RESUMO
BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.
Assuntos
Antineoplásicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Everolimo/uso terapêutico , Metformina/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Somatostatina/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Diabetes Mellitus Tipo 2/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Itália/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND/AIMS: Gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) are defined as neuroendocrine neoplasms (NENs) with a Ki-67 index >20% according to the 2010 WHO classification. Some reports suggest that this category is heterogeneous. We retrospectively studied a series of 136 patients affected by grade 3 GEP-NECs with the aim to clarify the prognostic role of tumor morphological differentiation, proliferation, defect in mismatch repair proteins (MMRd), CD117 expression, and site of origin. The primary endpoint was the correlation between these parameters and the overall survival (OS). METHODS: Univariate and multivariable Cox proportional hazards regression analyses were used to assess the prognostic significance of various clinical and histopathologic features. RESULTS: With a median follow-up of 81 months, the median OS was 12.9 months. At multivariate analysis, morphological differentiation, Ki-67 index, MMRd, stage, and CD117 expression were independent prognostic markers in NECs. Three different prognostic categories of NECs were identified according to the degree of morphologic differentiation (well vs. poorly differentiated) and Ki-67 index (<55% vs. ≥55%). On this basis, median OS was 43.6 months in well-differentiated neoplasms with a Ki-67 index 20-55% (named type A), 24.5 months in poorly differentiated neoplasms with a Ki-67 index 20-55% (type B), and 5.3 months (p < 0.0001) in poorly differentiated neoplasms with a Ki-67 index ≥55% (type C). CONCLUSIONS: The present study suggests that GEP-NECs represent a heterogeneous group of neoplasms which can be better classified in different prognostic categories using both tumor morphology and Ki-67 index.
Assuntos
Carcinoma Neuroendócrino/patologia , Diferenciação Celular , Proliferação de Células , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/mortalidade , Feminino , Humanos , Canais Iônicos/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/mortalidade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Proteínas Proto-Oncogênicas c-kit/metabolismo , Análise de Regressão , Análise de SobrevidaRESUMO
Metformin (MET) has recently emerged as a potentially active agent in cancer prevention and treatment. MET is thought to exert its antitumor effects either via modification of systemic metabolism or through cell-autonomous effects (e.g., activation of AMPK and inhibition of the mTOR pathway). Preliminary findings of the PRIME-NET study suggest that the addition of MET to treatment with everolimus (EVE) and/or somatostatin analogs (SSAs) can provide clinical benefit in diabetic neuroendocrine tumor (NET) patients. In light of this and other retrospective evidence of MET's anticancer activity in NETs, prospective studies are needed. A pilot, single-arm, open-label, prospective study (MetNET-2 trial, NCT02823691) was designed to evaluate the safety of MET in combination with lanreotide in well-differentiated gastrointestinal (WD GI) and lung NETs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos Clínicos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Metformina/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Projetos de Pesquisa , Somatostatina/administração & dosagem , Somatostatina/análogos & derivadosRESUMO
A bidirectional relationship seems to exist between diabetes mellitus and development of pancreatic tumors. Metformin, the most widely used drug in the treatment of Type 2 diabetes mellitus, has recently emerged as a potentially active agent in cancer chemoprevention and treatment. In this article, we discuss the potential correlation between glycemic status, administration of antiglycemic treatments, such as metformin or insulin, and prognosis of pancreatic neuroendocrine tumors patients treated with everolimus and octreotide, on the basis of existing evidence and our experience.
Assuntos
Antineoplásicos/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Comorbidade , Diabetes Mellitus/epidemiologia , Everolimo/uso terapêutico , Humanos , Metformina/uso terapêutico , Tumores Neuroendócrinos/epidemiologia , Octreotida/uso terapêutico , Neoplasias Pancreáticas/epidemiologiaRESUMO
Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors. The present review discusses current therapeutic strategies for the treatment of gastro-entero-pancreatic NEN. Several systemic options are currently available, including medical systemic chemotherapy, biological drugs, somatostatin analogs and peptide receptor radionuclide therapy. The carcinoid syndrome can be adequately controlled with somatostatin analogs; chemotherapy has shown positive outcomes in poor prognosis patients, and peptide receptor radionuclide therapy is a promising treatment based on the use of radioisotopes for advanced disease expressing somatostatin receptors. Targeted therapies, such as multikinase inhibitors and monoclonal antibodies are also recommended or under evaluation for the treatment of advanced NENs, but some critical issues in clinical practice remain unresolved. Depending upon the development of the disease, a multimodal approach is recommended. The treatment strategy for metastatic patients should be planned by a multidisciplinary team in order to define the optimal sequence of treatments.
Assuntos
Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Receptores de Peptídeos/uso terapêutico , Somatostatina/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Radioisótopos/uso terapêutico , Receptores de Somatostatina/biossíntese , Receptores de Somatostatina/genética , Somatostatina/análogos & derivadosRESUMO
This case report highlights a patient with atrial fibrillation, severe mitral stenosis, and left atrial dilatation who developed a large thrombus, despite being on anticoagulant therapy. The complexity of thrombus formation in patients with multiple risk factors is described, emphasising the need for regular echocardiographic assessments to detect and monitor thrombi, even in patients undergoing anticoagulant treatment. The interplay between atrial fibrillation, mitral stenosis, and left atrial dilatation contributes to thrombus formation, requiring a multidisciplinary approach to the management of these patients. Further research is needed to improve our understanding of the optimal treatment strategies for such cases. Timely identification and intervention are critical to mitigate the risk of thromboembolic complications in these high-risk patients.
RESUMO
AIMS: The primary objectives were to investigate the incidence rate (IR) of type 1 diabetes (T1D) in Sardinian children aged 0-14 years in 2019-2022 and to examine the temporal trend from 1989-1999. METHODS: Data from new-onset T1D patients aged 0-14 years who were residents of Sardinia were collected from all pediatric diabetology clinics. The overall, sex- and age specific (groups 0-4, 5-9, and 10-14 years), and calendar year IRs were calculated. The standardized IR (SIR) was also calculated using the direct method. Poisson regression was used to estimate the temporal trend in the SIRs from 1989-1999 to 2019-2022. RESULTS: In 2019-2022, 512 patients aged 0-14 years were diagnosed with T1D in Sardinia. The overall IR was 73.9 per 100,000 person-years (95 % CI 67.6-80.0). Since 1989, the SIR has increased by 2.3 % per year (CI 1.7-2.8, p < 0.0001). The frequency of ketoacidosis at onset was 26.4 %, with no significant differences among the four years. CONCLUSIONS: The incidence of T1D in Sardinia, unlike in other countries such as Finland, has almost doubled in the last 20 years, and currently, it appears to be the highest in the world.
Assuntos
Diabetes Mellitus Tipo 1 , Humanos , Diabetes Mellitus Tipo 1/epidemiologia , Criança , Itália/epidemiologia , Lactente , Adolescente , Pré-Escolar , Incidência , Masculino , Feminino , Recém-NascidoRESUMO
Neuroendocrine tumors (NETs) are a heterogeneous class of diseases characterized by challenging management. Preclinical evidence shows that the PI3K/AKT/mTOR signaling pathway plays a central role in the pathogenesis and progression of NETs. Everolimus is a direct inhibitor of this pathway, and therefore this molecule appears to be a well-grounded strategy for the treatment of NETs, capable of changing clinical practice. The efficacy and safety of everolimus was demonstrated in the RADIANT trials. In this work, we comment on the results of the RADIANT trials, and other recent key evidence from fully published clinical trials on everolimus, and we discuss the current role of everolimus in the treatment of NETs.
RESUMO
PURPOSE: Abnormal expression of succinate dehydrogenase, (SDH), in particular of the B subunit (SDHB), is implicated in the pathogenesis of neuroendocrine tumors. This study evaluates the distribution of SDHB in WHO grading G1 and G2 intestinal, well-differentiated neuroendocrine tumors and corresponding lymph node or liver metastases. METHODS: We collected ileal well-differentiated neuroendocrine tumors specimens from consecutive patients with prior primary resection and distant synchronous or metachronous liver metastases. We obtained 195 specimens from primary tumors (n = 106) and metastases (n = 89). The expression (E) of SDHB and the immunostaining intensity (I) were evaluated semiquantitatively and combined into a single score. SDHB score was evaluated in primitive tumor and metastatic specimens. RESULTS: SDHB was found in all tumor cells. Mean SDHB expression was 72.7 % ± 17.1 % in primitive specimens and 27.9 % ± 24.6 % in metastatic specimens (p < 0.0001). SDH intensity was higher in primitive specimens (p < 0.0001). SDHB score was 9-12 in 96 specimens of the primitive group and 2 metastatic specimens (p < 0.0001). None of the analyzed parameters was predictive of overall survival in the primitive subset. In the metastatic subset, loss of SDHB expression, intensity, and score were prognostic factors for survival. Lower expression and intensity of SDHB in metastatic lesions were associated with longer overall survival. When combining SDHB score and Ki-67 % in the metastatic subset, a lower SDHB score was associated with prolonged overall survival, independently from Ki-67 %. CONCLUSIONS: SDHB score was different in primitive and metastatic specimens. The combination of SDHB score and Ki-67 % was a stronger predictor of overall survival than Ki-67 % alone. This stratification might help predict survival.
Assuntos
Regulação para Baixo , Neoplasias do Íleo/metabolismo , Neoplasias Hepáticas/secundário , Fígado/metabolismo , Proteínas de Neoplasias/metabolismo , Tumores Neuroendócrinos/metabolismo , Succinato Desidrogenase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular , Feminino , Humanos , Neoplasias do Íleo/diagnóstico , Neoplasias do Íleo/mortalidade , Neoplasias do Íleo/patologia , Íleo/metabolismo , Íleo/patologia , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/secundário , Prognóstico , Análise de Sobrevida , Adulto JovemRESUMO
The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. One hundred and sixteen patients (62 males and 54 females, median age 55 years) with advanced PNETs were treated with everolimus for ≥3 months. According to a Receiver operating characteristics (ROC) analysis, patients were stratified into two groups, with CD ≤ 3000 mg (Group A; n = 68) and CD > 3000 mg (Group B; n = 48). The response rate and toxicity were comparable in the two groups. However, patients in group A experienced more dose modifications than patients in group B. Median OS was 24 months in Group A while in Group B it was not reached (HR: 26.9; 95% CI: 11.0-76.7; P < 0.0001). Patients who maintained a DI higher than 9 mg/day experienced a significantly longer OS and experienced a trend to higher response rate. Overall, our study results showed that both CD and DI of everolimus play a prognostic role for patients with advanced PNETs treated with everolimus. This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.
Assuntos
Antineoplásicos/administração & dosagem , Everolimo/administração & dosagem , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/mortalidade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Curva ROC , Resultado do Tratamento , Adulto JovemRESUMO
In the last five years, everolimus has demonstrated efficacy in the treatment of neuroendocrine tumors (NETs) of different origins; its efficacy and safety were explored in the RADIANT trials, the last of which (RADIANT-4) has been recently published (December 2015). Overall, evidence collected from the RADIANT studies holds promise to change clinical practice for the treatment of NETs.In this paper, we comment on the role of everolimus within the therapeutic algorithm for NETs treatment, based on the systematic analysis of the RADIANT trials and our experience.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Everolimo/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Everolimo/administração & dosagem , Humanos , Octreotida/administração & dosagem , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de SobrevidaRESUMO
INTRODUCTION: Small intestinal (SI) neuroendocrine tumors (NETs) are relatively rare tumors. Due to the lack of symptom or specific symptoms, SI-NETs are often diagnosed at an advanced stage, making therapy challenging. The management of patients with advanced stage SI-NETS requires a multidisciplinary approach that combines surgical and medical treatment including novel targeted molecular therapies. AREAS COVERED: This article summarizes current strategies for the medical treatment of SI-NETS. Expert commentary: The treatment plan of advanced-stage SI-NETs should be tailored in a case-by-case manner with the adoption of a multidisciplinary approach that combines different treatment options, including biological targeted therapies. In particular, we believe that the identification of the optimal treatment sequence(s), correct treatment timing and the selection of patients eligible to different treatments need specific investigation in controlled clinical trials.
Assuntos
Neoplasias Intestinais/terapia , Intestino Delgado/patologia , Tumores Neuroendócrinos/terapia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Terapia Combinada , Humanos , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/patologia , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Seleção de PacientesRESUMO
We report the case of a 38-year-old patient who was diagnosed with a cerebellar well-differentiated neuroendocrine tumor (WDNET) in 2009. At first glance, we believed that it was a metastasis from an unrecognized WDNET arising outside the cerebellum. However, despite a prolonged follow-up of 6 years, an extracranial WDNET has never been found. During this time, the tumor recurred locally twice, and the patient was treated with surgery and radiotherapy. At the moment, he enjoys good general conditions and his tumor is under control. Due to the histopathological characteristics and clinical behavior of the tumor, we believe that this is the first report to date of a primary cerebellar WDNET.
RESUMO
Abnormal PI3K-AKT-mTOR pathway signalling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor-1, have been implicated in the proliferation of pancreatic neuroendocrine tumor (pNET) cells. Everolimus, an mTOR inhibitor, has shown antitumor benefit in pNETs alone and in combination with octreotide LAR in RADIANT-1 and RADIANT-3 studies. Although everolimus-based phase II/III trials have improved progression-free survival for pNET, its use has not impacted on prolonging overall survival. Metformin has recently shown some anti-cancer activity in both in vitro and in vivo studies by its indirect properties to decrease insulin and insulin-like growth factor-1 (IGF-1) levels and by its antitumour effect to promote AMPK activation and consequently inhibition to TSC1-2/mTOR complex. In light of even more retrospective evidence of metformin's anticancer activity, a prospective evaluation is required to either confirm or discard these preliminary findings. With the aim to evaluate the antiproliferative effect of metformin in combination with everolimus and octreotide LAR in pancreatic well-differentiated neuroendocrine tumor patients, a single arm, prospective, single center phase II study was designed (MetNET-1 trial, NCT 02294006). Forty-three patients are expected to be evaluated. The study is ongoing, and recruitment is estimated to be completed in August 2016. The results will be anticipated in 2017.