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1.
Endocrine ; 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32691271

RESUMO

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.

2.
Neuroendocrinology ; 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32512564

RESUMO

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.

3.
Dig Liver Dis ; 52(5): 473-492, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32234416

RESUMO

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.

4.
Eur J Nucl Med Mol Imaging ; 47(10): 2372-2382, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32123969

RESUMO

PURPOSE: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-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 177Lu-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 177Lu-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: 177Lu-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.

5.
Eur J Nucl Med Mol Imaging ; 47(10): 2358-2371, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32062681

RESUMO

PURPOSE: PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with 177Lu-DOTATOC or 177Lu-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.

6.
Eur J Endocrinol ; 182(4): R29-R58, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31999619

RESUMO

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.


Assuntos
Síndrome de ACTH Ectópico/diagnóstico , Síndrome de ACTH Ectópico/terapia , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/terapia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , Síndrome de ACTH Ectópico/complicações , Síndrome de Cushing/etiologia , Endocrinologia/métodos , Humanos , Tumores Neuroendócrinos/complicações , Resultado do Tratamento
7.
Neuroendocrinology ; 110(5): 404-412, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31430756

RESUMO

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.

8.
Eur J Surg Oncol ; 46(4 Pt A): 650-655, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31582321

RESUMO

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.

9.
Eur J Cancer ; 123: 92-100, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31678771

RESUMO

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).

10.
Neuroendocrinology ; 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31639792

RESUMO

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 RT, pathological characteristics, overall survival, response to treatment of secondary neuroendocrine carcinoma were analyzed. RESULTS: From January 1995 to December 2017, 847 cases of NEC were seen at Gustave Roussy. Among them, 95 (11.2%) pts 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 pts) developed a NEC within the previous irradiated organ (median dose of 50 Gy, range 36-67.5)). Most frequent first cancers were breast (n=4) and Hodgkin lymphoma (n=3). NEC arose within a median time from radiation of 21.7 years (range 5.1-36.4) in the thorax (n=5), digestive tract (n=3) and other sites. Five large cell NEC, 3 small Cell NEC, 1 MiNEN 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-NA]). Three pts (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.

11.
Thyroid ; 29(10): 1457-1464, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31530235

RESUMO

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

12.
Clin Cancer Res ; 25(22): 6692-6699, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31375514

RESUMO

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 (TGR3m) 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 (ΔTGR3m-BL; paired T test), and Aim-2: validate TGR3m (<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) TGR0 and TGR3m were 5.4%/m (14.9) and -1.4%/m (11.8), respectively. Mean (SD) ΔTGR3m-BL paired-difference was -6.8%/m (19.3; P < 0.001). Most marked ΔTGR3m-BL [mean (SD)] were identified with targeted therapies [-11.3%/m (4.7); P = 0.0237] and chemotherapy [-7.9%/m (3.4); P = 0.0261]. Multivariable analysis confirmed the absence of previous treatment (OR = 4.65; 95% CI, 1.31-16.52; P = 0.018) and low TGR3m (continuous variable; OR 1.09; 95% CI, 1.01-1.19; P = 0.042) to be independent predictors of radiologic objective response. When the multivariable survival analysis for PFS (Cox regression) was adjusted to grade (P = 0.004) and stage (P = 0.017), TGR3m ≥ 0.8 (vs. <0.8) maintained its significance as a prognostic factor (P < 0.001), whereas TGR0 and ΔTGR3m-BL did not. TGR3m ≥ 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; P = 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.

13.
JAMA Oncol ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31294750

RESUMO

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.

14.
Int J Oncol ; 54(6): 2149-2156, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942448

RESUMO

Mitotane (also termed o,p'­DDD) is the most effective therapy for advanced adrenocortical carcinoma (ACC). Mitotane­induced dyslipidemia is treated with statins. Mitotane and statins are known to exert anti­proliferative 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 NCI­H295R human ACC cells using proliferation assays, gene expression analyses and free intracellular cholesterol measurements. The results revealed that mitotane dose­dependently 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 3­hydroxy­3­methylglutaryl­CoA 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.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Mitotano/farmacologia , Rosuvastatina Cálcica/farmacologia , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Mitotano/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico
15.
Eur J Endocrinol ; 180(5): 311-320, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30970324

RESUMO

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.


Assuntos
Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/mortalidade , Neoplasias Ósseas/mortalidade , Internacionalidade , Adolescente , Neoplasias do Córtex Suprarrenal/sangue , Neoplasias do Córtex Suprarrenal/diagnóstico , Carcinoma Adrenocortical/sangue , Carcinoma Adrenocortical/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/sangue , Neoplasias Ósseas/diagnóstico , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Morbidade , Mortalidade/tendências , Estudos Retrospectivos , Adulto Jovem
16.
Thyroid ; 29(5): 735-742, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30880598

RESUMO

A 59-year-old woman with locally invasive poorly differentiated thyroid cancer with synchronous lung, mediastinal, and bone metastases and a somatic BRAFK601E 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.

17.
J Med Genet ; 56(8): 513-520, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30877234

RESUMO

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.

18.
Eur Radiol ; 29(10): 5655-5663, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30877460

RESUMO

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.


Assuntos
Vértebras Cervicais , Criocirurgia/métodos , Detecção Precoce de Câncer/métodos , Vértebras Lombares , Imagem por Ressonância Magnética/métodos , Neoplasias da Coluna Vertebral/diagnóstico , Vértebras Torácicas , Adulto , Idoso , Tomografia Computadorizada de Feixe Cônico , Feminino , Fluoroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/secundário , Neoplasias da Coluna Vertebral/cirurgia , Cirurgia Assistida por Computador/métodos , Resultado do Tratamento , Adulto Jovem
19.
J Thorac Oncol ; 14(6): 993-1002, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30771520

RESUMO

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.

20.
J Clin Endocrinol Metab ; 104(6): 2367-2374, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30715419

RESUMO

BACKGROUND: Malignant pheochromocytoma and paraganglioma (MPP) are characterized by prognostic heterogeneity. Our objective was to look for prognostic parameters of overall survival (OS) in MPP patients. PATIENTS AND METHODS: Retrospective multicenter study of MPP characterized by a neck-thoraco-abdomino-pelvic CT or MRI at the time of malignancy diagnosis in European centers between 1998 and 2010. RESULTS: One hundred sixty-nine patients from 18 European centers were included. Main characteristics of patients with MPP were: primary pheochromocytoma in 53% of patients; tumor- or hormone-related symptoms in 57% or 58% of cases; positive plasma or urine hormones in 81% of patients; identification of a mutation in SDHB in 42% of cases. Metastatic sites included bone (64%), lymph node (40%), lung (29%), and liver (26%); mean time between initial and malignancy diagnosis was 43 months (range, 0 to 614). Median follow-up was 68 months and median survival 6.7 years. Using univariate analysis, better survival was associated with head and neck paraganglioma, age <40 years, metanephrines less than fivefold the upper limits of the normal range, and low proliferative index. In multivariate analysis, hypersecretion [hazard ratio 3.02 (1.65 to 5.55); P = 0.0004] was identified as an independent significant prognostic factor of worst OS. CONCLUSIONS: Our results do not confirm SDHB mutations as a major prognostic parameter in MPP and suggest additional key molecular events involved in MPP tumor progression. Aside from SDHB mutation, the biology of aggressive MPP remains to be understood.


Assuntos
Neoplasias das Glândulas Suprarrenais/mortalidade , Paraganglioma/mortalidade , Feocromocitoma/mortalidade , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Paraganglioma/genética , Feocromocitoma/genética , Prognóstico , Estudos Retrospectivos , Succinato Desidrogenase/genética
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