Publications by authors named "Eric Baudin"

198 Publications

What Is the Optimal Duration of Adjuvant Mitotane Therapy in Adrenocortical Carcinoma? An Unanswered Question.

J Pers Med 2021 Apr 4;11(4). Epub 2021 Apr 4.

Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, 10043 Turin, Italy.

A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.
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http://dx.doi.org/10.3390/jpm11040269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066814PMC
April 2021

Can preoperative ultrasound predict extrathyroidal extension of differentiated thyroid cancer?

Eur J Endocrinol 2021 Apr 1. Epub 2021 Apr 1.

D Hartl, Surgery, Gustave Roussy, Villejuif, France.

Objective The presence of extrathyroidal extension (ETE) is generally considered an indication for total thyroidectomy for differentiated thyroid cancer. The accuracy of neck ultrasound for the diagnosis of ETE is controversial. The aim of this study was to assess the diagnostic accuracy of preoperative ultrasound evaluation of ETE. Methods Retrospective and observational study of consecutive patients operated between 2016 and 2019 for cytologically suspicious or indeterminate thyroid nodules. US images obtained preoperatively were retrospectively reviewed to identify signs of minimal or gross ETE. Histology was considered the gold standard for diagnosis of ETE. The sensitivity, specificity, positive (PPV) and negative predictive values (NPV), and accuracy of US were evaluated. Results A cohort of 305 patients (75% females, median age 48 years) with 378 nodules (median size 18 mm) was studied. Seventy-five percent of the nodules (n=228) were malignant on histology and ETE was present in 106 cases (28%): 83 minimal ETE and 23 gross ETE. Suspicion of minimal ETE on preoperative ultrasound was found in 50 (13%) with a sensitivity of 30%, a specificity of 93%, a PPV 62% and a NPV of 78%, with an accuracy of 76%. Gross ETE on ultrasound was found in 19 (5%) nodules with a sensitivity of 78%, a specificity of 99.7% a PPV 94.7% an NPV of 98.6% and an accuracy of 98%. Conclusions Preoperative US is very specific and accurate in diagnosing gross ETE which impacts the extent of initial surgery for thyroid cancers.
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http://dx.doi.org/10.1530/EJE-21-0091DOI Listing
April 2021

Recurrence-free survival analysis in locally advanced pheochromocytoma: first appraisal.

J Clin Endocrinol Metab 2021 Mar 30. Epub 2021 Mar 30.

Endocrine oncology unit, Gustave Roussy, F-94805, Villejuif, France.

Context: Locally advanced pheochromocytoma (LAP) behavior remains unknown.

Objective: To characterize this population and its recurrence-free survival (RFS).

Design: A retrospective multicentric study run within the ENDOCAN-COMETE network and GTE from 2003 to 2018.

Setting: 11 French Referral centers.

Patients: Patients with LAP as defined by capsular invasion, vascular invasion, adipose tissue invasion and/or positive locoregional lymph nodes at diagnosis without evidence of distant metastasis.

Main Outcome Measures: Recurrence was defined as the reappearance of the tumor, including local site and/or distant metastasis. The primary endpoint was RFS analysis. The secondary endpoints were characterization, overall survival (OS) and prognostic factors of recurrence.

Results: Among 950 patients, 90 exhibited LAP criteria (9%). 55 met the inclusion criteria (median age: 53 years-old, 61% males, 14% with a germline mutation, 84% with a catecholamine excess). LAP was defined by 31 (56%) capsular invasions, 27 (49%) fat invasions, 6 (11%) positive lymph nodes and 22 (40%) vascular invasions. After a median follow-up of 54 months (range, 6-180), 12 patients (22%) had recurrences and 3 (5%) died of a metastatic disease. Median RFS was 115 months (range, 6-168). The recurrences were local in 2 patients, distant in 2 and both local and distant in 8 patients. Median OS of patients was not reached. Size above 6.5cm (p=0.019) and Ki-67>2% (p=0.028) were identified as independent significant prognostic factors in multivariate analysis.

Conclusions: LAP represents 9% of pheochromocytoma's population and is characterized by a metastatic behavior. This study paved the way of a future pathological TNM classification.
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http://dx.doi.org/10.1210/clinem/dgab202DOI Listing
March 2021

Consensus on molecular imaging and theranostics in neuroendocrine neoplasms.

Eur J Cancer 2021 Mar 12;146:56-73. Epub 2021 Feb 12.

Department of Nuclear Medicine, Universitätsklinikum, Essen, Germany. Electronic address:

Nuclear medicine plays an increasingly important role in the management neuroendocrine neoplasms (NEN). Somatostatin analogue (SSA)-based positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT) have been used in clinical trials and approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs). NETs form in cells that interact with the nervous system or in glands that produce hormones. These cells, called neuroendocrine cells, can be found throughout the body, but NETs are most often found in the abdomen, especially in the gastrointestinal tract. These tumours may also be found in the lungs, pancreas and adrenal glands. In addition to being rare, NETs are also complex and may be difficult to diagnose. Most NETs are non-functioning; however, a minority present with symptoms related to hypersecretion of bioactive compounds. NETs often do not cause symptoms early in the disease process. When diagnosed, substantial number of patients are already found to have metastatic disease. Several societies' guidelines address Neuroendocrine neoplasms (NENs) management; however, many issues are still debated, due to both the difficulty in acquiring strong clinical evidence in a rare and heterogeneous disease and the different availability of diagnostic and therapeutic options across countries. EANM Focus 3 reached consensus on employing gallium-labelled somatostatin analogue ([Ga]Ga-DOTA-SSA)-based PET/CT with diagnostic CT or magnetic resonance imaging (MRI) for unknown primary NET detection, metastatic NET, NET staging/restaging, suspected extra-adrenal pheochromocytoma/paraganglioma and suspected paraganglioma. Consensus was reached on employing fluorine-fluoro-2-deoxyglucose ([F]FDG) PET/CT in neuroendocrine carcinoma, G3 NET and in G1-2 NET with mismatched lesions (CT-positive/[Ga]Ga-DOTA-SSA-negative). Peptide receptor radionuclide therapy (PRRT) was recommended for second line treatment for gastrointestinal NET with [Ga]Ga-DOTA-SSA uptake in all lesions, in G1/G2 NET at disease progression, and in a subset of G3 NET provided all lesions are positive at [F]FDG and [Ga]Ga-DOTA-SSA. PRRT rechallenge may be used for in patients with stable disease for at least 1 year after therapy completion. An international consensus is not only a prelude to a more standardised management across countries but also serves as a guide for the direction to follow when designing new research studies.
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http://dx.doi.org/10.1016/j.ejca.2021.01.008DOI Listing
March 2021

Practical recommendations for the management of patients with gastroenteropancreatic and thoracic (carcinoid) neuroendocrine neoplasms in the COVID-19 era.

Eur J Cancer 2021 02 25;144:200-214. Epub 2020 Dec 25.

Department of Medical Oncology and Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada. Electronic address:

Neuroendocrine neoplasms (NENs) are a heterogeneous family of uncommon tumours with challenging diagnosis, clinical management and unique needs that almost always requires a multidisciplinary approach. In the absence of guidance from the scientific literature, along with the rapidly changing data available on the effect of COVID-19, we report how 12 high-volume NEN centres of expertise in 10 countries at different stages of the evolving COVID-19 global pandemic along with members of international neuroendocrine cancer patient societies have suggested to preserve high standards of care for patients with NENs. We review the multidisciplinary management of neuroendocrine neoplasms during the COVID-19 pandemic, and we suggest potential strategies to reduce risk and aid multidisciplinary treatment decision-making. By sharing our joint experiences, we aim to generate recommendations for proceeding to other institutions facing the same challenges.
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http://dx.doi.org/10.1016/j.ejca.2020.11.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836777PMC
February 2021

Screening of a Large Cohort of Asymptomatic SDHx Mutation Carriers in Routine Practice.

J Clin Endocrinol Metab 2021 Mar;106(3):e1301-e1315

Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.

Context: When an SDHx mutation is identified in a patient with a pheochromocytoma (PCC) or a paraganglioma (PGL), predictive genetic testing can detect mutation carriers that would benefit from screening protocols.

Objective: To define the tumor detection rate in a large cohort of asymptomatic SDHX mutation carriers.

Design And Setting: Retrospective multicentric study in 6 referral centers.

Patients: Between 2005 and 2019, 249 asymptomatic SDHx (171 SDHB, 31 SDHC, 47 SDHD) mutation carriers, with at least 1 imaging work-up were enrolled.

Results: Initial work-up, including anatomical (98% of subjects [97-100% according to center]) and/or functional imaging (67% [14-90%]) detected 48 tumors in 40 patients. After a negative initial work-up, 124 patients benefited from 1 to 9 subsequent follow-up assessments (mean: 1.9 per patient), with a median follow-up time of 5 (1-13) years. Anatomical (86% [49-100 %]) and/or functional imaging (36% [7-60 %]) identified 10 new tumors (mean size: 16 mm [4-50]) in 10 patients. Altogether, 58 tumors (55 paraganglioma [PGL], including 45 head and neck PGL, 2 pheochromocytoma [PCC], 1 gastrointestinal stromal tumor [GIST]), were detected in 50 patients (22 [13%] SDHB, 1 [3.2%] SDHC, and 27 [57%] SDHD), with a median age of 41 years old [11-86], 76% without catecholamine secretion and 80% during initial imaging work-up.

Conclusions: Imaging screening enabled detection of tumors in 20% of asymptomatic SDHx mutation carriers, with a higher detection rate in SDHD (57%) than in SDHB (13%) and SDHC (3%) mutation carriers, arguing for a gene-by-gene approach. Prospective studies using well-defined protocols are needed to obtain strong and useful data.
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http://dx.doi.org/10.1210/clinem/dgaa888DOI Listing
March 2021

Thyroid Lobectomy for Low to Intermediate Risk Differentiated Thyroid Cancer.

Cancers (Basel) 2020 Nov 6;12(11). Epub 2020 Nov 6.

Department of Nuclear Medicine and Endocrine Oncology, Anesthesia and Interventional Medicine Gustave Roussy, 94805 Villejuif, France.

Many recent publications and guidelines have promoted a "more is less" approach in terms of treatment for low to intermediate risk differentiated thyroid cancer (DTC), which comprise the vast majority of thyroid cancers: less extensive surgery, less radioactive iodine, less or no thyroid hormone suppression, and less frequent or stringent follow-up. Following this approach, thyroid lobectomy has been proposed as a means of decreasing short- and long-term postoperative morbidity while maintaining an excellent prognosis for tumors meeting specific macroscopic and microscopic criteria. This article will examine the pros and cons of thyroid lobectomy for low to intermediate risk cancers and discuss, in detail, criteria for patient selection and oncological outcomes.
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http://dx.doi.org/10.3390/cancers12113282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694652PMC
November 2020

ENSAT registry-based randomized clinical trials for adrenocortical carcinoma.

Eur J Endocrinol 2021 Feb;184(2):R51-R59

Department of Endocrinology & Diabetes Mellitus, c/o Department of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Galway, Ireland.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.
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http://dx.doi.org/10.1530/EJE-20-0800DOI Listing
February 2021

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

Endocrine 2020 Oct 31. 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
October 2020

Phase I Study of Lysine-Specific Demethylase 1 Inhibitor, CC-90011, in Patients with Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma.

Clin Cancer Res 2021 Jan 12;27(2):438-446. Epub 2020 Oct 12.

The Institute of Cancer Research and Royal Marsden, London, United Kingdom.

Purpose: Lysine-specific demethylase 1 (LSD1) is implicated in multiple tumor types, and its expression in cancer stem cells is associated with chemoresistance. CC-90011 is a potent, selective, and reversible oral LSD1 inhibitor. We examined CC-90011 in advanced solid tumors and relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL).

Patients And Methods: CC-90011-ST-001 (NCT02875223; 2015-005243-13) is a phase I, multicenter, first-in-human dose-escalation study. Nine dose levels of CC-90011 (1.25-120 mg) given once per week were explored. Primary objectives were to determine safety, maximum tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to evaluate preliminary efficacy and pharmacokinetics.

Results: Fifty patients were enrolled, 49 with solid tumors (27 neuroendocrine tumors/carcinomas) and 1 with R/R NHL. Median age was 61 years (range, 22-75). Patients received a median of three (range, 1-9) prior anticancer regimens. The RP2D was 60 mg once per week; the nontolerated dose (NTD) and MTD were 120 mg once per week and 80 mg once per week, respectively. Grade 3/4 treatment-related toxicities were thrombocytopenia (20%; an on-target effect unassociated with clinically significant bleeding), neutropenia (8%; in the context of thrombocytopenia at the highest doses), and fatigue (2%). The patient with R/R NHL had a complete response, currently ongoing in cycle 34, and 8 patients with neuroendocrine tumors/carcinomas had stable disease ≥6 months, including bronchial neuroendocrine tumors, kidney tumor, and paraganglioma.

Conclusions: CC-90011 is well tolerated, with the RP2D established as 60 mg once per week. The MTD and NTD were determined to be 80 mg once per week and 120 mg once per week, respectively. Further evaluation of CC-90011 is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2380DOI Listing
January 2021

Long-term follow-up and safety of vandetanib for advanced medullary thyroid cancer.

Endocrine 2021 Feb 20;71(2):434-442. Epub 2020 Jul 20.

Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, Villejuif, France.

Introduction: Vandetanib is indicated for adults with advanced medullary thyroid cancer (MTC).

Objectives: To describe the efficacy and toxicity profile of vandetanib treatment with a maximal follow-up of 11 years at Institut Gustave Roussy/France.

Methods: A review of the clinical files of the 76 MTC patients treated with vandetanib. Efficacy was estimated by markers and imaging.

Results: A total of 76 patients received vandetanib. Nine were excluded from efficacy analysis because lack of morphological data. The overall (N = 76) median treatment duration was 17.6 (range: 0.7-130.6) months and the median progression-free survival (PFS) was 22.7 (95% CI, 13.9-37.3) months. In total, 21/76 (27.6%) patients were classified as long-term users because have received vandetanib for more than 48 months, with a median treatment duration of 68.1 (range: 49.1-130.6) months. For long-term vandetanib users, the objective response rate was 85.7%, the median time to best response was 27.8 (11.6.1-110) months and the median duration of response was 70.4 (38.3-127.5) (95% CI 49.5-102.8) months with a median PFS of 73.2 (95% CI, 53.1-105.6) months. Duration of response had a significant negative correlation with patient age at diagnosis (p = 0.03) and was significantly higher in patients that did not have confirmed tumor progression before treatment onset (p = 0.007). After 48 months of vandetanib use, renal failure took place in two patients and heart failure, cholecystitis, acute pancreatitis, posterior encephalopathy, and skin cancer first occurred in one patient, each.

Conclusions: Our findings suggest that a substantial number of patients receiving first-/second-line vandetanib may sustain long clinical benefit and that a younger age at diagnosis and the absence of progression before treatment could be considered as predictors of durable response.
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http://dx.doi.org/10.1007/s12020-020-02426-xDOI Listing
February 2021

Long term results after surgical resection of peritoneal metastasis from neuroendocrine tumors.

Neuroendocrinology 2020 Jun 8. Epub 2020 Jun 8.

Introduction: Peritoneal metastases from neuroendocrine tumors are associated with 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 maintain 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 groups of resection 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-years 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 pre-operative CgA level and tumor grade ≤1.

Conclusion: Despite a high recurrence rate, long term overall survival can be achieved after 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 peritoneal metastases in patients with resectable disease.
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http://dx.doi.org/10.1159/000509220DOI Listing
June 2020

Digestive Neuroendocrine Neoplasms (NEN): French Intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, GTE, RENATEN, TENPATH, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR).

Dig Liver Dis 2020 05 28;52(5):473-492. Epub 2020 Mar 28.

Department of Hepato-Gastroenterology and Digestive Oncology, Robert Debré University Hospital, Reims, France. Electronic address:

Introduction: This document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org).

Methods: All French medical societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019.

Results: The management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET.

Conclusion: These guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed.
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http://dx.doi.org/10.1016/j.dld.2020.02.011DOI Listing
May 2020

Cancer-testis Antigen FATE1 Expression in Adrenocortical Tumors Is Associated with A Pervasive Autoimmune Response and Is A Marker of Malignancy in Adult, but Not Children, ACC.

Cancers (Basel) 2020 Mar 14;12(3). Epub 2020 Mar 14.

NEOGENEX-CANCER CNRS International Associated Laboratory, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France; 1532 Av. Silva Jardim, Curitiba PR 80250-200, Brazil.

The SF-1 transcription factor target gene encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy.
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http://dx.doi.org/10.3390/cancers12030689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140037PMC
March 2020

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with Lu-Dotatate: an analysis of the NETTER-1 study.

Eur J Nucl Med Mol Imaging 2020 09 2;47(10):2372-2382. Epub 2020 Mar 2.

Department of Nuclear Medicine, Hôpital de la Timone, Marseille, France.

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with Lu-Dotatate.

Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression.

Results: Significantly prolonged median PFS occurred with Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden.

Conclusions: Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.
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http://dx.doi.org/10.1007/s00259-020-04709-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396396PMC
September 2020

Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice.

Eur J Nucl Med Mol Imaging 2020 09 15;47(10):2358-2371. Epub 2020 Feb 15.

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with Lu-DOTATOC or Lu-DOTATATE (LAN-peptide receptor radionuclide therapy [PRRT]) in patients with progressive neuroendocrine tumours (NETs).

Methods: International, non-interventional, retrospective, non-comparative analysis of medical records from patients with progressive metastatic or locally advanced grade 1 or 2 gastroenteropancreatic (GEP)- or lung-NETs. The primary endpoint was progression-free survival (PFS) at end of last LAN-PRRT cycle. Secondary endpoints included PFS at last available follow-up, best overall response, objective response rate (ORR), presence and severity of diarrhoea and flushing, and safety. Post-hoc analyses were conducted to determine pre-treatment tumour growth rate (TGR) cutoffs that best predicted the ORR during treatment.

Results: Forty patients were enrolled (GEP-NETs, n = 39; lung-NETs, n = 1). PFS rates were 91.7% at end of last LAN-PRRT cycle and 95.0% at last available follow-up. In the full analysis set, best overall response among patients with GEP-NETs (n = 23) was stable disease (n = 14, 60.9%), partial response (n = 8, 34.8%) and progressive disease (n = 1, 4.3%). The ORR was 27.3% at end of last LAN-PRRT cycle and 36.8% at last available follow-up. Optimal baseline TGR cutoffs for predicting ORR at these time points were 1.18% and 0.33%, respectively. At baseline, 81.0% of patients had diarrhoea or flushing; both remained stable or improved in most cases. No increased adverse drug reactions were reported.

Conclusion: Despite the major recruitment shortfall for the PRELUDE study, effectiveness data were encouraging in this selected population, highlighting the potential usefulness and feasibility of LAN combined with and after PRRT in patients with GEP-NETs. The study also identified challenges associated with evaluating clinical practice in a rare-disease setting and highlighted the need for standardisation of PRRT procedures.

Trial Registration: Trial number: NCT02788578; URL: https://clinicaltrials.gov/ct2/show/NCT02788578.
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http://dx.doi.org/10.1007/s00259-020-04712-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396404PMC
September 2020

MANAGEMENT OF ENDOCRINE DISEASE: Cushing's syndrome due to ectopic ACTH secretion: an expert operational opinion.

Eur J Endocrinol 2020 Apr;182(4):R29-R58

Department of Endocrinology, Bordeaux University, Haut-Lévêque Hospital, Pessac, France.

Ectopic ACTH syndrome (EAS) is rare but is frequently a severe condition because of the intensity of the hypercortisolism that may be dissociated from the tumoral condition. EAS should often be considered as an endocrine emergency requiring an emergency response both in terms of diagnostic procedures and therapeutic interventions. Patient management is complex and necessitates dual skills, in the diagnosis and treatment of CS and in the specific management of neuroendocrine tumors (NET). Therefore, initial management should be performed ideally by experienced endocrinology teams in collaboration with specialized hormonal laboratory, modern imaging platforms and intensive care units. Diagnostic procedures vary according to the endocrine and tumoral contexts but should be reduced to a minimum in intense hypercortisolism. Preventive and curative treatments of cortisol-induced comorbidities, non-specific management of hypercortisolism and etiological treatments should be considered simultaneously. Therapeutic strategies vary according to (1.) the intensity of hypercortisolism, the general condition of the patient and associated comorbidities and (2.) the tumoral status, ranging from resectable ACTH secreting tumors to non-resectable metastatic endocrine tumors or occult tumors. The ideal treatment is complete excision of the ACTH-secreting tumor that can be performed rapidly or after preoperative preparation using cortisol-lowering drugs. When this is not possible, the therapeutic strategy should be discussed by a multidisciplinary experienced team in a personalized perspective and include variable combinations of pharmacological agents, bilateral adrenalectomy and non-specific tumoral interventions. Here we discuss the diagnosis and therapeutic strategies including the modern, currently available tools and emphasize on the operational effectiveness of care.
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http://dx.doi.org/10.1530/EJE-19-0877DOI Listing
April 2020

Everolimus after hepatic arterial embolisation therapy of metastases from gastrointestinal neuroendocrine tumours: The FFCD 1104-EVACEL-GTE phase II study.

Eur J Cancer 2019 12 31;123:92-100. Epub 2019 Oct 31.

Interventional Radiology Department, Gustave Roussy Villejuif & UFR Medecine Kremlin Bicetre Paris Sud University, Villejuif, France.

Background: Hepatic arterial embolisation therapy (HAET) is a treatment of liver metastases of gastrointestinal neuroendocrine tumours (GI-NETs). HAET increases circulating vascular endothelial growth factor levels. Everolimus is a treatment in NETs that may have antiangiogenic activity.

Methods: This phase II study was conducted in patients with predominant and progressive liver metastases from GI-NETs. Everolimus was initiated 7-30 days after HAET. The hypothesis was that everolimus after HAET would increase hepatic progression-free survival (hPFS) rate at 24 months from 35% to 50%.

Results: Among the 74 patients included, 88% had small-bowel primary tumour, 43% had grade I and 57% grade II tumour, and 51% had extrahepatic metastases. Patients underwent one (n = 19), two (n = 54), or three (n = 1) HAET procedures. hPFS at 24 months was 33% (95% confidence interval [CI], 22.5-43.7); 40 (54%) patients had objective response. Median (95% CI) hPFS, PFS, and overall survival were 19 (14-23), 17 (13-22), and 51 (33-60) months. The most common grade III-IV toxicities (>5%) in patients receiving both HAET and everolimus (n = 67) were elevated liver enzymes (55%), fatigue (18%), diarrhoea (16%), anaemia (12%), hypertriglyceridaemia (7%) and mucositis (6%).

Conclusions: The primary end-point was not reached. This sequence allows high liver response with HAET, and everolimus controls the extrahepatic disease.

Trial Registration: NCT01678664 (clinicaltrials.gov).
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http://dx.doi.org/10.1016/j.ejca.2019.09.021DOI Listing
December 2019

Post-Radiation Grade 3 Neuroendocrine Carcinoma: A New Entity?

Neuroendocrinology 2021 22;111(1-2):139-145. Epub 2019 Oct 22.

Département d'Imagerie, Service d'Oncologie Endocrinienne, Université Paris-Saclay, Villejuif, France,

Background: Cancer survivors have a 14% increased risk of developing a malignancy compared with the general population. Second radiation-induced malignancies with different histologies have been described in different organs. Based on individual observations, we hypothesized that neuroendocrine carcinoma (NEC) could arise in irradiated organs.

Methods: In a retrospective analysis of Gustave Roussy database of NEC patients (small cell lung cancer excluded) diagnosed as a second cancer, we looked for the frequency of grade 3 NEC that arose in patients who had received previous radiation therapy for a first cancer. Radiation therapy for the first cancer, dose, location of radiation therapy, pathological characteristics, overall survival, and response to treatment of secondary NEC were analyzed.

Results: From January 1995 to December 2017, 847 cases of NEC were seen at Gustave Roussy. Among them, 95 (11.2%) patients had a history of previous malignancy of which 36 (4%) had been treated with radiation therapy. Out of these 36 patients, 12 (1.4% of all NEC patients) developed a NEC within the previous irradiated organ (median dose of 50 Gy, range 36-67.5). Most frequent first cancers were breast cancer (n = 4) and Hodgkin lymphoma (n = 3). NEC arose within a median time of 21.7 years (range 5.1-36.4) from radiation in the thorax (n = 5), digestive tract (n = 3), and other sites. Five large cell NEC, 3 small cell NEC, 1 mixed neuroendocrine neoplasm and 3 not otherwise specified NEC were diagnosed. Ten patients had stage IV disease at diagnosis; median overall survival was 37.8 months (95% CI [17.6 to NA]). Three patients (25%) achieved complete response with multimodal treatment.

Conclusions: NEC can arise from previously irradiated organs and may have a better outcome in this setting. Other risk factors should be investigated to explain the high rate of previous cancer in this population of neuroendocrine neoplasm.
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http://dx.doi.org/10.1159/000504255DOI Listing
October 2019

Surgery in the context of kinase inhibitor therapy for locally invasive thyroid cancer.

Eur J Surg Oncol 2020 04 25;46(4 Pt A):650-655. Epub 2019 Sep 25.

Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Paris Saclay University, Villejuif, France.

Kinase inhibitors (KI) for advanced and aggressive forms of differentiated, medullary and anaplastic thyroid carcinoma have been shown to provide significant tumor response, locally and in distant metastases. Their use, however, may also increase the risk for local complications such as fistula formation and bleeding, and head and neck surgeons may be solicited to palliatively remove potentially dangerous lesions before initiating these systemic treatments. During KI therapy for progressive metastatic and/or locally invasive disease, surgery may be urgently necessary to secure the airway or for symptomatic neck lesions. Finally, there are more and more reports of surgery following KI therapy that suggest a new neoadjuvant paradigm for extensive lesions. In this review, we aim to discuss the literature regarding surgery before, during and after KI therapy in the context of progressive metastatic and/or locally invasive thyroid cancer.
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http://dx.doi.org/10.1016/j.ejso.2019.09.184DOI Listing
April 2020

F-18-Dopa Positron Emission Tomography/Computed Tomography Is More Sensitive Than Whole-Body Magnetic Resonance Imaging for the Localization of Persistent/Recurrent Disease of Medullary Thyroid Cancer Patients.

Thyroid 2019 10;29(10):1457-1464

Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Université Paris Saclay, Villejuif, France.

Elevated postoperative serum calcitonin (Ctn) level indicates persistent/recurrent disease in patients with medullary thyroid carcinoma (MTC). Its location is a challenge. The aim of our study was to compare the disease detection rates of F-18-Dopa (fluoro dihydroxyphenylalanine) positron emission tomography (PET)/computed tomography (CT), whole-body (WB) magnetic resonance imaging (MRI), F-18-FDG (fluorodeoxyglucose) PET/CT, WB CT scanning, neck ultrasonography, and bone scintigraphy in MTC patients with increased Ctn levels and unknown localization of the source. We compared the independent reading of each imaging procedure with a reference assessment for structural disease defined by pathology or concordance between two imagings or with subsequent follow-up. The detection rate of each imaging modality was determined in per patient, per organ, and per lesion analysis. Thirty-six consecutive patients (21 females, mean age: 57 years, sporadic MTC in 26 cases, median serum Ctn level: 760 pg/mL; range: 21-10,121) were analyzed. The reference assessment localized disease in 24 (64%) patients with 74 lesions detected in the thyroid bed (8), in neck lymph nodes (15), mediastinal lymph nodes (6), lungs (1), liver (2), bones (3), and other site (1). At the patient level, the detection rates were 64% (CI 0.48-0.80) for F-18-Dopa PET/CT with early acquisitions, 40% (CI 0.24-0.56) for F-18-FDG PET/CT, 40% (CI 0.24-0.56) for WB MRI, and 48% (CI 0.31-0.66) for WB CT scan. In MTC patients with increased Ctn and no known distant metastases, F-18-Dopa PET/CT is more sensitive to detect structural disease than any other imaging modality, including WB MRI.
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http://dx.doi.org/10.1089/thy.2018.0351DOI Listing
October 2019

Chemotherapy in Resected Neuroendocrine Carcinomas of the Digestive Tract: A National Study from the French Group of Endocrine Tumours.

Neuroendocrinology 2020 21;110(5):404-412. Epub 2019 Aug 21.

Department of Medical Oncology, Saint-Antoine Hospital, Paris, France.

Background: Neuroendocrine carcinomas (NECs) of the digestive tract are rare and aggressive tumours. In localised disease the treatment is surgery. Based on expert consensus, international guidelines recommend the administration of adjuvant chemotherapy combining etoposide and platinum derivatives, justified by the high risk of metastatic relapse. However, no clinical study has proven the benefit of neoadjuvant or adjuvant chemotherapy.

Objectives: We aimed to evaluate the effect of neoadjuvant +/- adjuvant and adjuvant therapy in this indication.

Methods: We performed a retrospective observational French study to evaluate overall survival (OS) and disease-free survival (DFS), prognostic factors for survival, and chemotherapy toxicity.

Results: Seventy-three patients had surgical resection of a localised digestive NEC between January 1, 2000 and December 31, 2016. The majority of patients presented colorectal (35%) tumours and the median Ki-67 value was 70%. Forty-three patients received chemotherapy, either perioperative (neoadjuvant +/- adjuvant) or adjuvant. The median OS and DFS for the whole population was 24 and 9 months, respectively. The median OS and DFS for patients receiving chemotherapy was 62 and 13 months, respectively. Positive postoperative node status and Ki-67 ≥80% had a negative prognostic impact on OS and DFS. Administration of chemotherapy had a positive prognostic impact on OS and DFS. Sixteen grade 3/4 toxicities were reported without toxic death.

Conclusions: Our results suggest a positive effect on survival of chemotherapy in resected digestive NECs, but further studies are needed to confirm these results.
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http://dx.doi.org/10.1159/000502825DOI Listing
February 2021

Tumor Growth Rate as a Validated Early Radiological Biomarker Able to Reflect Treatment-Induced Changes in Neuroendocrine Tumors: The GREPONET-2 Study.

Clin Cancer Res 2019 11 2;25(22):6692-6699. Epub 2019 Aug 2.

Department of Radiology, CHUV University Hospital, Lausanne, Switzerland.

Purpose: Tumor growth rate (TGR) represents the percentage change in tumor volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in neuroendocrine tumors (NET).

Experimental Design: Patients from 7 centers with advanced grade (G) 1/2 NETs from the pancreas (P)/small bowel (SB) initiating ST/WW were eligible. Computed tomography (CT)/MRI performed at prebaseline, baseline, and 3(±1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (ΔTGR; paired test), and Aim-2: validate TGR (<0.8%/m vs. ≥0.8%/m) as an early biomarker in an independent cohort (Kaplan-Meier/Cox regression).

Results: Of 785 patients screened, 127 were eligible. Mean (SD) TGR and TGR were 5.4%/m (14.9) and -1.4%/m (11.8), respectively. Mean (SD) ΔTGR paired-difference was -6.8%/m (19.3; < 0.001). Most marked ΔTGR [mean (SD)] were identified with targeted therapies [-11.3%/m (4.7); = 0.0237] and chemotherapy [-7.9%/m (3.4); = 0.0261]. Multivariable analysis confirmed the absence of previous treatment (OR = 4.65; 95% CI, 1.31-16.52; = 0.018) and low TGR (continuous variable; OR 1.09; 95% CI, 1.01-1.19; = 0.042) to be independent predictors of radiologic objective response. When the multivariable survival analysis for PFS (Cox regression) was adjusted to grade ( = 0.004) and stage ( = 0.017), TGR ≥ 0.8 (vs. <0.8) maintained its significance as a prognostic factor ( < 0.001), whereas TGR and ΔTGR did not. TGR ≥ 0.8%/m was confirmed as an independent prognostic factor for PFS [external validation; Aim-2; multivariable HR 2.21 (95% CI, 1.21-3.70; = 0.003)].

Conclusions: TGR has a role as a biomarker for monitoring response to therapy for early identification of treatment-induced changes and for early prediction of PFS and radiologic objective response.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0963DOI Listing
November 2019

Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma.

JAMA Oncol 2019 Oct;5(10):1440-1447

Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, Paris, France.

Importance: The risk stratification of adrenocortical carcinoma (ACC) based on tumor proliferation index and stage is limited. Adjuvant therapy after surgery is recommended for most patients. Pan-genomic studies have identified distinct molecular groups closely associated with outcome.

Objective: To compare the molecular classification for prognostic assessment of ACC with other known prognostic factors.

Design, Setting, And Participants: In this retrospective biomarker analysis, ACC tumor samples from 368 patients who had undergone surgical tumor removal were collected from March 1, 2005, to September 30, 2015 (144 in the training cohort and 224 in the validation cohort) at 21 referral centers with a median follow-up of 35 months (interquartile range, 18-74 months). Data were analyzed from March 2016 to March 2018.

Exposures: Meta-analysis of pan-genomic studies (transcriptome, methylome, chromosome alteration, and mutational profiles) was performed on the training cohort. Targeted biomarker analysis, including targeted gene expression (BUB1B and PINK1), targeted methylation (PAX5, GSTP1, PYCARD, and PAX6), and targeted next-generation sequencing, was performed on the training and validation cohorts.

Main Outcomes And Measures: Disease-free survival. Cox proportional hazards regression and C indexes were used to assess the prognostic value of each model.

Results: Of the 368 patients (mean [SD] age, 49 [16] years), 144 were in the training cohort (100 [69.4%] female) and 224 were in the validation cohort (142 [63.4%] female). In the training cohort, pan-genomic measures classified ACC into 3 molecular groups (A1, A2, and A3-B), with 5-year survival of 9% for group A1, 45% for group A2, and 82% for group A3-B (log-rank P < .001). Molecular class was an independent prognostic factor of recurrence in stage I to III ACC after complete surgery (hazard ratio, 55.91; 95% CI, 8.55-365.40; P < .001). The combination of European Network for the Study of Adrenal Tumors (ENSAT) stage, tumor proliferation index, and molecular class provided the most discriminant prognostic model (C index, 0.88). In the validation cohort, the molecular classification, determined by targeted biomarker measures, was confirmed as an independent prognostic factor of recurrence (hazard ratio, 5.96 [95% CI, 1.81-19.58], P = .003 for the targeted classifier combining expression, methylation, and chromosome alterations; and 2.61 [95% CI, 1.31-5.19], P = .006 for the targeted classifier combining methylation, chromosome alterations, and mutational profile). The prognostic value of the molecular markers was limited for patients with stage IV ACC.

Conclusions And Relevance: The findings suggest that in localized ACC, targeted classifiers may be used as independent markers of recurrence. The determination of molecular class may improve individual prognostic assessment and thus may spare unnecessary adjuvant treatment.
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http://dx.doi.org/10.1001/jamaoncol.2019.1558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624825PMC
October 2019

Morbidity and mortality of bone metastases in advanced adrenocortical carcinoma: a multicenter retrospective study.

Eur J Endocrinol 2019 May;180(5):311-320

Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, Orbassano, University of Turin, Turin, Italy.

Introduction Adrenocortical carcinoma (ACC) is a rare cancer that commonly spreads to the liver, lungs and lymph nodes. Bone metastases are infrequent. Objective The aim of this report was to describe the clinical characteristics, survival perspective, prognostic factors and frequency of adverse skeletal-related events (SREs) in patients with ACC who developed bone metastasis. Methods This is a retrospective, observational, multicenter, multinational study of patients diagnosed with bone metastases from ACC who were treated and followed up in three European countries (France, Italy and The Netherlands) and one center in the United States. Results Data of 156 patients were captured. The median overall survival was 11 months. SREs occurred in 47% of patients: 17% bone fractures, 17% spinal cord compression, 1% hypercalcemia, 12% developed more than one SRE. In multivariate analysis, cortisol hypersecretion was the only prognostic factor significantly associated with a higher mortality risk (hazard ratio (HR) 2.24, 95% confidence interval (CI): 1.19-4.23, P = 0.013) and with the development of a SREs (of border line significance). The administration of antiresorptive therapies (bisphosphonates and denosumab) was associated with a lower risk of death, even if not significant, and their survival benefit appeared confined in patients attaining serum mitotane levels within the therapeutic range. Conclusion Bone metastases in ACC patients are associated with poor prognosis and high risk of SREs. Cortisol hypersecretion was the only prognostic factor suggesting a potential benefit from antisecretory medications. The therapeutic role of bisphosphonates and denosumab to improve patient outcome deserves to be tested in a prospective clinical trial.
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http://dx.doi.org/10.1530/EJE-19-0026DOI Listing
May 2019

Potentiation of mitotane action by rosuvastatin: New insights for adrenocortical carcinoma management.

Int J Oncol 2019 Jun 3;54(6):2149-2156. Epub 2019 Apr 3.

INSERM UMR‑S 1185, 94276 Le Kremlin‑Bicêtre Cedex, France.

Mitotane (also termed o,p'‑DDD) is the most effective therapy for advanced adrenocortical carcinoma (ACC). Mitotane‑induced dyslipidemia is treated with statins. Mitotane and statins are known to exert anti‑proliferative effects in vitro; however, the effects of statins have never been directly evaluated in patients with ACC and ACC cells, at least to the best of our knowledge. Thus, in this study, we aimed to examine the effects of the rosuvastatin on ACC cells. It has been shown that the combined use of mitotane and statins significantly increases the tumor control rate in patients with ACC; however, it would be of interest to elucidate the molecular mechanisms involved in this potentiation. In this study, we examined the effects of mitotane, rosuvastatin and their combination in NCI‑H295R human ACC cells using proliferation assays, gene expression analyses and free intracellular cholesterol measurements. The results revealed that mitotane dose‑dependently reduced cell viability, induced apoptosis and increased intracellular free cholesterol levels, considered as one of the key features of mitotane action, while rosuvastatin alone reduced cell viability and increased apoptosis at high concentrations. We also demonstrated that rosuvastatin potentiated the effects of mitotane by reducing cell viability, inducing apoptosis, increasing intracellular free cholesterol levels, and by decreasing the expression of 3‑hydroxy‑3‑methylglutaryl‑CoA reductase (HMGCR) and ATP binding cassette subfamily a member 1 (ABCA1), genes involved in cholesterol metabolism, and inhibiting steroidogenesis. Collectively, potentiating the effects of mitotane with the use of rosuvastatin may provide novel therapeutic strategies for ACC, given that the combination of these drugs, pending clinical validation, may lead to the better management of ACC.
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http://dx.doi.org/10.3892/ijo.2019.4770DOI Listing
June 2019

Redifferentiation of a -Mutated Poorly Differentiated Thyroid Cancer Patient with Dabrafenib and Trametinib Treatment.

Thyroid 2019 05;29(5):735-742

3 Department of Medical Biology and Pathology, Gustave Roussy and Paris Saclay University, Villejuif, France.

A 59-year-old woman with locally invasive poorly differentiated thyroid cancer with synchronous lung, mediastinal, and bone metastases and a somatic mutation with contraindication for antiangiogenic drugs was treated with dabrafenib and trametinib. During treatment, serum levels of thyroglobulin increased as early as day 7 up to 10-fold over baseline at week 4. Concurrently, clinical hyperthyroidism occurred, with free triiodothyronine and free thyroxine levels increasing to 6.6 and 4.4 times their upper reference limit. Fludeoxyglucose positron emission tomography/computed tomography at one and two months after treatment initiation showed a PERCIST metabolic response with a 82% decrease in fludeoxyglucose uptake, whereas disease remained morphologically stable according to RECIST criteria. A diagnostic radioactive iodine whole-body scan performed when the patient was thyrotoxic with an undetectable serum thyrotropin level, in the absence of any exogenous thyrotropin stimulation, showed high radioactive iodine uptake in the lung, mediastinum, and skull metastases. A biopsy performed two months after treatment initiation showed a more differentiated growth pattern and a decrease in the mitotic activity compared to baseline. An increase of thyroglobulin and thyroid peroxidase was observed at both the protein and mRNA levels. Sodium-iodide symporter mRNA expression increased by >750 times over its initial level, and sodium-iodide symporter protein expression became detectable under treatment. A decrease in general status due to thyrotoxicosis led to treatment discontinuation. Thyrotoxicosis resolved rapidly and radioactive iodine uptake decreased by >90%. This clinical case shows that redifferentiation itself is not necessarily associated with an antitumor effect.
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http://dx.doi.org/10.1089/thy.2018.0457DOI Listing
May 2019

Early detection with MRI of incomplete treatment of spine metastases after percutaneous cryoablation.

Eur Radiol 2019 Oct 15;29(10):5655-5663. Epub 2019 Mar 15.

Department of Interventional Radiology, Gustave Roussy Cancer Center, 114 rue Edouard Vaillant, 94805, Villejuif, France.

Objectives: To evaluate post-ablation MRI for the detection of incompletely treated spinal osseous metastases (SOM) after cryoablation and to propose a post-ablation imaging classification.

Methods: After IRB consent, all patients treated with cryoablation of SOM between 2011 and 2017 having at least 1-year minimum follow-up and a spine MRI within 4 months after cryoablation were retrospectively included. A classification of MRI images into four types was set up. The primary endpoint of our study was to assess the diagnostic performance of the post-ablation MRI. The secondary endpoints were the 1-year complete treatment rate (CTR) and complications.

Results: Fifty-four SOMs in 39 patients were evaluated. Post-ablation MRI was performed with a median delay of 25 days after cryoablation. Images were evaluated by two independent readers according to the pre-established image classification. Sensitivity and specificity for the detection of residual tumor were 77.3% (95%CI = 62.2-88.5) and 85.9% (95%CI = 75.0-93.4), respectively. Types I, II, III, and IV of the classification were associated with a 1-year complete treatment in 100%, 83.3%, 35.7%, and 10% of cases, respectively. The 1-year CTR was 59.3% for all 54 metastases, and 95.8% for metastases measuring less than 25 mm and at least 2 mm or more away from the spinal canal. Two grade 3 and two grade 2 adverse events according to the CTCAE were reported.

Conclusions: MRI after cryoablation is useful for the evaluation of the ablation efficacy. The classification of post-cryoablation MRI provides reliable clues for the prediction of complete treatment at 1 year.

Key Points: • MRI performed 25 days after cryoablation is useful to evaluate the efficacy. • The proposed classification provides a reliable clue for complete cryoablation. • Percutaneous cryoablation of spinal metastases is highly effective for lesions less than 25 mm in diameter and of at least 2 mm away from the spinal canal.
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http://dx.doi.org/10.1007/s00330-019-06040-yDOI Listing
October 2019

Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma.

J Med Genet 2019 08 15;56(8):513-520. Epub 2019 Mar 15.

Genetics department, Assistance Publique-Hôpitaux de Paris, Hôpitaleuropéen Georges Pompidou, F-75015, Paris, France.

Background: Knowing the genetic status of patients affected by paragangliomas and pheochromocytomas (PPGL) is important for the guidance of their management and their relatives. Our objective was to improve the diagnostic performances of PPGL genetic testing by next-generation sequencing (NGS).

Methods: We developed a custom multigene panel, which includes 17 PPGL genes and is compatible with both germline and tumour DNA screening. The NGS assay was first validated in a retrospective cohort of 201 frozen tumour DNAs and then applied prospectively to 623 DNAs extracted from leucocytes, frozen or paraffin-embedded PPGL tumours.

Results: In the retrospective cohort, the sensitivity of the NGS assay was evaluated at 100% for point and indels mutations and 86% for large rearrangements. The mutation rate was re-evaluated from 65% (132/202) to 78% (156/201) after NGS analysis. In the prospective cohort, NGS detected not only germline and somatic mutations but also co-occurring variants and mosaicism. A mutation was identified in 74% of patients for whom both germline and tumour DNA were available.

Conclusion: The analysis of 824 DNAs from patients with PPGL demonstrated that NGS assay significantly improves the performances of PPGL genetic testing compared with conventional methods, increasing the rate of identified mutations and identifying rare genetic mechanisms.
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http://dx.doi.org/10.1136/jmedgenet-2018-105714DOI Listing
August 2019

Characterization, Prognosis, and Treatment of Patients With Metastatic Lung Carcinoid Tumors.

J Thorac Oncol 2019 06 13;14(6):993-1002. Epub 2019 Feb 13.

Service d'Oncologie Médicale, Groupement Hospitalier Centre, Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France; University of Lyon, Lyon, France. Electronic address:

Introduction: Metastatic lung carcinoids (MLCs) remain poorly characterized and no prognostic stratification exists.

Methods: We conducted a retrospective study including patients with MLCs in two European expert centers. The aims were to characterize these cases and to identify prognostic factors of survival and effectiveness of their treatments.

Results: A total of 162 patients with MLC were included: 50% were women, and the median age was 61 years. Half of the patients had synchronous metastases, mainly located in the liver (75%), bone (42%), and lung (25%). According to WHO classification, MLCs were typical (28%), atypical (60%), or unspecified (12%). A functioning syndrome was observed in 43% of cases and an uptake at somatostatin receptor scintigraphy in 76% of cases. The 5-year overall survival rate was 60% and at 10 years this was 25%. In multivariate analysis, Eastern Cooperative Oncology Group performance status of 0-1 (hazard ratio [HR]: 5.81, 95% confidence interval [CI]: 2.10-16.11), uptake on SRS (HR: 0.38, 95% CI: 0.22-0.66), low serum chromogranin A (HR: 2.27, 95% CI: 1.36-3.81), and typical carcinoid (HR: 1.87, 95% CI: 1.26-2.78) were associated with better survival. According to Response Evaluation Criteria in Solid Tumors version 1.0, the highest objective response rates were obtained after radiofrequency ablation of metastases (86%), liver embolization (56%), peptide receptor radionuclide therapy (27%), and oxaliplatin-based chemotherapy (18%).

Conclusions: MLCs are characterized by a high frequency of atypical carcinoids, functioning syndrome, and liver/bone metastases. WHO classification, performance status, somatostatin receptor scintigraphy, and chromogranin A were associated with longer survival. Partial response was more frequent with locoregional therapies, peptide receptor radionuclide therapy, or oxaliplatin-based chemotherapy.
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http://dx.doi.org/10.1016/j.jtho.2019.02.002DOI Listing
June 2019