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- Author: Eric Baudin x
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INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane is the most effective medical therapy for adrenocortical carcinoma, but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mt dysfunction has never been established. We examined the functional consequences of mitotane exposure on proliferation, steroidogenesis, and mt respiratory chain, biogenesis and morphology, in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration of 50 μM (14 mg/l), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mt proteins involved in steroidogenesis (STAR, CYP11B1, and CYP11B2). In both H295R and SW13 cells, 50 μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase (COX)). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by blue native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 (MT-CO2) and nuclear DNA-encoded COX4 (COX4I1) subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mt biogenesis (increase in mtDNA content and PGC1 α (PPARGC1A) expression) and triggered fragmentation of the mt network. Altogether, our results provide first evidence that mitotane induced a mt respiratory chain defect in human adrenocortical cells.
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Recent studies suggest that the somatostatin receptor scintigraphy (SRS) grade of uptake is a predictor of response to peptide receptor radionuclide therapy (PRRT). To identify and characterize patients with well-differentiated (WD) neuroendocrine neoplasm (NEN) displaying a high-grade uptake at SRS. Patients with WD-NEN, whose SRS films were available for review, were retrospectively included. SRS was reviewed by three independent readers and classified into four subgroups based on a modified Krenning's scale (mKS): no uptake (group-0), homogeneous grade 1–2 uptake (group-1), homogeneous grade 3–4 (group-2), and heterogeneous grade 1–4 (group-3). A simplified scale (sS) of SRS was also used to look for characteristics of patients with high-grade uptake. One hundred and six WD-NEN patients were enrolled. Group-0, group-1, group-2, and group-3 were found in 17, 8, 33, and 42% of cases respectively. High-grade uptake at sS (75% of cases) was correlated with older age, functioning NEN, high chromogranin-A level, and grade 1 (G1) NEN based on mitotic count. Based on the mKS or sS scales, no difference on survival was found. Thirty-three to seventy-five percent of metastatic NEN patients can be considered candidates for PRRT based on homogeneous or heterogeneous high-grade uptake. Functioning G1 NEN patients could be the best candidates for PRRT. Randomized trials are expected to confirm this result.
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Survival of metastatic gastroenteropancreatic well-differentiated endocrine carcinoma (GEP WDEC) is not well characterized. We evaluated the long-term outcome and prognostic factors for survival in 118 patients with distant metastases from GEP WDEC. Inclusion criteria were 1) pathological review by a single pathologist according to the present WHO criteria, 2) absence of previous therapy apart from surgery, 3) complete morphological evaluation within 3 months including somatostatin receptor scintigraphy, and 4) follow-up at Gustave-Roussy Institute until death or study's end. Clinical, biological marker, and pathological parameters were analyzed in univariate and multivariate statistical models. Survival after the first complete imaging work-up of the metastatic disease was determined using Kaplan–Meier method. Overall, survival for 5 years after the diagnosis of metastatic disease was 54%. In multivariate analysis, age (hazard ratio (HR): 1.05, 95% confidence interval (CI): 1.01–1.08, P=0.01), the number of liver metastases (HR: 3.4, 95% CI: 1.4–8.3, P=0.01), tumor slope (HR: 1.1, 95% CI: 1.0–1.1, P=0.001), and initial surgery (HR: 0.3, 95% CI: 0.1–0.8, P=0.01) were predictive of survival. Five-year survival was 100%, 91% (95% CI, 51–98%), 62% (95% CI, 37–83%), and 9% (95% CI, 6–32%) when patients had 0, 1, 2, 3 or more poor prognostic features respectively. This study enables the stratification of metastatic GEP WDEC patients into distinct risk groups. These risk categories can be used to tailor therapeutic approaches and also to design and interpret clinical trials.
Institut des Neurosciences Cellulaires et Intégratives, CNRS (UPR 3212), Strasbourg, France
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ICube, UMR 7357 Université de Strasbourg/CNRS et FMTS, Faculté de Medécine, Strasbourg, France
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Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France
INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France
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Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France
INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France
Centre Expert National COMETE-Cancer de la surrénale, Paris, France
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Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC)/CNRS/INSERM/Université de Strasbourg, Illkirch, France
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Endocrinology Department, Cochin Hospital, Paris, France
Département de Médecine Nucléaire et de Tumeurs Endocrines, Institut Gustave Roussy, Université Paris Sud, Villejuif, France
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To progress in the stratification of the first-line therapeutic management of metastatic adrenocortical carcinoma (ACC), we searched for prognostic parameters of survival in patients treated with combined mitotane- and cisplatinum-based chemotherapy as first-line. We retrospectively studied prospectively collected parameters from 131 consecutive patients with metastatic ACC (44 with a tissue specimen available) treated at the Gustave Roussy Institute with mitotane- and platinum-based chemotherapy. Fifty-five patients with clinical, pathological, and morphological data available together with treatment characteristics including detailed follow-up were enrolled. Plasma mitotane levels and ERCC1 protein staining were analyzed. Response was analyzed according to RECIST criteria as well as overall survival (OS) from the start of cisplatinum-based chemotherapy. Parameters impacting on OS were evaluated by univariate analysis, and then analyzed by multivariate analysis. Using a landmark method, OS according to response to chemotherapy was analyzed. Objective response to combined mitotane- and cisplatinum-based chemotherapy was 27.3%. Median OS was 1 year. In the univariate analysis, resection of the primary, time since diagnosis, mitotane monotherapy as single first-line treatment, number of affected organs, plasma mitotane above 14 mg/l, and objective response were predictors of survival. In the multivariate analysis, mitotane level ≥14 mg/l and objective response to platinum-based chemotherapy were found to be independent predictors of survival (P=0.03 and <0.001). Our study suggests a prognostic role for mitotane therapy and objective response to platinum-based chemotherapy.
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Department of Endocrinology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
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The prognosis of poorly differentiated thyroid carcinomas (PDTC) defined by the Turin criteria is variable. The aim of this study on 51 PDTC patients was to determine clinical, histological and molecular prognostic factors associated with recurrence in patients with localized disease at initial treatment and with overall survival in patients with distant metastases. Of 40 patients for whom next-generation sequencing (NGS) by ThyroSeq v3 was able to be performed on historical samples, we identified high-risk molecular signature (TERT, TP53 mutations) in 24 (60%) cases, intermediate risk signature in 9 (22.5%) cases and low-risk signature in 7 (17.5%) cases. Potentially actionable mutations were identified in 10% of cases. After a median follow-up of 57.5 months, recurrence occurred in 11 (39%) of the 28 patients with localized disease. The American Thyroid Association (ATA) high risk of relapse, high mitotic count, high molecular risk signature and CD163 expression were associated with recurrence (P = 0.009, 0.01, 0.049, 0.03 respectively). After a median follow-up of 49.5 months, thyroid cancer-related death occurred in 53% of the patients with distant metastases. There was no significant prognostic factor associated with death in univariate analysis. However, none of the patients with intermediate ATA risk of recurrence and none of the patients with low-risk molecular signature died from the disease. In addition, high molecular-risk signature was associated with the presence of synchronous or metachronous distant metastasis (P = 0.007) and with poor overall survival (P = 0.01). In conclusion, ATA risk of relapse and high mitotic count was associated with higher rate of recurrence in localized PDTC. High molecular-risk signature was associated with the presence of distant metastasis and poor overall survival. Further studies are needed to determine if molecular testing adds to ATA risk stratification or response to therapy in predicting outcomes.
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Departments of Nuclear Medicine and Endocrine Oncology, Pathology, Department of Biostatistics and Epidemiology, Departments of Gastroenterology, Thoracic Oncology, Digestive Surgery, Medical Imaging, Faculté de Médecine Paris Sud, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France
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Departments of Nuclear Medicine and Endocrine Oncology, Pathology, Department of Biostatistics and Epidemiology, Departments of Gastroenterology, Thoracic Oncology, Digestive Surgery, Medical Imaging, Faculté de Médecine Paris Sud, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France
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Departments of Nuclear Medicine and Endocrine Oncology, Pathology, Department of Biostatistics and Epidemiology, Departments of Gastroenterology, Thoracic Oncology, Digestive Surgery, Medical Imaging, Faculté de Médecine Paris Sud, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France
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The new WHO classification of gastroenteropancreatic (GEP) neuroendocrine tumors (NET) implies that G3 neoplasms with mitotic index >20 and/or Ki67 index >20% are neuroendocrine carcinomas (NEC), described as poorly differentiated, small or large cell types, by analogy with lung NEC. To characterize the subgroup of non-small-cell-type GEP and thoracic NET with mitotic index >20 and/or Ki67 >20% according to their pathological features, response to cisplatin and overall survival (OS). We reviewed pathological and clinical presentation of G3 non-small-cell-type NET referred to our institution for 5 years. Data from 166 patients with metastatic thoracic and GEP-NET were collected. Twenty-eight patients (17%) fulfill the inclusion criteria. Tumors were classified as well-differentiated NET (G3-WDNET) in 42.8% of cases and poorly differentiated, large-cell NEC (G3-LCNEC) in 57.2% of cases. Plasma chromogranin A or neuron-specific enolase were elevated in 42 and 25% respectively of G3-WDNET and 31 and 50% of G3-LCNEC. Somatostatin receptor scintigraphy was positive in 88 and 50% of G3-WDNET or G3-LCNEC respectively. Complete or partial response to cisplatin was observed in 31% of cases, all classified as G3-LCNEC. The median OS was 41 months for G3-WDNET but 17 months for G3-LCNEC (P=0.34). Short survival was observed in 25% of G3-WDNET but 62.5% of G3-LCNEC patients (P=0.049). G3 ENETS GEP and thoracic neuroendocrine neoplasms (NEN) could constitute a heterogeneous subgroup of NEN as regards diagnosis, prognosis, and treatment. If confirmed, future classifications may consider splitting them into two groups according to their morphological differentiation.
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Laboratoire GReD, Université Clermont Auvergne, Clermont-Ferrand, France
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Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France
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Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France
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Neuroendocrine carcinomas (NEC) are aggressive malignant diseases. Etoposide-based rechallenge (EBR) and the prognostic role of RB transcriptional corepressor 1 (RB1) status in second-line chemotherapy (2L) have not been studied. The objectives of this study were to report the results of 2L including EBR as well as prognostic factors in a national retrospective multicentre study. NEC patients treated with 2L and further, with tissue samples available, were included. RB1 status and morphological classification were reviewed centrally. Among the 121 NEC patients (40% female, median age 61 years) included, there were 73 small-cell NEC (60%), 34 large-cell NEC (28%) and 14 NEC (not otherwise specified, 12%). Primary sites were lung (39%), gastroenteropancreatic (36%), other (13%) and unknown (12%). Median Ki-67 index was 80%. Median progression-free survival (PFS) and overall survival (OS) under 2L were 2.1 and 6.2 months, respectively. No difference was observed between patients who received an ‘adenocarcinoma-like’ or a ‘neuroendocrine-like’ 2L or according to the RB1 status. Thoracic NEC primary was the only adverse prognostic factor for OS. EBR, administered to 31 patients, resulted in a 62% disease control rate with a median PFS and OS of 3.2 and 11.7 months, respectively. In the 94 patients with a relapse-free interval of ≥3 months after first-line platinum–etoposide chemotherapy, the median OS was 12 months in patients who received EBR as compared to 5.9 months in patients who did not (P = 0.043). EBR could be the best 2L option for patient with initial response to first-line platinum–etoposide lasting at least 3 months. RB1 status does not provide prognostic information in this setting.
