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1.
J Pharmacol Exp Ther ; 373(1): 122-134, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32102919

RESUMO

The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT3 receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g., severe constipation). The present study investigates the potential of a novel 5-HT3 receptor partial agonist, CSTI-300, to treat patients with IBS-d and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The in vitro and in vivo preclinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. CSTI-300 displayed selective high affinity for the human and rat 5-HT3 receptor (Ki approximately 2.0 nM) and acted as a partial agonist (approximately 30%-50% intrinsic efficacy) in vitro. In an in vivo model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, oral administration of CSTI-300 to dogs that achieved plasma levels of the drug exceeding the Ki value for the 5-HT3 receptor failed to either evoke emesis or alter the state of feces. Pharmacokinetics for CSTI-300 in rat and dog identified high levels of oral availability with t 1/2 range of 1.6-4.4 hours. The preclinical pharmacology of the lead candidate drug, CSTI-300, supports the potential of this novel drug to offer symptomatic relief to patients with irritable bowel syndrome and carcinoid syndrome with a rationale for a reduced "on-target" side-effect profile relative to 5-HT3 receptor antagonists, such as alosetron. SIGNIFICANCE STATEMENT: There is a lack of effective current treatment for diarrhea-predominant irritable bowel syndrome and carcinoid syndrome, and in both conditions, overactivity of the 5-hydroxytryptamine (5-HT) 5-HT3 receptor is thought to be implicated in the pathophysiology. Because 5-HT3 receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT3 receptor partial agonist will alleviate some symptoms associated with these conditions yet, without fully inhibiting the receptor, predict a less pronounced side-effect profile associated with this therapeutic strategy.


Assuntos
Agonismo Parcial de Drogas , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Agonistas do Receptor 5-HT3 de Serotonina/química , Agonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Animais , Cães , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Síndrome do Carcinoide Maligno/fisiopatologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
2.
World J Gastroenterol ; 25(47): 6857-6865, 2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31885426

RESUMO

BACKGROUND: The burden of carcinoid syndrome (CS) among patients with neuroendocrine tumors is substantial and has been shown to result in increased healthcare resource use and costs. The incremental burden of CS diarrhea (CSD) is less well understood, particularly among working age adults who make up a large proportion of the population of patients with CS. AIM: To estimate the direct medical costs of CSD to a self-insured employer in the United States. METHODS: CS patients with and without CSD were identified in the IBM® MarketScan® Database, including the Medicare Supplemental Coordination of Benefits database. Eligible patients had ≥ 1 medical claim for CS with continuous health plan enrollment for ≥ 12 mo prior to their first CS diagnosis and for ≥ 30 d after, no claims for acromegaly, and no clinical trial participation during the study period (2014-2016). Baseline demographic and clinical characteristics, including comorbidities and treatment, were analyzed using descriptive statistics. Measures of healthcare resource use and costs were compared between patients with and without CSD, including Emergency Department (ED) visits, hospital admissions and length of stay, physician office visits, outpatient services, and prescription claims, using univariate and multivariate analyses to evaluate associations of CSD with healthcare resource use and costs, controlling for baseline characteristics. RESULTS: Overall, 6855 patients with CS were identified of which 4,043 were eligible for the analysis (1352 with CSD, 2691 with CS only). Baseline demographic and clinical characteristics were similar between groups with the exception of age, underlying tumor type, and health insurance plan. Patients with CSD were older, had more comorbidities, and received more somatostatin analog therapy at baseline. Patients with CSD required greater use of healthcare resources and incurred higher costs than their peers without CSD, including hospitalizations (44% vs 25%) and ED visits (55% vs 31%). The total adjusted annual healthcare costs per patient were 50% higher (+ $23865) among those with CSD, driven by outpatient services (+ 56%), prescriptions (+ 48%), ED visits (+ 26%), physician office visits (+ 21%), and hospital admissions (+ 11%). CONCLUSION: The economic burden of CSD is greater than that of CS alone among insured working age adults in the United States, which may benefit from timely diagnosis and management.


Assuntos
Efeitos Psicossociais da Doença , Diarreia/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Síndrome do Carcinoide Maligno/economia , Adulto , Idoso , Diarreia/epidemiologia , Diarreia/etiologia , Diarreia/terapia , Feminino , Humanos , Masculino , Síndrome do Carcinoide Maligno/complicações , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Prevalência , Estudos Retrospectivos , Estados Unidos/epidemiologia
3.
Oncology ; 96(6): 273-289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31018209

RESUMO

BACKGROUND: Carcinoid syndrome symptoms significantly reduce quality of life in patients with neuroendocrine tumors. Evidence supporting the use of somatostatin analogues in carcinoid syndrome symptom control dates back 30 years. The introduction of new treatment options for carcinoid syndrome, such as telotristat ethyl in 2017, highlights the need for a review of high-level evidence of new and established systemic treatments. OBJECTIVE: To examine the efficacy and safety of systemic treatment options for patients with carcinoid syndrome. METHOD: A systematic review of English language articles was conducted using PubMed, EMBASE, and the Cochrane Controlled Trials Register using the search terms carcinoid syndrome, clinical trial, clinical study, and prospective study. Additional studies were identified by searching abstracts from oncology or neuroendocrine tumor congresses during the previous year. Prospective, interventional, phase II or III clinical trials or pivotal trials leading to drug approval were included. Studies were required to have >85% of patients with carcinoid syndrome; secondary publications were excluded. RESULTS: The search identified 233 unique records, of which 12 trials met the criteria for inclusion. Interventions assessed in these trials included short-acting and long-acting octreotide, lanreotide prolonged-release and autogel/depot, short-acting and long-acting pasireotide, telotristat ethyl, everolimus, and peptide receptor radionuclide therapy. Somatostatin analogues provided substantial symptom relief for patients with carcinoid syndrome. For refractory symptoms, an increased dose of somatostatin analogue or addition of telotristat ethyl were valuable options. Interventions were generally well tolerated, with few serious treatment-related adverse events. CONCLUSIONS: By critically evaluating high-level evidence in a rigorous manner, this review highlights the general lack of consensus regarding what defines symptom control in studies of carcinoid syndrome and the need for standardized treatment guidelines for this disease. More prospective trials of treatments for carcinoid syndrome are warranted to assist oncologists with optimizing treatment selection and sequencing in this patient population.


Assuntos
Antineoplásicos/uso terapêutico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/uso terapêutico , Somatostatina/análogos & derivados , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Fenilalanina/uso terapêutico , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento
4.
BMC Cancer ; 19(1): 274, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30922252

RESUMO

BACKGROUND: There is limited information on changes over time in carcinoid syndrome (CS) symptoms and quality of life (QoL). This study assessed change in CS symptoms and QoL in patients treated with somatostatin analogs (SSAs) using the Functional Assessment of Cancer Therapy-General (FACT-G) and Patient-Reported Outcomes Measurement Information System (PROMIS)-29 instruments. METHODS: Patients ≥18 years old with CS symptoms and treated with SSA or non-SSA agents in the United States were recruited through a patient advocacy group to complete a two-part, anonymous online survey. Time point (T) 1 survey was fielded from July-October 2016, and T2 survey followed 6 months later. Clinical characteristics and SSA treatment duration were assessed at T1. FACT-G and PROMIS-29 QoL surveys were administered and CS symptoms were assessed at T1 and T2; proportions of patients not experiencing symptoms were compared by McNemar's test. Healthcare resource utilization (HRU) was assessed for the T1-T2 interval, and mean difference in QoL score from T1 to T2 by SSA duration was calculated. RESULTS: Of 117 participants at T1, 89 (76%) completed the T2 survey and served as the study sample; 11 (13%) were treated with SSAs for > 0-2 years, 37 (42%) for > 2-5 years, and 39 (45%) for > 5 years. A higher proportion of patients at T2 vs. T1 reported the following symptoms as not applicable: diarrhea (16% vs. 7%, p < 0.05), flushing (28% vs. 18%, p < 0.05), wheezing (78% vs 66%, p = 0.008). Most patients (89%) had a physical exam and a mean of 7.2 healthcare provider visits between T1 and T2. Patients treated with SSAs for ≤2 years had a mean positive change of 3.7 in their FACT-G total score between surveys, and 6.0 in an additional set of CS-specific questions. Patients receiving SSAs for > 2 years did not appear to associate with a clinically meaningful improvement in QoL score as assessed by FACT-G between T1 and T2; patients also had no clinically meaningful improvement as assessed by PROMIS-29. CONCLUSIONS: There may be clinically important improvement in QoL as measured by FACT-G in patients in earlier years of receiving SSA, which may not appear in later years of SSA treatment.


Assuntos
Recursos em Saúde/estatística & dados numéricos , Antagonistas de Hormônios/uso terapêutico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Qualidade de Vida/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Síndrome do Carcinoide Maligno/psicologia , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Medidas de Resultados Relatados pelo Paciente , Somatostatina/antagonistas & inibidores , Adulto Jovem
5.
Dig Dis Sci ; 64(8): 2140-2146, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30788684

RESUMO

BACKGROUND: Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a group of cytoplasmic sensors that survey danger signals released by invading pathogens or damaged tissue. Mutations in the NLRP subfamily affect pro-inflammatory mediators and cause nonspecific systemic symptoms. AIMS: We sought to identify a potential genetic etiology of an inflammatory syndrome in a patient that presented with an atypical multisystem illness with carcinoid syndrome as well as atopic and autoimmune features. METHODS: Exome sequencing was performed using the Agilent SureSelect Clinical Research Exome XT kit on an Illumina HiSeq 2500. Longitudinal monitoring of pro-inflammatory cytokines was performed. RESULTS: We identified a novel variant (heterozygous c.536C > T [p.Thr179Ile]) in the NLRP12 gene in a 63-year-old woman and her daughter, who presented with an unusual clinical syndrome that differs from autoinflammatory disorders previously reported in association with the NLRP subfamily gene mutations. This NLRP12 variant was predicted to be pathogenic by functional analysis through Hidden Markov Models (FATHMM). Both the mother and the daughter had episodes of abdominal pain, fever, diarrhea, skin rash, hypothyroidism, and elevated urine 5-hydroxyindoleacetic acid (5-HIAA) levels. The proband also had elevated serum levels of pro-inflammatory (IL-1ß, IL-6, IL-12, and TNF-α), Th1 (IL-2, IFN-γ), and Th2 (IL-4, IL-5, IL-13) cytokines, but not of Th17 (IL-17) and IL-10. CONCLUSION: This report adds to the expanding spectrum of clinical manifestations attributed to the NLRP subfamily gene variants and suggests a role of NLRP12 in the regulation of multiple cytokines.


Assuntos
Doenças Autoimunes/genética , Citocinas/sangue , Mediadores da Inflamação/sangue , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndrome do Carcinoide Maligno/genética , Mutação , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Síndrome do Carcinoide Maligno/sangue , Síndrome do Carcinoide Maligno/diagnóstico , Pessoa de Meia-Idade , Fenótipo , Regulação para Cima
6.
Eur J Cancer Care (Engl) ; 28(2): e12983, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30652364

RESUMO

The objective was to estimate the cost-of-illness of grades 1 and 2 metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in Sweden in 2013 in a population-based study including all patients diagnosed between 2005 and 2013. Data were obtained from national registers, and patients who utilised healthcare resources due to metastatic GEP-NETs in 2013 were included. The study included 478 patients (mean age 64 [SD=11] years, 51% men). The majority (80%) had small intestinal NET, 10% had pancreatic NET, and 41% had carcinoid syndrome. The total cost-of-illness was €12,189,000 in 2013, of which direct costs constituted 77% and costs from production loss constituted 22%. The largest contributor to the direct medical costs was prescription drugs (54%; primarily somatostatin analogues [91% of the total drug cost]). Production loss due to sickness absence constituted 52% of the total costs of production loss. The total annual cost per patient was €25,500. By patient group, the cost was €24,800 (95% CI €21,600-€28,100) for patients with small intestinal NET, €37,300 (95% CI €23,300-€51,300) for those with pancreatic NET and €18,600 (95% CI €12,600-€24,500) for patients with other GEP-NETs. To conclude, the total annual cost of grades 1 and 2 metastatic GEP-NETs in Sweden was €25,500 per patient and year.


Assuntos
Efeitos Psicossociais da Doença , Neoplasias Intestinais/economia , Tumores Neuroendócrinos/economia , Neoplasias Pancreáticas/economia , Neoplasias Gástricas/economia , Feminino , Custos de Cuidados de Saúde , Gastos em Saúde/estatística & dados numéricos , Humanos , Neoplasias Intestinais/epidemiologia , Neoplasias Intestinais/terapia , Masculino , Síndrome do Carcinoide Maligno/economia , Síndrome do Carcinoide Maligno/epidemiologia , Síndrome do Carcinoide Maligno/terapia , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/terapia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Sistema de Registros , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/terapia , Suécia/epidemiologia
7.
Surgery ; 165(3): 657-663, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30377003

RESUMO

BACKGROUND: The incidence, clinical characteristics, and long-term outcomes of patients with gastroenteropancreatic neuroendrocrine tumors and carcinoid syndrome undergoing operative resection have not been well characterized. METHODS: Patients undergoing resection of primary or metastatic gastroenteropancreatic neuroendrocrine tumors between 2000 and 2016 were identified from an 8-institution collaborative database. Clinicopathologic and postoperative characteristics as well as overall survival and disease-free survival were compared among patients with and without carcinoid syndrome. RESULTS: Among 2,182 patients who underwent resection, 139 (6.4%) had preoperative carcinoid syndrome. Patients with carcinoid syndrome were more likely to have midgut primary tumors (44.6% vs 21.4%, P < .001), lymph node metastasis (63.4% vs 44.3%, P < .001), and metastatic disease (62.8% vs 26.7%, P < .001). There was no difference in tumor differentiation, grade, or Ki67 status. Perioperative carcinoid crisis was rare (1.6% vs 0%, P < .01), and the presence of preoperative carcinoid syndrome was not associated with postoperative morbidity (38.8% vs 45.5%, P = .129). Substantial symptom improvement was reported in 59.5% of patients who underwent curative-intent resection, but occurred in only 22.7% who underwent debulking. Despite an association on univariate analysis (P = .04), carcinoid syndrome was not independently associated with disease-free survival after controlling for confounding factors (hazard ratio 0.97, 95% confidence interval 0.64-1.45). Preoperative carcinoid syndrome was not associated with overall survival on univariate or multivariate analysis. CONCLUSION: Among patients undergoing operative resection of gastroenteropancreatic neuroendrocrine tumors, the prevalence of preoperative carcinoid syndrome was low. Although operative intervention with resection or especially debulking in patients with carcinoid syndrome was disappointing and often failed to improve symptoms, after controlling for markers of tumor burden, carcinoid syndrome was not independently associated with worse disease-free survival or overall survival.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/métodos , Neoplasias Intestinais/complicações , Síndrome do Carcinoide Maligno/etiologia , Tumores Neuroendócrinos/complicações , Neoplasias Pancreáticas/complicações , Neoplasias Gástricas/complicações , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Incidência , Neoplasias Intestinais/secundário , Neoplasias Intestinais/cirurgia , Metástase Linfática , Masculino , Síndrome do Carcinoide Maligno/epidemiologia , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/secundário , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/secundário , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/secundário , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia
8.
Oncologist ; 24(2): 255-258, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30171068

RESUMO

OBJECTIVES: Somatostatin analogs (SSAs) are standard for symptomatic patients with neuroendocrine tumors (NETs). However, most patients experience tachyphylaxis, and limited options exist for this so-called "refractory carcinoid syndrome." Recently, 5-HT3 antagonist ondansetron has been associated with reduction of bowel movement in a small series. The aim of this analysis was to assess effectiveness of ondansetron for symptomatic treatment of carcinoid syndrome. DESIGN AND PATIENTS: We have analyzed patients given ondansetron as bridging therapy for refractory carcinoid syndrome. The dose was 2 × 8 mg for 5 days, followed by reduction to 1 × 8 mg in case of benefit. RESULTS: A total of 14 patients with small bowel NETs metastatic to the liver were identified. All patients had been treated with SSAs for a median time of 18 months before aggravation of diarrhea. One patient had to be excluded because of an underlying infectious cause of diarrhea. The median number of daily bowel movements was 7 (range, 5-13) before initiation of therapy. At this time, seven patients had stable disease, whereas six patients showed radiological progression with symptomatic breakthrough. All 13 patients were scheduled for salvage therapy. Remarkably, in 85% (11/13) ondansetron resulted in a clinically relevant decrease of bowel movements to a median of 3 (1-4). The median time of ondansetron intake was 29 days (7 days to 29 months). In four patients, diarrhea recurred after initial improvement at an interval of 22-43 days, whereas the remaining seven had an ongoing benefit, including two long-term responders who refused further therapy because of pronounced decrease of symptoms (ondansetron for 14+ and 29+ months). CONCLUSION: Ondansetron offers symptomatic relief in the majority of patients. Although there was no influence on 5-HIAA levels, evidence from two patients suggests prolonged benefit. IMPLICATIONS FOR PRACTICE: Somatostatin analogs are standard treatment in patients with carcinoid syndrome and have an overall response rate of up to 50%. This symptomatic benefit, however, is lost in many patients because of the development of tachyphylaxis or tumor progression. Patients with this "refractory carcinoid syndrome" pose a therapeutic challenge and are sometimes faced with a detrimental effect on quality of life. In this article, the authors suggest the 5-HT3 receptor antagonist ondansetron as potential symptomatic therapy for patients with refractory diarrhea due to carcinoid syndrome. Although the number of patients in this retrospective series is limited, treatment was easily applicable, feasible, and safe and resulted in an ongoing symptomatic benefit in 85% of patients, including two long-term responders.


Assuntos
Antidiarreicos/uso terapêutico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Ondansetron/uso terapêutico , Antagonistas da Serotonina/uso terapêutico , Somatostatina/análogos & derivados , Administração Oral , Idoso , Antidiarreicos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ondansetron/farmacologia , Estudos Retrospectivos , Antagonistas da Serotonina/farmacologia
9.
Surgery ; 165(1): 158-165, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30415870

RESUMO

BACKGROUND: Sudden massive release of serotonin, histamine, kallikrein, and bradykinin is postulated to cause an intraoperative carcinoid crisis. The exact roles of each of these possible agents, however, remain unknown. Optimal treatment will require an improved understanding of the pathophysiology of the carcinoid crisis. METHODS: Carcinoid patients with liver metastases undergoing elective abdominal operations were studied prospectively, using intraoperative, transesophageal echocardiography, pulmonary artery catheterization, and intraoperative blood collection. Serotonin, histamine, kallikrein, and bradykinin levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: Of 46 patients studied, 16 had intraoperative hypotensive crises. Preincision serotonin levels were greater in patients who had crises (1,064 vs 453 ng/mL, P = .0064). Preincision hormone profiles were otherwise diverse. Cardiac function on transesophageal echocardiography during the crisis was normal, but intracardiac hypovolemia was observed consistently. Pulmonary artery pressure decreased during crises (P = .025). Linear regression of preincision serotonin levels showed a positive relationship with mid-crisis cardiac index (r = 0.73, P = .017) and a negative relationship with systemic vascular resistance (r=-0.61, P = .015). There were no statistically significant increases of serotonin, histamine, kallikrein, or bradykinin levels during the crises. CONCLUSION: The pathophysiology of carcinoid crisis appears consistent with distributive shock. Hormonal secretion from carcinoid tumors varies widely, but increased preincision serotonin levels correlate with crises and with hemodynamic parameters during the crises. Statistically significant increases of serotonin, histamine, kallikrein, or bradykinin during the crises were not observed.


Assuntos
Hipotensão/fisiopatologia , Hipovolemia/fisiopatologia , Síndrome do Carcinoide Maligno/fisiopatologia , Artéria Pulmonar/fisiopatologia , Serotonina/sangue , Bradicinina/sangue , Tumor Carcinoide/fisiopatologia , Tumor Carcinoide/cirurgia , Ecocardiografia Transesofagiana , Feminino , Histamina/sangue , Humanos , Neoplasias Intestinais/fisiopatologia , Neoplasias Intestinais/cirurgia , Complicações Intraoperatórias , Calicreínas/sangue , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/cirurgia , Masculino , Síndrome do Carcinoide Maligno/sangue , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Prospectivos
10.
Neuro Endocrinol Lett ; 40(7-8): 315-318, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32304367

RESUMO

BACKGROUND: The assessment of hormonal function of neuroendocrine neoplasm (NEN) is an important stage in the diagnosis and monitoring of these diseases treatment. Objective of this study was to analyze the results of urinary excretion of 5-hydroxyindoloacetic acid (5-HIAA) in patients with carcinoid syndrome treated with somatostatin analogues, depending on the histologic maturity, degree of liver involvement and stage of the disease. METHODS: The final group comprised of 41 patients. All patients were subject to surgical removal of the primary site. Presence of hepatic metastases was determined in all patients. All patients were treated with somatostatin analogues. The 5-HIAA urine excretion was determined using the ELISA immunoenzymatic method. RESULTS: The mean excretion of 5-HIAA in patients with histological maturity grade G1 was 45.64 mg/24h, while in the group G2 the mean excretion was 108.41 mg/24h and was higher than in the group G1 (p=0.003). In the analysis of 5-HIAA value depending on the degree of liver involvement, the mean value of 5-HIAA excretion in patients with 10% liver involvement was 38.99 mg/24h, whereas in patients with 25% liver involvement this value was considerably higher and amounted 131.00 mg/24h (p< 0.001). In patients with disease progression the mean excretion was 117.37 mg/24h compared to the group of patients with stabilization of the disease, where the mean value was lower and amounted to 39.39 mg/24h (p<0.001). CONCLUSION: Assessment of 5-HIAA excretion in patients with carcinoid syndrome is of considerable significance in the diagnostics and monitoring of the treatment.


Assuntos
Ácido Hidroxi-Indolacético/urina , Neoplasias Intestinais/urina , Intestino Delgado , Neoplasias Hepáticas/urina , Síndrome do Carcinoide Maligno/urina , Tumores Neuroendócrinos/urina , Idoso , Antineoplásicos Hormonais/uso terapêutico , Feminino , Humanos , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Síndrome do Carcinoide Maligno/tratamento farmacológico , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico
11.
Scand J Gastroenterol ; 53(12): 1509-1518, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30449217

RESUMO

OBJECTIVES: To quantify healthcare resource use (HRU) and costs in relation to carcinoid syndrome (CS) and carcinoid heart disease (CHD) in a real-world setting, and to provide perspective on treatment patterns. MATERIALS AND METHODS: Patient data and HRU were collected retrospectively from three Swedish healthcare registers. Adult patients diagnosed with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) grade 1 or 2 and CS who purchased somatostatin analogs (SSAs), and experienced controlled (defined by SSAs use) and uncontrolled (defined by SSAs dose escalation) CS for ≥8 months during the study period were included. Patients diagnosed with CHD from the date of the GEP-NET diagnosis were included in the CHD study group. RESULTS: Overall, total HRU cost increased with uncontrolled CS and CHD. Total resource cost was 15,500€/patient during controlled CS (8 months), rising to 21,700€/patient during uncontrolled CS (8 months), representing an increase of ∼40% (6200€/patient). Costs/patient were driven mainly by SSA use, tumor-related medical interventions and examinations. The total mean cost/year of disease was 1100€/patient without CHD, compared to 4600€/patient with CHD, a difference of 3500€/patient. Excluding SSA cost burden, the main drivers of increased cost in CHD patients were surgical interventions and echocardiography. CONCLUSIONS: This study provides a comprehensive overview of the treatment patterns and burden of uncontrolled CS symptoms and CHD using Swedish national register data. Increases in medical interventions and examinations HRU and increased SSA use suggest that SSA dose escalation alone may not effectively control the symptoms associated with uncontrolled CS, highlighting an unmet treatment need in this patient group.


Assuntos
Doença Cardíaca Carcinoide/economia , Doença Cardíaca Carcinoide/terapia , Neoplasias Intestinais/complicações , Síndrome do Carcinoide Maligno/economia , Síndrome do Carcinoide Maligno/terapia , Tumores Neuroendócrinos/complicações , Neoplasias Pancreáticas/complicações , Antagonistas da Serotonina/economia , Neoplasias Gástricas/complicações , Idoso , Doença Cardíaca Carcinoide/diagnóstico , Custos e Análise de Custo , Feminino , Custos de Cuidados de Saúde , Humanos , Masculino , Síndrome do Carcinoide Maligno/diagnóstico , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Antagonistas da Serotonina/uso terapêutico , Suécia
12.
Medicine (Baltimore) ; 97(47): e13390, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30461659

RESUMO

To evaluate association of carcinoid syndrome (CS) symptom burden and somatostatin analog (SSA) duration with quality of life (QoL) using Functional Assessment of Cancer Therapy-General (FACT-G) and Patient-Reported Outcomes Measurement Information System (PROMIS-29) instruments.Adults who received treatment for CS symptoms in the US were recruited to participate in a cross-sectional online survey (July-October, 2016). Demographic, clinical, and QoL questions (FACT-G, 29 CS-related supplemental questions, PROMIS-29) were included. Descriptive and multivariable regression analyses adjusting for demographic and clinical characteristics followed.Most (98%) of the 117 patients received SSAs in the prior month. Multivariable regression analysis showed ≥4 bowel movements/day (vs <4) and each additional CS symptom was associated with 7.1 (P = .043) and 3.4 (P = .034) point FACT-G total score decreases, respectively. Requiring bed rest (vs normal activity) was associated with significant decreases in FACT-G total score (P < .001). There were similar associations for FACT-G subscales, supplemental questions, and PROMIS-29. After adjustment, FACT-G total score was significantly higher (11.3 points; P = .033) for patients treated with SSA >8 years versus <2.7 years.CS symptom burden was observed to be associated with lower QoL scores, measured by FACT-G. Patients with >8 years SSA treatment duration versus <2.7 years had higher QoL.


Assuntos
Síndrome do Carcinoide Maligno/tratamento farmacológico , Qualidade de Vida , Somatostatina/uso terapêutico , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Síndrome do Carcinoide Maligno/psicologia , Pessoa de Meia-Idade
13.
Clin Ther ; 40(12): 2006-2020.e2, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30477789

RESUMO

PURPOSE: Patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS) may experience chronic, recurring symptoms despite somatostatin analogue therapy. Little is known about the relationship between bowel movement (BM) frequency, patient-reported symptoms and health-related quality of life (QoL). Data from the TELESTAR study were used in exploratory, post hoc analyses to understand the relationship between durable reductions in BM frequency, symptom relief, and health-related QoL. METHODS: Patients with metastatic neuroendocrine tumors and CS in the Phase III TELESTAR study were randomized (1:1:1) to receive telotristat ethyl (TE) 250 mg, TE 500 mg, or placebo three times daily (TID) during a 12-week double-blind treatment period (DBTP). All patients received TE 500 mg TID in an open-label extension (OLE) to Week 48. Durable response was predefined. Analyses compared durable responders (DRs) and non-durable responders (NDRs), irrespective of treatment group, at Weeks 12, 24, and 48. FINDINGS: At the start of the DBTP, 135 patients were randomized, 45 patients each to TE 250 mg, TE 500 mg, and placebo. After the 12-week DBTP, 48 of 135 patients were DRs (TE 250 mg, n = 20; TE 500 mg, n = 19; placebo, n = 9). Of the 115 patients who entered the OLE, 35 were DRs initially randomized to TE 250 mg (n = 18) or 500 mg (n = 17), 29 of whom maintained a durable response throughout the OLE. Of the 71 DBTP-NDRs (inclusive of patients initially randomized to placebo), 28 became OLE-DRs. There were 29 NDRs initially randomized to placebo who entered the OLE, 16 of whom became DRs when switched to TE 500 mg. DRs during the DBTP had greater symptom improvements in the DBTP; these improvements continued over the OLE. DBTP-DRs also maintained more meaningful QoL improvements in EORTC QLQ-C30 global health status, nausea and vomiting, pain, diarrhea, and EORTC QLQ-GINET21 gastrointestinal symptoms over the DBTP and OLE periods than DBTP-NDRs. IMPLICATIONS: These results suggest that sustained improvements in BM frequency in patients with CS may have multifaceted, long-term effects on a patient's well-being. ClinicalTrials.gov identifiers: NCT01677910.


Assuntos
Diarreia/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/uso terapêutico , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Fenilalanina/uso terapêutico , Qualidade de Vida , Resultado do Tratamento , Triptofano Hidroxilase/antagonistas & inibidores
14.
Drugs Today (Barc) ; 54(8): 457-465, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30209440

RESUMO

Carcinoid tumors are rare and usually slow-growing. Some patients with advanced metastatic disease however can develop symptoms of carcinoid syndrome, which results in debilitating diarrhea and flushing. Many treatments including chemotherapy were tried unsuccessfully in the past to treat this syndrome. The symptoms of carcinoid syndrome are thought to be related to the ability of the tumors to produce serotonin. The discovery that the production of this hormone can be inhibited by somatostatin led to the development of somatostatin analogues octreotide and lanreotide, which differ from native somatostatin in that they have a longer half-life. These compounds have shown dramatic responses in symptom control and reduction of serotonin metabolites including urinary 5-hydroxyindoleacetic acid (5-HIAA) levels. This review researches the origins of carcinoid tumors, the development of lanreotide as a treatment and future directions for the treatment of carcinoid syndrome.


Assuntos
Antineoplásicos/uso terapêutico , Tumor Carcinoide/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Antineoplásicos/efeitos adversos , Tumor Carcinoide/epidemiologia , Tumor Carcinoide/patologia , Humanos , Síndrome do Carcinoide Maligno/diagnóstico , Síndrome do Carcinoide Maligno/epidemiologia , Estadiamento de Neoplasias , Octreotida/efeitos adversos , Peptídeos Cíclicos/efeitos adversos , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Resultado do Tratamento
15.
Cardiovasc J Afr ; 29(4): e1-e7, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30204224

RESUMO

Although carcinoid syndrome is regarded as a rare entity, carcinoid patients with evidence of cardiac involvement show a markedly reduced survival time. Patients with advanced signs of right-sided heart failure represent a subgroup at particularly high risk. Echocardiography remains the gold standard to diagnose or confirm structural cardiac involvement in patients with underlying carcinoid disease. This is the notion that propelled us to report on cases of carcinoid syndrome with cardiac involvement. We also review carcinoid syndrome and carcinoid heart disease, and challenges regarding the diagnosis and management of carcinoid heart disease.


Assuntos
Doença Cardíaca Carcinoide , Síndrome do Carcinoide Maligno , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Cardíaca Carcinoide/diagnóstico por imagem , Doença Cardíaca Carcinoide/fisiopatologia , Doença Cardíaca Carcinoide/terapia , Ecocardiografia Doppler em Cores , Evolução Fatal , Feminino , Humanos , Masculino , Síndrome do Carcinoide Maligno/diagnóstico por imagem , Síndrome do Carcinoide Maligno/fisiopatologia , Síndrome do Carcinoide Maligno/terapia , Pessoa de Meia-Idade , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
18.
J Clin Anesth ; 51: 93-96, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30098573

RESUMO

STUDY OBJECTIVE: Partial hepatic resection reduces tumor burden in patients with metastatic neuroendocrine tumors, thereby improving quality and length of life. These procedures can be challenging as well as life-threatening. Our aim was to evaluate our patients' perioperative outcomes and propose a definition for an intraoperative carcinoid crisis relevant to this surgery, given its unique surgical considerations. DESIGN: Retrospective study. SETTING: Mayo Clinic, Rochester, Minnesota. PATIENTS: One hundred sixty-nine patients undergoing partial hepatic resection for metastatic neuroendocrine tumors between 1997 and 2015 were identified retrospectively from a surgical database at Mayo Clinic Rochester. INTERVENTIONS: None. MEASUREMENTS: Intraoperative carcinoid crisis for patients undergoing hepatic resection of neuroendocrine tumors was defined. Patients' medical records were reviewed and data were abstracted describing patient and procedural characteristics and perioperative outcomes. MAIN RESULTS: There were no documented cases of carcinoid crisis (0.0%, 95% C.I. 0.0% to 2.2%). One patient developed clinical findings of an emerging carcinoid crisis, but was successfully treated with doses of octreotide and findings resolved in <10 min. Prophylactically 500 µg octreotide was given subcutaneously in 77% (130/169) of patients preoperatively. CONCLUSIONS: There were no documented cases of carcinoid crisis (0.0%, 95% C.I. 0.0% to 2.2%). Adverse events were infrequent.


Assuntos
Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Hepatectomia/efeitos adversos , Neoplasias Hepáticas/cirurgia , Síndrome do Carcinoide Maligno/epidemiologia , Tumores Neuroendócrinos/cirurgia , Idoso , Antineoplásicos Hormonais/administração & dosagem , Procedimentos Cirúrgicos de Citorredução/métodos , Feminino , Hepatectomia/métodos , Humanos , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/secundário , Masculino , Síndrome do Carcinoide Maligno/diagnóstico , Síndrome do Carcinoide Maligno/prevenção & controle , Pessoa de Meia-Idade , Tumores Neuroendócrinos/secundário , Octreotida/administração & dosagem , Período Perioperatório/estatística & dados numéricos , Estudos Retrospectivos , Resultado do Tratamento
19.
Endocrinol Metab Clin North Am ; 47(3): 557-576, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30098716

RESUMO

Neuroendocrine tumors, including carcinoids, are rare and insidiously growing tumors. Related to their site of origin, tumors can be functional, causing various forms of the carcinoid syndrome, owing to the overproduction of serotonin, histamine, or other bioactive substances. They often invade adjacent structures or metastasize to the liver and elsewhere. Treatment includes multimodal approaches, including cytoreductive surgery, locoregional embolization, cytotoxic therapy, peptide receptor radionuclide therapy, and various targeted therapies with goals of symptom relief and control of tumor growth. This article summarizes current and emerging approaches to management and reviews several promising future therapies.


Assuntos
Antineoplásicos/uso terapêutico , Síndrome do Carcinoide Maligno/terapia , Tumores Neuroendócrinos/terapia , Humanos , Síndrome do Carcinoide Maligno/tratamento farmacológico , Síndrome do Carcinoide Maligno/radioterapia , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/radioterapia , Serina-Treonina Quinases TOR/antagonistas & inibidores
20.
Drugs Today (Barc) ; 54(7): 423-432, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30090879

RESUMO

Telotristat ethyl (Xermelo), developed by Lexicon Pharmaceuticals, is an oral tryptophan hydroxylase inhibitor blocking peripheral conversion of tryptophan to serotonin (5-hydroxytryptamine [5-HT]). It was approved by the U.S. Food and Drug Administration (FDA) in February 2017 and by the European Commission in September 2017 for patients with carcinoid syndrome in whom diarrhea is not adequately controlled by somatostatin analogues (SSAs). Diarrhea, secondary to the release of serotonin, is the predominant gastrointestinal symptom in patients with carcinoid syndrome and has a significant impact on patients' quality of life. Telotristat is not meant for all patients with diarrhea and carcinoid syndrome. Prescribing of telotristat for patients with diarrhea refractory to SSAs requires careful consideration and an approach that involves identifying and ruling out other common causes of diarrhea in patients with carcinoid syndrome. Delineating the timing of diarrhea and whether it occurs in patients with stable disease versus cancer progression can help identify the right drug candidates for therapy.


Assuntos
Diarreia/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Fenilalanina/análogos & derivados , Pirimidinas/uso terapêutico , Somatostatina/análogos & derivados , Ensaios Clínicos como Assunto , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Fenilalanina/efeitos adversos , Fenilalanina/farmacologia , Fenilalanina/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia
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