Publications by authors named "Jean-Yves Scoazec"

414 Publications

Prognostic factors of metastatic neuroendocrine carcinoma under first-line treatment with platinum etoposide with a focus on NEC score and Rb expression: Results from the multicentre RBNEC study of the Groupe d'Etude des Tumeurs Endocrines (GTE) and the ENDOCAN-RENATEN network.

Eur J Cancer 2021 Jun 2;152:100-115. Epub 2021 Jun 2.

Oncologie endocrinienne, Département d'imagerie, Gustave Roussy, Villejuif, F-94805, France.

Introduction And Aim: Neuroendocrine carcinomas (NECs) are aggressive malignant diseases. Platinum-etoposide (PE) combination is the standard first-line treatment, whatever the primary location. The NEC score and also retinoblastoma protein (Rb) status have been suggested to be predictive/prognostic factors in NEC. The primary objective of our multicentric retrospective study was to evaluate the prognostic relevance of the NEC score and Rb status, assessed by immunohistochemistry in PE-treated patients with metastatic NEC.

Methods: Seven centres participated. The inclusion criteria were NEC, whatever the primary site, metastatic stage, first-line treatment with PE and tissue samples available. Rb status was determined centrally.

Results: We report multicentric data from 185 metastatic patients (37% women, median age 63). There were 108 small-cell NECs (SCNECs, 58.4%), 50 large-cell NECs (LCNECs, 27%) and 27 not otherwise specified NECs (nosNECs, 14.6%). The primary sites were the thorax (37%), gastroenteropancreatic sites (38%), unknown (15%) and other (9%). The mean Ki-67 index was 76% (range 20-100). Rb status was interpretable in 122 cases. Rb expression was lost in 74% of the cases: 84% of SCNEC vs. 60% and 63% of LCNEC and nosNEC, respectively (p = 0.016). Objective response was seen in 70% of SCNEC, 45% of LCNEC and 48% of nosNEC (p < 0.001) and in 62% of Rb-negative tumours vs. 46% of Rb-positive tumours (p = 0.3). There was no difference in median progression-free survival or overall survival (OS) as per Rb status. Age, NEC score and response to chemotherapy were the main factors associated with OS in our cohort.

Conclusion: In our series, Rb status had no prognostic impact in PE-treated metastatic patients with NEC, whereas age, NEC score and response to chemotherapy were the main factors associated with OS.
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http://dx.doi.org/10.1016/j.ejca.2021.04.030DOI Listing
June 2021

FOLFIRINEC: a randomized phase II trial of mFOLFIRINOX vs platinum-etoposide for metastatic neuroendocrine carcinoma of gastroenteropancreatic or unknown origin.

Dig Liver Dis 2021 May 12. Epub 2021 May 12.

Hepato-gastroenterology department, Centre Hospitalier de Saint-Malo, Saint-Malo F-35403, France.

Background: Poorly differentiated neuroendocrine carcinomas (NEC) are rare diseases with a poor prognosis. Platinum-etoposide (PE) has been the recommended first-line treatment for decades. FOLFIRINEC (NCT04325425) is a national multicenter randomized phase II study which aims to challenge this standard regimen.

Methods: The primary objective is to compare the median progression-free survival (PFS) under mFOLFIRINOX versus PE. The secondary objectives are to evaluate the objective response rates (ORR), median overall survival (OS), safety and quality of life. The associated real-time translational study will establish a molecular profile for each patient enrolled.

Main Inclusion Criteria Are: NEC of gastroenteropancreatic (GEP) or unknown origin, metastatic and RECIST 1.1 evaluable disease, tumor sample available and no contraindication to chemotherapy. Patients will be randomized 1:1 between PE every 21 days for 6-8 cycles and mFOLFIRINOX every 14 days for up to 12 cycles and stratified according to center, performance status, Ki67 and pathological subtype. This trial will randomize 218 patients (24 months of follow-up) to have 80% power to detect an improvement of the median PFS from 5 months under PE to 7.5 months under mFOLFIRINOX (HR of 0.67, α =5%, two-sided). An intermediate analysis is planned at 50% of events. Recruitment started on October 20, 2020.
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http://dx.doi.org/10.1016/j.dld.2021.04.016DOI Listing
May 2021

Response to systemic therapy in fumarate hydratase-deficient renal cell carcinoma.

Eur J Cancer 2021 Jul 8;151:106-114. Epub 2021 May 8.

Department of Medical Oncology, Gustave Roussy, Villejuif, France; Réseau National de Référence pour Cancers Rares de l'Adulte PREDIR labellisé par l'INCa, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France. Electronic address:

Purpose: Fumarate hydratase-deficient (FHdef) renal cell carcinoma (RCC) is a rare entity associated with the hereditary leiomyomatosis and RCC syndrome with no standard therapy approved. The aim of this retrospective study was to evaluate the efficacy of different systemic treatments in this population.

Methods: We performed a multicentre retrospective analysis of Fhdef RCC patients to determine the response to systemic treatments. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and overall survival (OS). The two latter were estimated using the Kaplan-Meier method.

Results: Twenty-four Fhdef RCC patients were identified, and 21 under systemic therapy were included in the analysis: ten received cabozantinib, 14 received sunitinib, nine received "other antiangiogenics" (sorafenib, pazopanib, and axitinib), three received erlotinib-bevacizumab (E-B), three received mTOR inhibitors, and 11 received immune checkpoint blockers (ICBs). ORR for treatments were 50% for cabozantinib, 43% for sunitinib, 63% for "other antiangiogenics," and 30% for E-B, whereas ORR was 0% for mTOR inhibitors and 18% for ICBs. The median TTF (mTTF) was significantly higher with antiangiogenics (11.6 months) than with mTOR inhibitors (4.4 months) or ICBs (2.7 months). In the first-line setting, antiangiogenics presented a higher ORR compared with nivolumab-ipilimumab (64% versus 25%) and a significantly superior mTTF (11.0 months vs 2.5 months; p = 0.0027). The median OS from the start of the first systemic treatment was 44.0 months (95% confidence interval: 13.0-95.0).

Conclusions: We report the first European retrospective study of Fhdef RCC patients treated with systemic therapy with a remarkably long median OS of 44.0 months. Our results suggest that antiangiogenics may be superior to ICB/mTOR inhibitors in this population.
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http://dx.doi.org/10.1016/j.ejca.2021.04.009DOI Listing
July 2021

Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSé-ESMART, a trial of the European Innovative Therapies for Children With Cancer Consortium.

Eur J Cancer 2021 Jun 20;150:53-62. Epub 2021 Apr 20.

Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France; INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. Electronic address:

Purpose: AcSé-ESMART is a European multicentre, proof-of-concept multiarm phase I/II platform trial in paediatric patients with relapsed/refractory cancer. Arm G assessed the activity and safety of nivolumab in combination with metronomic cyclophosphamide +/- irradiation.

Experimental Design: Following a Phase II Simon two-stage design, nivolumab was administered intravenously at 3 mg/kg every 2 weeks of a 28-day cycle, oral cyclophosphamide at 25 mg/m twice a day, 1 week on/1 week off. The primary endpoint was objective response rate. Irradiation/radioablation of primary tumour or metastasis could be administered as per physician's choice. Biomarker evaluation was performed by tumour immunohistochemistry, whole exome and RNA sequencing, and immunophenotyping of peripheral blood by flow cytometry.

Results: Thirteen patients were treated with a median age of 15 years (range: 5.5-19.4). The main histologies were high-grade glioma, neuroblastoma, and desmoplastic small round cell tumour (DSRCT). The safety profile was similar to those of single-agent nivolumab, albeit haematologic toxicity, mainly lymphocytopenia, was commonly reported with the addition of cyclophosphamide +/- irradiation. Two patients with DSRCT and ependymoma presented unconfirmed partial response and prolonged disease stabilisation. Low mutational load with modest intratumour CD3+ T-cell infiltration and immunosuppressive tumour microenvironment were observed in the tumour samples. Under combined treatment, no positive modulation of circulating T cells was displayed, while derived neutrophil-to-lymphocyte ratio increased.

Conclusions: Nivolumab in combination with cyclophosphamide was well tolerated but had limited activity in this paediatric setting. Metronomic cyclophosphamide did not modulate systemic immune response that could compensate limited T-cell infiltration and the immunosuppressive tumour microenvironment. CLINICALTRIALS.

Gov Identifier: NCT2813135.
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http://dx.doi.org/10.1016/j.ejca.2021.03.032DOI Listing
June 2021

[Spindle cell tumor: Infection or neoplasm?]

Ann Pathol 2021 Apr 17. Epub 2021 Apr 17.

Service de pathologie morphologique, département de biologie et pathologie médicales, Gustave-Roussy Cancer Campus, Villejuif, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2021.03.010DOI Listing
April 2021

Phenotypic discordance between primary and metastatic breast cancer in the large-scale real-life multicenter French ESME cohort.

NPJ Breast Cancer 2021 Apr 16;7(1):41. Epub 2021 Apr 16.

Gustave Roussy Cancer Campus, Villejuif, France.

Expression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.
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http://dx.doi.org/10.1038/s41523-021-00252-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052407PMC
April 2021

Perspectives in pathomics in head and neck cancer.

Curr Opin Oncol 2021 05;33(3):175-183

INSERM U1030, Molecular Radiotherapy and Therapeutic Innovation, Gustave Roussy Cancer Campus, Paris-Saclay University.

Purpose Of Review: Pathology is the cornerstone of cancer care. Pathomics, which represents the use of artificial intelligence in digital pathology, is an emerging and promising field that will revolutionize medical and surgical pathology in the coming years. This review provides an overview of pathomics, its current and future applications and its most relevant applications in Head and Neck cancer care.

Recent Findings: The number of studies investigating the use of artificial intelligence in pathology is rapidly growing, especially as the utilization of deep learning has shown great potential with Whole Slide Images. Even though numerous steps still remain before its clinical use, Pathomics has been used for varied applications comprising of computer-assisted diagnosis, molecular anomalies prediction, tumor microenvironment and biomarker identification as well as prognosis evaluation. The majority of studies were performed on the most frequent cancers, notably breast, prostate, and lung. Interesting results were also found in Head and Neck cancers.

Summary: Even if its use in Head and Neck cancer care is still low, Pathomics is a powerful tool to improve diagnosis, identify prognostic factors and new biomarkers. Important challenges lie ahead before its use in a clinical practice, notably the lack of information on how AI makes its decisions, the slow deployment of digital pathology, and the need for extensively validated data in order to obtain authorities approval. Regardless, pathomics will most likely improve pathology in general, including Head and Neck cancer care in the coming years.
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http://dx.doi.org/10.1097/CCO.0000000000000731DOI Listing
May 2021

Multifocal in situ mantle cell neoplasia of the ileocecal region: a case report with simultaneous nodal and extranodal involvement.

Virchows Arch 2021 Mar 1. Epub 2021 Mar 1.

Department of Pathology, Gustave Roussy Cancer Campus, 144 rue Edouard Vaillant, 94805, Villejuif cedex, France.

In situ mantle cell neoplasia (ISMCN) is a rare entity of disputed clinical significance. We report an additional case, unusual by its presentation in the large intestine and its multifocal involvement of several nodal and extranodal sites. The diagnosis was made in a 46-year-old male patient from a surgical specimen resected for cecal adenocarcinoma. Gross examination showed multiple small polypoid lesions surrounding the ileocecal valve, corresponding to lymphoid aggregates with hyperplastic follicles. Numerous cyclin D1/SOX11+ lymphoid cells, harboring the t(11;14)(q13;q32) translocation, were present in the inner layers of mantle zones. The same lesions were found in the ileum, the appendix, and the regional lymph nodes. The final diagnosis was multifocal ISMCN of the ileocecal region, with both nodal and extra-nodal involvement. A simple surveillance was decided. Our observation expands the clinical spectrum of the disease and underlines the necessity to closely examine even normal-appearing reactive lymphoid tissues.
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http://dx.doi.org/10.1007/s00428-021-03065-xDOI Listing
March 2021

Genomics of High-Grade Neuroendocrine Neoplasms: Well-Differentiated Neuroendocrine Tumor with High-Grade Features (G3 NET) and Neuroendocrine Carcinomas (NEC) of Various Anatomic Sites.

Endocr Pathol 2021 Mar 12;32(1):192-210. Epub 2021 Jan 12.

Department of Oncology, University of Turin, Torino, Italy.

High-grade neuroendocrine neoplasms (HG-NENs) are clinically aggressive diseases, the classification of which has recently been redefined. They now include both poorly differentiated NENs (neuroendocrine carcinoma, NECs) and high proliferating well-differentiated NENs (called grade 3 neuroendocrine tumors, G3 NETs, in the digestive system). In the last decade, the "molecular revolution" that has affected all fields of medical oncology has also shed light in the understanding of HG NENs heterogeneity and has provided new diagnostic and therapeutic tools, useful in the management of these malignancies. Considering the kaleidoscopic aspects of HG NENs in various anatomical sites, this review systematically addresses the genomic landscape of such neoplasm throughout the more common thoracic and digestive locations, as well as it will consider other rare but not exceptional primary sites, including the skin, the head and neck, and the urogenital system. The revision of the available literature will then be oriented to understand the translational relevance of molecular data, by analyzing conceptual issues, clinicopathological correlations, and unmet needs in this field.
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http://dx.doi.org/10.1007/s12022-020-09660-zDOI Listing
March 2021

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

[Gastric bacterial overgrowth: An unusual histological observation, not to be overlooked].

Ann Pathol 2021 Apr 14;41(2):196-200. Epub 2020 Dec 14.

Service de Pathologie Morphologique, Département de Biologie et Pathologie Médicales, Gustave-Roussy Cancer Campus, 94805 Villejuif, France; Université Paris Sud, Faculté de Médecine de Bicêtre, 94270 Le Kremlin-Bicêtre, France.

Gastric bacterial overgrowth is a rare situation, which may be associated with short- and long-term complications. It must be known from pathologists, since it might be detected incidentally at histological examination of gastric biopsies. We report here the case of a 74-year old woman, obese, without significant medical history, apart from a gastro-esophageal reflux treated by the long-term administration of proton pump inhibitors (PPI). In this patient, gastric bacterial overgrowth was detected at histological examination of gastric biopsies performed after colectomy for left colon adenocarcinoma. Large clusters of small, round, "coccoid" bacteria were present in the gastric mucus. Their characteristics were suggestive of enterobacteria. Bacterial proliferation was associated with severe and diffuse lesions of active gastritis. The course was rapidly unfavorable, and the patient rapidly deceased with multiple infections and multi-organ failure. In our observation, the pathogenesis of gastric bacterial overgrowth was probably multifactorial. It might have been facilitated by long-term PPI treatment and obesity, which are known risk factors, and promoted, in the post-operative setting, by multiple infections and immune failure. Our observation underlines that gastric bacterial overgrowth might be associated with severe gastritis, which might justify antibiotherapy. Other consequences of prolonged gastric dysbiosis cannot be excluded, such as the promotion of neoplastic lesions.
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http://dx.doi.org/10.1016/j.annpat.2020.11.005DOI Listing
April 2021

Ileal immune tonus is a prognosis marker of proximal colon cancer in mice and patients.

Cell Death Differ 2021 May 1;28(5):1532-1547. Epub 2020 Dec 1.

Gustave Roussy Cancer Campus (GRCC), Villejuif, France.

Ileal epithelial cell apoptosis and the local microbiota modulate the effects of oxaliplatin against proximal colon cancer by modulating tumor immunosurveillance. Here, we identified an ileal immune profile associated with the prognosis of colon cancer and responses to chemotherapy. The whole immune ileal transcriptome was upregulated in poor-prognosis patients with proximal colon cancer, while the colonic immunity of healthy and neoplastic areas was downregulated (except for the Th17 fingerprint) in such patients. Similar observations were made across experimental models of implanted and spontaneous murine colon cancer, showing a relationship between carcinogenesis and ileal inflammation. Conversely, oxaliplatin-based chemotherapy could restore a favorable, attenuated ileal immune fingerprint in responders. These results suggest that chemotherapy inversely shapes the immune profile of the ileum-tumor axis, influencing clinical outcome.
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http://dx.doi.org/10.1038/s41418-020-00684-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167112PMC
May 2021

Melanoma Persister Cells Are Tolerant to BRAF/MEK Inhibitors via ACOX1-Mediated Fatty Acid Oxidation.

Cell Rep 2020 11;33(8):108421

INSERM U981, Villejuif, France; Université Paris-Saclay, Kremlin-Bicêtre, France; Dermato-Oncology, Gustave Roussy Cancer Campus, Villejuif, France; Gustave Roussy Cancer Campus, Villejuif, France. Electronic address:

Emerging evidence indicates that non-mutational drug tolerance mechanisms underlie the survival of residual cancer "persister" cells. Here, we find that BRAF(V600E) mutant melanoma persister cells tolerant to BRAF/MEK inhibitors switch their metabolism from glycolysis to oxidative respiration supported by peroxisomal fatty acid β-oxidation (FAO) that is transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPARα). Knockdown of the key peroxisomal FAO enzyme, acyl-CoA oxidase 1 (ACOX1), as well as treatment with the peroxisomal FAO inhibitor thioridazine, specifically suppresses the oxidative respiration of persister cells and significantly decreases their emergence. Consistently, a combination treatment of BRAF/MEK inhibitors with thioridazine in human-melanoma-bearing mice results in a durable anti-tumor response. In BRAF(V600E) melanoma samples from patients treated with BRAF/MEK inhibitors, higher baseline expression of FAO-related genes and PPARα correlates with patients' outcomes. These results pave the way for a metabolic strategy to overcome drug resistance.
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http://dx.doi.org/10.1016/j.celrep.2020.108421DOI Listing
November 2020

CD103CD8 T Cells Accumulate in Tumors of Anti-PD-1-Responder Lung Cancer Patients and Are Tumor-Reactive Lymphocytes Enriched with Tc17.

Cell Rep Med 2020 Oct 20;1(7):100127. Epub 2020 Oct 20.

INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, 94805 Villejuif, France.

Accumulation of CD103CD8 resident memory T (T) cells in human lung tumors has been associated with a favorable prognosis. However, the contribution of T to anti-tumor immunity and to the response to immune checkpoint blockade has not been clearly established. Using quantitative multiplex immunofluorescence on cohorts of non-small cell lung cancer patients treated with anti-PD-(L)1, we show that an increased density of CD103CD8 lymphocytes in immunotherapy-naive tumors is associated with greatly improved outcomes. The density of CD103CD8 cells increases during immunotherapy in most responder, but not in non-responder, patients. CD103CD8 cells co-express CD49a and CD69 and display a molecular profile characterized by the expression of PD-1 and CD39. CD103CD8 tumor T, but not CD103CD8 tumor-infiltrating counterparts, express Aiolos, phosphorylated STAT-3, and IL-17; demonstrate enhanced proliferation and cytotoxicity toward autologous cancer cells; and frequently display oligoclonal expansion of TCR-β clonotypes. These results explain why CD103CD8 T are associated with better outcomes in anti-PD-(L)1-treated patients.
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http://dx.doi.org/10.1016/j.xcrm.2020.100127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659589PMC
October 2020

Impact of expert review of histological diagnosis of papillary and follicular thyroid cancer.

Endocrine 2021 Jun 31;72(3):791-797. Epub 2020 Oct 31.

Department of Endocrine Oncology and Nuclear Medicine, Gustave Roussy and Paris Saclay University, 114 Rue Edouard Vaillant, 94805, Villejuif, France.

Purpose: Histologic and pTNM classification of differentiated thyroid cancer (DTC) is mandatory to assess risk of relapse, risk of death, and radioactive iodine administration. The impact of an expert central review of external pathology reports has not yet been reported.

Methods: Monocentric retrospective study to evaluate the difference between initial and second-opinion histopathologic diagnosis for DTC patients referred for post-operative radioactive iodine administration between January 2014 and December 2016. We evaluated major discordance (change of diagnosis from malignant to benign or in main histological subtype or a description of aggressive pathological subtypes), minor discordance (change in histological subtype or description of an aggressive component, multifocality or extrathyroidal extension), and change in ATA classification.

Results: A second-opinion histological diagnosis was available for 199 patients. A major discordance was observed in 42 (21%) cases (changes in malignancy in 4 cases, changes in main histological subtype in 22, changes in aggressive pathology variants of PTC in 16). One hundred and four minor discordances were observed regarding 92 patients. These histopathological changes led to changes in the ATA 2015 risk stratification classification in 61 (31%) of cases. There were no predictive factors of major/minor histologic changes or ATA risk stratification changes.

Conclusion: Expert central review of pathology has an impact on the 2015 ATA risk stratification classification that can lead to changes in the management of patients with differentiated thyroid cancer.
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http://dx.doi.org/10.1007/s12020-020-02531-xDOI Listing
June 2021

[A new case report and review of the literature].

Ann Pathol 2021 Apr 16;41(2):207-211. Epub 2020 Oct 16.

Service de pathologie morphologique, département de biologie et pathologie médicales, Gustave Roussy Cancer Campus, 114, rue Edouard-Vaillant, 94800 Villejuif, France; Faculté de médecine de Bicêtre, université Paris Saclay, Le Kremlin-Bicêtre, France.

Sarcoma with EWSR1-PATZ1 gene fusion is an exceedingly rare and newly described Ewing-like sarcoma harboring EWSR1 rearrangements involving fusion partners other than ETS family genes. The clinical, histopathologic and immunophenotypic features of cases reported in literature are fairly diverse and not specific. We report a new case report posing real challenges for histological and molecular diagnosis.
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http://dx.doi.org/10.1016/j.annpat.2020.08.004DOI Listing
April 2021

Digital Multiplexed Gene Expression Analysis of mRNA and miRNA from Routinely Processed and Stained Cytological Smears: A Proof-of-Principle Study.

Acta Cytol 2021 2;65(1):88-98. Epub 2020 Oct 2.

INSERM UMR 981, Villejuif, France,

Objective: Although transcriptomic assessments of small samples using high-throughput techniques are usually performed on fresh or frozen tissues, there is a growing demand for those performed on stained cellular specimens already used for diagnostic purposes.

Study Design: The possibility of detecting mRNAs and microRNAs (miRNAs) from routinely processed cytological samples using nCounter® technology was explored. Fresh samples from pleural and peritoneal effusions were analyzed using 2 parallel methods: samples were smeared and routinely stained using the May-Grünwald-Giemsa or Diff-Quik® method and mounted using conventional methods, and they were also studied following a snap freezing method, in which samples were maintained at -80°C until use. mRNAs and miRNAs were assessed and compared after total RNA extraction from both routinely processed samples and their matched frozen controls.

Results: A good concordance was found between the gene expression measured in routinely processed samples and their matched frozen controls for the majority of mRNAs and miRNAs tested. However, the standard deviation of low-expressed miRNA was high.

Conclusions: Although nCounter® technology is a robust method to measure and characterize both mRNAs and miRNAs from routinely processed cytological samples, caution is recommended for the interpretation of low-expressed miRNA.
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http://dx.doi.org/10.1159/000510174DOI Listing
January 2021

Histological classification of mucinous ovarian tumors: inter-observer reproducibility, clinical relevance, and role of genetic biomarkers.

Virchows Arch 2021 May 3;478(5):885-891. Epub 2020 Oct 3.

Department of Pathology, Université Claude Bernard Lyon 1, Villeurbanne, France.

The morphological distinction between the various types of mucinous ovarian tumors has major prognostic implications but may be challenging. The aims of our study were to describe inter-observer reproducibility in the morphological diagnosis of mucinous ovarian tumors, to evaluate the clinical relevance of possible diagnostic discrepancies, and to identify molecular abnormalities correlated with the histological type. Seventy-nine ovarian mucinous borderline tumors (MOB) and either expansile or infiltrative carcinomas (MOC) were independently reviewed by two gynecological pathologists. Molecular analysis was performed in 32 cases. Concordance between the two pathologists was reached in 67 cases (k: 0.78). The main discrepancies (8/12) were the evaluation of nuclear grade 3 or that of microfoci (< 5 mm) of infiltrative-type carcinoma in an otherwise typical expansile MOC. Our follow-up analysis showed that infiltrative MOC had a lower overall survival (OS) (p < 0.0024) and progression-free survival (PFS) (p = 0.0060) as compared with MOB and expansile MOC. The presence of nuclear grade 3 or microfoci (< 5 mm) of infiltrative-type pattern of invasion in an otherwise typical expansile MOC did not alter the prognosis as compared with expansile MOC without these features, in terms of OS (p < 0.0028) and PFS (p = 0.0074). KRAS mutations were more frequent in MOB (71%), than in expansile (50%) and infiltrative MOC (14%). In contrast, the prevalence of TP53 mutation was lower in MOB (43%), than in expansile (58%) and infiltrative MOC (71%). Our results confirm that in MOC, the expansile pattern of invasion is associated with a better prognosis than extensive (> 5 mm) infiltrative-type pattern of invasion. No specific or sensitive molecular profile might help in the differential diagnosis of mucinous ovarian tumors.
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http://dx.doi.org/10.1007/s00428-020-02939-wDOI Listing
May 2021

A consensus developed morphological re-evaluation of 196 high-grade gastroenteropancreatic neuroendocrine neoplasms and its clinical correlations.

Neuroendocrinology 2020 Oct 1. Epub 2020 Oct 1.

High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are classified according to morphology as well differentiated neuroendocrine tumours (NET) G3 or poorly differentiated neuroendocrine carcinomas (NEC). Little data exist concerning which morphological criteria this subdivision should be based on. Uncertainty exists if the NEC group should be further subdivided according to proliferation rate. Clinical data on NET G3 and NEC with a lower Ki-67 range are limited. 213 patients with high-grade GEP-NEN (Ki-67>20%) were included from the Nordic NEC Registries. Four experienced NET pathologists re-evaluated the cases to develop the best morphological criteria to separate NET G3 from NEC, assuming longer survival in NET G3. Organoid growth pattern, capillary network in direct contact to tumour cells and absence of desmoplastic stroma were found to best separate NET G3 from NEC. Of 196 patients with metastatic disease, NET G3 was found in 12.3%, NEC with a Ki-67<55% (NEC <55) in 29.6%, and NEC with a Ki-67≥55% (NEC ≥55) in 56.6%. Only in 1.5% the morphology was ambiguous. Of 164 patients receiving 1-line chemotherapy, 88% received platinum/etoposide treatment. Response-rate was higher for NEC ≥55 (44%) compared to NEC <55 (25%) and NET G3 (24%) (P=0.025 and P=0.026). Median progression free survival was 5 months for all groups. Median overall survival was 33 months for NET G3 compared to 11 months for both NEC <55 and NEC ≥55 (P=0.004 and 0.003).
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http://dx.doi.org/10.1159/000511905DOI Listing
October 2020

Feasibility and first reports of the MATCH-R repeated biopsy trial at Gustave Roussy.

NPJ Precis Oncol 2020 8;4:27. Epub 2020 Sep 8.

Experimental and Translational Pathology Platform (PETRA), Genomic Platform - Molecular Biopathology unit (BMO) and Biological Resource Center, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.

Unravelling the biological processes driving tumour resistance is necessary to support the development of innovative treatment strategies. We report the design and feasibility of the MATCH-R prospective trial led by Gustave Roussy with the primary objective of characterizing the molecular mechanisms of resistance to cancer treatments. The primary clinical endpoints consist of analyzing the type and frequency of molecular alterations in resistant tumours and compare these to samples prior to treatment. Patients experiencing disease progression after an initial partial response or stable disease for at least 24 weeks underwent a tumour biopsy guided by CT or ultrasound. Molecular profiling of tumours was performed using whole exome sequencing, RNA sequencing and panel sequencing. At data cut-off for feasibility analysis, out of 333 inclusions, tumour biopsies were obtained in 303 cases (91%). From these biopsies, 278 (83%) had sufficient quality for analysis by high-throughput next generation sequencing (NGS). All 278 samples underwent targeted NGS, 215 (70.9%) RNA sequencing and 222 (73.2%) whole exome sequencing. In total, 163 tumours were implanted in NOD scid gamma (NSG) or nude mice and 54 patient-derived xenograft (PDX) models were established, with a success rate of 33%. Adverse events secondary to invasive tumour sampling occurred in 24 patients (7.6%). Study recruitment is still ongoing. Systematic molecular profiling of tumours and the development of patient-derived models of acquired resistance to targeted agents and immunotherapy is feasible and can drive the selection of the next therapeutic strategy.
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http://dx.doi.org/10.1038/s41698-020-00130-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478969PMC
September 2020

DNA FISH Diagnostic Assay on Cytological Samples of Thyroid Follicular Neoplasms.

Cancers (Basel) 2020 Sep 6;12(9). Epub 2020 Sep 6.

Department of Endocrinology, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France.

Although fine-needle aspiration cytology (FNAC) is helpful in determining whether thyroid nodules are benign or malignant, this distinction remains a cytological challenge in follicular neoplasms. Identification of genomic alterations in cytological specimens with direct and routine techniques would therefore have great clinical value. A series of 153 cases consisting of 72 and 81 histopathologically confirmed classic follicular adenomas (cFAs) and classic follicular thyroid carcinomas (cFTCs), respectively, was studied by means of different molecular techniques in three different cohorts of patients (pts). In the first cohort (training set) of 66 pts, three specific alterations characterized by array comparative genomic hybridization (aCGH) were exclusively found in half of cFTCs. These structural abnormalities corresponded to losses of 1p36.33-35.1 and 22q13.2-13.31, and gain of whole chromosome X. The second independent cohort (validation set) of 60 pts confirmed these data on touch preparations of frozen follicular neoplasms by triple DNA fluorescent in situ hybridization using selected commercially available probes. The third cohort, consisting of 27 archived cytological samples from an equal number of pts that had been obtained for preoperative FNAC and morphologically classified as and histologically verified to be follicular neoplasms, confirmed our previous findings and showed the feasibility of the DNA FISH (DNA fluorescent in situ hybridization) assay. All together, these data suggest that our triple DNA FISH diagnostic assay may detect 50% of cFTCs with a specificity higher than 98% and be useful as a low-cost adjunct to cytomorphology to help further classify follicular neoplasms on already routinely stained cytological specimens.
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http://dx.doi.org/10.3390/cancers12092529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564487PMC
September 2020

Rhabdomyosarcoma associated with germline TP53 alteration in children and adolescents: The French experience.

Pediatr Blood Cancer 2020 09 13;67(9):e28486. Epub 2020 Jul 13.

Gustave Roussy Cancer Center, Department of Children and Adolescents Oncology, Paris-Saclay University, Villejuif, France.

Objective: To describe the clinical characteristics and outcome of patients with Li-Fraumeni-associated rhabdomyosarcoma (RMS).

Method: Retrospective analysis of data from 31 French patients with RMS diagnosed before the age of 20 years associated with a TP53 pathogenic germline variant. Cases were identified through the French Li-Fraumeni database. Central histologic review was performed in 16 cases.

Results: The median age at diagnosis was 2.3 years, and the median follow-up was 9.1 years (0.3-34.8). The main tumor sites were head and neck (n = 13), extremities (n = 8), and trunk (n = 8). The local pathology report classified the 31 tumors in embryonal (n = 26), alveolar (n = 1), pleomorphic (n = 1), and spindle-cell (n = 1) RMS (missing = 2). After histological review, anaplasia (diffuse or focal) was reported in 12/16 patients. Twenty-five patients had localized disease, three had lymph node involvement, and three distant metastases. First-line therapy combined surgery (n = 27), chemotherapy (n = 30), and radiotherapy (n = 14) and led to RMS control in all, but one patient. Eleven patients relapsed, and 18 patients had second malignancies. The 10-year event-free, progression-free, and overall survival rates were 36% (95% CI: 20-56), 62% (95% CI: 43-77) and 76% (95% CI: 56-88), respectively. The 10-year cumulative risk of second malignancies was 40% (95% CI: 22-60).

Conclusion: The high incidence of multiple primary tumors strongly influences the long-term prognosis of RMS associated with TP53 pathogenic germline variants. Anaplastic RMS in childhood, independently of the familial history, should lead to TP53 analysis at treatment initiation to reduce, whenever possible, the burden of genotoxic drugs and radiotherapy in carriers and to ensure the early detection of second malignancies.
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http://dx.doi.org/10.1002/pbc.28486DOI Listing
September 2020

Long-Term Results after Surgical Resection of Peritoneal Metastasis from Neuroendocrine Tumors.

Neuroendocrinology 2021 8;111(6):599-608. Epub 2020 Jun 8.

Department of Nuclear Medicine, Gustave Roussy Cancer Campus, Villejuif, France.

Introduction: Peritoneal metastases from neuroendocrine tumors are associated with a bad prognosis. The objective of our study was to evaluate whether surgical resection could lead to prolonged survival in selected patients. This survival was compared to that of patients operated for liver metastasis.

Methods: From our prospectively maintained database we included 88 patients who underwent the complete resection of peritoneal and/or liver metastasis between January 1995 and December 2016 in Gustave-Roussy. Three resection groups were compared: peritoneal metastasis alone, liver metastasis alone, and the combined resection of liver and peritoneal metastases.

Results: The median peritoneal cancer index was 10 in the peritoneal group and 11 in the peritoneal + liver group. The 5-year overall survival was 81% (60-100) in the peritoneal group compared to 78% (65.2-92.8) in the liver group, and 72% (58.7-89.7) in the peritoneal + liver group (p = 0.71). The 3-year disease-free survival reached 26.9% (16.1-45.1) in the liver group, 12.5% (2.3-68.2) in the peritoneal group, and 32.4% (19.9-52.6) in the combined liver + peritoneal group (p = 0.45). In the univariate analysis, the prognosis factors for a longer survival were: small bowel primary tumor origin, low preoperative chromogranin A level, and tumor grade ≤1.

Conclusion: Despite a high recurrence rate, long-term overall survival can be achieved after the resection of peritoneal metastasis in selected patients. This survival is comparable to that of patients operated for liver metastasis only. Surgery should stand as a standard treatment for peritoneal metastases in patients with resectable disease.
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http://dx.doi.org/10.1159/000509220DOI Listing
June 2020

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer.

Nat Med 2020 06 25;26(6):919-931. Epub 2020 May 25.

Service de Chirurgie Digestive et Oncologique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (T) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of T cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of T cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1 T cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC.
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http://dx.doi.org/10.1038/s41591-020-0882-8DOI Listing
June 2020

[The "Conseil national professionnel d'anatomie et cytologie pathologiques" (CNPath): At the service of the profession].

Ann Pathol 2020 Sep 21;40(5):384-388. Epub 2020 May 21.

Service de pathologie, département de biologie et pathologie médicales, institut Gustave-Roussy, 114, rue Édouard-Vaillant, 94805 Villejuif cedex, France.

The « conseils nationaux professionnels » (CNP) are professional boards existing since 2010. Their missions, organization and functioning have been defined by the decree 2019-17 of January 9, 2019. CNPs represent all the members of a medical specialty (or health profession). CNPs must include all the learned societies and all the representative structures and associations of the same medical specialty. Their bodies must strictly respect the parity between public and private health sectors. The main missions of CNPs include the contribution to the elaboration of the national priority directions for continuous medical education and the definition of the individual plan for continuous professional development (DPC) recommended for the specialty. CNPs also behave as a single window for ministries, State agencies, welfare system and colleges of physicians. They are likely to be strongly involved in the process of re-certification of physicians, established in July 2019. The Conseil national professionnel d'anatomie et cytologie pathologiques, termed CNPath, has been created in 2010 and officially recognized by the Ministry of Health in August 2019. The main current actions of CNPath are: the elaboration of the individual DPC scheme for the specialty and the definition of the minimal obligations requested for its validation, the long-expected recognition of the expertal consultation in pathology, the support to the nation-wide effort for the production of structured pathological reports and the launching of a plan for implementing digital pathology. An internet site is under construction, to diffuse all the relevant information and make available the documents useful to all pathologists.
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http://dx.doi.org/10.1016/j.annpat.2020.04.004DOI Listing
September 2020

Molecular mechanisms of resistance to BRAF and MEK inhibitors in BRAF non-small cell lung cancer.

Eur J Cancer 2020 06 6;132:211-223. Epub 2020 May 6.

Department of Cancer Medicine, Gustave Roussy Cancer Centre, Villejuif, France.

Introduction: BRAF is a confirmed therapeutic target in non-small cell lung cancer (NSCLC), as the BRAF inhibitor dabrafenib, in combination with the MEK inhibitor trametinib, is approved for the treatment of NSCLC harbouring BRAF V600E mutation. Scant evidence is available concerning the mechanisms of resistance to BRAF/MEK inhibitors in BRAF NSCLC.

Patients And Methods: Patients with BRAF NSCLC with acquired resistance to BRAF/MEK inhibitors were included in the institutional, prospective MATCH-R (from "Matching Resistance") trial and underwent tumour and liquid biopsies at the moment of radiological progression. Extensive molecular analyses were performed, including targeted next-generation sequencing (NGS), whole-exome sequencing (WES), RNA sequencing and comparative genomic hybridisation (CGH) array.

Results: Of the 11 patients included, eight had progressed on dabrafenib-trametinib combination, two on dabrafenib monotherapy and one on vemurafenib (BRAF inhibitor). Complete molecular analyses were available for seven patients, whereas an additional case had only targeted NGS and CGH array data. Among these eight patients, acquired molecular events potentially responsible for resistance were detected in three who progressed on dabrafenib-trametinib combination, that is, MEK1 K57N, RAS viral (v-ras) oncogene homolog (NRAS) Q61R and rat sarcoma viral oncogene homolog (KRAS) Q61R mutations. One patient progressing on dabrafenib monotherapy developed a PTEN frameshift mutation. No molecular hints addressing resistance emerged in the remaining four patients with analyses performed. Tumour mutational burden, evaluated by WES in seven patients, was low (median = 2.06 mutations/megabase, range = 1.57-3.75 mut/Mb).

Conclusions: Novel resistance mechanisms to BRAF/MEK inhibitors in BRAF NSCLC were identified, pointing out the recurring involvement of the MAPK pathway and guiding the development of new treatment strategies.
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http://dx.doi.org/10.1016/j.ejca.2020.03.025DOI Listing
June 2020

Corrigendum to: "BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA" [J Hepatol (2020) 1-13].

J Hepatol 2020 Jul 29;73(1):225-226. Epub 2020 Apr 29.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; Functional Genomics of Solid Tumors laboratory, équipe labellisée Ligue Nationale contre le Cancer, Labex OncoImmunology, F-75006, Paris, France; Hôpital Européen Georges Pompidou, APHP, F-75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.04.004DOI Listing
July 2020

Extrapulmonary poorly differentiated NECs, including molecular and immune aspects.

Endocr Relat Cancer 2020 07;27(7):R219-R238

Department of Gastroenterology and Medical Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.

Patients with extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PD-NECs) have a poor prognosis. Surgery is offered for those with localised disease, but the majority of patients present with advanced disease. Treatment strategies adopted are analogous to that of high grade NECs of the lung, with platinum/etoposide-based regimens advocated in the first-line setting for advanced disease. There is no standard second-line therapy. Research into their molecular and immune pathways may pave the way for novel drug discovery. The molecular drivers of NEC are best identified in small cell lung carcinoma, which present with near universal genomic alterations in TP53 and RB1. The genetics of EP-PD-NEC remain poorly understood; TP53, KRAS, PIK3CA/PTEN and BRAF mutations have been identified, with alterations in the BRCA pathway reported additionally in small cell NEC of the cervix and absence of argininosuccinate synthetase 1 expression in NEC of the urinary bladder. The use of cell lines and patient-derived xenografts (PDX) to predict response to treatment in NEC and the emergence of alternative biomarkers, such as circulating tumour cells and cell-free DNA, will also be explored. Despite limited published data on the immune microenvironment of EP-NEC, there are a number of clinical trials investigating the use of immune-targeted agents in this disease category, with conflicting emerging data from studies thus far. This review will summarise the treatment and available molecular and immune data in this under researched diagnosis and may stimulate the direction of future exploratory studies.
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http://dx.doi.org/10.1530/ERC-19-0483DOI Listing
July 2020

Genetic characterization of a unique neuroendocrine transdifferentiation prostate circulating tumor cell-derived eXplant model.

Nat Commun 2020 04 20;11(1):1884. Epub 2020 Apr 20.

INSERM, U981 "Identification of Molecular Predictors and new Targets for Cancer Treatment", 94805, Villejuif, France.

Transformation of castration-resistant prostate cancer (CRPC) into an aggressive neuroendocrine disease (CRPC-NE) represents a major clinical challenge and experimental models are lacking. A CTC-derived eXplant (CDX) and a CDX-derived cell line are established using circulating tumor cells (CTCs) obtained by diagnostic leukapheresis from a CRPC patient resistant to enzalutamide. The CDX and the derived-cell line conserve 16% of primary tumor (PT) and 56% of CTC mutations, as well as 83% of PT copy-number aberrations including clonal TMPRSS2-ERG fusion and NKX3.1 loss. Both harbor an androgen receptor-null neuroendocrine phenotype, TP53, PTEN and RB1 loss. While PTEN and RB1 loss are acquired in CTCs, evolutionary analysis suggest that a PT subclone harboring TP53 loss is the driver of the metastatic event leading to the CDX. This CDX model provides insights on the sequential acquisition of key drivers of neuroendocrine transdifferentiation and offers a unique tool for effective drug screening in CRPC-NE management.
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http://dx.doi.org/10.1038/s41467-020-15426-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171138PMC
April 2020

[A nodule of the rectal wall].

Ann Pathol 2020 Jun 8;40(3):238-242. Epub 2020 Apr 8.

Service de Pathologie Morphologique, Département de Biologie et Pathologie Médicales, Gustave-Roussy Cancer Campus, 94805 Villejuif, France; Faculté de Médecine de Bicêtre, Université Paris Sud, 94270 Le Kremlin-Bicêtre, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2020.03.001DOI Listing
June 2020