Publications by authors named "Guillaume Assie"

76 Publications

Pituitary surgery as alternative to dopamine agonists treatment for microprolactinomas: a cohort study.

Eur J Endocrinol 2021 Oct 21;185(6):783-791. Epub 2021 Oct 21.

Department of Neurosurgery, Foch Hospital, Suresnes, France.

Objective: Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment.

Design: Follow-up of a cohort of consecutive patients treated by surgery.

Methods: Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients presented with a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan-Meier representation. A cox regression model was used to predict remission.

Results: Median follow-up was 18.2 months (range: 2.8-155). In this cohort, 14/114 (12%) patients were not cured by surgery, including ten early surgical failures and four late relapses occurring 37.4 months (33-41.8) after surgery. From Kaplan-Meier estimates, 1-year and 5-year disease free survival was 90.9% (95% CI: 85.6-96.4%) and 81% (95% CI: 71.2-92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P < 0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty.

Conclusions: In well-selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-21-0293DOI Listing
October 2021

Somatotroph Tumors and the Epigenetic Status of the Locus.

Int J Mol Sci 2021 Jul 15;22(14). Epub 2021 Jul 15.

Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, La Conception, Hospital Laboratory of Molecular Biology, 13385 Marseille, France.

Forty percent of somatotroph tumors harbor recurrent activating mutations, historically called the oncogene. In -negative somatotroph tumors, expression itself is highly variable; those with overexpression most resemble phenotypically those carrying the oncogene. is monoallelically expressed in the normal pituitary due to methylation-based imprinting. We hypothesize that changes in imprinting of -negative tumors affect expression levels and tumorigenesis. We characterized the locus in two independent somatotroph tumor cohorts: one of 23 tumors previously published (PMID: 31883967) and classified by pan-genomic analysis, and a second with 82 tumors. Multi-omics analysis of the first cohort identified a significant difference between -negative and -positive tumors in the methylation index at the known differentially methylated region (DMR) of the A/B transcript promoter, which was confirmed in the larger series of 82 tumors. allelic expression was analyzed using a polymorphic Fok1 cleavage site in 32 heterozygous -negative tumors. expression was significantly reduced in the 14 tumors with relaxed imprinting and biallelic expression, compared to 18 tumors with monoallelic expression. Tumors with relaxed imprinting showed significantly lower and expression levels. Altered A/B DMR methylation was found exclusively in -negative somatotroph tumors. 43% of -negative tumors showed imprinting relaxation, which correlated with lower , and expression, indicating lower sensitivity to somatostatin analogues and potentially aggressive behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22147570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306130PMC
July 2021

Prognostic transcriptome classes of duodenopancreatic neuroendocrine tumors.

Endocr Relat Cancer 2021 Jun 21;28(8):563-571. Epub 2021 Jun 21.

Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, F-75014, Paris, France.

Duodenopancreatic neuroendocrine tumors (DPNETs) aggressiveness is heterogeneous. Tumor grade and extension are commonly used for prognostic determination. Yet, grade classes are empirically defined, with regular updates changing the definition of classes. Genomic screening may provide more objective classes and reflect tumor biology. The aim of this study was to provide a transcriptome classification of DPNETs. We included 66 DPNETs, covering the entire clinical spectrum of the disease in terms of secretion, grade, and stage. Three distinct molecular groups were identified, associated with distinct outcomes (log-rank P < 0.01): (i) better-outcome DPNETs with pancreatic beta-cell signature. This group was mainly composed of well-differentiated, grade 1 insulinomas; (ii) poor-outcome DPNETs with pancreatic alpha-cell and hepatic signature. This group included all neuroendocrine carcinomas and grade 3 DPNETs, but also some grade 1 and grade 2 DPNETs and (iii) intermediate-outcome DPNETs with pancreatic exocrine and progenitor signature. This group included grade 1 and grade 2 DPNETs, with some insulinomas. Fibrinogen gene FGA expression was one of the topmost expressed liver genes. FGA expression was associated with disease-free survival (HR = 1.13, P = 0.005) and could be validated on two independent cohorts. This original pathophysiologic insight provides new prognostic classification perspectives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/ERC-21-0051DOI Listing
June 2021

Preoperative Detection of Liver Involvement by Right-Sided Adrenocortical Carcinoma Using CT and MRI.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Department of Diagnostic and Interventional Imaging, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.

The major prognosis factor of adrenocortical carcinoma (ACC) is the completeness of surgery. The aim of our study was to identify preoperative imaging features associated with direct liver involvement (DLI) by right-sided ACC. Two radiologists, blinded to the outcome, independently reviewed preoperative CT and MRI examinations for eight signs of DLI, in patients operated for right-sided ACC and retrospectively included from November 2007 to January 2020. DLI was confirmed using surgical and histopathological findings. Kappa values were calculated. Univariable and multivariable analyses were performed by using a logistic regression model. Receiver operating characteristic (ROC) curves were built for CT and MRI. Twenty-nine patients were included. Seven patients had DLI requiring resection. At multivariable analysis, focal ACC bulge was the single independent sign associated with DLI on CT (OR: 60.00; 95% CI: 4.60-782.40; < 0.001), and ACC contour disruption was the single independent sign associated with DLI on MRI (OR: 126.00; 95% CI: 6.82-2328.21; < 0.001). Both signs were highly reproducible, with respective kappa values of 0.85 and 0.91. The areas under ROC curves of MRI and CT models were not different ( = 0.838). Focal ACC bulge on CT and ACC contour disruption on MRI are independent and highly reproducible signs, strongly associated with DLI by right-sided ACC on preoperative imaging. MRI does not improve the preoperative assessment of DLI by comparison with CT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13071603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036813PMC
March 2021

Corticotroph tumor progression after bilateral adrenalectomy (Nelson's syndrome): systematic review and expert consensus recommendations.

Eur J Endocrinol 2021 Mar;184(3):P1-P16

Section on Genetics & Endocrinology Eunice Kennedy Shriver National Insitute of Child Health & Human Development (NICHD) National Institute of Health (NIH), NIH Clinical Research Center, Bethesda, Maryland, USA.

Background: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing.

Methods: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018.

Results: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients).

Conclusions: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-20-1088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060870PMC
March 2021

Targeted Metabolomics as a Tool in Discriminating Endocrine From Primary Hypertension.

J Clin Endocrinol Metab 2021 03;106(4):1111-1128

Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Zurich, Switzerland.

Context: Identification of patients with endocrine forms of hypertension (EHT) (primary hyperaldosteronism [PA], pheochromocytoma/paraganglioma [PPGL], and Cushing syndrome [CS]) provides the basis to implement individualized therapeutic strategies. Targeted metabolomics (TM) have revealed promising results in profiling cardiovascular diseases and endocrine conditions associated with hypertension.

Objective: Use TM to identify distinct metabolic patterns between primary hypertension (PHT) and EHT and test its discriminating ability.

Methods: Retrospective analyses of PHT and EHT patients from a European multicenter study (ENSAT-HT). TM was performed on stored blood samples using liquid chromatography mass spectrometry. To identify discriminating metabolites a "classical approach" (CA) (performing a series of univariate and multivariate analyses) and a "machine learning approach" (MLA) (using random forest) were used.The study included 282 adult patients (52% female; mean age 49 years) with proven PHT (n = 59) and EHT (n = 223 with 40 CS, 107 PA, and 76 PPGL), respectively.

Results: From 155 metabolites eligible for statistical analyses, 31 were identified discriminating between PHT and EHT using the CA and 27 using the MLA, of which 16 metabolites (C9, C16, C16:1, C18:1, C18:2, arginine, aspartate, glutamate, ornithine, spermidine, lysoPCaC16:0, lysoPCaC20:4, lysoPCaC24:0, PCaeC42:0, SM C18:1, SM C20:2) were found by both approaches. The receiver operating characteristic curve built on the top 15 metabolites from the CA provided an area under the curve (AUC) of 0.86, which was similar to the performance of the 15 metabolites from MLA (AUC 0.83).

Conclusion: TM identifies distinct metabolic pattern between PHT and EHT providing promising discriminating performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993566PMC
March 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-20-0800DOI Listing
February 2021

Genomic classification of benign adrenocortical lesions.

Endocr Relat Cancer 2021 01;28(1):79-95

Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France.

Benign adrenal tumors cover a spectrum of lesions with distinct morphology and steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical tumors is proposed, aiming at unbiased classification and new pathophysiological insights. Benign adrenocortical tumors (n = 146) were analyzed by transcriptome, methylome, miRNome, chromosomal alterations and mutational status, using expression arrays, methylation arrays, miRNA sequencing, SNP arrays, and exome or targeted next-generation sequencing respectively. Pathological and hormonal data were collected for all tumors. Pangenomic analysis identifies four distinct molecular categories: (1) tumors responsible for overt Cushing, gathering distinct tumor types, sharing a common cAMP/PKA pathway activation by distinct mechanisms; (2) adenomas with mild autonomous cortisol excess and non-functioning adenomas, associated with beta-catenin mutations; (3) primary macronodular hyperplasia with ARMC5 mutations, showing an ovarian expression signature; (4) aldosterone-producing adrenocortical adenomas, apart from other benign tumors. Epigenetic alterations and steroidogenesis seem associated, including CpG island hypomethylation in tumors with no or mild cortisol secretion, miRNA patterns defining specific molecular groups, and direct regulation of steroidogenic enzyme expression by methylation. Chromosomal alterations and somatic mutations are subclonal, found in less than 2/3 of cells. New pathophysiological insights, including distinct molecular signatures supporting the difference between mild autonomous cortisol excess and overt Cushing, ARMC5 implication into the adreno-gonadal differentiation faith, and the subclonal nature of driver alterations in benign tumors, will orient future research. This first genomic classification provides a large amount of data as a starting point.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/ERC-20-0128DOI Listing
January 2021

Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma.

Endocr Connect 2020 Jul;9(7):705-714

Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.

Background: The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level.

Methods: Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12).

Results: Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients, respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were 'Noisy' (numerous and anarchic alterations) in 8/14 and 'Chromosomal' (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%).

Conclusions: Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable and might be more robust for the prognostic assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EC-20-0228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424337PMC
July 2020

Glucocorticoid Excess in Patients with Pheochromocytoma Compared with Paraganglioma and Other Forms of Hypertension.

J Clin Endocrinol Metab 2020 09;105(9)

Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Context: Catecholamines and adrenocortical steroids are important regulators of blood pressure. Bidirectional relationships between adrenal steroids and catecholamines have been established but whether this is relevant to patients with pheochromocytoma is unclear.

Objective: This study addresses the hypothesis that patients with pheochromocytoma and paraganglioma (PPGL) have altered steroid production compared with patients with primary hypertension.

Design: Multicenter cross-sectional study.

Setting: Twelve European referral centers.

Patients: Subjects included 182 patients with pheochromocytoma, 36 with paraganglioma and 270 patients with primary hypertension. Patients with primary aldosteronism (n = 461) and Cushing syndrome (n = 124) were included for additional comparisons.

Intervention: In patients with PPGLs, surgical resection of tumors.

Outcome Measures: Differences in mass spectrometry-based profiles of 15 adrenal steroids between groups and after surgical resection of PPGLs. Relationships of steroids to plasma and urinary metanephrines and urinary catecholamines.

Results: Patients with pheochromocytoma had higher (P < .05) circulating concentrations of cortisol, 11-deoxycortisol, 11-deoxycorticosterone, and corticosterone than patients with primary hypertension. Concentrations of cortisol, 11-deoxycortisol, and corticosterone were also higher (P < .05) in patients with pheochromocytoma than with paraganglioma. These steroids correlated positively with plasma and urinary metanephrines and catecholamines in patients with pheochromocytoma, but not paraganglioma. After adrenalectomy, there were significant decreases in cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, aldosterone, and 18-oxocortisol.

Conclusions: This is the first large study in patients with PPGLs that supports in a clinical setting the concept of adrenal cortical-medullary interactions involving an influence of catecholamines on adrenal steroids. These findings could have implications for the cardiovascular complications of PPGLs and the clinical management of patients with the tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413598PMC
September 2020

Frequency and Incidence of Carney Complex Manifestations: A Prospective Multicenter Study With a Three-Year Follow-Up.

J Clin Endocrinol Metab 2020 03;105(3)

INSERM U1016, CNRS UMR8104, Institut Cochin, Université Paris Descartes, Paris.

Introduction: Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far.

Methods: This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation.

Results: The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype.

Conclusion: This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa002DOI Listing
March 2020

Pangenomic Classification of Pituitary Neuroendocrine Tumors.

Cancer Cell 2020 01 26;37(1):123-134.e5. Epub 2019 Dec 26.

INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes-Université de Paris, 75006 Paris, France; Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France. Electronic address:

Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and gonadotroph (NR5A1/SF1 lineage). We report a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2019.11.002DOI Listing
January 2020

EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness.

Br J Cancer 2019 08 31;121(5):384-394. Epub 2019 Jul 31.

CNRS, UMR 6293, GReD, Inserm U1103, Université Clermont Auvergne, 63001, Clermont-Ferrand, France.

Background: EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription.

Methods: We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis.

Results: We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC.

Conclusions: Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-019-0538-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738105PMC
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2019.1558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624825PMC
October 2019

Driver mutations in USP8 wild-type Cushing's disease.

Neuro Oncol 2019 10;21(10):1273-1283

Department of Medicine I, Division of Endocrinology and Diabetes, University Hospital Würzburg (UKW), Würzburg, Germany.

Background: Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients.

Methods: Exome sequencing was performed on 18 paired tumor-blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays.

Results: Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on pro-opiomelanocortin production and adrenocorticotropic hormone secretion.

Conclusions: USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/neuonc/noz109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784271PMC
October 2019

Genomics of benign adrenocortical tumors.

J Steroid Biochem Mol Biol 2019 10 14;193:105414. Epub 2019 Jun 14.

Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris Descartes University, Paris, France; Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Hôpital Cochin, Paris, France. Electronic address:

Benign adrenocortical adenomas and hyperplasia are relatively common and include a spectrum of distinct entities, which diagnosis depends on the macroscopic aspect and the secretion profile. Recent advances in genomics have proposed high-throughput molecular characterization of adrenal tumors, thereby improving our knowledge on the pathophysiology and tumorigenesis of these tumors. Genomic (exome and chromosome alteration profiles), epigenomic (micro-RNAs expression and methylation profiles) and transcriptomic (gene expression profiles) studies highlighted the major roles of intracellular calcium signaling in aldosterone-producing adenomas (APA), of protein kinase A (PKA)/cAMP pathway in cortisol-producing tumors, and of Wnt/beta-catenin pathway in non-secreting tumors. Exome sequencing revealed new major drivers in all tumor types, including KCNJ5, ATP1A1, ATP2B3, CACNA1D and CACNA1H mutations in APA, PRKACA mutations in cortisol-producing adenomas (CPA) and ARMC5 mutations in primary macronodular adrenocortical hyperplasia (PMAH). The clinical impact of these findings is just starting to evolve. The identification of genetic syndromes, such as germline ARMC5 mutations in PMAH, has allowed genetic counseling. Key molecular alterations could serve as a basis for the development of targeted medical treatments for benign adrenal tumors. The recent developments in genomics, including single-cell technologies, and in proteomics and metabolomics will probably offer new perspectives for characterizing benign adrenal tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jsbmb.2019.105414DOI Listing
October 2019

Pharmacokinetic interaction between mitotane and etoposide in adrenal carcinoma: a pilot study.

Endocr Connect 2018 Dec;7(12):1409-1414

Pharmacokinetics and Pharmacochemistry Unit, Cochin Hospital, Paris Descartes University, AP-HP, Paris, France.

Background The combination of mitotane and platinum-etoposide chemotherapy is a front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Pharmacokinetic drug-drug interaction between mitotane, a strong CYP3A4 inducer, and etoposide, which is a substrate of CYP3A4, may contribute to chemoresistance. The aim of this pilot study was to assess the pharmacokinetic interaction between mitotane and etoposide in ACC patients. Methods Five consecutive ACC patients treated with platinum etoposide (120-150 mg/m2 day 1-2-3 at cycle 1), with or without concomitant mitotane, were included. In the absence of limiting toxicity, a dose escalation of etoposide was proposed since cycle 2. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24 h after each infusion. Clearance and area under the curve (AUC) of etoposide were determined at each cycle. Results Patients received two to six chemotherapy cycles, in association with mitotane (N = 4) or after mitotane discontinuation (N = 1). Etoposide clearance was two-fold higher with concomitant mitotane (4.95 L/h) than after mitotane discontinuation (2.53 L/h, P = 0.014), and 2.5-fold higher than that in reference population not treated with mitotane (1.81 L/h). Etoposide dose escalation was performed in four patients under mitotane, resulting in two minor tumor responses and one severe toxicity (febrile aplasia) at dose of 300 mg/m2/day. Tumor response was associated with higher etoposide AUC (267.3 vs 188.8 mg.h/L, P = 0.04). Conclusion A drug-drug interaction between mitotane and etoposide may contribute to the low efficacy of platinum-etoposide chemotherapy. This pilot study suggests further a potential benefit of increasing etoposide dose in ACC patients receiving mitotane.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EC-18-0428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301193PMC
December 2018

Fascin-1 Is a Novel Prognostic Biomarker Associated With Tumor Invasiveness in Adrenocortical Carcinoma.

J Clin Endocrinol Metab 2019 05;104(5):1712-1724

Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy.

Context: Novel tumor markers are urgently needed to better stratify adrenocortical cancer (ACC) patients and improve therapies for this aggressive neoplasm.

Objective: To assess the diagnostic and prognostic value of the actin-bundling protein fascin-1 (FSCN1) in adrenocortical tumors.

Design, Setting And Participants: A local series of 37 malignant/37 benign adrenocortical tumors at Careggi University Hospital and two independent validation ACC cohorts (Cochin, TCGA) from the European Network for the Study of Adrenal Tumors were studied.

Main Outcome Measures: FSCN1 expression was quantified by immunohistochemistry, Western blot and quantitative RT-PCR in ACC specimens; overall and disease-free survival associated with FSCN1 expression were assessed by Kaplan-Meier analysis and compared with that of Ki67 labeling index and tumor stage.

Results: Despite the low diagnostic power, in the Florence ACC series, FSCN1 immunohistochemical detection appeared as an independent prognostic factor, also refining results obtained with staging and Ki67 labeling index. The robust prognostic power of FSCN1 levels was further confirmed in two independent ACC cohorts. A positive correlation was found between FSCN1 and steroidogenic factor-1 (SF-1), with a substantially higher expression of both factors in ACCs at advanced stages and with at least one of the three Weiss score parameters associated with invasiveness. Moreover, we demonstrated FSCN1 role in promoting cell invasion in a human ACC cell line only in the case of increased SF-1 dosage.

Conclusions: These findings show that FSCN1 is a novel independent prognostic marker in ACC and may serve as a potential therapeutic target to block tumor spread.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2018-01717DOI Listing
May 2019

European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors

Eur J Endocrinol 2018 10 1;179(4):G1-G46. Epub 2018 Oct 1.

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

Adrenocortical carcinoma (ACC) is a rare and in most cases steroid hormone-producing tumor with variable prognosis. The purpose of these guidelines is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with ACC based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions, which we judged as particularly important for the management of ACC patients and performed systematic literature searches: (A) What is needed to diagnose an ACC by histopathology? (B) Which are the best prognostic markers in ACC? (C) Is adjuvant therapy able to prevent recurrent disease or reduce mortality after radical resection? (D) What is the best treatment option for macroscopically incompletely resected, recurrent or metastatic disease? Other relevant questions were discussed within the group. Selected Recommendations: (i) We recommend that all patients with suspected and proven ACC are discussed in a multidisciplinary expert team meeting. (ii) We recommend that every patient with (suspected) ACC should undergo careful clinical assessment, detailed endocrine work-up to identify autonomous hormone excess and adrenal-focused imaging. (iii) We recommend that adrenal surgery for (suspected) ACC should be performed only by surgeons experienced in adrenal and oncological surgery aiming at a complete en bloc resection (including resection of oligo-metastatic disease). (iv) We suggest that all suspected ACC should be reviewed by an expert adrenal pathologist using the Weiss score and providing Ki67 index. (v) We suggest adjuvant mitotane treatment in patients after radical surgery that have a perceived high risk of recurrence (ENSAT stage III, or R1 resection, or Ki67 >10%). (vi) For advanced ACC not amenable to complete surgical resection, local therapeutic measures (e.g. radiation therapy, radiofrequency ablation, chemoembolization) are of particular value. However, we suggest against the routine use of adrenal surgery in case of widespread metastatic disease. In these patients, we recommend either mitotane monotherapy or mitotane, etoposide, doxorubicin and cisplatin depending on prognostic parameters. In selected patients with a good response, surgery may be subsequently considered. (vii) In patients with recurrent disease and a disease-free interval of at least 12 months, in whom a complete resection/ablation seems feasible, we recommend surgery or alternatively other local therapies. Furthermore, we offer detailed recommendations about the management of mitotane treatment and other supportive therapies. Finally, we suggest directions for future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-18-0608DOI Listing
October 2018

Genomic insights into Cushing syndrome.

Authors:
Guillaume Assié

Ann Endocrinol (Paris) 2018 Jun 4;79(3):119-122. Epub 2018 May 4.

Service d'endocrinologie, centre de référence des maladies rares de la surrénale, Assistance publique-Hôpitaux de Paris, hôpital Cochin, 75014 Paris, France; Inserm U1016, CNRS 8104, institut Cochin, université Paris Descartes, 75014 Paris, France. Electronic address:

In the setting of Cushing syndrome, genomic analyses can be performed either in tumors responsible for endogenous Cushing, or in patients exposed to glucocorticoid excess. Genomics of tumors identified several new genes - including ZNRF3 in adrenocortical carcinomas, PRKACA in cortisol-producing adrenal adenomas, ARMC5 in primary macronodular adrenal hyperplasia and USP8 in pituitary corticotroph adenomas. These genes shed new lights on the mechanisms responsible for these tumors. Integrated genomic studies of adrenal carcinomas identified distinct molecular classes, with remarkably different prognostic outcome. Beyond the mechanistic novelties, a new generation of prognostic markers emerges, with potentially important impact on patients care. For the future, genomic efforts should be pursued, focusing on poorly characterized tumors responsible for Cushing syndrome - including endocrine tumors secreting ACTH. In addition, epigenomics is emerging as an outstanding set of tools for characterizing tumors, unraveling unprecedented aspects of tumorigenesis. Applying these tools to endocrine tumors responsible for Cushing syndrome may also lead to important discoveries. Genomics of patients exposed to glucocorticoid excess is an emerging research field. Proof of principle studies have been performed, identifying molecular markers of glucocorticoid excess in blood. Research efforts should now concentrate on markers of mild glucocorticoid excesses - endogenous or exogenous -, owing to their high prevalence in general population. In addition, markers of individual susceptibility to each type of glucocorticoid complication are needed. It remains to be determined whether genomics can identify such markers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ando.2018.03.011DOI Listing
June 2018

Activating PRKACB somatic mutation in cortisol-producing adenomas.

JCI Insight 2018 04 19;3(8). Epub 2018 Apr 19.

Cochin Institute, Paris Descartes University, CNRS (UMR 8104)/Inserm (U1016), Paris, France.

Mutations in the gene encoding the protein kinase A (PKA) catalytic subunit α have been found to be responsible for cortisol-producing adenomas (CPAs). In this study, we identified by whole-exome sequencing the somatic mutation p.S54L in the PRKACB gene, encoding the catalytic subunit β (Cβ) of PKA, in a CPA from a patient with severe Cushing syndrome. Bioluminescence resonance energy transfer and surface plasmon resonance assays revealed that the mutation hampers formation of type I holoenzymes and that these holoenzymes were highly sensitive to cAMP. PKA activity, measured both in cell lysates and with recombinant proteins, based on phosphorylation of a synthetic substrate, was higher under basal conditions for the mutant enzyme compared with the WT, while maximal activity was lower. These data suggest that at baseline the PRKACB p.S54L mutant drove the adenoma cells to higher cAMP signaling activity, probably contributing to their autonomous growth. Although the role of PRKACB in tumorigenesis has been suggested, we demonstrated for the first time to our knowledge that a PRKACB mutation can lead to an adrenal tumor. Moreover, this observation describes another mechanism of PKA pathway activation in CPAs and highlights the particular role of residue Ser54 for the function of PKA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.98296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931119PMC
April 2018

Somatic mutations are frequent events in corticotroph tumor progression causing Nelson's tumor.

Eur J Endocrinol 2018 Jan 5;178(1):57-63. Epub 2017 Oct 5.

Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.

Objective: Somatic mutations in the ubiquitin-specific protease 8 () gene are frequent in corticotroph tumors causing Cushing's disease (CD). Corticotroph tumor progression, the so-called Nelson's syndrome (NS), is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory CD that is caused by the development of an ACTH-secreting tumor of the pituitary gland. Whether alterations are also present in progressive Nelson's tumors has not been studied in detail so far.

Design And Methods: Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of the gene in the exon 14 with Sanger sequencing.

Results: Fifteen out of 33 tumors (45%) presented with a mutation in the exon 14 of , with c.2159C>A (p.Pro720Gln) being the most frequent (9/33), followed by c.2155_2157delTCC (p.Ser718del, 4/33) and c.2152T>C (p.Ser718Pro, 2/33). This prevalence is similar to that previously reported for CD. Mutations were found exclusively in females. Other variables, such as age at diagnosis with NS, body mass index, hyperpigmentation, visual field defects, adenoma size or mortality, did not significantly differ between patients with wild-type and mutant tumors. Patients with mutant tumors exhibited higher levels of plasma ACTH after surgery (median: 640 vs 112 pg/mL,  = 0.03). No differences were observed in ACTH normalization (<50 pg/mL) and tumor control after surgery for Nelson's tumor.

Conclusion: Somatic mutations in are common in Nelson's tumors, indicating that they do not drive the corticotroph tumor progression that leads to NS, and may be associated with a less favorable biochemical outcome after surgery for Nelson's tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-17-0634DOI Listing
January 2018

Assessment of VAV2 Expression Refines Prognostic Prediction in Adrenocortical Carcinoma.

J Clin Endocrinol Metab 2017 09;102(9):3491-3498

Université Côte d'Azur, Sophia Antipolis, 06560 Valbonne, France.

Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with overall poor prognosis. The Ki67 labeling index (LI) has a major prognostic role in localized ACC after complete resection, but its estimates may suffer from considerable intra- and interobserver variability. VAV2 overexpression induced by increased Steroidogenic Factor-1 dosage is an essential factor driving ACC tumor cell invasion.

Objective: To assess the prognostic role of VAV2 expression in ACC by investigation of a large cohort of patients.

Design, Setting, And Participants: A total of 171 ACC cases (157 primary tumors, six local recurrences, eight metastases) from seven European Network for the Study of Adrenal Tumors centers were studied.

Outcome Measurements: H-scores were generated to quantify VAV2 expression. VAV2 expression was divided into two categories: low (H-score, <2) and high (H-score, ≥2). The Ki67 LI retrieved from patients' pathology records was also categorized into low (<20%) and high (≥20%). Clinical and immunohistochemical markers were correlated with progression-free survival (PFS) and overall survival (OS).

Results: VAV2 expression and Ki67 LI were significantly correlated with each other and with PFS and OS. Heterogeneity of VAV2 expression inside the same tumor was very low. Combined assessment of VAV2 expression and Ki67 LI improved patient stratification to low-risk and high-risk groups.

Conclusion: Combined assessment of Ki67 LI and VAV2 expression improves prognostic prediction in ACC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2017-00984DOI Listing
September 2017

Calling Chromosome Alterations, DNA Methylation Statuses, and Mutations in Tumors by Simple Targeted Next-Generation Sequencing: A Solution for Transferring Integrated Pangenomic Studies into Routine Practice?

J Mol Diagn 2017 09;19(5):776-787

Institut Cochin, INSERMU1016, Centre National de la Recherche Scientifique UMR_8104, Paris, France; Department of Endocrinology, Reference Center for Rare Adrenal Diseases, Reference Center for Rare Adrenal Cancer Network COMETE, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris. Electronic address:

Pangenomic studies identified distinct molecular classes for many cancers, with major clinical applications. However, routine use requires cost-effective assays. We assessed whether targeted next-generation sequencing (NGS) could call chromosomal alterations and DNA methylation status. A training set of 77 tumors and a validation set of 449 (43 tumor types) were analyzed by targeted NGS and single-nucleotide polymorphism (SNP) arrays. Thirty-two tumors were analyzed by NGS after bisulfite conversion, and compared to methylation array or methylation-specific multiplex ligation-dependent probe amplification. Considering allelic ratios, correlation was strong between targeted NGS and SNP arrays (r = 0.88). In contrast, considering DNA copy number, for variations of one DNA copy, correlation was weaker between read counts and SNP array (r = 0.49). Thus, we generated TARGOMICs, optimized for detecting chromosome alterations by combining allelic ratios and read counts generated by targeted NGS. Sensitivity for calling normal, lost, and gained chromosomes was 89%, 72%, and 31%, respectively. Specificity was 81%, 93%, and 98%, respectively. These results were confirmed in the validation set. Finally, TARGOMICs could efficiently align and compute proportions of methylated cytosines from bisulfite-converted DNA from targeted NGS. In conclusion, beyond calling mutations, targeted NGS efficiently calls chromosome alterations and methylation status in tumors. A single run and minor design/protocol adaptations are sufficient. Optimizing targeted NGS should expand translation of genomics to clinical routine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2017.06.005DOI Listing
September 2017

Adrenalectomy for incidentaloma: lessons learned from a single-centre series of 274 patients.

ANZ J Surg 2018 May 7;88(5):468-473. Epub 2017 Jul 7.

Department of Digestive, Hepatobiliary and Endocrine Surgery, Referral Center for Rare Adrenal Diseases, Cochin Hospital, APHP, Paris, France.

Background: Adrenal incidentalomas are increasingly diagnosed and include a wide spectrum of lesions from benign adenomas to secreting or malignant lesions. The aim of the present study is to report a large single-institution experience of patients undergoing surgery for adrenal incidentaloma with particular attention to their diagnosis and post-operative course and the evolution of surgical practice over time.

Methods: From 1993 to 2013, 274 patients underwent adrenalectomy for incidentaloma. All patients underwent standardized clinical, hormonal and imaging assessments.

Results: Patients were mainly female (63.1%; n = 173), and the median age of patients was 56.5 years. After a complete hormonal evaluation, 47.9% (n = 129) of incidentalomas were classified as secreting tumours, including 24.4% (n = 67) subclinical cortisol-secreting adenomas and 18.9% (n = 52) pheochromocytomas. Adrenocortical carcinomas represented 9.5% (n = 26) of incidentalomas, and the risk of malignancy was significantly correlated with tumour size. The conversion rate after laparoscopic adrenalectomy (90.9%; n = 249) was 3.2% (n = 8). The overall morbidity rate was 13.9%, which included a 4.4% rate of severe morbidity (Clavien-Dindo ≥3). From 2008 onwards, there was a significant decrease (P < 0.001) in the use of surgical approaches for non-secreting adenomas.

Conclusion: After a complete work-up, half of the incidentalomas were classified as subclinical oversecreting adrenal lesions and 10% proved to be malignant adrenocortical carcinomas. The debatable use of surgical approaches for benign nonfunctioning adenomas significantly decreased over time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ans.14095DOI Listing
May 2018

Loss-of-function mutations in the gene are a novel cause of Cushing's disease.

Endocr Relat Cancer 2017 08 22;24(8):379-392. Epub 2017 May 22.

Section on Endocrinology and GeneticsEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

The cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/ERC-17-0131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510591PMC
August 2017

Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas.

Eur J Endocrinol 2017 Jun;176(6):769-777

Fédération d'EndocrinologieGroupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

Objectives: Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival.

Design: Multicenter retrospective study by members of the French Society of Endocrinology.

Methods: Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph ( = 23) or lactotroph ( = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment.

Results: The median treatment duration was 6.5 cycles (range 2-24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0-72). Overall survival was significantly higher among responders ( = 0.002); however, ten patients relapsed 5 months (0-57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success.

Discussion: Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-16-0979DOI Listing
June 2017

Efficacy of endoscopic endonasal transsphenoidal surgery for Cushing's disease in 230 patients with positive and negative MRI.

Acta Neurochir (Wien) 2017 07 9;159(7):1227-1236. Epub 2017 Mar 9.

Department of Neurosurgery, Hôpital Foch, Suresnes, France.

Object: The primary objective was to assess the remission rate, and the secondary objectives were to evaluate the early complications and recurrence rate and to define the predictive factors for the remission and recurrence rates.

Patients And Methods: This prospective single-center study included 230 consecutive patients, operated on by a single surgeon for Cushing's disease via a transsphenoidal endoscopic endonasal approach, over a 6-year period (2008-2013). The patients included in this series were all adults (>18 years of age), who presented with clinical and biological characteristics of Cushing's disease confirmed based on dedicated MRI pituitary imaging. Biochemical remission was defined as a postoperative serum cortisol level <5 μg/dl on the 2nd day following surgery that required glucocorticoid replacement therapy.

Results: The remission rate for the global population (n = 230) with a follow-up of 21 ± 19.2 months concerned 182 patients (79.1%) divided into 132 patients (82.5%) with positive MRI and 50 patients (71.4%) with negative MRI with no statistically significant difference (p = 0.077). Complications occurred in 77 patients with no deaths. A total of 22% of patients had transient diabetes insipidus and 6.4% long-term diabetes insipidus, and no postoperatively CSF leakage was observed. The recurrence rate was 9.8% with a mean time of 32.7 ± 15.2 months. The predictive factors for the remission rate were the presence of pituitary microadenoma and a positive histology. No risk factors were involved regarding the recurrence rate.

Conclusion: Whatever the MRI results, the transsphenoidal endonasal endoscopic approach remains the gold standard treatment for Cushing's disease. It was maximally effective with a remission rate of 79.1% and lower morbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00701-017-3140-1DOI Listing
July 2017

Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas.

J Pathol 2017 05 29;242(1):10-15. Epub 2017 Mar 29.

INSERM UMR-S1147, Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Université Paris Descartes, Paris, France.

Germline alterations in DNA repair genes are implicated in cancer predisposition and can result in characteristic mutational signatures. However, specific mutational signatures associated with base excision repair (BER) defects remain to be characterized. Here, by analysing a series of colorectal cancers (CRCs) using exome sequencing, we identified a particular spectrum of somatic mutations characterized by an enrichment of C > A transversions in NpCpA or NpCpT contexts in three tumours from a MUTYH-associated polyposis (MAP) patient and in two cases harbouring pathogenic germline MUTYH mutations. In two series of adrenocortical carcinomas (ACCs), we identified four tumours with a similar signature also presenting germline MUTYH mutations. Taken together, these findings demonstrate that MUTYH inactivation results in a particular mutational signature, which may serve as a useful marker of BER-related genomic instability in new cancer types. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.4880DOI Listing
May 2017
-->