Targeted Cancer Therapy: What’s New in the Field of Neuroendocrine Neoplasms?

Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also characterized by the common expression of somatostatin receptors, a target that has been extremely useful for diagnosis and treatment (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Chemotherapy is of limited use for NETs of non-pancreatic origin, and the only approved targeted agents for advanced progressive NETs are sunitinib for those of pancreatic origin, and everolimus for lung, gastrointestinal and pancreatic primaries. Despite recent therapeutic achievements, thus, systemic treatment options remain limited. In this review we will discuss the state-of-the-art targeted therapies in the field of NETs, and also future perspectives of novel therapeutic drugs or strategies in clinical development, including recently presented results from randomized trials of yet unapproved antiangiogenic agents (i.e., pazopanib, surufatinib and axitinib), PRRT including both approved radiopharmaceuticals (177Lu-Oxodotreotide) and others in development (177Lu-Edotreotide, 177Lu-Satoreotide Tetraxetan), immunotherapy and other innovative targeted strategies (antibody-drug conjugates, bites,…) that shall soon improve the landscape of personalized treatment options in NET patients

Metabolomic profile of neuroendocrine tumors (NETs) identifies methionine, porphyrin and tryptophan metabolism as key dysregulated pathways associated with patient survival

Objective: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways.Design and Methods: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA).Results: Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs.Conclusions: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients

Comprehensive Plasma Metabolomic Profile of Patients with Advanced Neuroendocrine Tumors (NETs). Diagnostic and Biological Relevance

Purpose: High-throughput “-omic” technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC−MS, CE−MS and LC−MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research

XVI International Congress of Control Electronics and Telecommunications: "Techno-scientific considerations for a post-pandemic world intensive in knowledge, innovation and sustainable local development"

Este título, sugestivo por los impactos durante la situación de la Covid 19 en el mundo, y que en Colombia lastimosamente han sido muy críticos, permiten asumir la obligada superación de tensiones sociales, políticas, y económicas; pero sobre todo científicas y tecnológicas. Inicialmente, esto supone la existencia de una capacidad de la sociedad colombiana por recuperar su estado inicial después de que haya cesado la perturbación a la que fue sometida por la catastrófica pandemia, y superar ese anterior estado de cosas ya que se encontraban -y aún se encuentran- muchos problemas locales mal resueltos, medianamente resueltos, y muchos sin resolver: es decir, habrá que rediseñar y fortalecer una probada resiliencia social existente - producto del prolongado conflicto social colombiano superado parcialmente por un proceso de paz exitoso - desde la tecnociencia local; como lo indicaba Markus Brunnermeier - economista alemán y catedrático de economía de la Universidad de Princeton- en su libro The Resilient Society…La cuestión no es preveerlo todo sino poder reaccionar…aprender a recuperarse rápido.This title, suggestive of the impacts during the Covid 19 situation in the world, and which have unfortunately been very critical in Colombia, allows us to assume the obligatory overcoming of social, political, and economic tensions; but above all scientific and technological. Initially, this supposes the existence of a capacity of Colombian society to recover its initial state after the disturbance to which it was subjected by the catastrophic pandemic has ceased, and to overcome that previous state of affairs since it was found -and still is find - many local problems poorly resolved, moderately resolved, and many unresolved: that is, an existing social resilience test will have to be redesigned and strengthened - product of the prolonged Colombian social conflict partially overcome by a successful peace process - from local technoscience; As Markus Brunnermeier - German economist and professor of economics at Princeton University - indicates in his book The Resilient Society...The question is not to foresee everything but to be able to react...learn to recover quickly.Bogot

Análisis del perfil de expresión de micrornas en neoplasias neuroendocrinas de origen gastroenteropancreático y pulmonar

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 17/12/2020Las neoplasias neuroendocrinas (NNEs) son una familia de tumores de una gran heterogeneidad biológica. Globalmente son neoplasias con un índice mutacional bajo y no se han identificado mutaciones genéticas conductoras o driver sobre las que se pueda actuar desde el punto de vista terapéutico. Sin embargo, los mecanismos epigenéticos juegan un papel determinante en la biología e historia natural de estos tumores. La expresión de los miRNAs está desregulada en cáncer a través de distintos mecanismos, incluidos la amplificación o delección de los genes que los codifican, alteraciones en la regulación de su transcripción, modificaciones epigenéticas y alteraciones en la maquinaria de su biogénesis, y pueden funcionar como oncogenes o como genes supresores de tumores dependiendo de los genes diana sobre los que actúen. Múltiples estudios han demostrado su utilidad como biomarcadores diagnósticos, pronósticos y terapéuticos en otras neoplasias, pero la evidencia en NNEs es escasa. La hipótesis que fundamenta este trabajo es que las NNEs presentan un perfil de expresión de miRNAs característico y que la identificación de estos miRNAs desregulados puede tener una utilidad clínica diagnóstica, pronóstica, y potencialmente terapéutica. En base a ello, el objetivo global fue caracterizar el perfil de expresión de miRNAs en NNEs de origen GEP y pulmonar, y evaluar su utilidad como potenciales biomarcadores en la clínica. Con este fin hemos analizado retrospectivamente en una cohorte de 128 pacientes con NNEs la expresión de un panel de 84 miRNAs relacionados con cáncer mediante PCR-arrays en muestras pareadas tumorales y no tumorales, con los siguientes objetivos específicos: 1) identificar el perfil de expresión diferencial de miRNAs en tejido tumoral respecto al tejido sano; 2) identificar el perfil de expresión de miRNAs en función de distintas variables clínicas y patológicas de interés, 3) evaluar su valor pronóstico añadido respecto a las variables pronósticas clínicas ya conocidas, y 4) explorar los genes regulados por estos miRNAs con el fin de identificar las rutas moleculares implicadas y su relación con los hallmarks o rasgos distintivos de cáncer, identificar potenciales nuevas dianas terapéuticas y sentar las bases para estudios funcionales futuros...Neuroendocrine neoplasms (NENs) are a family of tumors of great biological heterogeneity. Overall, they are neoplasms with a low mutational burden and no driver mutations have been identified that may be adequate targets for therapy. However, epigenetic mechanisms play a determining role in the biology and natural history of these tumors. The expression of miRNAs is deregulated in cancer through different mechanisms, including the amplification or deletion of the genes that encode them, alterations in the regulation of their transcription, epigenetic modifications and alterations in the machinery of their biogenesis. MiRNAs may function as oncogenes or as tumor suppressor genes depending on the target genes they regulate. Multiple studies have demonstrated their utility as diagnostic, prognostic, and therapeutic biomarkers in other malignancies, but the evidence in NENs is scarce. The hypothesis underlying this work is that NENs present a characteristic miRNA expression profile and that the identification of these deregulated miRNAs can be of potential diagnostic, prognostic or therapeutic utility. Based on this, the overall objective of this study was to characterize the expression profile of miRNAs in NENs of gastroentero-pancreatic (GEP) and pulmonary origin, and to evaluate their utility as potential biomarkers in the clinic. To this end, we have retrospectively analyzed in a cohort of 128 NENs patients the expression of a panel of 84 cancer-related miRNAs using PCR-arrays in paired tumor and non-tumor samples, with the following specific objectives: 1) to identify the differential miRNAs expression profile in tumor versus non-tumor tissue; 2) to identify the differential miRNA expression profile based on different clinical and pathological variables of interest, 3) to evaluate their added prognostic value with respect to the already known clinical prognostic variables, and 4) to explore the genes regulated by these miRNAs in order to identify the molecular pathways involved and their relationship to the hallmarks of cancer, identify potential new therapeutic targets, and pave the way for future functional studies...Fac. de MedicinaTRUEunpu

Diagnosis in Neuroendocrine Neoplasms: From Molecular Biology to Molecular Imaging

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours with a diverse behaviour, biology and prognosis, whose incidence is gradually increasing. Their diagnosis is challenging and a multidisciplinary approach is often required. The combination of pathology, molecular biomarkers, and the use of novel imaging techniques leads to an accurate diagnosis and a better treatment approach. To determine the functionality of the tumour, somatostatin receptor expression, differentiation, and primary tumour origin are the main determining tumour-dependent factors to guide treatment, both in local and metastatic stages. Until recently, little was known about the biological behaviour of these tumours. However, in recent years, many advances have been achieved in the molecular characterization and diagnosis of NENs. The incorporation of novel radiotracer-based imaging techniques, such as 68Gallium-DOTATATE PET-CT, has significantly increased diagnostic sensitivity, while introducing the theragnosis concept, offering new treatment strategies. Here, we will review current knowledge and novelties in the diagnosis of NENs, including molecular biology, pathology, and new radiotracers

Epidemiología de pacientes atendidos por uso de sustancias psicoactivas en el servicio de Toxicología de Colsubsidio 2011-2012

Introducción: Es una necesidad para los países del mundo, tener información epidemiológica mucho más precisa y oportuna sobre las sustancias psicoactivas (SPA), partiendo del conocimiento científico de porqué unas personas abusan de las sustancias y otras no. El objetivo de investigación es establecer el perfil epidemiológico y evolución de los pacientes consumidores de SPA que acuden al servicio de toxicología de Colsubsidio durante el 2011 y 2012. Caracterizar la población, identificar su patrón de consumo y explorar las tendencias, para poder generar estrategias dirigidas de atención y prevención. Metodología: Estudio descriptivo observacional exploratorio retrospectivo. 610 historias clínicas fueron analizadas para variables epidemiológicas y clínicas, por medio de análisis univariados acorde al tipo de variable y análisis bivariados exploratorios en los cuales se compararon proporciones. Resultados: Se evaluaron un total de 610 pacientes, 475 hombres y 135 mujeres. El promedio de edad, la mediana y la moda fue de 24,9, 17 y 16 años respectivamente; la mayoría solteros y cursando bachillerato; la mayoría menores de 18 años fueron remitidos por ICBF y psiquiatría. Los patrones de abuso y dependencia representaron los porcentajes más elevados. Las sustancias más consumidas fueron marihuana, etanol y tabaco. El tratamiento para el 44,3% de los pacientes fue valoración por especialidades, seguido de básico (33,1%), y sólo 1,1% asistieron para prevención en el consumo de SPA. Discusión: Es necesario dirigir los esfuerzos y recursos a la generación de campañas de diagnóstico temprano y prevención en el consumo de SPA principalmente para la población adolescente.Introduction: In all the countries of the world there is a necessity of having more precise and opportune epidemiological information about psychoactive substances, starting with the   scientific   knowledge   of   why   some   people   abuse   these   substances   and   some   don’t.   The   objective of this investigation is to establish a epidemiological profile of the patients that use psychoactive substances and that have use the toxicology services of Colsubsidio during the years 2011 and 2012. Also to characterize their population, to identify the consume pattern and their tendencies to be able to create strategies directed toward attention and prevention. Methodology: Descriptive observational exploratory and retrospective study. 610 clinical cases were analyzed for clinical and epidemiological variables, thought out univariate analysis according to the type of variable and exploratory bivariate analysis in which proportions were compare. Results: There were a total of 610 patients, 475 men and 135 women. The average age, the medium and the style was 24,9,17 and 16 years old respectively; the majority were single and in high school. The majority of patients under 18 were remitted by ICBF and psychiatry. The abuse and dependence patterns represent the highest percentages. The most consume substances were marihuana, ethanol and tobacco. The treatment for 44.3% of the patients was evaluation per specialty, followed by basic (33.1%) and only (1.1%) went to the consumption prevention of psychoactive substances. Discussion: There is a necessity to lead efforts and resources for the creation of campaigns for early diagnosis and prevention of the consumption ofpsychoactive substances, primarily for the adolescence population

Epidemiología de pacientes atendidos por uso de sustancias psicoactivas en el servicio de Toxicología de Colsubsidio 2011-2012

Introducción: Es una necesidad para los países del mundo, tener información epidemiológica mucho más precisa y oportuna sobre las sustancias psicoactivas (SPA), partiendo del conocimiento científico de porqué unas personas abusan de las sustancias y otras no. El objetivo de investigación es establecer el perfil epidemiológico y evolución de los pacientes consumidores de SPA que acuden al servicio de toxicología de Colsubsidio durante el 2011 y 2012. Caracterizar la población, identificar su patrón de consumo y explorar las tendencias, para poder generar estrategias dirigidas de atención y prevención. Metodología: Estudio descriptivo observacional exploratorio retrospectivo. 610 historias clínicas fueron analizadas para variables epidemiológicas y clínicas, por medio de análisis univariados acorde al tipo de variable y análisis bivariados exploratorios en los cuales se compararon proporciones. Resultados: Se evaluaron un total de 610 pacientes, 475 hombres y 135 mujeres. El promedio de edad, la mediana y la moda fue de 24,9, 17 y 16 años respectivamente; la mayoría solteros y cursando bachillerato; la mayoría menores de 18 años fueron remitidos por ICBF y psiquiatría. Los patrones de abuso y dependencia representaron los porcentajes más elevados. Las sustancias más consumidas fueron marihuana, etanol y tabaco. El tratamiento para el 44,3% de los pacientes fue valoración por especialidades, seguido de básico (33,1%), y sólo 1,1% asistieron para prevención en el consumo de SPA. Discusión: Es necesario dirigir los esfuerzos y recursos a la generación de campañas de diagnóstico temprano y prevención en el consumo de SPA principalmente para la población adolescente.Introduction: In all the countries of the world there is a necessity of having more precise and opportune epidemiological information about psychoactive substances, starting with the   scientific   knowledge   of   why   some   people   abuse   these   substances   and   some   don’t.   The   objective of this investigation is to establish a epidemiological profile of the patients that use psychoactive substances and that have use the toxicology services of Colsubsidio during the years 2011 and 2012. Also to characterize their population, to identify the consume pattern and their tendencies to be able to create strategies directed toward attention and prevention. Methodology: Descriptive observational exploratory and retrospective study. 610 clinical cases were analyzed for clinical and epidemiological variables, thought out univariate analysis according to the type of variable and exploratory bivariate analysis in which proportions were compare. Results: There were a total of 610 patients, 475 men and 135 women. The average age, the medium and the style was 24,9,17 and 16 years old respectively; the majority were single and in high school. The majority of patients under 18 were remitted by ICBF and psychiatry. The abuse and dependence patterns represent the highest percentages. The most consume substances were marihuana, ethanol and tobacco. The treatment for 44.3% of the patients was evaluation per specialty, followed by basic (33.1%) and only (1.1%) went to the consumption prevention of psychoactive substances. Discussion: There is a necessity to lead efforts and resources for the creation of campaigns for early diagnosis and prevention of the consumption ofpsychoactive substances, primarily for the adolescence population

Targeted Cancer Therapy: What’s New in the Field of Neuroendocrine Neoplasms?

Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also characterized by the common expression of somatostatin receptors, a target that has been extremely useful for diagnosis and treatment (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Chemotherapy is of limited use for NETs of non-pancreatic origin, and the only approved targeted agents for advanced progressive NETs are sunitinib for those of pancreatic origin, and everolimus for lung, gastrointestinal and pancreatic primaries. Despite recent therapeutic achievements, thus, systemic treatment options remain limited. In this review we will discuss the state-of-the-art targeted therapies in the field of NETs, and also future perspectives of novel therapeutic drugs or strategies in clinical development, including recently presented results from randomized trials of yet unapproved antiangiogenic agents (i.e., pazopanib, surufatinib and axitinib), PRRT including both approved radiopharmaceuticals (177Lu-Oxodotreotide) and others in development (177Lu-Edotreotide, 177Lu-Satoreotide Tetraxetan), immunotherapy and other innovative targeted strategies (antibody-drug conjugates, bites,…) that shall soon improve the landscape of personalized treatment options in NET patients