A Randomized Trial Evaluating Patient Experience and Preference Between Octreotide Long-Acting Release and Lanreotide for Treatment of Well-Differentiated Neuroendocrine Tumors.

PURPOSE: Somatostatin analogs octreotide long-acting release (octLAR) and lanreotide are equally acceptable in National Comprehensive Cancer Network guidelines for neuroendocrine tumors (NETs). Lanreotide is more expensive and given by deep subcutaneous injection, whereas octLAR is given intramuscularly. We evaluated patient preference between these agents in terms of injection site pain. MATERIALS AND METHODS: Randomized, single-blinded study. Patients with NETs received injections every 4 weeks. Arm 1: octLAR × 3, then lanreotide × 3; arm 2: reverse order. Self-reported injection site pain scores (range, 0-10) were obtained after each of the first three injections. Primary end point was comparison of mean pain scores over the first three injections. Secondary end points included patient-reported preference. RESULTS: Fifty-one patients enrolled (26 in arm 1 and 25 arm 2), all evaluable for primary end point. No significant difference was identified in the mean pain score over the first three injections (2.4 ± 1.9 v 1.9 ± 1.5, P = .5). Thirty-four of 51 (67%) patients (15 in arm 1 and 19 in arm 2) completed post-therapy questionnaires and were evaluable for secondary end points. Seven patients (47%) in arm 1 and eight patients (42%) in arm 2 indicated no drug preference at the end of treatment. In the other 19 patients, more patients indicated mild or strong preference for octLAR over lanreotide. CONCLUSION: We found minimal pain with octLAR and lanreotide and no significant pain score differences between the two. Patients indicating a drug preference trended toward favoring octLAR.

Pharmacological Acromegaly Treatment: Cost-Utility and Value of Information Analysis.

OBJECTIVES: To conduct a cost-utility analysis comparing drug strategies involving octreotide, lanreotide, pasireotide, and pegvisomant for the treatment of patients with acromegaly who have failed surgery, from a Brazilian public payer perspective. METHODS: A probabilistic cohort Markov model was developed. One-year cycles were employed. The patients started at 45 years of age and were followed lifelong. Costs, efficacy, and quality of life parameters were retrieved from the literature. A discount rate (5%) was applied to both costs and efficacy. The results were reported as costs per quality-adjusted life year (QALY), and incremental cost-effectiveness ratios (ICERs) were calculated when applicable. Scenario analyses considered alternative dosages, discount rate, tax exemption, and continued use of treatment despite lack of response. Value of information (VOI) analysis was conducted to explore uncertainty and to estimate the costs to be spent in future research. RESULTS: Only lanreotide showed an ICER reasonable for having its use considered in clinical practice (R$ 112,138/US$ 28,389 per QALY compared to no treatment). Scenario analyses corroborated the base-case result. VOI analysis showed that much uncertainty surrounds the parameters, and future clinical research should cost less than R$ 43,230,000/US$ 10,944,304 per year. VOI also showed that almost all uncertainty that precludes an optimal strategy choice involves quality of life. CONCLUSIONS: With current information, the only strategy that can be considered cost-effective in Brazil is lanreotide treatment. No second-line treatment is recommended. Significant uncertainty of parameters impairs optimal decision-making, and this conclusion can be generalized to other countries. Future research should focus on acquiring utility data.

Cluster headache: state of the art of pharmacological treatments and therapeutic perspectives.

Cluster headache (CH) is the most common form of trigeminal autonomic cephalalgia. Current treatments have several limitations, and new drugs are required. This article first briefly reviews present acute and preventive treatments in CH, their mechanism of action and limitations, then describes the state of the art in recent clinical drug trials since 2015, and ends with a critique of trials in the CH field. Research is limited by lack of knowledge of pathophysiology and lack of animal models. In the past 5 years, no brand-new treatment has emerged, but promising drugs, such as CGRP(R) antibodies, are under study. According to the literature and guidelines, clinicians and researchers should be aware of many limitations in study protocols: concomitant medication, patient sample size, patients' protocol compliance, and study designs that tend to restrict patient recruitment.

El presente dictamen expone la evaluación de la eficacia y seguridad de lanreotida comparado con la mejor terapia de soporte para el tratamiento de tumor neuroendocrino (TNE) primario gastrointestinal, estadio clínico IV, grado 2, sin tratamiento previo / This opinion exposes the evaluation of the efficacy and safety of lanreotide compared to the best supportive therapy for the treatment of primary gastrointestinal neuroendocrine tumor (NET), clinical stage IV, grade 2, without previous treatment

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de lanreotida comparado con la mejor terapia de soporte para el tratamiento de tumor neuroendocrino (TNE) primario gastrointestinal, estadio clínico IV, grado 2, sin tratamiento previo. Los tumores neuroendocrinos (TNE) son un grupo heterogéneo de neoplasias que surgen de las células del sistema endocrino y el nervioso. No se han identificado datos epidemiológicos locales. No obstante, en los Estados Unidos se ha observado un crecimiento gradual en la incidencia, de 1.9 a 5.2/100 000 personas por año, a lo largo de las últimas tres décadas. Los TNE del tracto gastrointestinal (TNE-GI) representan aproximadamente dos tercios de todos los casos de TNE y son el segundo tipo de tumor gastrointestinal más común. La primera línea de tratamiento para los pacientes con TNE localizados, es la cirugía. Sin embargo, en casos avanzados (cuando se presentan las metástasis), el tratamiento es paliativo y limitado al control de la progresión de la enfermedad. En el contexto de EsSalud, actualmente no se cuenta con un tratamiento que permita el control de la progresión de enfermedad de estos pacientes. Así, especialistas locales consideran que lanreotida podría brindar un beneficio en el control del crecimiento y progresión tumoral para dichos pacientes. Lanreotida (Somatuline® Depot) es un octapéptido cíclico sintético análogo a la somatostatina natural. Lanreotida ha sido aprobado por la FDA y EMA para el tratamiento de pacientes con tumores neuroendocrinos gastroenteroprancreáticos (TNE-GEP). METODOLOGÍA: La búsqueda de la literatura se realizó con el objetivo de identificar evidencia sobre la eficacia y seguridad de lanreotida comparado con placebo para el tratamiento de tumor neuroendocrino primario gastrointestinal estadio clínico IV, grado 2, sin tratamiento previo. La búsqueda de la evidencia se realizó en las bases de datos bibliográficas: PubMed, Scopus y OVID. Adicionalmente, se revisó la evidencia generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como The National Institute for Health and Care Excellence (NICE), The National Comprehensive Cancer Network (NCCN), The Guidelines International Network (G-I-N), el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), The Canadian Agency for Drugs and Technologies in Health (CADTH), Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Quality and Efficiency in Health Care (IQWiG), The European Society for Medical Oncology (ESMO), European Medicines Agency (EMA), y Scottish Medicines Consortium (SMC). Finalmente, se realizó una búsqueda manual en el portal clinicaltrials.gov del National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o que no hayan sido publicados aún. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de la lanreotida para el tratamiento de pacientes con tumores neuroendocrinos gastrointestinales. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: En el presente documento, se evaluó la mejor evidencia científica disponible hasta la actualidad en relación con la eficacia y seguridad de lanreotida para el tratamiento en pacientes adultos con diagnóstico de tumor neuroendocrino primario gastrointestinal estadio clínico IV, grado 2, sin tratamiento previo.  A la fecha, la búsqueda de la literatura científica identificó tres GPC, dos ETS, y un ECA fase III con dos publicaciones. Las tres GPC (NCCN, Singh et al, Alberta Health Services) recomiendan el uso de lanreotida como tratamiento en pacientes con TNE. Dentro de la evidencia empleada incluyen al único ECA, CLARINET (Caplin et al. 2014). Sin embargo, las GPC de NCCN y Singh et al, concuerdan en que la evidencia es de baja calidad, es decir brindan resultados imprecisos y con un alto riesgo de sesgo. Y los autores de las tres GPC reportaron tener conflicto de interés por haber recibido honorarios de la empresa farmacéutica Ipsen. La ETS de CADTH no brinda ninguna recomendación sobre el uso de lanreotida en la población de interés. Sólo determina que la evidencia demuestra que lanreotida tiene un efecto antiproliferativo y que es efectivo para el control de síntomas. La ETS realizada por el Ministerio de Salud de Chile, aprobó el uso de lanreotida como tratamiento de alto costo en pacientes con TNE. Esto teniendo en cuenta que el medicamento contaba con una aprobación de la FDA para la población a evaluar, no tenía ninguna orden de restricción de uso. El ECA de doble ciego realizado por Caplin et al. en el 2014, evalúa la eficacia y seguridad de lanreotida comparado con placebo en pacientes con tumores neuroendocrinos avanzados, bien o moderadamente diferenciados, no funcionales, receptores de somatostatina positivos, de grado 1 o 2 y con registro de la progresión de la enfermedad. En total participaron 204 sujetos, de los cuales 101 recibieron lanreotida (120 mg) y 103 recibieron placebo cada 28 días durante 96 semanas. Del total de participantes, el 42.2 % de los pacientes enrolados tenían TNE de origen en el intestino medio y posterior (población de interés del presente dictamen). En el subgrupo de pacientes con tumores primarios en el intestino medio el HR fue de 0.35 (IC 95 %: 0.16-0.80), y en el grupo de intestino posterior el HR fue de 1.47 (IC 95 %: 0.16-13.24). Sin embargo, los autores usaron el modelo estratificado de riesgos proporcionales de Cox, pese a que no se cumple el supuesto de proporcionalidad de riesgos (entrecruzamiento de curvas de K-M). De esta manera, los resultados no son precisos y son difíciles de interpretar. Además, en el grupo de intestino posterior los intervalos de confianza son demasiado amplios, evidenciando la falta de precisión de los datos (HR: 1.47; IC 95 %: 0.16-13.24). Los análisis de la SLP en los subgrupos son considerados exploratorios ya que no fueron considerados en el cálculo de tamaño de muestra. Además, la SLP, pese a ser un desenlace planteado en la pregunta PICO, no se ha demostrado que sea un desenlace de relevancia clínica desde la perspectiva del paciente. No se encontraron diferencias en la sobrevida global ni en la calidad de vida entre lanreotida y el uso de placebo en pacientes con TNE. Sobre el desenlace de valores de cromogranina A, se encontró incertidumbre sobre su valor predictivo en desenlaces de relevancia clínica como la SG o calidad de vida, debido a la baja calidad de la evidencia que evalúa esta asociación. Los eventos adversos serios fueron reportados por el 24.8 % de pacientes del grupo de lanreotida y 31.1 % en el grupo de placebo, sin presentar diferencias significativas en el riesgo relativo de tener un evento adverso serio entre lanreotida y placebo. Por su parte, los eventos adversos serios relacionados al tratamiento fueron 3/101 y 1/103, respectivamente. A la fecha, con la evidencia disponible, no existen argumentos técnicos que respalden un beneficio neto a favor del uso de lanreotida en pacientes con TNE gastrointestinal, sobre desenlaces clínicamente relevantes como la SG, calidad de vida, control de síntomas neuroendocrinos y seguridad. Los resultados en la SLP y cromogranina A, si bien mostraron diferencia a favor de lanreotida, no han demostrado que sean predictores de desenlaces de relevancia clínica como la SG y calidad de vida. En tal sentido, no se justificaría la inversión de recursos en un medicamento que no ha demostrado tener beneficios adicionales aun frente a placebo. Por lo expuesto, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación ­ IETSI no aprueba el uso de lanreotida como terapia en pacientes adultos con diagnóstico de tumor neuroendocrino primario gastrointestinal estadio clínico IV, grado 2, sin tratamiento previo.

Cost-effectiveness analysis of second-line pharmacological treatment of acromegaly in Spain.

Objective: To estimate the cost-effectiveness of second-line pharmacological treatments in patients with acromegaly resistant to first-generation somatostatin analogues (FG SSA) from the Spanish National Health System (NHS) perspective.Methods: A Markov model was developed to analyze the cost-effectiveness of pegvisomant and pasireotide in FG SSA-resistant acromegaly, simulating a cohort of patients from the treatment beginning to death. Treatment with pegvisomant or pasireotide was compared to FG SSA retreatment. Efficacy data were obtained from clinical trials and utilities from the literature. Direct health costs were obtained from Spanish sources (€2018).Results: The Incremental Cost Effectiveness Ratio (ICER) of pegvisomant vs. FG SSA was €85,869/Quality-adjusted life years (QALY). The ICER of pasireotide vs. FG SSA was €551,405/QALY. The ICER was mainly driven by the incremental efficacy (4.41 QALY for pegvisomant vs. FG SSA and 0.71 QALY for pasireotide vs. FG SSA), with a slightly lower increase in costs with pegvisomant (€378,597 vs. FG SSA) than with pasireotide (€393,151 vs. FG SSA).Conclusion: The ICER of pasireotide compared to FG SSA was six times higher than the ICER of pegvisomant vs. FG SSA. Pegvisomant is a more cost-effective alternative for the treatment of acromegaly in FG SSA-resistant patients in the Spanish NHS.

Multifaceted NIR-responsive polymer-peptide-enveloped drug-loaded copper sulfide nanoplatform for chemo-phototherapy against highly tumorigenic prostate cancer.

Targeted, biocompatible, and synergistic "all in one" systems should be designed to combat the heterogeneity of cancer. In this study, we constructed a dual function nanosystem, copper sulfide nanoplatform loaded with the chemotherapeutic drug docetaxel wrapped by a conjugated polymer-peptide for targeted chemo-phototherapy. The nanoconstruct has been successfully designed with a size of 186.1 ±â€¯5.2 nm, a polydispersity index of 0.18 ±â€¯0.01, and zeta potential of -16.4 ±â€¯0.1 mV. The enhanced uptake and near-infrared-responsive behavior of the nanosystem resulted in efficient drug release, photothermal ablation, effective cytotoxic activity, and potentiated reactive oxygen species generation. The induction of apoptotic markers, enhanced accumulation in the tumor site, and maximum tumor growth inhibition were seen during in vivo studies compared to non-targeted nanoformulations and free drug. Cumulatively, our results indicate that, with low systemic toxicity and better biocompatibility, this nanoconstruct could provide a promising strategy for treating prostate cancer.

Postprandial hypoglycaemia after Roux-en-Y gastric bypass and the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide.

AIM: To investigate the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide on post-bariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass. MATERIALS AND METHODS: In a randomized crossover study, 11 women who had undergone Roux-en-Y gastric bypass and had documented hypoglycaemia were each evaluated during a baseline period without treatment and during five treatment periods with the following interventions: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks and pasireotide 300 µg as a single dose. Treatment effects were evaluated by a mixed-meal tolerance test (MMTT) and, for all treatment periods except pasireotide, by 6 days of continuous glucose monitoring (CGM). RESULTS: Treatment with acarbose and treatment with pasireotide both significantly lifted nadir glucose levels (mean ± SEM 3.9 ± 0.2 and 7.9 ± 0.4 vs 3.4 ± 0.2; P < .03) and reduced time in hypoglycaemia during the MMTTs. Acarbose reduced peak glucose levels and time in hyperglycaemia, whereas pasireotide greatly increased both variables. Acarbose and pasireotide reduced insulin and C-peptide levels, and pasireotide also diminished glucagon-like peptide-1 levels. Sitagliptin lowered nadir glucose values, while verapamil and liraglutide had no effect on hypoglycaemia. During the CGM periods, the treatments had no impact on hypoglycaemia, whereas acarbose and liraglutide reduced hyperglycaemia and glycaemic variability. CONCLUSIONS: In an experimental setting, treatment with acarbose and pasireotide reduced PBH. Acarbose appears to have an overall glucose-stabilizing effect, whereas pasireotide leads to increased and sustained hyperglycaemia.

Surgical-pharmacological interactions in the treatment of acromegaly.

INTRODUCTION: Acromegaly requires a multimodal treatment approach that includes surgery by an expert pituitary neurosurgeon, pharmacological treatment with one or more of the available drugs and radiation therapy. These treatment alternatives are not mutually exclusive but rather complement each other when properly indicated in the individual patient. In this review, we summarize and analyze the available data concerning the choice of the surgical approach (microscopy vs. endoscopy) and the interactions between medical treatment with somatostatin analogs and pituitary surgery. AREAS COVERED: Technical aspects, complications and outcome of transsphenoidal surgery (TSS); Advantages and disadvantages of the microscopic and endoscopic approaches; Safety and efficacy of somatostatin analogs (SSA); Primary pharmacological therapy versus primary TSS; Benefits of the preoperative treatment with SSA; and the effect of surgical tumor debulking in the therapeutic response to SSA. EXPERT COMMENTARY: Continuing efforts at improving surgical techniques and at generating more efficacious pharmacological therapies for acromegaly are likely to improve the outcome of these patients. However, an integral approach of the patient aimed not only at achieving biochemical criteria of cure but also at treating the individual comorbidities is mandatory to improve the quality of life of these patients and to reduce their mortality rate.

Pasireotide: A potential therapeutic alternative for resistant prolactinoma.

CONTEXT: About 10% of prolactinomas are resistant to dopamine-agonists (DAs). The only alternatives for tumor and prolactin control are surgery or radiotherapy. While studies on first generation somatostatin analogs have shown no efficacy against prolactinomas, no study has been conducted on the new multireceptor-targeted somatostatin receptor ligand pasireotide, which presents high affinity for 5, 3, 2 and 1 receptor subtypes. CASE DESCRIPTION: A 41 year-old woman presented with a macroprolactinoma showing resistance to all available DAs. She was first diagnosed at 17 years old after which she had undergone two incomplete debulking surgeries. Under pasireotide long-acting release (LAR) treatment, plasma prolactin levels normalized and symptoms disappeared within one month after initiation. The clinical benefits of the monotherapy (specifically, prolactin levels within normal range and stable tumor volume) were maintained for seven years. Glucose tolerance was satisfactory. Pathological analysis of the tumor revealed high SSTR5 and low SSTR2 expression (25 and 5% of cells respectively). CONCLUSION: This is a promising first report of a patient with a DA-resistant macroprolactinoma who achieved long-term control, in terms of prolactin normalization and tumor volume, under pasireotide treatment alone. Pasireotide could thus be an alternative in prolactinomas resistant to DA. SSTR expression analysis on pathology could guide patient selection.

Eficacia y seguridad de lanreotida para el tratamiento de tumor neuroendocrino pancreático bien diferenciado, metastásico o no resecable, sin tratamiento sistémico previo / Efficacy and safety of lanreotide for the treatment of well-differentiated, metastatic or unresectable pancreatic neuroendocrine tumor, without prior systemic treatment

INTRODUCCIÓN: Los tumores neuroendocrinos del páncreas (TNEP) son neoplasias infrecuentes que se originan del tejido endocrino pancreático, representan el 1 a 2 % de todos los casos de tumores pancreáticos y tienen una incidencia menor a un caso por 100 000 individuos/año. Aparecen con mayor frecuencia en la cuarta década de vida, y algunos TNEP se asocian con endocrinopatías hereditarias. Para el tratamiento de los TNEP bien diferenciados, metastásico o no resecable, en EsSalud se cuenta con octreotide (análogo de somatostatina) 0.2 mg/ml, y octreotide acetato 20 mg de liberación lenta (en adelante octreotide LAR); sin embargo, en los últimos años se autorizaron para comercialización otros análogos de somatostatina que han sido propuestos como una alternativa terapéutica de primera línea para este grupo de pacientes. Ante ello, es necesario evaluar si las nuevas alternativas terapéuticas presentan un mejor beneficio clínico y adecuado perfil de seguridad en pacientes que por sus características clínicas sean candidatos a recibirlas. OBJETIVO: Evaluar la mejor evidencia disponible a la fecha sobre la eficacia y seguridad del uso de lanreotida comparado con octreotide LAR en pacientes adultos con diagnóstico de tumor neuroendocrino pancreático bien diferenciado, metastásico o no resecable, sin tratamiento sistémico previo. TECNOLOGÍA SANITARIA DE INTERÉS: Lanreotida es un octapéptido análogo de la somatostatina natural que inhibe procesos endocrinos, neuroendocrinos, exocrinos y paracrinos. Su mecanismo de acción parece ser similar a la somatostatina natural. Tiene gran afinidad por los receptores de la somatostatina 2 y 5, y en menor grado por los receptores 1, 3 y 4, mostrando mayor actividad que la somatostatina natural y mayor duración de la acción en estudios preclínicos. METODOLOGÍA: Se incluye en el presente dictamen, la revisión de la literatura publicada a enero 2019 (incluyó alertas diarias de PubMed sobre nuevas publicaciones) y la síntesis de resultados sobre el uso de lanreotida comparado con octreotide LAR para el tratamiento de pacientes adultos con tumor neuroendocrino pancreático bien diferenciado, metastásico, no resecable, sin tratamiento sistémico previo. En tal sentido, no se identificó evidencia específica que compare lanreotida con octreotide. RESULTADOS: Considerando que el único ECA de fase III (Caplin et al., 2014) que podría responder la pregunta PICO, incluyó pacientes que recibieron lanreotida vs. placebo en el tratamiento de tumores neuroendocrinos; se decidió reportar dicho estudio (estudio CLARINET), que incluyó un 44.6 % de pacientes con TNEP (la población de interés en la pregunta PICO del presente dictamen). Así, el presente dictamen incluye tres GPC (National Comprehensive Cancer Network, 2018; Singh et al., 2017; Alberta Health Services, 2015), tres ETS (Canadian Agency for Drugs and Technologies in Health, 2017; Comissão Nacional de Incorporação de Tecnologias no SUS, 2018; Ministerio de Salud de Chile, 2017), y un ECA fase III del cual se derivaron dos publicaciones (Caplin et al., 2014; Caplin et al., 2016). Todas las recomendaciones y/o resultados presentados en las GPC y ETS incluidas en el presente dictamen se basaron en los hallazgos del estudio CLARINET (2014) que evaluó la eficacia y seguridad de lanreotida 120 mg por vía subcutánea profunda cada 28 días frente placebo en pacientes con tumores neuroendocrinos avanzados, bien o moderadamente diferenciados. En relación a las GPC identificadas, dos de ellas (National Comprehensive Cancer Network 2018 y Alberta Health Services 2015) consideran a lanreotida y octreotide como alternativas de tratamiento en pacientes con TNEP avanzando o metastásico, bien o moderadamente diferenciado, no resecable, sin tratamiento sistémico previo. Asimismo, una tercera guía (Singh et al., 2017) no emite recomendaciones a favor o en contra del uso de análogos de somatostatina. Por otro lado, todas las ETS incluidas concuerdan en sus hallazgos acerca de la falta de beneficios de lanreotida en la sobrevida global (SG) de pacientes con tumores neuroendocrinos; sin embargo, el Ministerio de Salud de Chile decidió su financiamiento considerándolo como de alto costo. CONCLUSIONES: En el presente documento se evaluó la evidencia científica publicada hasta enero 2019 en relación al uso de lanreotida en pacientes adultos con diagnóstico de tumor neuroendocrino pancreático bien diferenciado, metastásico o no resecable, sin tratamiento sistémico previo. En tal sentido, no se identificó evidencia específica que compare lanreotida con placebo. A la fecha, la evidencia acerca del uso de lanreotida en tumores neuroendocrinos, recaen sobre un ECA (estudio CLARINET) publicado por Caplin et al., 2014, que lo compara con placebo y donde solo se incluyeron cerca de 45 % de pacientes con TNEP. Al respecto, se debe tener en consideración que la pregunta PICO del presente dictamen incluye a paciente con TNEP en los cuales se plantea como comparador a octreotide LAR (tecnología sanitaria disponible en EsSalud), por lo cual no se tienen ensayos clínicos que permitan responder directamente a la pregunta PICO. En relación a las GPC identificadas, dos de ellas (NCCN 2018 y Alberta Health Services 2015) consideran a lanreotida y octreotide como alternativas de tratamiento en pacientes con TNEP avanzando o metastásico, bien o moderadamente diferenciado, no resecable, sin tratamiento sistémico previo. Una tercera guía (Singh et al., 2017) no brinda recomendaciones a favor o en contra de las dos alternativas. Por su parte, las ETS identificadas concuerdan en sus hallazgos acerca de la falta de beneficios de lanreotida en la SG como desenlace clínico de relevancia para el paciente. El Ministerio de Salud de Chile decidió financiar a lanreotida para el tratamiento de tumores neuroendocrinos, considerándola como un medicamento de alto costo. Por otro lado, CONITEC acordó no recomendar la inclusión de lanreotida para el tratamiento de tumores neuroendocrinos gastropancreáticos en el sistema de salud de Brasil. El resultado de un análisis por subgrupo (que puede ser considerado como exploratorio ya que el estudio no fue diseñado para evaluar diferencias en esta subpoblación) en pacientes con TNEP en el estudio CLARINET mostró que no existen diferencias significativas entre lanreotida y placebo en la SLP (desenlace primario del estudio CLARINET). El estudio no reportó resultados de desenlaces clínicamente relevantes como SG o calidad de vida en la población de interés de la pregunta PICO. No se encontraron diferencias en la SG, calidad de vida o eventos adversos serios en la población total del estudio con tumores neuroendocrinos. En consecuencia, la evidencia proveniente del estudio CLARINET no permite identificar un beneficio neto de lanreotida, aun frente al placebo, en nuestra población de interés. En cuanto al desenlace considerado en la pregunta PICO sobre la mejora en la calidad de vida para el paciente por tener menor frecuencia de aplicación y vía de administración más conveniente, la evidencia disponible no hace mención sobre la superioridad lanreotida en este desenlace. placebo, en nuestra población de interés. Así, no se puede tener en este momento, con la evidencia disponible, los argumentos técnicos que respalden su uso de lanreotida en los pacientes con tumor neuroendocrino pancreático bien diferenciado, metastásico o no resecable, sin tratamiento sistémico previo incluidos, más aún cuando se dispone de una alternativa terapéutica en EsSalud del mismo grupo farmacológico (octreotide LAR) que es recomendada por las principales guías internacionales. Por lo expuesto, y con la evidencia disponible sobre la tecnología evaluada, el Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI no aprueba el uso de lanreotida para el tratamiento de tumor neuroendocrino pancreático bien diferenciado, metastásico o no resecable, sin tratamiento sistémico previo.

Self-assembly synthesis of vapreotide­gold hybrid nanoflower for photothermal antitumor activity.

Based on the self-assembly properties of vapreotide acetate (Vap), one kind of novel vapreotide acetate­gold nanoflowers (Vap-AuNFs) was fabricated for the first time by biomimetic mineralization method using Vap as a template. The Vap-AuNFs possessed anisotropic structure with a large absorption cross-section, which were face-centered cubic crystalline, exhibiting a remarkable monodisperse, narrow size (154 nm) distribution and good stability in aqueous solution. The apparent anisotropy of the gold nanostructure with high molar extinction coefficient can cause significantly higher plasmon absorption of Vap-AuNFs in the near infrared (NIR) region compared with Au nanoparticles (AuNPs), so the nanocomplex can induce remarkably enhanced photothermal conversion efficiency under NIR light irradiation. Breathtakingly, Vap-AuNFs exhibited superior biocompatibilities compared to AuNPs, as well as enhanced Hela cells lethality under NIR irradiation. This novel method was simple, low cost and green for the design and preparation of anisotropic gold nanoflowers with outstanding NIR laser-induced local hyperthermia, highlighting their potential applications in biomedical fields.

Targeted Delivery of Functionalized Upconversion Nanoparticles for Externally Triggered Photothermal/Photodynamic Therapies of Brain Glioblastoma.

Therapeutic efficacy of glioblastoma multiforme (GBM) is often severely limited by poor penetration of therapeutics through blood-brain barrier (BBB) into brain tissues and lack of tumor targeting. In this regard, a functionalized upconversion nanoparticle (UCNP)-based delivery system which can target brain tumor and convert deep tissue-penetrating near-infrared (NIR) light into visible light for precise phototherapies on brain tumor was developed in this work. Methods: The UCNP-based phototherapy delivery system was acquired by assembly of oleic acid-coated UCNPs with angiopep-2/cholesterol-conjugated poly(ethylene glycol) and the hydrophobic photosensitizers. The hybrid nanoparticles (ANG-IMNPs) were characterized by DLS, TEM, UV/vis and fluorescence spectrophotometer. Cellular uptake was examined by laser scanning confocal microscopy and flow cytometry. The PDT/PTT effect of ANG-IMNPs was evaluated using MTT assay. Tumor accumulation of NPs was determined by a non-invasive in vivo imaging system (IVIS). The in vivo anti-glioma effect of ANG-IMNPs was evaluated by immunohistochemical (IHC) examination of tumor tissues and Kaplan-Meier survival analysis. Results: In vitro data demonstrated enhanced uptake of ANG-IMNPs by murine astrocytoma cells (ALTS1C1) and pronounced cytotoxicity by combined NIR-triggered PDT and PTT. In consistence with the increased penetration of ANG-IMNPs through endothelial monolayer in vitro, the NPs have also shown significantly enhanced accumulation at brain tumor by IVIS. The IHC tissue examination confirmed prominent apoptotic and necrotic effects on tumor cells in mice receiving targeted dual photo-based therapies, which also led to enhanced median survival (24 days) as compared to the NP treatment without angiopep-2 (14 days). Conclusion: In vitro and in vivo data strongly indicate that the ANG-IMNPs were capable of selectively delivering dual photosensitizers to brain astrocytoma tumors for effective PDT/PTT in conjugation with a substantially improved median survival. The therapeutic efficacy of ANG-IMNPs demonstrated in this study suggests their potential in overcoming BBB and establishing an effective treatment against GBM.

Management of Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEPNETs): A Review.

PURPOSE: Neuroendocrine tumors (NETs) are heterogeneous tumors that arise from the neuroendocrine cells of the digestive tract and other organs, such as the lung, ovary, and thyroid glands. They can be well differentiated or poorly differentiated, and management of these tumors differs for each histologic subtype. We have performed a review of NETs and focused on management of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEPNETs) and carcinoid syndrome. METHODS: A PubMed search was performed to obtain articles on the management of well-differentiated NETs. Using the key words neuroendocrine tumors, carcinoid, pNET, octreotide, somatostatin analogues, and radiolabeled therapy, we reviewed Phase II and III trials that were published over the past 30 years. We also reviewed guidelines from the European Neuroendocrine Tumor Society, North America Neuroendocrine Tumor Society, and National Comprehensive Cancer Network in our search. FINDINGS: NETs are usually slow-growing tumors that remain asymptomatic for a long duration and can be either nonfunctioning or functioning. Surgical resection is recommended for locoregional disease, impending obstruction, symptom control, and advanced disease. Nonsurgical treatment options include somatostatin analogues (SSAs), multikinase inhibitors, targeted therapy, chemotherapy, and radiolabeled SSAs. Carcinoid syndrome is mainly treated with SSAs. IMPLICATIONS: Although GEPNETs are slow-growing tumors, most patients are diagnosed with metastatic disease, and therefore it is important that the management of each patient be discussed in a multidisciplinary setting to optimize the treatment strategy. Patients should be considered for clinical trials and refractory cases referred to a specialty center.

Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver-disease.

AIM: To develop a MRI-based method for accurate determination of liver volume (LV) and to explore the effect of long-term everolimus (EVR) treatment on LV in PCK rats with hepatomegaly. METHODS: Thirty-one female PCK rats (model for polycystic-liver-disease: PCLD) were randomized into 3 groups and treatment was started at 16 wk, at the moment of extensive hepatomegaly (comparable to what is done in the human disease). Animals received: controls (n = 14), lanreotide (LAN: 3 mg/kg per 2 wk) (n = 10) or everolimus (EVR: 1 mg/kg per day) (n = 7). LV was measured at week 16, 24, 28. At week 28, all rats were sacrificed and liver tissue was harvested. Fibrosis was evaluated using quantitative image analysis. In addition, gene (quantitative RT-PCR) and protein expression (by Western blot) of the PI3K/AkT/mTOR signaling pathway was investigated. RESULTS: LV determination by MRI correlated excellent with the ex vivo measurements (r = 0.99, P < 0.001). The relative changes in LV at the end of treatment were: (controls) +31.8%; (LAN) +5.1% and (EVR) +8.8%, indicating a significantly halt of LV progression compared with controls (respectively, P = 0.01 and P = 0.04). Furthermore, EVR significantly reduced the amount of liver fibrosis (P = 0.004) thus might also prevent the development of portal hypertension. There was no difference in phosphorylation of Akt (Threonine 308) between LAN-treated PCK rats control PCK rats, whereas S6 was significantly more phosphorylated in the LAN group. Phosphorylation of Akt was not different between controls and EVR treated rats, however, for S6 there was significantly less phosphorylation in the EVR treated rats. Thus, both drugs interact with the PI3K/AkT/mTOR signaling cascade but acting at different molecular levels. CONCLUSION: Everolimus halts cyst growth comparable to lanreotide and reduces the development of fibrosis. mTOR-inhibition should be further explored in PCLD patients especially those that need immunosuppression.

Systematic review: pharmacotherapy for high-output enterostomies or enteral fistulas.

BACKGROUND: High-output enterocutaneous fistula or enterostomies can cause intestinal failure. There is a wide variety of options in medical management of patients with high output. AIM: To systematically review the literature on available pharmacotherapy to reduce output and to propose an algorithm for standard of care. METHODS: Relevant databases were systematically reviewed to identify studies on pharmacotherapy for reduction in (high-) output enterostomies or fistula. Randomised controlled trials and within subjects controlled prospective trials were included. An algorithm for standard of care was generated based on the outcomes of the systematic review. RESULTS: Two studies on proton pump inhibitors, six on anti-motility agents, three on histamine receptor antagonists, one on an α2- receptor agonist and eight on somatostatin (analogues) were included. One study examined a proton pump inhibitor and a histamine receptor antagonist within the same patients. Overall, we found evidence for the following medical therapies to be effective: omeprazole, loperamide and codeine, ranitidine and cimetidine. On the basis of these outcomes and clinical experience, we proposed an algorithm for standard of care which consists of high-dose proton pump inhibitors combined with high-dose loperamide as the first step followed by addition of codeine in case of insufficient output reduction. So far, there is insufficient evidence for the standard use of somatostatin (analogues). CONCLUSIONS: The available evidence on the efficacy of medication to reduce enterostomy or enterocutaneous fistula output is hampered by low quality studies. We propose an algorithm for standard of care output reduction in these patients.

µ-Opioid and 5-HT1A receptors in the dorsomedial hypothalamus interact for the regulation of panic-related defensive responses.

The dorsomedial hypothalamus (DMH) and the dorsal periaqueductal gray (DPAG) have been implicated in the genesis and regulation of panic-related defensive behaviors, such as escape. Previous results point to an interaction between serotonergic and opioidergic systems within the DPAG to inhibit escape, involving µ-opioid and 5-HT1A receptors (5-HT1AR). In the present study we explore this interaction in the DMH, using escape elicited by electrical stimulation of this area as a panic attack index. The obtained results show that intra-DMH administration of the non-selective opioid receptor antagonist naloxone (0.5 nmol) prevented the panicolytic-like effect of a local injection of serotonin (20 nmol). Pretreatment with the selective µ-opioid receptor (MOR) antagonist CTOP (1 nmol) blocked the panicolytic-like effect of the 5-HT1AR agonist 8-OHDPAT (8 nmol). Intra-DMH injection of the selective MOR agonist DAMGO (0.3 nmol) also inhibited escape behavior, and a previous injection of the 5-HT1AR antagonist WAY-100635 (0.37 nmol) counteracted this panicolytic-like effect. These results offer the first evidence that serotonergic and opioidergic systems work together within the DMH to inhibit panic-like behavior through an interaction between µ-opioid and 5-HT1A receptors, as previously described in the DPAG.

TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling.

Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m-tolyl 5-chloro-2-[ethylsulfonyl] pyrimidine-4-carboxylate [SBI-115]), and (3) a combination of SBI-115 and pasireotide, a somatostatin receptor analogue. In vivo, we examined hepatic cystogenesis in OA-treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5-/- ;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq ) proteins was increased 2-fold to 3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by short hairpin RNA. OA increased cystogenesis in polycystic kidney rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5-/- ;Pkhd1del2/del2 mice. TGR5 expression and its colocalization with Gαs were increased ∼2-fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI-115 alone and by ∼50% when SBI-115 was combined with pasireotide. CONCLUSION: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (Hepatology 2017;66:1197-1218).

Therapeutic Targets in Polycystic Liver Disease.

Polycystic liver diseases (PLD) are a group of genetic disorders initiated by mutations in several PLD-related genes and characterized by the presence of multiple cholangiocyte-derived hepatic cysts that progressively replace liver tissue. PLD co-exists with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Recessive PKD as well as occurs alone (i.e., Autosomal Dominant Polycystic Liver Disease [ADPLD]). PLD associated with ADPKD and ARPKD belong to a group of disorders known as cholangiociliopathies since many disease-causative and disease-related proteins are expressed in primary cilia of cholangiocytes. Aberrant expression of these proteins in primary cilia affects their structures and functions promoting cystogenesis. Current medical therapies for PLD include symptomatic management and surgical interventions. To date, the only available drug treatment for PLD patients that halt disease progression and improve quality of life are somatostatin analogs. However, the modest clinical benefits, need for long-term maintenance therapy, and the high cost of treatment justify the necessity for more effective treatment options. Substantial evidence suggests that experimental manipulations with components of the signaling pathways that influence cyst development (e.g., cAMP, intracellular calcium, receptor tyrosine kinase, transient receptor potential cation channel subfamily V member 4 (TRPV4) channel, mechanistic target of rapamycin (mTOR), histone deacetylase (HDAC6), Cdc25A phosphatase, miRNAs and metalloproteinases) attenuate growth of hepatic cysts. Many of these targets have been evaluated in pre-clinical trials suggesting their value as potential new therapies. This review outlines the current clinical and preclinical treatment strategies for PLD.