma. Six-month-old BAFF-Tg mice were treated with TNFi for 12 months. Histological examination of the spleen, assessment of the cellular composition of the spleen by flow cytometry and assessment of B cell clonality were performed at euthanasia. Crude mortality and incidence of lymphoma were significantly higher in mice treated with monoclonal anti-TNF antibodies compared to both controls and mice treated with the soluble TNF receptor, even at a high dose. Flow cytometry analysis revealed decreased splenic macrophage infiltration in mice treated with monoclonal anti-TNF antibodies. Overall, this study demonstrates, for the first time, that a very prolonged treatment with monoclonal anti-TNF antibodies increase the risk of lymphoma in B cell-driven autoimmunity. These data suggest a closer monitoring for lymphoma development in patients suffering from B cell-driven autoimmune disease with long-term exposure to monoclonal anti-TNF antibodies., (© 2021 British Society for Immunology.)
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- 2021
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27. The spectrum of kidney biopsies in hospitalized patients with COVID-19, acute kidney injury, and/or proteinuria.
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Ferlicot S, Jamme M, Gaillard F, Oniszczuk J, Couturier A, May O, Grünenwald A, Sannier A, Moktefi A, Le Monnier O, Petit-Hoang C, Maroun N, Brodin-Sartorius A, Michon A, Dobosziewicz H, Andreelli F, Guillet M, Izzedine H, Richard C, Dekeyser M, Arrestier R, Sthelé T, Lefèvre E, Mathian A, Legendre C, Mussini C, Verpont MC, Pallet N, Amoura Z, Essig M, Snanoudj R, Brocheriou-Spelle I, François H, Belenfant X, Geri G, Daugas E, Audard V, Buob D, Massy ZA, and Zaidan M
- Abstract
We report a multicentric retrospective case series of patients with COVID-19 who developed acute kidney injury and/or proteinuria and underwent a kidney biopsy in the Paris and its metropolitan area. Forty-seven patients (80.9% men) with COVID-19 who underwent a kidney biopsy between March 08 and May 19, 2020 were included. Median age was 63 years IQR [52-69]. Comorbidities included hypertension (66.0%), diabetes mellitus (27.7%), obesity (27.7%), history of chronic kidney (25.5%), cardiac (38.6%) and respiratory (27.3%) diseases. Initial symptoms were fever (85.1%), cough (63.8%), shortness of breath (55.3%), and diarrhea (23.4%). Almost all patients developed acute kidney injury (97.9%) and 63.8% required renal replacement therapy. Kidney biopsy showed two main histopathological patterns, including acute tubular injury in 20 (42.6%) patients, and glomerular injury consisting of collapsing glomerulopathy and focal segmental glomerulosclerosis in 17 (36.2%) patients. Two (4.3%) patients had acute vascular nephropathy, while eight (17%) had alternative diagnosis most likely unrelated to COVID-19. Acute tubular injury occurred almost invariably in the setting of severe forms of COVID-19, whereas patients with glomerular injury had various profiles of COVID-19 severity and collapsing glomerulopathy was only observed in patients harboring a combination of APOL1 risk variants. At last follow-up, 16 of the 30 patients who initially required dialysis were still on dialysis, and 9 died. The present study describes the spectrum of kidney lesions in patients with COVID-19. While acute tubular injury is correlated with COVID-19 severity, the pattern of glomerular injury is intimately associated with the expression of APOL1 risk variants., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)
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- 2021
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28. Response to plasma exchange and graft survival in recurrent focal and segmental glomerulosclerosis after transplantation: does the time of recurrence matter? A retrospective study.
- Author
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Dudreuilh C, Barbet C, Gatault P, Ferlicot S, Lebranchu Y, Rabot N, Beaudreuil S, Dürrbach A, and Büchler M
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- Graft Survival, Humans, Plasma Exchange, Recurrence, Retrospective Studies, Treatment Outcome, Glomerulosclerosis, Focal Segmental therapy
- Abstract
Recurrence of primary focal and segmental glomerulosclerosis following kidney transplantation (rFSGS) is a frequent and severe disease. We studied the time to recurrence of FSGS and its impact on the response to plasma exchange (PE) and graft survival. Between 1990 and 2013, 2730 kidney transplants were performed, including 52 patients with a primary diagnosis of FSGS. Of these patients with primary FSGS, 34 (67%) developed rFSGS. We retrospectively divided these patients into two groups depending on the time to recurrence: early (up to three months after transplantation, n = 26) or late (more than three months after transplantation, n = 8). Survival did not significantly differ between the two groups. In cases of late recurrence, PE was started later and was performed less frequently, and remission was achieved after more PE sessions and longer PE treatment than for the early group (P = 0.01). In early recurrence, resistance to PE at 40 days was associated with no long-term response to PE. PE should be performed as soon as possible after rFSGS. Patients with late rFSGS need to be offered the same treatment regime as those with early rFSGS., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)
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- 2021
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29. Immunodynamics of explanted human tumors for immuno-oncology.
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Dubuisson A, Fahrner JE, Goubet AG, Terrisse S, Voisin N, Bayard C, Lofek S, Drubay D, Bredel D, Mouraud S, Susini S, Cogdill A, Rebuffet L, Ballot E, Jacquelot N, Thomas de Montpreville V, Casiraghi O, Radulescu C, Ferlicot S, Figueroa DJ, Yadavilli S, Waight JD, Ballas M, Hoos A, Condamine T, Parier B, Gaudillat C, Routy B, Ghiringhelli F, Derosa L, Breuskin I, Rouanne M, André F, Lebacle C, Baumert H, Wislez M, Fadel E, Cremer I, Albiges L, Geoerger B, Scoazec JY, Loriot Y, Kroemer G, Marabelle A, Bonvalet M, and Zitvogel L
- Subjects
- Humans, Medical Oncology, Prospective Studies, Tumor Microenvironment, Immunotherapy, Neoplasms therapy
- Abstract
Decision making in immuno-oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno-assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti-PD-1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
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- 2021
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30. Severe acute respiratory syndrome coronavirus 2 indirectly damages kidney structures.
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Dargelos M, Couturier A, Ferlicot S, Goujon JM, Roque-Afonso AM, Gault E, Touchard G, Ory C, Kaaki S, Vilaine E, Essig M, and Massy ZA
- Abstract
Background: The objectives were to characterize Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) in patients with acute kidney injury (AKI)., Methods: Kidney biopsy samples in two Caucasian patients and one African with COVID-19 AKI were investigated., Results: All patients had a high-level non-selective glomerular proteinuria. SARS-CoV-2 samples by real-time polymerase chain reaction (RT- PCR) assay were all-negative, as well as for virus particles in the kidney by electron microscopy. The three patients and patients with other AKI did not differ significantly with regard to angiotensin-converting enzyme 2 and transmembrane protease serine 2 kidney staining., Conclusions: The kidney damage particularly in Caucasians in COVID-19 seems to be an AKI, possibly by the systemic inflammatory response., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)
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- 2020
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31. Fluorescence Emitted by Papanicolaou-Stained Urothelial Cells Improves Sensitivity of Urinary Conventional Cytology for Detection of Urothelial Tumors.
- Author
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Alsibai KD, Daste G, Ferlicot S, Fabre M, Steenkeste K, Salleron J, Hammoudi Y, Fontaine-Aupart MP, and Eschwege P
- Abstract
Background: Urinary conventional cytology (UCCy) is easy to perform, but its low sensitivity, especially for low-grade urothelial neoplasms (LGUNs), limits its indications in the management of patients at risk of bladder cancer. The authors aim at obtaining a complementary test that would effectively increase the sensitivity of UCCy on voided urines by analyzing fluorescence of Papanicolaou-stained urothelial cells with no change of method in slide preparation., Methods: In this retrospective study of 155 patients, 91 Papanicolaou-stained voided urines were considered satisfactory under fluorescence microscopy (FMi). The results of FMi were compared with UCCy (using transmission microscopy) and correlated to cystoscopy, histology and follow-up data., Results: The results are given for all patients and for two groups of them according to the patients' main complaints (group 1: 33 patients followed up for a previously treated bladder tumor; group 2: 58 patients with persistent urinary symptoms). Overall negative predictive value (NPV) and sensitivity of FMi were 100% vs. 73.7% and 64.3% respectively for UCCy (P = 0.0001). Sensitivity of FMi for LGUN was unexpectedly high with a value of 100% vs. 46.2% for UCCy (P = 0.0002). FMi was significantly superior to UCCy for detecting urothelial tumors in every group of patients and would allow a better characterization of atypical urothelial cells (AUCs) defined by the Paris System for Reporting Urine Cytology (TPS)., Conclusions: Because of its sensitivity and NPV of 100%, FMi could complement UCCy to screen voided urines allowing a better detection of primary urothelial tumors or early recurrences of previously treated urothelial carcinoma. Moreover, this "dual screening" would allow completing efficiently cystoscopy to detect flat dysplasia, carcinoma in situ (CIS) and extra bladder carcinoma., Competing Interests: This method of detecting tumor cells by fluorescence signals is protected by the United States Patent US8597905 B2 2013.2. The owners are Fabre M, Ferlicot S, Fontaine Aupart MP, Steenkeste K, Eschwege P., (Copyright 2020, Alsibai et al.)
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- 2020
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32. Organ Transplantation in Hereditary Fibrinogen A α-Chain Amyloidosis: A Case Series of French Patients.
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Meyer L, Ulrich M, Ducloux D, Garrigue V, Vigneau C, Nochy D, Bobrie G, Ferlicot S, Colombat M, Boffa JJ, Clabault K, Mansour J, Mousson C, Azar R, Bacri JL, Dürrbach A, Duvic C, El Karoui K, Hoffmann M, Lionet A, Panescu V, Plaisier E, Ratsimbazafy A, Guerrot D, Vrigneaud L, Valleix S, and François H
- Subjects
- Adolescent, Adult, Aged, Amyloidosis, Familial genetics, Amyloidosis, Familial pathology, Child, Combined Modality Therapy, Disease Progression, Female, Follow-Up Studies, Frameshift Mutation, France epidemiology, Genetic Association Studies, Humans, Kidney pathology, Kidney Failure, Chronic epidemiology, Kidney Failure, Chronic etiology, Kidney Failure, Chronic surgery, Kidney Failure, Chronic therapy, Male, Middle Aged, Mutation, Missense, Point Mutation, Renal Dialysis, Treatment Outcome, Young Adult, Amyloidosis, Familial surgery, Fibrinogen genetics, Kidney Transplantation statistics & numerical data, Liver Transplantation statistics & numerical data
- Abstract
Rationale & Objective: Fibrinogen A α-chain amyloidosis (AFib amyloidosis) is a form of amyloidosis resulting from mutations in the fibrinogen A α-chain gene (FGA), causing progressive kidney disease leading to kidney failure. Treatment may include kidney transplantation (KT) or liver-kidney transplantation (LKT), but it is not clear what factors should guide this decision. The aim of this study was to characterize the natural history and long-term outcomes of this disease, with and without organ transplantation, among patients with AFib amyloidosis and various FGA variants., Study Design: Case series., Setting & Participants: 32 patients with AFib amyloidosis diagnosed by genetic testing in France between 1983 and 2014, with a median follow-up of 93 (range, 4-192) months, were included., Results: Median age at diagnosis was 51.5 (range, 12-77) years. Clinical presentation consisted of proteinuria (93%), hypertension (83%), and kidney failure (68%). Manifestations of kidney disease appeared on average at age 57 (range, 36-77) years in patients with the E526V variant, at age 45 (range, 12-59) years in those with the R554L variant (P<0.001), and at age 24.5 (range, 12-31) years in those with frameshift variants (P<0.001). KT was performed in 15 patients and LKT was performed in 4. In KT patients with the E526V variant, recurrence of AFib amyloidosis in the kidney graft was less common than with a non-E526V (R554L or frameshift) variant (22% vs 83%; P=0.03) and led to graft loss less frequently (33% vs 100%). Amyloid recurrence was not observed in patients after LKT., Limitations: Analyses were based on clinically available historical data. Small number of patients with non-E526V and frameshift variants., Conclusions: Our study suggests phenotypic variability in the natural history of AFib amyloidosis, depending on the FGA mutation type. KT appears to be a viable option for patients with the most common E526V variant, whereas LKT may be a preferred option for patients with frameshift variants., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)
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- 2020
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33. Clinical interest of PD-L1 immuno-histochemistry expression as a predictive factor of Bacillus Calmette Guerin (BCG) efficacy in refractory high-risk non-muscle-invasive bladder cancer (NMIBC).
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Delcourt C, Gemival P, Nouhaud FX, Gobet F, Gillibert A, Ferlicot S, Sabourin JC, Irani J, and Pfister C
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- Aged, Aged, 80 and over, B7-H1 Antigen analysis, Cohort Studies, Female, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Invasiveness, Predictive Value of Tests, Retrospective Studies, Risk Assessment, Treatment Outcome, Urinary Bladder Neoplasms chemistry, Urinary Bladder Neoplasms pathology, Adjuvants, Immunologic therapeutic use, B7-H1 Antigen biosynthesis, BCG Vaccine therapeutic use, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms metabolism
- Abstract
Objective: To assess PD-L1 expression in tumor (TC) and tumor infiltrating immune cells (IC) as a predictive factor of BCG therapy failure in high-risk NMIBC., Materials and Methods: Patients treated with complete resection followed by bladder BCG instillation for high-risk NMIBC were included. Early recurrence (ER) was defined as tumor recurrence after BCG induction course. The association between ER and immuno-histochemistry PD-L1 (E1L3N clone) expression by tumors cells (TC) and tumor infiltrating immune cells (IC) was investigated using an exact Fisher test variant., Results: A total of 186 patients were included, of whom 38 (20.4%) were ER, 35 (18.8%) were positive for TC PD-L1 expression and 60 (32.3%) were positive for IC PD-L1. ER was not significantly (p = 0.97) more frequent in the TC PD-L1 ≥ 1% group (n = 7, 20.0%) than in the TC PD-L1-negative group (n = 31, 20.5%). Patients with IC PD-L1 negative had ER in 15 (19.2%) cases and patients with IC PD-L1 ≥ 1% had ER in 23 (21.3%) cases. PD-L1-positive expression for IC (threshold > 1%) was correlated with immune infiltrate density (95.2% dense immune infiltrate vs 47.2% low immune infiltrate, p < 0.05), with increased expression of PD-L1 by IC after BCG therapy (p = 0.006)., Conclusion: No association was observed between immuno-histochemistry PD-L1 positivity and ER after BCG therapy. Nevertheless, the relationship between immune infiltrate and PD-L1 positivity confirmed the interest of assessing the immune infiltrate density to define tumor's profile.
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- 2020
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34. Indirect effects of severe acute respiratory syndrome coronavirus 2 on the kidney in coronavirus disease patients.
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Couturier A, Ferlicot S, Chevalier K, Guillet M, Essig M, Jauréguiberry S, Collarino R, Dargelos M, Michaut A, Geri G, Roque-Afonso AM, Zaidan M, and Massy ZA
- Abstract
Among patients hospitalized for novel coronavirus disease (COVID-19), between 10 and 14% develop an acute kidney injury and around half display marked proteinuria and haematuria. Post-mortem analyses of COVID-19 kidney tissue suggest that renal tubular cells and podocytes are affected. Here we report two cases of collapsing glomerulopathy and tubulointerstitial lesions in living COVID-19 patients. Despite our use of sensitive reverse transcription polymerase chain reaction techniques in this study, we failed to detect the virus in blood, urine and kidney tissues. Our observations suggest that these kidney lesions are probably not due to direct infection of the kidney by severe acute respiratory syndrome coronavirus 2., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)
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- 2020
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35. Ultrasound Molecular Imaging of Renal Cell Carcinoma: VEGFR targeted therapy monitored with VEGFR1 and FSHR targeted microbubbles.
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Ingels A, Leguerney I, Cournède PH, Irani J, Ferlicot S, Sébrié C, Benatsou B, Jourdain L, Pitre-Champagnat S, Patard JJ, and Lassau N
- Subjects
- Animals, Carcinoma, Renal Cell drug therapy, Female, Humans, Immunotherapy, Kidney Neoplasms drug therapy, Mice, Mice, Inbred BALB C, Molecular Imaging, Neoplasm Transplantation, Perfusion, Protein Kinase Inhibitors therapeutic use, Sunitinib therapeutic use, Ultrasonography, Carcinoma, Renal Cell diagnostic imaging, Kidney Neoplasms diagnostic imaging, Microbubbles, Receptors, FSH chemistry, Vascular Endothelial Growth Factor Receptor-1 chemistry
- Abstract
Recent treatment developments for metastatic renal cell carcinoma offer combinations of immunotherapies or immunotherapy associated with tyrosine kinase inhibitors (TKI). There is currently no argument to choose one solution or another. Easy-to-use markers to assess longitudinal responses to TKI are necessary to determine when to switch to immunotherapies. These new markers will enable an earlier adaptation of therapeutic strategy in order to prevent tumor development, unnecessary toxicity and financial costs. This study evaluates the potential of ultrasound molecular imaging to track the response to sunitinib in a clear cell renal carcinoma model (ccRCC). We used a patient-derived xenograft model for this imaging study. Mice harboring human ccRCC were randomized for sunitinib treatment vs. control. The tumors were imaged at days 0, 7, 14 and 28 with ultrasound molecular imaging. Signal enhancement was quantified and compared between the two groups after injections of non-targeted microbubbles and microbubbles targeting VEGFR1 and FSHR. The tumor growth of the sunitinib group was significantly slower. There was a significantly lower expression of both VEGFR-1 and FSHR molecular ultrasound imaging signals in the sunitinib group at all times of treatment (Days 7, 14 and 28). These results confirm the study hypothesis. There was no significant difference between the 2 groups for the non-targeted microbubble ultrasound signal. This study demonstrated for the first time the potential of VEGFR1 and FSHR, by ultrasound-based molecular imaging, to follow-up the longitudinal response to sunitinib in ccRCC. These results should trigger developments for clinical applications.
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- 2020
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36. Usefulness of morphometric image analysis with Sirius Red to assess interstitial fibrosis after renal transplantation from uncontrolled circulatory death donors.
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Dao M, Pouliquen C, Duquesne A, Posseme K, Mussini C, Durrbach A, Guettier C, François H, and Ferlicot S
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- Adult, Biopsy, Female, Fibrosis, Humans, Male, Middle Aged, Reproducibility of Results, Treatment Outcome, Young Adult, Azo Compounds metabolism, Blood Circulation, Image Processing, Computer-Assisted, Kidney Transplantation adverse effects, Tissue Donors
- Abstract
Early interstitial fibrosis (IF) correlates with long-term renal graft dysfunction, highlighting the need for accurate quantification of IF. However, the currently used Banff classification exhibits some limitations. The aim of our study was to precisely describe the progression of IF after renal transplantation using a new morphometric image analysis method relying of Sirius Red staining. The morphometric analysis we developed showed high inter-observer and intra-observer reproducibility, with ICC [95% IC] of respectively 0.75 [0.67-0.81] (n = 151) and 0.88 [0.72-0.95] (n = 21). We used this method to assess IF (mIF) during the first year after the kidney transplantation from 66 uncontrolled donors after circulatory death (uDCD). Both mIF and interstitial fibrosis (ci) according to the Banff classification significantly increased the first three months after transplantation. From M3 to M12, mIF significantly increased whereas Banff classification failed to highlight increase of ci. Moreover, mIF at M12 (p = 0.005) correlated with mean time to graft function recovery and was significantly associated with increase of creatininemia at M12 and at last follow-up. To conclude, the new morphometric image analysis method we developed, using a routine and cheap staining, may provide valuable tool to assess IF and thus to evaluate new sources of grafts.
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- 2020
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37. [Hereditary kidney cancers: The pathologist's view in 2020].
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Verkarre V, Morini A, Denize T, Ferlicot S, and Richard S
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- Angiomyolipoma diagnosis, Angiomyolipoma genetics, Angiomyolipoma pathology, Biomarkers, Tumor genetics, Carcinoma, Renal Cell diagnosis, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell pathology, Fumarate Hydratase genetics, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Humans, Immunohistochemistry, Kidney Neoplasms diagnosis, Kidney Neoplasms genetics, Neoplastic Syndromes, Hereditary diagnosis, Kidney Neoplasms pathology, Neoplastic Syndromes, Hereditary pathology
- Abstract
Hereditary predispositions to adult kidney tumors involve around 5% of tumors and include a dozen of autosomal dominant syndromes. The most frequent tumors encountered in these setting are clear cell renal cell carcinomas, papillary renal cell carcinomas, chromophobe renal cell carcinomas and angiomyolipomas. Their detection is essential in order to adapt individual care and perform genetic screening of at-risk relatives, especially in the national french network PREDIR, labeled by the National Cancer Institute and dedicated to hereditary predispositions to kidney tumors. Targeted genetic analysis, which was guided in particular by the renal tumor subtype, has recently evolved into genetic analysis using panels of genes. Pathologist contribution's remains however central in the diagnosis of hereditary forms since we currently have immunohistochemical biomarkers that allow us to diagnose two specifically hereditary entities: hereditary leiomyomatosis and renal cell carcinoma associated-renal cell carcinoma, associated with a loss of fumarate hydratase and succinate dehydrogenase-deficient renal cell carcinoma associated with a loss of succinate deshydrogenase B expression. These diagnoses must however be confirmed by the identification of pathogenic germline variation in the corresponding genes. Improvement of kidney tumors characterization has also lead to identify new subtypes, expanding the algorithm of renal tumors associated with hereditary setting. Here we aim to review all subtypes of adult renal tumors encountered in predisposition syndromes., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
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- 2020
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38. The cannabinoid receptor 1 is involved in renal fibrosis during chronic allograft dysfunction: Proof of concept.
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Dao M, Lecru L, Vandermeersch S, Ferreira M, Ferlicot S, Posseme K, Dürrbach A, Hermeziu B, Mussini C, Chatziantoniou C, and François H
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- Animals, Cells, Cultured, Chronic Disease, Female, Fibrosis metabolism, Fibrosis pathology, Humans, Immunosuppressive Agents toxicity, Male, Mice, Mice, Inbred C57BL, Middle Aged, Primary Graft Dysfunction surgery, Receptor, Cannabinoid, CB1 genetics, Retrospective Studies, Tacrolimus toxicity, Fibrosis etiology, Kidney Transplantation adverse effects, Primary Graft Dysfunction complications, Receptor, Cannabinoid, CB1 metabolism
- Abstract
Chronic allograft dysfunction (CAD), defined as the replacement of functional renal tissue by extracellular matrix proteins, remains the first cause of graft loss. The aim of our study was to explore the potential role of the cannabinoid receptor 1 (CB1) during CAD. We retrospectively quantified CB1 expression and correlated it with renal fibrosis in 26 kidney-transplanted patients who underwent serial routine kidney biopsies. Whereas CB1 expression was low in normal kidney grafts, it was highly expressed during CAD, especially in tubular cells. CB1 expression significantly increased early on after transplantation, from day 0 (D0) to month 3 post-transplant (M3) (22.5% ± 15.4% vs 33.4% ± 13.8%, P < .01), and it remained stable thereafter. CB1 expression correlated with renal fibrosis at M3 (P = .04). In an in vitro model of tacrolimus-mediated fibrogenesis by tubular cells, we found that tacrolimus treatment significantly induced mRNA and protein expression of CB1 concomitantly to col3a1 and col4a3 up regulation. Administration of rimonabant, a CB1 antagonist, blunted collagen synthesis by tubular cells (P < .05). Overall, our study strongly suggests an involvement of the cannabinoid system in the progression of fibrosis during CAD and indicates the therapeutic potential of CB1 antagonists in this pathology., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
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- 2019
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39. iPSC-Derived Embryoid Bodies as Models of c- Met -Mutated Hereditary Papillary Renal Cell Carcinoma.
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Hwang JW, Desterke C, Féraud O, Richard S, Ferlicot S, Verkarre V, Patard JJ, Loisel-Duwattez J, Foudi A, Griscelli F, Bennaceur-Griscelli A, and Turhan AG
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- Alleles, Carcinoma, Papillary diagnosis, Carcinoma, Renal Cell diagnosis, Embryoid Bodies metabolism, Embryoid Bodies ultrastructure, Fluorescent Antibody Technique, Gene Expression, Genotype, Humans, Immunohistochemistry, Magnetic Resonance Imaging methods, Reproducibility of Results, Carcinoma, Papillary etiology, Carcinoma, Renal Cell etiology, Embryoid Bodies cytology, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells metabolism, Mutation, Proto-Oncogene Proteins c-met genetics
- Abstract
Hereditary cancers with cancer-predisposing mutations represent unique models of human oncogenesis, as a driving oncogenic event is present in germline. Currently, there are no satisfactory models to study these malignancies. We report the generation of IPSC from the somatic cells of a patient with hereditary c- met- mutated papillary renal cell carcinoma (PRCC). From these cells we have generated spontaneous aggregates organizing in structures which expressed kidney markers such as PODXL and Six2. These structures expressed PRCC markers both in vitro and in vivo in NSG mice. Gene-expression profiling showed striking molecular similarities with signatures found in a large cohort of PRCC tumor samples. This analysis, applied to primary cancers with and without c- met mutation, showed overexpression of the BHLHE40 and KDM4C only in the c- met -mutated PRCC tumors, as predicted by c- met -mutated embryoid bodies transcriptome. These data therefore represent the first proof of concept of "hereditary renal cancer in a dish" model using c- met -mutated iPSC-derived embryoid bodies, opening new perspectives for discovery of novel predictive progression markers and for drug-screening for future precision-medicine strategies.
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- 2019
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40. Characterization of Testicular Masses in Adults: Performance of Combined Quantitative Shear Wave Elastography and Conventional Ultrasound.
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Rocher L, Criton A, Gennisson JL, Creze M, Albiges L, Ferlicot S, Bellin MF, Izard V, and Correas JM
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- Adult, Aged, Aged, 80 and over, Diagnosis, Differential, Elasticity Imaging Techniques, Humans, Male, Middle Aged, Prospective Studies, Reproducibility of Results, Sensitivity and Specificity, Testis diagnostic imaging, Young Adult, Testicular Neoplasms diagnostic imaging, Ultrasonography methods
- Abstract
We prospectively evaluated the performance of combined shear wave elastography (SWE) and conventional ultrasound (US) for the characterization of 89 testicular focal masses. Testes were evaluated with B-mode, color Doppler and SWE measurements, locating a region of interest on the normal and pathologic parenchyma. Thirty-seven malignant tumors (MTs), 12 burned out tumors (BOTs), 28 Leydig cell tumors (LCTs), 2 dermoid cysts and other benign lesions were included. MTs + BOTs exhibited more microliths and macrocalcifications compared with benign lesions (p < 10
-4 ). LCTs manifested mostly a dominant peripheral vascularization pattern compared with other lesions. MTs + BOTs were stiffer compared with benign lesions (p < 2 × 10-4 ) but with a moderate area under the receiver operating characteristic curve (AUROC) of 80%. By focusing on LCTs versus MTs + BOTs, diagnostic performance led to an AUROC of 89% for the best stiffness parameter. For combined conventional US and SWE, the diagnostic performance to differentiate all benign lesions versus MTs + BOTs and LCTs versus MTs + BOTs increased to AUROCs of 93% and 98%, respectively., (Copyright © 2018 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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41. Integrative analysis of dysregulated microRNAs and mRNAs in multiple recurrent synchronized renal tumors from patients with von Hippel-Lindau disease.
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Gattolliat CH, Couvé S, Meurice G, Oréar C, Droin N, Chiquet M, Ferlicot S, Verkarre V, Vasiliu V, Molinié V, Méjean A, Dessen P, Giraud S, Bressac-De-Paillerets B, Gardie B, Tean Teh B, Richard S, and Gad S
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Renal Cell epidemiology, Carcinoma, Renal Cell pathology, Case-Control Studies, Cell Line, Tumor, Female, Gene Expression Profiling methods, Humans, Kidney pathology, Kidney Neoplasms epidemiology, Kidney Neoplasms pathology, Male, MicroRNAs metabolism, Middle Aged, Neoplasm Recurrence, Local epidemiology, Neoplasm Recurrence, Local pathology, Neoplasms, Multiple Primary epidemiology, Neoplasms, Multiple Primary pathology, Oligonucleotide Array Sequence Analysis methods, RNA, Messenger metabolism, Von Hippel-Lindau Tumor Suppressor Protein genetics, Young Adult, Carcinoma, Renal Cell genetics, Gene Expression Regulation, Neoplastic, Kidney Neoplasms genetics, Neoplasm Recurrence, Local genetics, Neoplasms, Multiple Primary genetics, von Hippel-Lindau Disease genetics
- Abstract
Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome that is the main cause of inherited clear-cell renal cell carcinoma (ccRCC), which generally occurs in the form of multiple recurrent synchronized tumors. Affected patients are carriers of a germline mutation in the VHL tumor suppressor gene. Somatic mutations of this gene are also found in sporadic ccRCC and numerous pan-genomic studies have reported a dysregulation of microRNA (miRNA) expression in these sporadic tumors. In order to investigate the molecular mechanisms underlying the pathogenesis of VHL-associated ccRCC, particularly in the context of multiple tumors, the present study characterized the mRNA and miRNA transcriptome through an integrative analysis compared with sporadic renal tumors. In the present study, two series of ccRCC samples were used. The first set consisted of several samples from different tumors occurring in the same patient, for two independent patients affected with VHL disease. The second set consisted of 12 VHL-associated tumors and 22 sporadic ccRCC tumors compared with a pool of normal renal tissue. For each sample series, an expression analysis of miRNAs and mRNAs was conducted using microarrays. The results indicated that multiple tumors within the kidney of a patient with VHL disease featured a similar pattern of miRNA and gene expression. In addition, the expression levels of miRNA were able to distinguish VHL-associated tumors from sporadic ccRCC, and it was identified that 103 miRNAs and 2,474 genes were differentially expressed in the ccRCC series compared with in normal renal tissue. The majority of dysregulated genes were implicated in 'immunity' and 'metabolism' pathways. Taken together, these results allow a better understanding of the occurrence of ccRCC in patients with VHL disease, by providing insights into dysregulated miRNA and mRNA. In the set of patients with VHL disease, there were few differences in miRNA and mRNA expression, thus indicating a similar molecular evolution of these synchronous tumors and suggesting that the same molecular mechanisms underlie the pathogenesis of these hereditary tumors.
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- 2018
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42. Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.
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Lenglet M, Robriquet F, Schwarz K, Camps C, Couturier A, Hoogewijs D, Buffet A, Knight SJL, Gad S, Couvé S, Chesnel F, Pacault M, Lindenbaum P, Job S, Dumont S, Besnard T, Cornec M, Dreau H, Pentony M, Kvikstad E, Deveaux S, Burnichon N, Ferlicot S, Vilaine M, Mazzella JM, Airaud F, Garrec C, Heidet L, Irtan S, Mantadakis E, Bouchireb K, Debatin KM, Redon R, Bezieau S, Bressac-de Paillerets B, Teh BT, Girodon F, Randi ML, Putti MC, Bours V, Van Wijk R, Göthert JR, Kattamis A, Janin N, Bento C, Taylor JC, Arlot-Bonnemains Y, Richard S, Gimenez-Roqueplo AP, Cario H, and Gardie B
- Subjects
- Adolescent, Adult, Child, Female, Heterozygote, Humans, Male, Middle Aged, Pedigree, Polycythemia classification, Polycythemia pathology, Young Adult, von Hippel-Lindau Disease pathology, Exons, Genetic Predisposition to Disease, Mutation, Polycythemia genetics, RNA Splicing, Von Hippel-Lindau Tumor Suppressor Protein genetics, von Hippel-Lindau Disease genetics
- Abstract
Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau ( VHL ) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1' in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1' in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway., (© 2018 by The American Society of Hematology.)
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- 2018
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43. Pattern multiplicity and fumarate hydratase (FH)/S-(2-succino)-cysteine (2SC) staining but not eosinophilic nucleoli with perinucleolar halos differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas from kidney tumors without FH gene alteration.
- Author
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Muller M, Guillaud-Bataille M, Salleron J, Genestie C, Deveaux S, Slama A, de Paillerets BB, Richard S, Benusiglio PR, and Ferlicot S
- Subjects
- Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell metabolism, Carcinoma, Renal Cell pathology, Diagnosis, Differential, Fumarate Hydratase genetics, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Kidney Neoplasms genetics, Kidney Neoplasms metabolism, Kidney Neoplasms pathology, Leiomyomatosis genetics, Leiomyomatosis metabolism, Leiomyomatosis pathology, Carcinoma, Renal Cell diagnosis, Fumarate Hydratase metabolism, Kidney Neoplasms diagnosis, Leiomyomatosis diagnosis
- Abstract
Hereditary leiomyomatosis and renal cell carcinoma syndrome is characterized by an increased risk of agressive renal cell carcinoma, often of type 2 papillary histology, and is caused by FH germline mutations. A prominent eosinophilic macronucleolus with a perinucleolar clear halo is distinctive of hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma according to the 2012 ISUP and 2016 WHO kidney tumor classification. From an immunohistochemistry perspective, tumors are often FH-negative and S-(2-succino)-cysteine (2SC) positive. We performed a pathology review of 24 renal tumors in 23 FH mutation carriers, and compared them to 12 type 2 papillary renal cell carcinomas from FH wild-type patients. Prominent eosinophilic nucleoli with perinucleolar halos were present in almost all FH-deficient renal cell carcinomas (23/24). Unexpectedly, they were also present in 58% of type 2 papillary renal cell carcinomas from wild-type patients. Renal cell carcinoma in mutation carriers displayed a complex architecture with multiple patterns, typically papillary, tubulopapillary, and tubulocystic, but also sarcomatoid and rhabdoid. Such pattern diversity was not seen in non-carriers. FH/2SC immunohistochemistry was informative as all hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas were either FH- or 2SC+. For FH and 2SC immunohistochemistries taken separately, sensitivity of negative anti-FH immunohistochemistry was 87.5% and specificity was 100%. For positive anti-2SC immunohistochemistry, sensitivity, and specificity were 91.7% and 91.7%, respectively. All FH wild-type renal cell carcinoma were FH-positive, and all but one were 2SC-negative. In conclusion, multiplicity of architectural patterns, rhabdoid/sarcomatoid components and combined FH/2SC staining, but not prominent eosinophilic nucleoli with perinucleolar halos, differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma from type 2 papillary renal cell carcinoma with efficient FH gene. Our findings are crucial in identifying who should be referred to Cancer Genetics clinics for genetic counseling and testing.
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- 2018
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44. Testicular ultrasensitive Doppler preliminary experience: a feasibility study.
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Rocher L, Gennisson JL, Ferlicot S, Criton A, Albiges L, Izard V, Bellin MF, and Correas JM
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- Adolescent, Adult, Aged, Aged, 80 and over, Feasibility Studies, Humans, Male, Middle Aged, Prospective Studies, Reproducibility of Results, Sensitivity and Specificity, Young Adult, Scrotum diagnostic imaging, Testicular Diseases diagnostic imaging, Ultrasonography, Doppler methods
- Abstract
Background Ultrasensitive Doppler is a novel non-invasive ultrasound (US) Doppler technique that improves sensitivity and resolution for the detection of slow flow. Purpose To investigate the feasibility of ultrasensitive Doppler (USD) for testicular disease diagnosis, using both qualitative and quantitative results. Material and Methods This prospective study was conducted in 160 successive men referred for scrotal US including B-mode and conventional Color-Doppler. A new USD sequence and algorithm dedicated to academic research were implemented into the US system. The quality criterion for a successful examination was the detection of well delineated intratesticular vessels. Qualitative USD results were described in terms of tumor vascular architecture and flow intensity for different pathologies for 41 patients. The testicular vascularization (TV), defined as a vessel's surface ratio, was quantified using customized MATLAB® software and compared in azoospermic and normal patients. Results USD was acquired successfully in 153/160 patients (95.6%). The tumor vascular architecture differed depending on the nature of the tumors. Leydig cell tumors exhibited mostly circumferential vascularization, while germ cell tumors exhibited straight vessels through the tumors, or anarchic vascular maps. USD improved the diagnostic performance of testicular Doppler US in a case of incomplete spermatic cord torsion and acute epididymitis. The reproducibility of TV measurements established an interclass correlation of 0.801. Non-Klinefelter syndrome non-obstructive azoospermia patients exhibited a lower TV compared to normal patients, to Klinefelter syndrome, and to obstructive azoospermia patients ( P < 0.002, P < 0.005, and P < 0.05, respectively). Conclusion Testicular USD can become a promising technique for improving US diagnosis of tumors, acute scrotum, and for determining infertility status.
- Published
- 2018
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45. BK virus-associated collecting duct carcinoma of the renal allograft in a kidney-pancreas allograft recipient.
- Author
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Dao M, Pécriaux A, Bessede T, Dürrbach A, Mussini C, Guettier C, and Ferlicot S
- Abstract
BK polyomavirus (BKV) nephropathy is a major concern in renal transplantation. Its main consequence is graft loss, which occurs in more than 50% of the cases. De novo renal cell carcinoma in renal allograft is a very rare event. Most of these tumors are papillary or clear cell carcinomas. We report herein the first case of collecting duct carcinoma of the renal allograft in a kidney-pancreas allograft adult recipient. Collecting duct carcinoma occurs long after the cure of a BKV nephropathy. At this time, BKV viremia and viruria were negative as well as the immunostaining for SV40 in the non-tumor kidney. The viral oncoprotein Tag persists only in the tumor cells. To preserve pancreas graft function, we maintained immunosuppression levels. After a 9-months follow-up, the evolution was free from clinical and radiological progression. The oncogenic role of BKV remains controversial in human cancers. However, strong experimental data have shown an association between BKV infection and urologic neoplasms. Further works might precise the exact role of polyomaviruses in renal carcinogenesis. In the meantime, clinical vigilance for early diagnostic of these tumors is mandatory after BKV nephropathy., Competing Interests: CONFLICTS OF INTEREST The authors of this manuscript have no conflicts of interest to disclose as described by Oncotarget.
- Published
- 2018
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46. Transcriptional response to hypoxic stress in melanoma and prognostic potential of GBE1 and BNIP3.
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Buart S, Terry S, Noman MZ, Lanoy E, Boutros C, Fogel P, Dessen P, Meurice G, Gaston-Mathé Y, Vielh P, Roy S, Routier E, Marty V, Ferlicot S, Legrès L, Bouchtaoui ME, Kamsu-Kom N, Muret J, Deutsch E, Eggermont A, Soria JC, Robert C, and Chouaib S
- Abstract
Gradients of hypoxia occur in most solid tumors and cells found in hypoxic regions are associated with the most aggressive and therapy-resistant fractions of the tumor. Despite the ubiquity and importance of hypoxia responses, little is known about the variation in the global transcriptional response to hypoxia in melanoma. Using microarray technology, whole genome gene expression profiling was first performed on established melanoma cell lines. From gene set enrichment analyses, we derived a robust 35 probes signature (hypomel for HYPOxia MELanoma) associated with hypoxia-response pathways, including 26 genes up regulated, and 9 genes down regulated. The microarray data were validated by RT-qPCR for the 35 transcripts. We then validated the signature in hypoxic zones from 8 patient specimens using laser microdissection or macrodissection of Formalin fixed-paraffin-embedded (FFPE) material, followed with RT-qPCR. Moreover, a similar hypoxia-associated gene expression profile was observed using NanoString technology to analyze RNAs from FFPE melanoma tissues of a cohort of 19 patients treated with anti-PD1. Analysis of NanoString data from validation sets using Non-Negative Matrix Factorization (NMF) analysis (26 genes up regulated in hypoxia) and dual clustering (samples and genes) further revealed that the increased level of BNIP3 (Bcl-2 adenovirus E1B 19 kDa-interacting protein 3)/GBE1 (glycogen branching enzyme1) differential pair correlates with the lack of response of melanoma patients to anti-PD1 (pembrolizumab) immunotherapy. These studies suggest that through elevated glycogenic flux and induction of autophagy, hypoxia is a critical molecular program that could be considered as a prognostic factor for melanoma., Competing Interests: CONFLICTS OF INTEREST We declare no competing financial interests.
- Published
- 2017
- Full Text
- View/download PDF
47. Oddities Sporadic Neurofibroma of the Urinary Bladder. A Case Report.
- Author
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Zugail AS, Benadiba S, Ferlicot S, and Irani J
- Abstract
Neurofibromas of the urinary bladder are an exceedingly rare entity and are considered mostly in conjunction with the disease of neurofibromatosis type 1. The fortuitous discovery of vesical plexiform neurofibromas without other stigmata of the disease is presented in a 57-year-old male patient. The course of his condition, modalities of investigation and a non-precedent treatment plan are demonstrated.
- Published
- 2017
- Full Text
- View/download PDF
48. [Prostate cancer histoseminar: Update of the 2016 WHO classification - case No. 8: Acinar prostatic adenocarcinoma, Gleason score 6 (3+3)].
- Author
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Ferlicot S
- Subjects
- Adenocarcinoma blood, Adenocarcinoma diagnosis, Aged, Biopsy, Needle, Humans, Male, Neoplasm Grading, Neoplasm Staging, Prostatic Neoplasms blood, Prostatic Neoplasms diagnosis, Watchful Waiting, Adenocarcinoma pathology, Prostate pathology, Prostate-Specific Antigen blood, Prostatic Neoplasms pathology
- Published
- 2017
- Full Text
- View/download PDF
49. [Prostate cancer histoseminar: Update of the 2016 WHO classification - case n o 3: Intraductal carcinoma].
- Author
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Ferlicot S
- Subjects
- Adenocarcinoma diagnosis, Adenocarcinoma secondary, Adenocarcinoma therapy, Aged, 80 and over, Anilides administration & dosage, Antineoplastic Agents, Hormonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Neoplasms drug therapy, Bone Neoplasms secondary, Fatal Outcome, Humans, Leuprolide administration & dosage, Male, Nitriles administration & dosage, Prostatectomy, Prostatic Neoplasms complications, Prostatic Neoplasms diagnosis, Prostatic Neoplasms surgery, Tosyl Compounds administration & dosage, Adenocarcinoma pathology, Lower Urinary Tract Symptoms etiology, Prostatic Neoplasms pathology
- Published
- 2017
- Full Text
- View/download PDF
50. [Prostate cancer histoseminar: Update of the 2016 WHO classification: Introduction].
- Author
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Ferlicot S
- Subjects
- Adenocarcinoma pathology, Humans, Male, Neoplasm Grading, Prostatic Neoplasms pathology, World Health Organization, Adenocarcinoma classification, Prostatic Neoplasms classification
- Published
- 2017
- Full Text
- View/download PDF
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