Publications by authors named "Sophie Ferlicot"

93 Publications

The spectrum of kidney biopsies in hospitalized patients with COVID-19, acute kidney injury, and/or proteinuria.

Nephrol Dial Transplant 2021 Feb 12. Epub 2021 Feb 12.

Université Paris Saclay, Université Paris-Sud, UVSQ, Villejuif, France.

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.
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http://dx.doi.org/10.1093/ndt/gfab042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928708PMC
February 2021

Severe acute respiratory syndrome coronavirus 2 indirectly damages kidney structures.

Clin Kidney J 2020 Dec 14;13(6):1101-1104. Epub 2020 Dec 14.

Service de Néphrologie et Dialyse, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Universitaire Ambroise Paré, Boulogne Billancourt, France.

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.
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http://dx.doi.org/10.1093/ckj/sfaa209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769537PMC
December 2020

Immunodynamics of explanted human tumors for immuno-oncology.

EMBO Mol Med 2021 Jan 29;13(1):e12850. Epub 2020 Dec 29.

Institut Gustave Roussy, Villejuif, France.

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.
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http://dx.doi.org/10.15252/emmm.202012850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799366PMC
January 2021

Response to plasma exchange and graft survival in recurrent focal and segmental glomerulosclerosis after transplantation: does the time of recurrence matter? A retrospective study.

Transpl Int 2021 Feb 31;34(2):302-312. Epub 2020 Dec 31.

Department of Nephrology - Hypertension, Dialysis, Transplantation, CHRU, Tours, France.

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.
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http://dx.doi.org/10.1111/tri.13796DOI Listing
February 2021

Fluorescence Emitted by Papanicolaou-Stained Urothelial Cells Improves Sensitivity of Urinary Conventional Cytology for Detection of Urothelial Tumors.

World J Oncol 2020 Oct 15;11(5):204-215. Epub 2020 Oct 15.

Service d'Urologie, Universite de Lorraine, CNRS UMR 7039 CRAN, Centre Hospitalier Regional Universitaire, 54035 Nancy Cedex, France.

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 (CIS) and extra bladder carcinoma.
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http://dx.doi.org/10.14740/wjon1305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575278PMC
October 2020

Indirect effects of severe acute respiratory syndrome coronavirus 2 on the kidney in coronavirus disease patients.

Clin Kidney J 2020 Jun 22;13(3):347-353. Epub 2020 May 22.

Service de Néphrologie et Dialyse, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Universitaire Ambroise Paré, Boulogne Billancourt, France.

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.
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http://dx.doi.org/10.1093/ckj/sfaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314263PMC
June 2020

Organ Transplantation in Hereditary Fibrinogen A α-Chain Amyloidosis: A Case Series of French Patients.

Am J Kidney Dis 2020 09 10;76(3):384-391. Epub 2020 Jul 10.

Department of Nephrology and Transplantation, Hôpital Tenon, Sorbonne Université, Paris, France. Electronic address:

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.
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http://dx.doi.org/10.1053/j.ajkd.2020.02.445DOI Listing
September 2020

Ultrasound Molecular Imaging of Renal Cell Carcinoma: VEGFR targeted therapy monitored with VEGFR1 and FSHR targeted microbubbles.

Sci Rep 2020 04 30;10(1):7308. Epub 2020 Apr 30.

IR4M, Univ. Paris-Sud, CNRS, Université Paris-Saclay, Orsay, France.

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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http://dx.doi.org/10.1038/s41598-020-64433-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193565PMC
April 2020

Usefulness of morphometric image analysis with Sirius Red to assess interstitial fibrosis after renal transplantation from uncontrolled circulatory death donors.

Sci Rep 2020 04 23;10(1):6894. Epub 2020 Apr 23.

AP-HP, Service d'Anatomie et de Cytologie Pathologiques, Hôpital de Bicêtre, 94270 Le Kremlin Bicêtre, France, Hôpitaux Universitaires Paris-Saclay, Le Kremlin-Bicêtre, France.

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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http://dx.doi.org/10.1038/s41598-020-63749-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181605PMC
April 2020

[Hereditary kidney cancers: The pathologist's view in 2020].

Ann Pathol 2020 Apr 18;40(2):148-167. Epub 2020 Mar 18.

Réseau national de référence pour cancers rares de l'adulte PREDIR (« Maladie de von Hippel-Lindau et prédispositions héréditaires au cancer rénal ») labellisée par l'Institut national du cancer, université Paris Saclay, Assistance publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France; Génétique oncologique EPHE, PSL Université, UMR 9019 CNRS, université Paris-Saclay, institut Gustave-Roussy, Villejuif, France.

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.
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http://dx.doi.org/10.1016/j.annpat.2020.02.022DOI Listing
April 2020

iPSC-Derived Embryoid Bodies as Models of c--Mutated Hereditary Papillary Renal Cell Carcinoma.

Int J Mol Sci 2019 Sep 30;20(19). Epub 2019 Sep 30.

INSERM UMR-S 935 and ESTeam Paris Sud, Université Paris Sud, 94800 Villejuif, France.

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-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- mutation, showed overexpression of the BHLHE40 and KDM4C only in the c--mutated PRCC tumors, as predicted by c--mutated embryoid bodies transcriptome. These data therefore represent the first proof of concept of "hereditary renal cancer in a dish" model using c--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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http://dx.doi.org/10.3390/ijms20194867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801716PMC
September 2019

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).

World J Urol 2020 Jun 5;38(6):1517-1524. Epub 2019 Sep 5.

Department of Urology, Charles Nicolle Rouen University Hospital, 1 rue de Germont, 76031, Rouen Cedex, France.

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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http://dx.doi.org/10.1007/s00345-019-02896-3DOI Listing
June 2020

The cannabinoid receptor 1 is involved in renal fibrosis during chronic allograft dysfunction: Proof of concept.

J Cell Mol Med 2019 11 30;23(11):7279-7288. Epub 2019 Aug 30.

Inserm UMR_S 1155, Hôpital Tenon, Paris, France.

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.
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http://dx.doi.org/10.1111/jcmm.14570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815790PMC
November 2019

Characterization of Testicular Masses in Adults: Performance of Combined Quantitative Shear Wave Elastography and Conventional Ultrasound.

Ultrasound Med Biol 2019 03 29;45(3):720-731. Epub 2018 Dec 29.

Institut Langevin, ESPCI Paris, PSL Research University CNRS UMR 7587, INSERM ERL U-979, Paris, France; Department of Adult Radiology, Necker University Hospital, Paris, France; Paris Descartes University, Paris, France.

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). LCTs manifested mostly a dominant peripheral vascularization pattern compared with other lesions. MTs + BOTs were stiffer compared with benign lesions (p < 2 × 10) 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.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2018.10.027DOI Listing
March 2019

Integrative analysis of dysregulated microRNAs and mRNAs in multiple recurrent synchronized renal tumors from patients with von Hippel-Lindau disease.

Int J Oncol 2018 Oct 19;53(4):1455-1468. Epub 2018 Jul 19.

Oncogenetics Laboratory, EPHE, PSL Research University, 75014 Paris, France.

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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http://dx.doi.org/10.3892/ijo.2018.4490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086628PMC
October 2018

Identification of a new exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.

Blood 2018 08 11;132(5):469-483. Epub 2018 Jun 11.

École Pratique des Hautes Études, PSL Research University, Paris, France.

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau () gene. Since this discovery, additional mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. 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 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 coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other exons. In this study, we show that the mutations induced a dysregulation of 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 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 alterations and reveals a novel complex splicing regulation of the gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway.
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http://dx.doi.org/10.1182/blood-2018-03-838235DOI Listing
August 2018

BK virus-associated collecting duct carcinoma of the renal allograft in a kidney-pancreas allograft recipient.

Oncotarget 2018 Mar 22;9(19):15157-15163. Epub 2018 Feb 22.

Pathology Department, CHU Bicêtre, Le Kremlin-Bicêtre, France.

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. 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.
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http://dx.doi.org/10.18632/oncotarget.24552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871106PMC
March 2018

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.

Mod Pathol 2018 06 6;31(6):974-983. Epub 2018 Feb 6.

Réseau National pour Cancers Rares de l'Adulte PREDIR AP-HP labellisé par l'Institut National du Cancer (INCa), Hôpital de Bicêtre, 94275, Le Kremlin Bicêtre, France.

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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http://dx.doi.org/10.1038/s41379-018-0017-7DOI Listing
June 2018

Transcriptional response to hypoxic stress in melanoma and prognostic potential of GBE1 and BNIP3.

Oncotarget 2017 Dec 30;8(65):108786-108801. Epub 2017 Oct 30.

INSERM UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par La Ligue Contre Le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.

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.
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http://dx.doi.org/10.18632/oncotarget.22150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752481PMC
December 2017

Oddities Sporadic Neurofibroma of the Urinary Bladder. A Case Report.

Urol Case Rep 2017 Sep 12;14:42-44. Epub 2017 Jul 12.

Department of Urology, Bicêtre Hospital, Le Kremlin Bicêtre, France.

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.
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http://dx.doi.org/10.1016/j.eucr.2017.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510488PMC
September 2017

Testicular ultrasensitive Doppler preliminary experience: a feasibility study.

Acta Radiol 2018 Mar 1;59(3):346-354. Epub 2017 Jun 1.

3 Institut Langevin, ESPCI Paris, PSL Research University CNRS UMR 7587, INSERM U979, Paris, France.

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.
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http://dx.doi.org/10.1177/0284185117713350DOI Listing
March 2018

[Prostate cancer histoseminar: Update of the 2016 WHO classification. Pre-test].

Authors:
Sophie Ferlicot

Ann Pathol 2017 Jun 16;37(3):224-227. Epub 2017 May 16.

Service d'anatomie et cytologie pathologiques, hôpital de Bicêtre, hôpitaux universitaires Paris-Sud, université Paris-Sud, 78, rue du Général Leclerc, 94275 Le Kremlin-Bicêtre cedex, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2017.02.003DOI Listing
June 2017

[Prostate cancer histoseminar: Update of the 2016 WHO classification: Introduction].

Authors:
Sophie Ferlicot

Ann Pathol 2017 Jun 15;37(3):223. Epub 2017 May 15.

Service d'anatomie et cytologie pathologiques, hôpital de Bicêtre, hôpitaux universitaires Paris-Sud, université Paris-Sud, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2017.02.002DOI Listing
June 2017

[Prostate cancer histoseminar: Update of the 2016 WHO classification - case n3: Intraductal carcinoma].

Authors:
Sophie Ferlicot

Ann Pathol 2017 Jun 16;37(3):235-240. Epub 2017 May 16.

Service d'anatomie et cytologie pathologiques, hôpital de Bicêtre, hôpitaux universitaires Paris-Sud, université Paris-Sud, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2017.02.008DOI Listing
June 2017

[Prostate cancer histoseminar: Update of the 2016 WHO classification. Pre-test answers].

Authors:
Sophie Ferlicot

Ann Pathol 2017 Jun 15;37(3):264-265. Epub 2017 May 15.

Service d'anatomie et cytologie pathologiques, hôpital de Bicêtre, hôpitaux universitaires Paris-Sud, université Paris-Sud, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2017.02.012DOI Listing
June 2017

[Prostate cancer histoseminar: Update of the 2016 WHO classification - case No. 8: Acinar prostatic adenocarcinoma, Gleason score 6 (3+3)].

Authors:
Sophie Ferlicot

Ann Pathol 2017 Jun 15;37(3):259-263. Epub 2017 May 15.

Service d'anatomie et cytologie pathologiques, hôpital de Bicêtre, hôpitaux universitaires Paris-Sud, université Paris-Sud, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2017.02.004DOI Listing
June 2017

Angiosarcoma of the Bladder: Review of the Literature and Discussion About a Clinical Case.

Urol Case Rep 2017 Jul 27;13:97-100. Epub 2017 Apr 27.

Department of Urology, Andrology and Renal Transplantation, CHU Bicêtre, Le Kremlin-Bicêtre, France.

Our reported case is a 72 year-old man who presented with hematuria. A transurethral resection of the bladder tumor (TURB-T) has been performed. Histopathological diagnosis was an epithelioid angiosarcoma. CT scan revealed a bladder thickening. The treatment consisted in a complete pelvectomy with urinary and digestive diversion. Following the operation, the patient developed liver and pulmonary metastasis. He died 5 months after the initial diagnosis.
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http://dx.doi.org/10.1016/j.eucr.2016.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412009PMC
July 2017

Erratum to "Non-palpable incidentally found testicular tumors: Differentiation between benign, malignant, and burned-out tumors using dynamic contrast-enhanced MRI" [Eur. J. Radiol. 85(11) (2016) 2072-2082].

Eur J Radiol 2017 03 6;88:171. Epub 2017 Jan 6.

Service de Radiologie Diagnostique et Interventionnelle Adulte, Groupe Hospitalier Paris Sud, Hôpital de Bicêtre, APHP, 78 avenue du Général Leclerc, 94275 Le Kremlin Bicêtre, France; Faculté de Médecine Paris-Saclay, 63 rue Gabriel Péri, 94270 Le Kremlin Bicêtre, France; Institut Langevin, ESPCI Paris, PSL Research University CNRS UMR 7587, INSERM ERL U-979, 35, 17 rue Moreau, 75012 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.ejrad.2016.12.022DOI Listing
March 2017

Testicular Shear Wave Elastography in Normal and Infertile Men: A Prospective Study on 601 Patients.

Ultrasound Med Biol 2017 04 3;43(4):782-789. Epub 2017 Jan 3.

Institut Langevin, ESPCI Paris, PSL Research University CNRS UMR 7587, INSERM ERL U-979, Paris, France; Department of Adult Radiology, Necker University Hospital, Paris, France; Paris Descartes University, Paris, France.

Our aim in the study described here was to prospectively establish the feasibility of using and reproducibility of testicular shear-wave elastography in the assessment of testicular stiffness in 62 normal patients and 539 infertile men with obstructive azoospermia (OA), non-Klinefelter syndrome non-obstructive azoospermia (non-KS NOA), Klinefelter syndrome NOA (KS NOA), oligoasthenoteratozoospermia (OAT) or a left varicocele. The feasibility rate was 96.9%, with an intra-class correlation coefficient of 0.85 (95% confidence interval: 0.83-0.88). Median stiffness (interquartile range) values were 2.4 kPa (2.0, 2.9), 2.1 kPa (1.8, 2.5), 2.4 kPa (2.0, 2.7), 2.0 kPa (1.7, 2.4), 2.6 kPa (2, 3.2) and 2.2 kPa (1.8, 2.6) for men with a normal testis (n = 108), OAT (n = 689), OA (n = 119), non-KS NOA (n = 183), KS NOA (n = 70) and varicocele (n = 132), respectively. Testicular shear wave elastography is a feasible and reproducible technique. A significant positive association was found between stiffness and testis volume (p = 0.001). Testicular stiffness was higher in OA than in non-KS NOA populations (p = 1.e-10) and in KS NOA than in NOA populations (p = 2.0e-8), but the substantial number of overlapping values limited the clinical impact.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2016.11.016DOI Listing
April 2017

A multicentre study of 95 biopsy-proven cases of renal disease in primary Sjögren's syndrome.

Rheumatology (Oxford) 2017 Mar;56(3):362-370

Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris.

Objective.: Renal involvement is a rare event during primary SS (pSS). We aimed to describe the clinico-biological and histopathological characteristics of pSS-related nephropathy and its response to treatment.

Methods.: We conducted a French nationwide, retrospective, multicentre study including pSS patients fulfilling American-European Consensus Group criteria or enlarged American-European Consensus Group criteria, and with biopsy-proven renal involvement.

Results.: A total of 95 patients were included (median age 49 years). An estimated glomerular filtration rate (eGFR) of <60 ml/min was found in 82/95 patients (86.3%). Renal biopsy demonstrated tubulointerstitial nephritis (TIN) in 93 patients (97.9%), and frequent (75%) plasma cell infiltrates. Glomerular lesions were found in 22 patients (23.2%), mainly related to cryoglobulin. The presence of anti-SSA (76.8%) and anti-SSB (53.8%) antibodies was particularly frequent among patients with TIN and was associated with a worse renal prognosis. Eighty-one patients (85.3%) were treated, with CSs in 80 (98.8%) and immunosuppressive agents (mostly rituximab) in 21 cases (25.9%). Despite marked interstitial fibrosis at initial biopsy, kidney function improved significantly during the 12-month period following diagnosis (final eGFR 49.9 vs 39.8 ml/min/1.73 m 2 at baseline, P < 0.001). No proven benefit of immunosuppressive agents over steroid therapy alone was found in this study.

Conclusion.: Renal involvement of pSS is mostly due to TIN with marked T, B and especially plasma cell infiltration. Renal dysfunction is usually isolated but can be severe. Use of CSs can improve the eGFR, but further studies are needed to define the best therapeutic strategy in this disease.
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http://dx.doi.org/10.1093/rheumatology/kew376DOI Listing
March 2017