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BACKGROUND & AIMS: Survival times vary among patients with neuroendocrine tumors (NETs) - even among those with the same site, stage, and grade of primary tumor. This makes it difficult to select treatment for patients with unresectable NETs because some patients can survive decades without treatment. 68Gallium-DOTATATE positron emission tomography with computed tomography (68Ga-DOTATATE PET/CT) is a sensitive imaging technique for detection of NETs. We investigated the prognostic accuracy of 68Ga-DOTATATE PET/CT-based analysis of tumor volume in patients with NETs. METHODS: We performed a prospective study of 184 patients with NETs (128 [69.6%] with metastases and 11 patients [6.0%] with locally advanced disease) at the National Institutes of Health Clinical Center (Bethesda, MD) from 2013 through 2017. All patients underwent 68Ga-DOTATATE PET/CT image analysis and total 68Ga-DOTATATE-Avid tumor volume (68Ga-DOTATATE TV) was determined. We also measured fasting serum chromogranin A, neuron-specific enolase, gastrin, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, and 24-hour urinary 5-hydroxyindoleacetic acid levels in all patients. Disease progression was defined as a new lesion or a growth of a known lesion during the interval between baseline 68Ga-DOTATATE PET/CT scan and follow-up imaging (14.0 ± 6.1 months; range, 1-35 months). The primary outcomes were progression-free survival (PFS) and disease-specific mortality during a median follow-up time of 18 months (range, 4-35 months). RESULTS: We found an inverse correlation between quartiles of 68Ga-DOTATATE TV and PFS (P = .001) and disease-specific survival (P = .002). A 68Ga-DOTATATE TV of 7.0 mL or more was associated with higher odds of disease progression (hazard ratio, 3.0; P = .04). A 68Ga-DOTATATE TV of 35.8 mL or more was associated with increased risk of disease-specific death (hazard ratio, 10.6) in multivariable analysis (P = .01), as well as in subgroup analysis of patients with pancreatic NETs. CONCLUSIONS: In a prospective study, we demonstrated the prognostic utility of 68Ga-DOTATATE TV in a large cohort of patients with NETs, in terms of PFS and disease-specific mortality.
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Neoplasias Gastrointestinais/diagnóstico por imagem , Tumores Neuroendócrinos/diagnóstico por imagem , Compostos Organometálicos/administração & dosagem , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/administração & dosagem , Adulto , Idoso , Distribuição de Qui-Quadrado , Progressão da Doença , Intervalo Livre de Doença , Feminino , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Maryland , Pessoa de Meia-Idade , Análise Multivariada , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/secundário , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Carga TumoralRESUMO
BACKGROUND: We sought to assess participation of underrepresented minorities with endocrine neoplasms in clinical trials conducted in the National Cancer Institute's (NCI) Intramural Research Program. METHODS: We performed a retrospective analysis of patients enrolled in Endocrine Oncology Branch (EOB) clinical trials, comparing demographics to regional and national demographics. We compared specific endocrine cancer patient data to data from NCI's Surveillance, Epidemiology, and End Results (SEER) program. RESULTS: Comparing EOB patients to national demographics, we found more white (77% vs 74%, Pâ¯<â¯0.001) and black patients (14% vs 12%, Pâ¯<â¯0.001). For thyroid cancer, there were more black (16% vs 7%, Pâ¯<â¯0.0001) and other minority patients (17% vs 11%, Pâ¯<â¯0.0001) compared to SEER. For gastroenteropancreatic neuroendocrine tumors (GEPNETs), there were fewer black (6% vs 19%, Pâ¯<â¯0.0001) and other minority patients (6% vs 8%, Pâ¯<â¯0.0001). CONCLUSION: Enrollment parity of underrepresented minorities into clinical trials is achievable, although possibly cancer type-specific.
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Ensaios Clínicos como Assunto , Neoplasias das Glândulas Endócrinas/etnologia , Neoplasias das Glândulas Endócrinas/terapia , Grupos Minoritários/estatística & dados numéricos , Seleção de Pacientes , Demografia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Programa de SEER , Estados Unidos/epidemiologiaRESUMO
PURPOSE: Patients with von Hippel-Lindau (VHL) disease may develop various tumors, including neuroendocrine tumors of the pancreas (PNETs) and adrenal, central nervous system and retinal hemangioblastomas, kidney tumors and more. 68Ga-DOTATATE positron emission tomography (PET)/computerized tomography (CT) has been shown to be highly accurate for tumors with cells expressing somatostatin receptors. We aimed to assess the performance of 68Ga-DOTATATE PET/CT in patients with VHL disease. METHODS: Patients with a diagnosis of VHL were enrolled in a prospective study and underwent surveillance imaging for pancreatic lesions (n = 301). The current analysis includes 73 evaluations with multiple imaging modalities of 36 patients (2.1 ± 0.8 evaluations/patient, range 1-4) for a head-to-head comparison of 68Ga-DOTATATE PET/CT, CT and/or MRI. In this post-hoc analysis we compared the detection rates of various imaging modalities for PNETs and for any extrapancreatic tumors located within the scan field of CT/MRI of the abdomen. RESULTS: 68Ga-DOTATATE PET/CT detected a total of 206 lesions, CT detected 208 lesions and MRI detected 94 lesions in 61, 66 and 33 scans, respectively. 68Ga-DOTATATE PET/CT (3.4 ± 0.1 per scan) was superior than CT (3.2 ± 0.1 per scan, p = 0.02) with a similar trend when comparing with MRI (2.8 ± 0.1 per scan, p = 0.03) in detecting lesions in any anatomic locations. CONCLUSIONS: 68Ga-DOTATATE PET/CT had a significantly higher detection rate when compared with anatomic imaging for all lesions, and comparable detection rate for pancreatic lesions in VHL patients. Hence, given the higher accuracy and lower radiation exposure associated with 68Ga-DOTATATE PET/CT, its potential role in the surveillance of VHL-associated lesions should be further studied.
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Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/diagnóstico , Compostos Organometálicos , Compostos Radiofarmacêuticos , Doença de von Hippel-Lindau/diagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estudos Prospectivos , Cintilografia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Because chronic kidney disease is an important comorbidity associated with primary hyperparathyroidism, we sought to evaluate the prevalence of chronic kidney disease and effects of parathyroidectomy on kidney function in patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism. METHODS: We performed a retrospective analysis of 112 patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism who had at least 1 operation for primary hyperparathyroidism at 2 tertiary referral centers. The preoperative and postoperative estimated glomerular filtration rates were compared. The prevalence of chronic kidney disease stage 3 or worse (estimated glomerular filtration rates less than 60 mL/min/1.73m2) in this cohort was compared to the rates in the US population reported by the Centers for Disease Control and Prevention. RESULTS: The median age at the time of parathyroidectomy was 36.5 years (range: 12-76 years). A total of 99 patients had biochemical remission. The rate of chronic kidney disease stage 3 or worse in patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism was greater than that observed in the US population for ages 20-39 and 40-59 (5% [nâ¯=â¯2/44] vs 0.39% [nâ¯=â¯18/4565], Pâ¯=â¯.015 and 10% [nâ¯=â¯4/40] vs 2.31% (nâ¯=â¯89/3848), Pâ¯=â¯.015, respectively). We observed improved estimated glomerular filtration rates in those with chronic kidney disease stage 3 or worse postoperatively (48 vs 57 mL/min/1.73m2, Pâ¯=â¯.047). A successful parathyroidectomy normalized all 24-hour urine calcium excretion. CONCLUSION: An indication for early parathyroidectomy should include estimated glomerular filtration rates less than 60mL/min/1.73m2 in patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism.
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Taxa de Filtração Glomerular , Hiperparatireoidismo Primário/cirurgia , Neoplasia Endócrina Múltipla Tipo 1/complicações , Paratireoidectomia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Adolescente , Adulto , Idoso , Cálcio/urina , Criança , Feminino , Humanos , Hiperparatireoidismo Primário/etiologia , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/cirurgia , Prevalência , Insuficiência Renal Crônica/classificação , Estudos Retrospectivos , Índice de Gravidade de Doença , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Thyroid cancer patients with radioiodine-refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. It was hypothesized that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment, and/or immune surveillance are associated with RAI-R disease. METHODS: Whole-genome genotyping data analysis was performed on 1145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, nine of whom were RAI-R. Germline-variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (n = 7), who were later determined to be AA patients of >80% African ancestry (n = 37). This led to the study focusing on germline single nucleotide polymorphisms uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of the common somatic mutations BRAFV600E, NRASQ61R, and HRASQ61R in AA patients whose primary tumor samples were available (28/55). RESULTS: TG, BRCA1, and NSMCE2 haplotypes were identified as being uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (n = 4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (n = 4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in three out of four patients with the NSMCE2 haplotype. The incidence of BRAFV600E appears lower in papillary thyroid carcinomas from AA patients of >80% African ancestry (3/14; 21%) than in AA patients of <80% African ancestry (6/9; 67%), albeit only just approaching statistical significance (p = 0.077). The tumors available from three RAI-R AA patients were negative for BRAFV600E, NRASQ61R, and HRASQ61R. CONCLUSIONS: The identification of candidate RAI-R risk haplotypes may allow early stratification of clinical manifestations of RAI-R disease followed by early intervention and personalized treatment strategies. Functional annotation of candidate RAI-R risk haplotypes may provide insights into the mechanisms underlying RAI-R disease.
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Biomarcadores Tumorais/genética , Negro ou Afro-Americano/genética , Mutação em Linhagem Germinativa , Radioisótopos do Iodo/uso terapêutico , Polimorfismo de Nucleotídeo Único , Tolerância a Radiação/genética , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/radioterapia , População Branca/genética , Adolescente , Adulto , Idoso , Proteína BRCA1/genética , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Incidência , Ligases/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Proteínas Proto-Oncogênicas B-raf/genética , Medição de Risco , Fatores de Risco , Tireoglobulina/genética , Neoplasias da Glândula Tireoide/etnologia , Neoplasias da Glândula Tireoide/patologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Histone deacetylase (HDAC) inhibition is a recent, clinically validated therapeutic strategy for cancer treatment. Small molecule HDAC inhibitors identified so far fall in to three distinct structural motifs: the zinc-binding group (ZBG), a hydrophobic linker, and a recognition cap group. Here we report the suitability of a 1,2,3-triazole ring as a surface recognition cap group-linking moiety in suberoylanilide hydroxamic acid-like (SAHA-like) HDAC inhibitors. Using "click" chemistry (Huisgen cycloaddition reaction), several triazole-linked SAHA-like hydroxamates were synthesized. Structure-activity relationship revealed that the position of the triazole moiety as well as the identity of the cap group markedly affected the in vitro HDAC inhibition and cell growth inhibitory activities of this class of compounds.
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Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Triazóis/síntese química , Triazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Humanos , Ácidos Hidroxâmicos/química , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/química , Células Tumorais CultivadasRESUMO
Context: Patients with von Hippel-Lindau (vHL) disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types. Objective: To define pancreatic neuroendocrine tumor (PNET) aggressiveness according to VHL genotype. Design: A prospective natural history study. Setting: The National Institutes of Health clinical center. Patients: Patients with vHL disease, pancreatic manifestations, and germline missense VHL gene mutations. Intervention: In-silico prediction of VHL mutation via five computational prediction models. Patients with >80% prediction for disease-causing mutations in all models [high predicted risk (HPR)] were compared with others [low predicted risk (LPR)]. Main Outcome Measure: Rates of metastases, surgical intervention, and disease progression. Results: Sixty-nine patients were included: 2 developed metastases, 12 needed surgery, and 31 had disease progression during a median follow-up of 60 months (range 13 to 84 months). Thirteen patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), the HPR group (n = 13) had a higher rate of disease progression than the LPR group (n = 43) in multivariable analysis (hazard ratio 3.6; 95% confidence interval, 1.1 to 11.9; P = 0.037). The HPR group also had a higher risk of developing metastases (P = 0.015). Among patients with codon 167 hotspot mutations (n = 26), those in the HPR group had a higher risk for disease progression (P = 0.03) than other patients. Conclusions: Computational models for predicting the impact of missense VHL gene mutations may be used as a prognostic factor in patients with PNETs in the context of vHL disease.
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Análise Mutacional de DNA/métodos , Mutação , Neoplasias Pancreáticas/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genética , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Simulação por Computador , Progressão da Doença , Feminino , Hemangioblastoma/genética , Hemangioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Feocromocitoma/genética , Feocromocitoma/patologia , Prognóstico , Estudos Prospectivos , Reprodutibilidade dos Testes , Doença de von Hippel-Lindau/patologiaRESUMO
Multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) are autosomal-dominant diseases caused by germline mutations in tumor-suppressor genes. A patient with a germline MEN1 mutation and a somatic VHL mutation in the tumor has not been reported. Herein, we report on a patient with MEN1 and a metastatic nonfunctioning pancreatic neuroendocrine tumor (PNET) with a somatic VHL mutation. This patient underwent a pancreaticoduodenectomy for a grade 2 PNET obstructing her pancreatic duct. The patient developed liver and regional lymph node metastases as well as growth of a PNET in the remnant pancreas. As part of a clinical trial for mutation-targeted therapy, a biopsy of the metastatic tumor was obtained. The clinical diagnosis, confirmed by OncoVAR-NET and molecular profiling analysis, revealed MEN1 with a germline deletion in exon 2 and a c.402 deletion C, p.Phe134LeufsX51. In addition, a somatic mutation in the VHL gene-a nonsense mutation, c.529A>T, p.Arg177Ter-was identified by hybrid capture sequencing. The mutations were confirmed by Sanger sequencing. Comparative genomic hybridization showed loss of heterozygosity in both the MEN1 and VHL genes. The patient was treated with sunitinib and had a partial response to treatment. This case illustrates not only that a second hit occurs in tumor suppressor genes but that somatic mutations are also possible in additional tumor suppressor genes. This suggests that targeted therapy selection should include analysis of somatic mutations even when the susceptibility gene is known.
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OBJECTIVE: To determine the association between neuroendocrine tumor (NET) biomarker levels and the extent of disease as assessed by 68Ga DOTATATE PET/CT imaging. DESIGN: A retrospective analysis of a prospective database of patients with NETs. METHODS: Fasting plasma chromogranin A (CgA), neuron-specific enolase (NSE), gastrin, glucagon, vasoactive intestinal peptide (VIP) and pancreatic polypeptide (PP), and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) levels were measured. Correlation between biomarkers and total 68Ga-DOTATATE-avid tumor volume (TV) was analyzed. RESULTS: The analysis included 232 patients. In patients with pancreatic NETs (n = 112), 68Ga-DOTATATE TV correlated with CgA (r = 0.6, P = 0.001, Spearman). In patients with multiple endocrine neoplasia type 1 (n = 39), 68Ga-DOTATATE TV correlated with glucagon (r = 0.5, P = 0.01) and PP levels (r = 0.5, P = 0.049). In patients with von Hippel-Lindau (n = 24), plasma VIP (r = 0.5, P = 0.02) and PP levels (r = 0.7, P < 0.001) correlated with 68Ga-DOTATATE TV. In patients with small intestine NET (SINET, n = 74), 68Ga-DOTATATE TV correlated with CgA (r = 0.5, P = 0.02) and 5-HIAA levels (r = 0.7, P < 0.001), with 5-HIAA ≥8.1 mg/24 h associated with metastatic disease with high positive (81.8%) and negative (85.7%) predictive values (P = 0.001). 68Ga-DOTATATE TV in patients with NET of unknown primary (n = 16) and those with NET of other primary location (n = 30) correlated with 5-HIAA levels (r = 0.8, P = 0.002 and r = 0.7, P = 0.02 respectively). CONCLUSIONS: Our data supports the use of specific NET biomarkers based on the site of the primary NET and the presence of hereditary syndrome-associated NET. High urinary 5-HIAA levels indicate the presence of metastatic disease in patients with SINET.