Implicaciones del endotelio en la insuficiencia cardiaca

The role of the endothelium in heart failure has been the focus of intense research, since it has important biologic implications. There are individual differences in the pattern of endothelial dysfunction according to the etiology and severity of heart failure. Endothelial dysfunction is also associated with negative outcomes. We are eagerly waiting for new pharmacological agents targeted specifically to the vascular endothelium. In this review, we aim to provide a critical analysis of the available evidence on the pathological consequences and prognosis of endothelial abnormalities as related to the onset and natural history of heart failure.El papel del endotelio en la insuficiencia cardíaca (IC) ha sido el centro de intensa investigación, puesto que tiene importantes implicaciones sistémicas expresadas en su efecto vasomotor, hemostático e inflamatorio. Existen diferencias individuales en el patrón de la disfunción endotelial de acuerdo a la etiología y severidad de la IC. La disfunción endotelial tiene un importante valor pronóstico en la IC y, aunque aún necesitamos conocer más aspectos de relevancia clínica, es evidente que esta condición se relaciona con desenlaces negativos en estos pacientes. Estamos a la espera de nuevos agentes farmacéuticos dirigidos específicamente al endotelio vascular. En esta revisión, nuestro objetivo es ofrecer un análisis crítico y contemporáneo de la evidencia disponible sobre las consecuencias patológicas y pronóstico de las anomalías endoteliales que definen el inicio, la historia natural y, en última instancia, los desenlaces en la IC

Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis

PURPOSE: Immune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption. METHODS: This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses assessed the association of clinical covariates and IMDC recurrence. RESULTS: Of the 167 patients in our analysis, 32 resumed an anti–cytotoxic T-cell lymphocyte-4 (CTLA-4) agent, and 135 an anti–programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years (interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti–CTLA-4 and 32% of those receiving an anti–PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients who received anti–PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45; 95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower after resumption of anti–PD-1/L1 therapy than after resumption of anti–CTLA-4 therapy (OR, 0.30; 95% CI, 0.11 to 0.81; P = .019). CONCLUSION: One third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Recurrence of IMDC was less frequent after resumption of anti–PD-1/L1 than after resumption of anti–CTLA-

Pemetrexed/Carboplatin/Bevacizumab followed by Maintenance Pemetrexed/Bevacizumab in Hispanic Patients with Non-Squamous Non-Small Cell Lung Cancer : Outcomes according to Thymidylate Synthase Expression

Q2Q1Artículo de investigación1-15Pacientes con cáncer de pulmón de células no pequeñas en estadio IVObjective To evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance therapy with pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS) protein and mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Methods A cohort of 144 patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance PB was administered until disease progression or unacceptable toxicity. Results One hundred forty-four Colombian patients with a median follow-up of 13.8 months and a median number of 6 maintenance cycles (range, 1–32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median PFS and (OS) rates were 7.9 months (95% CI, 5.9–10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. We documented grade 3/4 hematologic toxicities, including anemia (14%), neutropenia (8%), and thrombocytopenia (16%). The identified grade 3/4 non-hematologic toxicities were proteinuria (2%), venous thrombosis (4%), fatigue (11%), infection (6%), nephrotoxicity (2%), and sensory neuropathy (4%). No grade >3 hemorrhagic events or hypertension cases were reported. OS was significantly higher in patients with the lowest TS mRNA levels [median, 29.6 months (95% CI, 26.2–32.9)] compared with those in patients with higher levels [median, 9.3 months (95% CI, 6.6–12.0); p = 0.0001]. TS expression (mRNA levels or protein expression) did not influence the treatment response. Conclusion Overall, PCB followed by maintenance pemetrexed and bevacizumab was effective and tolerable in Hispanic patients with non-squamous NSCLC. This regimen was associated with acceptable toxicity and prolonged OS, particularly in patients with low TS expression. We found a role for Ki67 and TS expression as prognostic factors

CT694 and pgp3 as Serological Tools for Monitoring Trachoma Programs.

Defining endpoints for trachoma programs can be a challenge as clinical signs of infection may persist in the absence of detectable bacteria. Antibody-based tests may provide an alternative testing strategy for surveillance during terminal phases of the program. Antibody-based assays, in particular ELISAs, have been shown to be useful to document C. trachomatis genital infections, but have not been explored extensively for ocular C. trachomatis infections. An antibody-based multiplex assay was used to test two C. trachomatis antigens, pgp3 and CT694, for detection of trachoma antibodies in bloodspots from Tanzanian children (n = 160) collected after multiple rounds of mass azithromycin treatment. Using samples from C. trachomatis-positive (by PCR) children from Tanzania (n = 11) and control sera from a non-endemic group of U.S. children (n = 122), IgG responses to both pgp3 and CT694 were determined to be 91% sensitive and 98% specific. Antibody responses of Tanzanian children were analyzed with regard to clinical trachoma, PCR positivity, and age. In general, children with more intense ocular pathology (TF/TI = 2 or most severe) had a higher median antibody response to pgp3 (p = 0.0041) and CT694 (p = 0.0282) than those with normal exams (TF/TI = 0). However, 44% of children with no ocular pathology tested positive for antibody, suggesting prior infection. The median titer of antibody responses for children less than three years of age was significantly lower than those of older children. (p<0.0001 for both antigens). The antibody-based multiplex assay is a sensitive and specific additional tool for evaluating trachoma transmission. The assay can also be expanded to include antigens representing different diseases, allowing for a robust assay for monitoring across NTD programs

Acquired Resistance to Erlotinib in EGFR Mutation-Positive Lung Adenocarcinoma among Hispanics (CLICaP)

Q2Q1Artículo original513-523Background Lung cancer harboring epidermal growth factor receptor (EGFR) mutations and treated with EGFR tyrosine kinase inhibitors (TKIs) all eventually develop acquired resistance to the treatment, with half of the patients developing EGFR T790M resistance mutations. Objective The purpose of this study was to assess histological and clinical characteristics and survival outcomes in Hispanic EGFR mutated lung cancer patients after disease progression. Patients and Methods EGFR mutation-positive lung cancer patients (n = 34) with acquired resistance to the EGFR-TKI erlotinib were identified from 2011 to 2015. Post-progression tumor specimens were collected for molecular analysis. Post-progression interventions, response to treatment, and survival were assessed and compared among all patients and those with and without T790M mutations. Results Mean age was 59.4 +/- 13.9 years, 65% were never-smokers, and 53% had a performance status 0-1. All patients received erlotinib as first-line treatment. Identified mutations included: 60% DelE19 (Del746-750) and 40% L858R. First-line erlotinib overall response rate (ORR) was 61.8% and progression free survival (PFS) was 16.8 months (95% CI: 13.7-19.9). Acquired resistance mutations identified were T790M mutation (47.1%); PI3K mutations (14.7%); EGFR amplification (14.7%); KRAS mutation (5.9%); MET amplification (8.8%); HER2 alterations (5.9%, deletions/insertions in e20); and SCLC transformation (2.9%). Of patients, 79.4% received treatment after progression. ORR for post-erlotinib treatment was 47.1% (CR 2/PR 14) and median PFS was 8.3 months (95% CI: 2.2-36.6). Median overall survival (OS) from treatment initiation was 32.9 months (95% CI: 30.4-35.3), and only the use of post-progression therapy affected OS in a multivariate analysis (p = 0.05). Conclusions Hispanic patients with acquired resistance to erlotinib continued to be sensitive to other treatments after progression. The proportion of T790M+ patients appears to be similar to that previously reported in Caucasians

Genotyping low-grade gliomas among hispanics

Q2164-172Background. Low-grade gliomas (LGGs) are classified by the World Health Organization as astrocytoma (DA), oligodendroglioma (OD), and mixed oligoastrocytoma (OA). TP53 mutation and 1p19q codeletion are the most-commonly documented molecular abnormalities. Isocitrate dehydrogenase (IDH) 1/2 mutations are frequent in LGGs; however, IDH-negative gliomas can also occur. Recent research suggests that ATRX plays a significant role in gliomagenesis. Methods. We investigated p53 and Olig2 protein expression, and MGMT promoter methylation, 1p19q codeletion, IDH, and ATRX status in 63 Colombian patients with LGG. The overall survival (OS) rate was estimated and compared according to genotype. Results. The most common histology was DA, followed by OD and OA. IDH1/2 mutations were found in 57.1% and MGMT+ (positive status of MGMT promoter methylation methyl-guanyl-methyl-transferase gene) in 65.1% of patients, while overexpression of p53 and Olig2 was present in 30.2% and 44.4%, respectively, and 1p19q codeletion in 34.9% of the patients. Overexpression of ATRX was analyzed in 25 patients, 16% tested positive and were also mutations in isocitrate dehydrogenase and negative 1p19q-codelition. The median follow-up was 15.8 months (95% CI, 7.6–42.0) and OS was 39.2 months (95% CI, 1.3–114). OS was positively and significantly affected by MGMT+, 1p19q codeletion, surgical intervention extent, and number of lobes involved. Multivariate analysis confirmed that MGMT methylation status and 1p19q codeletion affected OS. Conclusions. This is the first study evaluating the molecular profile of Hispanic LGG patients. Findings confirmed the prognostic relevance of MGMT methylation and 1p19q codeletion, but do not support IDH1/2 mutation as a relevant marker. The latter may be explained by sample size and selection bias. ATRX alterations were limited to patients with DA and were mutations in isocitrate dehydrogenase and negative 1p19q-codelition

Cancer Genome Sequencing and Its Implications for Personalized Cancer Vaccines

New DNA sequencing platforms have revolutionized human genome sequencing. The dramatic advances in genome sequencing technologies predict that the $1,000 genome will become a reality within the next few years. Applied to cancer, the availability of cancer genome sequences permits real-time decision-making with the potential to affect diagnosis, prognosis, and treatment, and has opened the door towards personalized medicine. A promising strategy is the identification of mutated tumor antigens, and the design of personalized cancer vaccines. Supporting this notion are preliminary analyses of the epitope landscape in breast cancer suggesting that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines

Biodegradabilidad anaerobia y toxicidad de aguas residuales complejas o tóxicas

RESUMEN: Como una primera aproximación a la clasificación de las aguas residuales (A.R.) en términos de su susceptibilidad al tratamiento por sistemas biológicos anaeróbicos re realizaron ensayos de biodegrabilidad (BD) anaerobia al lixiviado de un relleno sanitario, a las A.R de un beneficiadero de café por vía húmeda y a las A.R. de una planta de recuperación de ácido fumárico. A esta última se le hicieron además ensayos de toxicidad anaerobia y toxicidad letal sobre el microcrustáceo Daphniapulex. La fase experimental se ejecutó en un lapso de 12 meses en los laboratorios del Departamento de Ingeniería Sanitaria y Ambiental y en el laboratorio de bioensayos del Centro de Investigaciones Ambientales Y de Ingeniería (CIA) ambos laboratorios de la Facultad de Ingeniería de la Universidad de Antioquia. Los bioensayos anaerobios se realizaron fundamentalmente con la metodología propuesta por la Universidad Agrícola de Wageningen, Holanda en 1987, y los bioensayos de toxicidad letal se ejecutaron con los procedimientos propuestos por el Standard Methods for the Examination of Water and Wastewater, 18 th edition, 1992, con las modificaciones efectuadas por los investigadores del CIA. En el desarrollo de esta investigación se encontró que el efluente de la planta de recuperación de ácido fumárico tiene como características una baja BD anaerobia, un alto grado de toxicidad anaerobia y toxicidad letal sobre Daphnia Pulex por lo que se puede catalogar como A.R. de características complejas y tóxicas. Las A.R. procedentes una planta beneficiadora de café por vía húmeda y del lixiviado de un relleno sanitario, resultaron ser altamente biodegradables y por lo tanto no tóxicas, resultado que permite catalogarlas como susceptibles de ser tratadas mediante sistema biológico anaerobio