A phase I trial of oncolytic adenovirus ICOVIR-5 administered intravenously to cutaneous and uveal melanoma patients

Oncolytic viruses represent a unique type of agents that combine self-amplification, lytic, and immunostimulatory properties against tumors. A local and locoregional clinical benefit has been demonstrated upon intratumoral injections of an oncolytic herpes virus in melanoma patients, leading to its approval in the United States and Europe for patients without visceral disease (up to stage IVM1a). However, in order to debulk and change the local immunosuppressive environment of tumors that cannot be injected directly, oncolyitc viruses need to be administered systemically. Among different viruses, adenovirus has been extensively used in clinical trials but with few evidences of activity upon systemic administration. Preclinical efficacy of a single intravenous administration of our oncolytic adenovirus ICOVIR5, an adenovirus type 5 responsive to the retinoblastoma pathway commonly deregulated in tumors, led us to use this virus in a dose-escalation phase 1 trial in metastatic melanoma patients. The results in 12 patients treated with a single infusion of a dose up to 1 × 1013 viral particles show that ICOVIR5 can reach melanoma metastases upon a single intravenous administration but fails to induce tumor regressions. These results support the systemic administration of armed oncolytic viruses to treat disseminated cancer

Mutanome and expression of immune response genes in microsatellite stable colon cancer

The aim of this study was to analyze the impact of the mutanome in the prognosis of microsatellite stable stage II CRC tumors. The exome of 42 stage II, microsatellite stable, colon tumors (21 of them relapse) and their paired mucosa were sequenced and analyzed. Although some pathways accumulated more mutations in patients exhibiting good or poor prognosis, no single somatic mutation was associated with prognosis. Exome sequencing data is also valuable to infer tumor neoantigens able to elicit a host immune response. Hence, putative neoantigens were identified by combining information about missense mutations in each tumor and HLAs genotypes of the patients. Under the hypothesis that neoantigens should be correctly presented in order to activate the immune response, expression levels of genes involved in the antigen presentation machinery were also assessed. In addition, CD8A level (as a marker of T-cell infiltration) was measured. We found that tumors with better prognosis showed a tendency to generate a higher number of immunogenic epitopes, and up-regulated genes involved in the antigen processing machinery. Moreover, tumors with higher T-cell infiltration also showed better prognosis. Stratifying by consensus molecular subtype, CMS4 tumors showed the highest association of expression levels of genes involved in the antigen presentation machinery with prognosis. Thus, we hypothesize that a subset of stage II microsatellite stable CRC tumors are able to generate an immune response in the host via MHC class I antigen presentation, directly related with a better prognosis

Community-acquired pneumonia management in a short-stay unit: analysis of safety and efficacy

Podeu consultar la versió en castellà a: http://hdl.handle.net/2445/119397Background and objective: Community-acquired pneumonia (CAP) is a highly prevalent disease that often requires hospital admission. We aimed to assess the safety and efficacy of treating CAP in a short-stay unit as an alternative to conventional hospitalization. Methods: Retrospective comparison of patients admitted to a tertiary care hospital with a diagnosis of CAP between November 2005 and April 2007. We compared outcomes for cases managed in the 2 locations (short-stay unit vs conventional hospital ward), excluding patients who required intensive care. Variables and outcomes analyzed were age, sex, Charlson index, mean weight in the diagnosis-related group, scores on the CURB-65 criteria and the Pneumonia Severity Index (PSI), findings of microbiology, and readmission and mortality rates. Results: A total of 606 patients were studied; 187 were treated in the short-stay unit and 419 were admitted to the conventional ward. The main significant differences between the 2 groups were mean age (77.3 vs 67.9 years, respectively; P<.0001) and mean stay (3.48 vs 7.89 days; P<.0001). These differences were also reflected in the comparison between severity subgroups (by PSI). Mortality rates did not differ. Conclusions: Our experience with the short-stay unit suggests it offers a safe and effective way to manage CAP and leads to a significantly shorter hospital stay in comparison with conventional hospitalization, without increasing readmission and mortality rates

Análisis de la seguridad y la eficacia de una unidad de corta estancia en el tratamiento de la neumonía adquirida en la comunidad

Podeu consultar la versió en anglès a: http://hdl.handle.net/2445/119414Introducción: La neumonía adquirida en la comunidad (NAC) es una patología de alta prevalencia que a menudo requiere ingreso hospitalario. El objetivo de nuestro estudio es evaluar la eficacia y seguridad en el tratamiento de la NAC de una unidad de corta estancia (UCE) como alternativa a las unidades de hospitalización convencional (UHC). Método: Estudio retrospectivo comparativo de pacientes ingresados en un hospital terciario con diagnóstico al alta de NAC entre noviembre del 2005 y abril del 2007. Se comparan dos grupos: pacientes ingresados en UCE frente a pacientes ingresados en UHC (se excluyen pacientes que requieren terapia intensiva). Variables analizadas: edad y sexo, índice de Charlson, peso según el grupo relacionado de diagnóstico (GRD), CURB 65 y Pneumonia Severity Index (PSI), hallazgos microbiológicos, tasas de readmisión y de mortalidad. Resultados: Un total de 606 pacientes fueron reclutados, 187 ingresados en el UCE (grupo 1) y 419 en UHC (grupo 2 o grupo control). Las diferencias más significativas entre los dos grupos fueron el promedio de edad (77,3 vs 67,9 p < 0,001) y la estancia promedio (3,48 vs 7,89 p < 0,001). Estas diferencias se objetivan en el comparativo general y por subgrupos según la escala de riesgo (PSI). No se observaron diferencias significativas en la tasa de mortalidad ni en la de reingreso entre las dos formas de hospitalización. Conclusiones: La UCE es eficaz y segura en el manejo de los pacientes con NAC, con una estancia media significativamente inferior respecto a las UHC, y sin diferencias en las tasas de mortalidad y reingreso

Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors

Background VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer. Methods Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed. Results 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1 x10(13) viral particles (vp)/patient (Part I), and 3.3x10(12) vp/patient (Part II). Fourteen patients were included in Part Ill: there were no DLTs and the RP2D was 1 x10(13) vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1x10(13) vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1 x10(13) vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon- r,soluble lymphocyte activation ne-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration. Conclusions Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paditaxel plus gemcitabine to patients with pancreatic adenocarcinoma

Circuits i dispositius electrònics : fonaments d'electrònica

Obra guardonada per la UPCL'obra ha estat concebuda de forma autocontinguda, de manera que la pugui seguir qualsevol lector que no tingui més coneixements previs que els que hagi adquirit durant l'etapa preuniversitària. La primera part del llibre conté una introducció a la teoria bàsica dels circuits electrònics, i a continuació se'n presenten els dispositius principals i la seva utilització en circuits elementals. Es fa una atenció especial a la utilització del programa SPICE per a l'anàlisi de circuits per ordinador. Així mateix, també es dedica un capitol a introduir la tecnologia de fabricació i la teoria de funcionament dels principals dispositius semiconductors.Award-winnin

Community-acquired pneumonia management in a short-stay unit: analysis of safety and efficacy

Podeu consultar la versió en castellà a: http://hdl.handle.net/2445/119397Background and objective: Community-acquired pneumonia (CAP) is a highly prevalent disease that often requires hospital admission. We aimed to assess the safety and efficacy of treating CAP in a short-stay unit as an alternative to conventional hospitalization. Methods: Retrospective comparison of patients admitted to a tertiary care hospital with a diagnosis of CAP between November 2005 and April 2007. We compared outcomes for cases managed in the 2 locations (short-stay unit vs conventional hospital ward), excluding patients who required intensive care. Variables and outcomes analyzed were age, sex, Charlson index, mean weight in the diagnosis-related group, scores on the CURB-65 criteria and the Pneumonia Severity Index (PSI), findings of microbiology, and readmission and mortality rates. Results: A total of 606 patients were studied; 187 were treated in the short-stay unit and 419 were admitted to the conventional ward. The main significant differences between the 2 groups were mean age (77.3 vs 67.9 years, respectively; P<.0001) and mean stay (3.48 vs 7.89 days; P<.0001). These differences were also reflected in the comparison between severity subgroups (by PSI). Mortality rates did not differ. Conclusions: Our experience with the short-stay unit suggests it offers a safe and effective way to manage CAP and leads to a significantly shorter hospital stay in comparison with conventional hospitalization, without increasing readmission and mortality rates

VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects

Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense desmoplastic stroma that limits the delivery of anticancer agents. VCN-01 is an oncolytic adenovirus designed to replicate in cancer cells with a dysfunctional RB1 pathway and express hyaluronidase. Here, we evaluated the mechanism of action of VCN-01 in preclinical models and in patients with pancreatic cancer. Methods VCN-01 replication and antitumor efficacy were evaluated alone and in combination with standard chemotherapy in immunodeficient and immunocompetent preclinical models using intravenous or intratumoral administration. Hyaluronidase activity was evaluated by histochemical staining and by measuring drug delivery into tumors. In a proof-of-concept clinical trial, VCN-01 was administered intratumorally to patients with PDAC at doses up to 1x10(11) viral particles in combination with chemotherapy. Hyaluronidase expression was measured in serum by an ELISA and its activity within tumors by endoscopic ultrasound elastography. Results VCN-01 replicated in PDAC models and exerted antitumor effects which were improved when combined with chemotherapy. Hyaluronidase expression by VCN-01 degraded tumor stroma and facilitated delivery of a variety of therapeutic agents such as chemotherapy and therapeutic antibodies. Clinically, treatment was generally well-tolerated and resulted in disease stabilization of injected lesions. VCN-01 was detected in blood as secondary peaks and in post-treatment tumor biopsies, indicating virus replication. Patients had increasing levels of hyaluronidase in sera over time and decreased tumor stiffness, suggesting stromal disruption. Conclusions VCN-01 is an oncolytic adenovirus with direct antitumor effects and stromal disruption capabilities, representing a new therapeutic agent for cancers with dense stroma

Análisis de la seguridad y la eficacia de una unidad de corta estancia en el tratamiento de la neumonía adquirida en la comunidad

Podeu consultar la versió en anglès a: http://hdl.handle.net/2445/119414Introducción: La neumonía adquirida en la comunidad (NAC) es una patología de alta prevalencia que a menudo requiere ingreso hospitalario. El objetivo de nuestro estudio es evaluar la eficacia y seguridad en el tratamiento de la NAC de una unidad de corta estancia (UCE) como alternativa a las unidades de hospitalización convencional (UHC). Método: Estudio retrospectivo comparativo de pacientes ingresados en un hospital terciario con diagnóstico al alta de NAC entre noviembre del 2005 y abril del 2007. Se comparan dos grupos: pacientes ingresados en UCE frente a pacientes ingresados en UHC (se excluyen pacientes que requieren terapia intensiva). Variables analizadas: edad y sexo, índice de Charlson, peso según el grupo relacionado de diagnóstico (GRD), CURB 65 y Pneumonia Severity Index (PSI), hallazgos microbiológicos, tasas de readmisión y de mortalidad. Resultados: Un total de 606 pacientes fueron reclutados, 187 ingresados en el UCE (grupo 1) y 419 en UHC (grupo 2 o grupo control). Las diferencias más significativas entre los dos grupos fueron el promedio de edad (77,3 vs 67,9 p < 0,001) y la estancia promedio (3,48 vs 7,89 p < 0,001). Estas diferencias se objetivan en el comparativo general y por subgrupos según la escala de riesgo (PSI). No se observaron diferencias significativas en la tasa de mortalidad ni en la de reingreso entre las dos formas de hospitalización. Conclusiones: La UCE es eficaz y segura en el manejo de los pacientes con NAC, con una estancia media significativamente inferior respecto a las UHC, y sin diferencias en las tasas de mortalidad y reingreso

A phase I trial of oncolytic adenovirus ICOVIR-5 administered intravenously to cutaneous and uveal melanoma patients

Oncolytic viruses represent a unique type of agents that combine self-amplification, lytic, and immunostimulatory properties against tumors. A local and locoregional clinical benefit has been demonstrated upon intratumoral injections of an oncolytic herpes virus in melanoma patients, leading to its approval in the United States and Europe for patients without visceral disease (up to stage IVM1a). However, in order to debulk and change the local immunosuppressive environment of tumors that cannot be injected directly, oncolyitc viruses need to be administered systemically. Among different viruses, adenovirus has been extensively used in clinical trials but with few evidences of activity upon systemic administration. Preclinical efficacy of a single intravenous administration of our oncolytic adenovirus ICOVIR5, an adenovirus type 5 responsive to the retinoblastoma pathway commonly deregulated in tumors, led us to use this virus in a dose-escalation phase 1 trial in metastatic melanoma patients. The results in 12 patients treated with a single infusion of a dose up to 1 × 1013 viral particles show that ICOVIR5 can reach melanoma metastases upon a single intravenous administration but fails to induce tumor regressions. These results support the systemic administration of armed oncolytic viruses to treat disseminated cancer