Dynamic nature of BRAF or KRAS p.G12C mutations in second-line therapy for advanced colorectal cancer patients: do early and late effects exist?

INTRODUCTION: The mitogen-activated protein kinase (MAPK) signalling network aberrations in metastatic colorectal cancer (mCRC) generate intrinsic dynamic effects and temporal variations that are crucial but often overlooked in clinical trial populations. Here, we investigate the time-varying impact of MAPK pathway mutation genotype on each treatment line's contribution to the overall clinical course. METHODS: The PROMETEO study focused on mCRC patients undergoing second-line treatment at 20 hospitals. We evaluated genotypes and employed flexible models to analyse the dynamic effect of each mutation. RESULTS: We examined data derived from 1160 patients. The effects of KRAS G12C or G12V, and BRAF V600E are clearly time-varying, with unexpected consequences such as the deleterious effect of BRAF V600E vs other genotypes dissipating over time when subjects receive antiangiogenics, or KRAS G12V and G12C showing increasing aggressiveness over time. Thus, contrary to expectations, the 12-month survival rate from the second line for those who survived >6 months was 49.9% (95% CI, 32.7-67.3) for KRAS G12C and 59% (95% CI, 38.5-80.6) for BRAF V600E. CONCLUSIONS: The dynamic perspective is essential for understanding the behaviour of tumours with specific genotypes, especially from the second line onward. This may be relevant in patient monitoring and treatment decision-making, particularly in cases with distinct mutations.

Effect of antiangiogenic-based treatment and systemic inflammatory factors on outcomes in patients with BRAF v600-mutated metastatic colorectal cancer: a real-world study in Spain.

BACKGROUND: Outcomes are poorer in metastatic colorectal cancer (mCRC) patients with BRAF V600E mutations than those without it, but the effect of these mutations on treatment response is unclear. This real-world study assessed the effects of antiangiogenic-based treatment and systemic inflammatory factors on outcomes in patients with BRAF V600-mutated mCRC. METHODS: This real-world, multicenter, retrospective, observational study included patients with BRAF V600-mutated mCRC treated in eight hospitals in Spain. The primary endpoints were overall survival (OS) and progression-free survival (PFS); overall response rate (ORR) and disease control rate (DCR) were also assessed. The effect of first- and second-line treatment type on OS, PFS, ORR, and DCR were evaluated, plus the impact of systemic inflammatory markers on these outcomes. A systemic inflammation score (SIS) of 1-3 was assigned based on one point each for platelet-lymphocyte ratio (PLR) ≥200, neutrophil-lymphocyte ratio (NLR) ≥3, and serum albumin < 3.6 g/dL. RESULTS: Of 72 patients, data from 64 were analyzed. After a median of 69.1 months, median OS was 11.9 months and median first-line PFS was 4.4 months. First-line treatment was triplet chemotherapy-antiangiogenic (12.5%), doublet chemotherapy-antiangiogenic (47.2%), doublet chemotherapy-anti-EGFR (11.1%), or doublet chemotherapy (18.1%). Although first-line treatment showed no significant effect on OS, antiangiogenic-based regimens were associated with prolonged median PFS versus non-antiangiogenic regimens. Negative predictors of survival with antiangiogenic-based treatment were NLR, serum albumin, and SIS 1-3, but not PLR. Patients with SIS 1-3 showed significantly prolonged PFS with antiangiogenic-based treatment versus non-antiangiogenic-based treatment, while those with SIS=0 showed no PFS benefit. CONCLUSIONS: Antiangiogenic-based regimens, SIS, NLR, and albumin were predictors of survival in patients with mCRC, while SIS, NLR and serum albumin may predict response to antiangiogenic-based chemotherapy. TRIAL REGISTRATION: GIT-BRAF-2017-01.

Risk of mortality among patients with moderate to severe obstructive sleep apnea and diabetes mellitus: results from the SantOSA cohort.

INTRODUCTION: Patients with obstructive sleep apnea (OSA) and comorbid diabetes mellitus (DM) are reported to have an increased risk of cardiovascular (CV) outcomes; however, data on CV mortality are scant. AIM: This study aimed to evaluate if patients with comorbid OSA and DM have an increased risk of CV mortality that is higher than the two diseases in isolation. METHODS: In this prospective cohort study, we included patients referred for a sleep study with and without DM at baseline. We developed four study groups as follows: group 1 (reference group), OSA (-) DM (-); group 2, OSA (-) DM (+); group 3, OSA (+) DM (-); group 4, OSA (+) DM (+). Intergroup differences were evaluated using the t test and χ2 test, and multivariate analysis was performed using logistic regression. The incidence rates of CV mortality were calculated using the Kaplan-Meier (log-rank) model, and adjusted HRs were calculated using the Cox regression model. RESULTS: A total of 1447 patients were included in the analysis-group 1: 441 participants; group 2: 141 participants; group 3: 736 participants; group 4: 151 participants. The mean follow-up was 5 years. The association between OSA + DM showed an independent risk of incident CV mortality (HR 2.37, CI 1.16-4.82, p = 0.02) and an increased prevalence of coronary heart disease (OR 3.44, CI 1.73-5.59, p < 0.01). In addition, T90% was also associated with CV mortality. CONCLUSION: The coexistence of OSA + DM was associated with an independent risk of CV mortality. In addition, T90% was also associated with CV mortality.

Predicting Outcome and Therapy Response in mCRC Patients Using an Indirect Method for CTCs Detection by a Multigene Expression Panel: A Multicentric Prospective Validation Study.

Colorectal cancer (CRC) is one of the major causes of cancer-related deaths. Early detection of tumor relapse is crucial for determining the most appropriate therapeutic management. In clinical practice, computed tomography (CT) is routinely used, but small tumor changes are difficult to visualize, and reliable blood-based prognostic and monitoring biomarkers are urgently needed. The aim of this study was to prospectively validate a gene expression panel (composed of GAPDH, VIL1, CLU, TIMP1, TLN1, LOXL3 and ZEB2) for detecting circulating tumor cells (CTCs) as prognostic and predictive tool in blood samples from 94 metastatic CRC (mCRC) patients. Patients with higher gene panel expression before treatment had a reduced progression-free survival (PFS) and overall-survival (OS) rates compared with patients with low expression (p = 0.003 and p ≤ 0.001, respectively). Patients with increased expression of CTCs markers during treatment presented PFS and OS times of 8.95 and 11.74 months, respectively, compared with 14.41 and 24.7 for patients presenting decreased expression (PFS; p = 0.020; OS; p ≤ 0.001). Patients classified as non-responders by CTCs with treatment, but classified as responders by CT scan, showed significantly shorter survival times (PFS: 8.53 vs. 11.70; OS: 10.37 vs. 24.13; months). In conclusion, our CTCs detection panel demonstrated efficacy for early treatment response assessment in mCRC patients, and with increased reliability compared to CT scan.

Clinical significance of baseline Pan-Immune-Inflammation Value and its dynamics in metastatic colorectal cancer patients under first-line chemotherapy.

Pan-Immune-Inflammation Value (PIV) has been recently proposed as a new blood-based prognostic biomarker in metastatic colorectal cancer (mCRC). Herein we aimed to validate its prognostic significance and to evaluate its utility for disease monitoring in patients with mCRC receiving first-line chemotherapy. We conducted a single-centre retrospective study involving 130 previously untreated mCRC patients under first-line standard chemotherapy in a real-world scenario. PIV was calculated as (neutrophil count × platelet count × monocyte count)/lymphocyte count at three different time-points: baseline, week 4 after therapy initiation, and at disease progression. We analyzed the influence of baseline PIV on overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and overall response rate (ORR). We also explored the utility of PIV dynamics for disease monitoring. Baseline PIV high was significantly associated with worse OS in univariate [hazard ratio (HR) = 2.10, 95% CI, 1.41-3.15; p = 0.000299] and multivariate (HR = 1.82, 95% CI, 1.15-2.90; p = 0.011) analyses. Baseline PIV was also associated with worse PFS in univariate (HR = 2.04, 95% CI, 1.40-2.97; p = 0.000187) and multivariate (HR = 1.56, 95% CI, 1.05-2.31; p = 0.026) analyses. Baseline PIV was not correlated either with DCR or ORR. Regarding PIV dynamics, there was a statistically significant increase from week 4 to disease progression (p = 0.0003), which was at the expense of cases with disease control as best response (p < 0.0001). In conclusion, this study validates the prognostic significance of baseline PIV in patients with mCRC receiving first-line standard chemotherapy in a real-world scenario. Moreover, it suggests the potential utility of PIV monitoring to anticipate the disease progression among those patients who achieve initial disease control.

Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA.

BACKGROUND: Current noninvasive assays have limitations in the early detection of colorectal cancer. We evaluated the clinical utility of promoter methylation of the long noncoding RNA LINC00473 as a noninvasive biomarker to detect colorectal cancer and associated precancerous lesions. METHODS: We evaluated the epigenetic regulation of LINC00473 through promoter hypermethylation in colorectal cancer cell lines using bisulfite genomic sequencing and expression analyses. DNA methylation of LINC00473 was analyzed in primary colorectal tumors using 450K arrays and RNA-seq from The Cancer Genome Atlas (TCGA). Tissue-based findings were validated in several independent cohorts of colorectal cancer and advanced colorectal polyp patients by pyrosequencing. We explored the clinical utility of LINC00473 methylation for the early detection of colorectal cancer in plasma cell-free DNA by quantitative methylation-specific PCR and droplet digital PCR. RESULTS: LINC00473 showed transcriptionally silencing due to promoter hypermethylation in colorectal cancer cell lines and primary tumors. Methylation of the LINC00473 promoter accurately detected primary colorectal tumors in two independent clinical cohorts, with areas under the receiver operating characteristic curves (AUCs) of 0.94 and 0.89. This biomarker also identified advanced colorectal polyps from two other tissue-based clinical cohorts with high diagnostic accuracy (AUCs of 0.99 and 0.78). Finally, methylation analysis of the LINC00473 promoter in plasma cell-free DNA accurately identified patients with colorectal cancer and advanced colorectal polyps (AUCs of 0.88 and 0.84, respectively), which was confirmed in an independent cohort of patients. CONCLUSIONS: Hypermethylation of the LINC00473 promoter is a new promising biomarker for noninvasive early detection of colorectal cancer and related precancerous lesions.

Association between cardiovascular mortality and STOP-Bang questionnaire scores in a cohort of hospitalized patients: a prospective study.

OBJECTIVE: Obstructive sleep apnea (OSA) is associated with an increased risk of mortality and cardiometabolic diseases. The STOP-Bang questionnaire is a tool to screen populations at risk of OSA and prioritize complementary studies. Our objective was to evaluate the clinical utility of this questionnaire in identifying patients at an increased risk of mortality after discharge in a cohort of hospitalized patients. METHODS: This was a prospective cohort study involving consecutive patients admitted to an internal medicine unit between May and June of 2017 who were reevaluated three years after discharge. At baseline, we collected data on comorbidities (hypertension, obesity, diabetes, and fasting lipid profile) and calculated STOP-Bang scores, defining the risk of OSA (0-2 score, no risk; ≥ 3 score, risk of OSA; and ≥ 5 score, risk of moderate-to-severe OSA), which determined the study groups. We also recorded data regarding all-cause and cardiovascular mortality at the end of the follow-up period. RESULTS: The sample comprised 435 patients. Of those, 352 (80.9%) and 182 (41.8%) had STOP-Bang scores ≥ 3 and ≥ 5, respectively. When compared with the group with STOP-Bang scores of 0-2, the two groups showed higher prevalences of obesity, hypertension, diabetes, and dyslipidemia. Multivariate analysis showed an independent association between cardiovascular mortality and STOP-Bang score ≥ 5 (adjusted hazard ratio = 3.12 [95% CI, 1.39-7.03]; p = 0.01). Additionally, previous coronary heart disease was also associated with cardiovascular mortality. CONCLUSIONS: In this cohort of hospitalized patients, STOP-Bang scores ≥ 5 were able to identify patients at an increased risk of cardiovascular mortality three years after discharge.

Evaluation of a Targeted Next-Generation Sequencing Panel for the Non-Invasive Detection of Variants in Circulating DNA of Colorectal Cancer.

Molecular profiling of circulating cell-free DNA (cfDNA) has shown utility for the management of colorectal cancer (CRC). TruSight Tumor 170 (TST170) is a next-generation sequencing (NGS) panel that covers 170 cancer-related genes, including KRAS, which is a key driver gene in CRC. We evaluated the capacity of TST170 to detect gene variants in cfDNA from a retrospective cohort of 20 metastatic CRC patients with known KRAS variants in tumor tissue and in cfDNA previously analyzed by pyrosequencing and BEAMing, respectively. The cfDNA of most of the patients (95%) was successfully sequenced. We frequently detected variants with clinical significance in KRAS (79%, 15/19) and PIK3CA (26%, 5/19) genes. Variants with potential clinical significance were also identified in another 27 cancer genes, such as APC. The type of KRAS variant detected in cfDNA by TST170 showed high concordance with those detected in tumor tissue (77%), and very high concordance with cfDNA analyzed by BEAMing (94%). The variant allele fractions for KRAS obtained in cfDNA by TST170 and BEAMing correlated strongly. This proof-of-principle study indicates that targeted NGS analysis of cfDNA with TST170 could be useful for non-invasive detection of gene variants in metastatic CRC patients, providing an assay that could be easily implemented for detecting somatic alterations in the clinic.

Prediction of survival in patients with advanced, refractory colorectal cancer in treatment with trifluridine/tipiracil: real-world vs clinical trial data.

Trifluridine/tipiracil increases overall survival (OS) in patients with refractory, metastatic colorectal cancer (mCRC). A post hoc exploratory analysis of the RECOURSE randomized clinical trial (RCT) established two categories, a good prognosis corresponding to subjects having a low tumor burden and indolent disease. Other models in refractory mCRC are the FAS-CORRECT and Colon Life nomogram. The main objective was to externally validate the prognostic factors of the RECOURSE and FAS-CORRECT trials, and the Colon Life nomogram in a multicenter, real-world series of mCRC treated in 3rd and successive lines with trifluridine/tipiracil. The secondary aim was to develop an OS predictive model, TAS-RECOSMO. Between 2016 and 2019, 244 patients were recruited. Median OS was 8.15 vs 8.12 months for the poor (85% of the subjects) and good (15%) prognosis groups from the RESOURCE trial, respectively, log-rank p = 0.9. The most common grade 3-4 toxicities were neutropenia (17%), asthenia (6%), and anemia (5%). The AFT lognormal model TAS-RECOSMO included six variables: ECOG-PS, KRAS/NRAS/BRAF mutation status, time between diagnosis of metastasis and beginning of trifluridine/tipiracil, NLR, CEA, and alkaline phosphatase. The model's bootstrapped bias-corrected c-index was 0.682 (95% CI, 0.636-0.722). The factors from the Colon Life model, FAS-CORRECT, and RECOURSE displayed a c-index of 0.690, 0.630, and 0.507, respectively. TAS-RECOSMO, FAS-CORRECT, and the Colon Life nomogram appear to predict OS in patients with refractory mCCR who begin trifluridine/tipiracil treatment in the real world. The prognostic groups of the RECOURCE RCT were unable to capture the situation of real-world subjects treated with trifluridine/tipiracil in this series.

Do Clinical Trials Meet Current Care Needs? Views of Digestive Oncology Specialists in Galicia (Spain) Using the Delphi Method.

Background: In recent years, abundant scientific evidence has been generated based on clinical trials (CT) in the field of oncology. The general objective of this paper is to find out the extent to which decision making is based on knowledge of the most recent CT. Its specific objectives are to pinpoint difficulties with decision making based on the CT performed and find out the motivations patients and clinicians have when taking part in a CT. Methodology: Combined, prospective study, based on the Delphi method. A lack of correspondence between the people who take part in CT and patients who come for consultation has been identified. A need for training in analysing and interpreting CT has also been identified and a lack of trust in the results of CT financed by the pharmaceutical industry itself has been perceived. Conclusions: There is a difficulty in selecting oncological treatment due to the lack of correspondence between the patients included in the CT and patients seen in consultation. In this process, real world data studies may be highly useful, as they may provide this group with greater training in interpreting CT and their results.

Clinical utility of oximetric parameters to identify a high-risk phenotype of moderate-severe Obstructive Sleep Apnea (OSA).

It is unclear if oximetric parameters, such as total time of SpO2  < 90%, (T90), oxygen desaturation index-3% (ODI), minimum SpO2 , are able to describe a high-risk subtype of cardiovascular (CV) comorbidities in patients with Obstructive sleep apnea (OSA) beyond the apnea-hypopnea index. OBJECTIVE: To analyzed oximetric variables in patients with moderate-severe OSA to assess their predictive value regarding as hypertension, type 2 diabetes mellitus (T2DM), coronary heart disease (CHD) and CV mortality. METHODS: Using data from SantOSA cohort, we develop receiver operating characteristic curve and area under the curve (AUC) for each parameter, defining the proposed cutoff point in a training set. Then, in a validation set with a 5 years follow-up, we evaluate the clinical differences between groups using the proposed cutoff. We also calculated adjusted Hazard Ratios (HR) of mortality using a Cox regression model. RESULTS: About 965 patients with moderate-severe OSA (525 in training and 440 in validation group) were included. The best AUC was achieved with T90 (AUC = 0.66) and ODI (AUC = 0.61). Proposed cutoffs of T90 were hypertension: 10%, T2DM: 20%, CHD: 15%, meanwhile, proposed cutoff of ODI was ≥ 30 ev for hypertension and T2DM. Regarding CV mortality, T90 ≥ 20% was independently associated with an adjusted HR 2.44 (CI, 1.21-4.94), P-value = 0.01, meanwhile, ODI ≥ 30 ev. reported and adjusted HR 1.59 (CI, 0.75-3.39), P-value = 0.22. CONCLUSION: In patients with moderate-severe OSA, oximetric parameters, especially T90 ≥ 20% remained a predictor of mortality after adjusting for a range of demographic and disease predictors.

A clinic-based cluster analysis in patients with moderate-severe obstructive sleep apnea (OSA) in Chile.

RATIONALE: Patients commonly report differences in either clinical or symptomatic profiles, despite having the same severity of obstructive sleep apnea (OSA). OBJECTIVE: To identify clinical and symptomatic phenotypes and to evaluate cardiovascular mortality in each phenotype. METHODS: Data from 1370 participants (788 with moderate-severe OSA and 582 controls as a reference group) were extracted using the SantOSA database. Sixteen variables were analyzed using latent class analysis to define clinical subtypes. The association between subtypes and cardiovascular mortality was evaluated using Kaplan-Meier survival analysis and the Cox proportional hazards model. Adjusted hazard ratios (HRs) with confidence intervals (CIs) were modified by cardiovascular confounders. RESULTS: The median observation period was 5.2 years. We found four clusters: cluster #1: symptomatic men with major comorbidities (n = 252); cluster #2: symptomatic women with comorbidities (n = 154); cluster #3: asymptomatic men with comorbidities (n = 143); and cluster #4: symptomatic young men without major comorbidities (n = 239). In cluster #1, mortality was 4.76% and was independently associated with age (HR 1.12; CI 1.07-1.17), type 2 diabetes mellitus (HR 3.37; CI 1.29-8.78) and coronary heart disease (HR 3.85; CI 1.27-11.56); in cluster #2, mortality was 3.89% and was independently associated with age (HR 1.12; CI 1.06-1.19) and the oxygen desaturation index (ODI, HR 1.02; CI 1.01-1.04); and in cluster #3, mortality was 3.49% (HR 3.50; CI 1.03-11.90) and was independently associated with age (HR 1.19; CI 1.10-1.29). In cluster #4, mortality was 1.25% and showed nonsignificant associations. CONCLUSION: In patients with moderate-severe OSA, we described four phenotypes of patients according to clinical features with different risks of cardiovascular mortality. STUDY REGISTER: ISRCTN62293645.

Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function.

Mutations in the genes encoding hepatocyte nuclear factor 4alpha (HNF-4alpha) and HNF-1alpha impair insulin secretion and cause maturity onset diabetes of the young (MODY). HNF-4alpha is known to be an essential positive regulator of HNF-1alpha. More recent data demonstrates that HNF-4alpha expression is dependent on HNF-1alpha in mouse pancreatic islets and exocrine cells. This effect is mediated by binding of HNF-1alpha to a tissue-specific promoter (P2) located 45.6 kb upstream from the previously characterized Hnf4alpha promoter (P1). Here we report that the expression of HNF-4alpha in human islets and exocrine cells is primarily mediated by the P2 promoter. Furthermore, we describe a G --> A mutation in a conserved nucleotide position of the HNF-1alpha binding site of the P2 promoter, which cosegregates with MODY. The mutation results in decreased affinity for HNF-1alpha, and consequently in reduced HNF-1alpha-dependent activation. These findings provide genetic evidence that HNF-1alpha serves as an upstream regulator of HNF-4alpha and interacts directly with the P2 promoter in human pancreatic cells. Furthermore, they indicate that this regulation is essential to maintain normal pancreatic function.

Development of psoriatic arthritis during nivolumab therapy for metastatic non-small cell lung cancer, clinical outcome analysis and review of the literature.

Lung cancer is the leading cause of cancer-related death worldwide. The most common type, non-small cell lung cancer (NSCLC), is further divided into two main types, squamous cell and non-squamous cell (which includes adenocarcinoma). Nivolumab, a fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody, has shown not only an overall survival advantage when compared to docetaxel, but also a relatively good side-effect profile among patients with previously treated advanced squamous and non-squamous NSCLC. Psoriatic arthritis (PsA), a heterogeneous chronic inflammatory disease, has a wide clinical spectrum and a variable clinical course that affects mainly musculoskeletal structures, skin and nails. Here we report the second case to the best of our knowledge of PsA development during nivolumab therapy. It is important to note that arthritis activity decreased without nivolumab discontinuation with the use of naproxen and a low dose of corticosteroid. Furthermore, a minimal disease activity was achieved adding methotrexate to the treatment and antitumor therapy efficacy was not influenced (a partial response was documented after eight and 39 cycles of nivolumab). Rheumatic immune-related adverse events management is a challenge and a coordinated multidisciplinary management by medical oncologists, rheumatologists and immunologists will be mandatory in the near future.

Association between cardiovascular mortality and STOP-Bang questionnaire scores in a cohort of hospitalized patients: a prospective study / Associação entre mortalidade cardiovascular e pontuação do questionário STOP-Bang em uma coorte de pacientes hospitalizados: um estudo prospectivo

ABSTRACT Objective: Obstructive sleep apnea (OSA) is associated with an increased risk of mortality and cardiometabolic diseases. The STOP-Bang questionnaire is a tool to screen populations at risk of OSA and prioritize complementary studies. Our objective was to evaluate the clinical utility of this questionnaire in identifying patients at an increased risk of mortality after discharge in a cohort of hospitalized patients. Methods: This was a prospective cohort study involving consecutive patients admitted to an internal medicine unit between May and June of 2017 who were reevaluated three years after discharge. At baseline, we collected data on comorbidities (hypertension, obesity, diabetes, and fasting lipid profile) and calculated STOP-Bang scores, defining the risk of OSA (0-2 score, no risk; ≥ 3 score, risk of OSA; and ≥ 5 score, risk of moderate-to-severe OSA), which determined the study groups. We also recorded data regarding all-cause and cardiovascular mortality at the end of the follow-up period. Results: The sample comprised 435 patients. Of those, 352 (80.9%) and 182 (41.8%) had STOP-Bang scores ≥ 3 and ≥ 5, respectively. When compared with the group with STOP-Bang scores of 0-2, the two groups showed higher prevalences of obesity, hypertension, diabetes, and dyslipidemia. Multivariate analysis showed an independent association between cardiovascular mortality and STOP-Bang score ≥ 5 (adjusted hazard ratio = 3.12 [95% CI, 1.39-7.03]; p = 0.01). Additionally, previous coronary heart disease was also associated with cardiovascular mortality. Conclusions: In this cohort of hospitalized patients, STOP-Bang scores ≥ 5 were able to identify patients at an increased risk of cardiovascular mortality three years after discharge.

RESUMO Objetivo: A apneia obstrutiva do sono (AOS) está associada a um risco maior de mortalidade e doenças cardiometabólicas. O questionário STOP-Bang é uma ferramenta para rastrear populações em risco de AOS e assim priorizar estudos complementares. Nosso objetivo foi avaliar a utilidade clínica desse questionário na identificação de pacientes com risco aumentado de mortalidade após a alta em uma coorte de pacientes hospitalizados. Métodos: Estudo de coorte prospectivo com pacientes consecutivos internados em uma unidade de medicina interna entre maio e junho de 2017 que foram reavaliados três anos após a alta. No momento basal, coletamos dados sobre comorbidades (hipertensão, obesidade, diabetes e perfil lipídico em jejum) e calculamos as pontuações no STOP-Bang, definindo o risco de OSA (pontuação 0-2, sem risco; pontuação ≥ 3, risco de AOS; e pontuação ≥ 5, risco de AOS moderada a grave), que determinou os grupos de estudo. Também registramos dados sobre mortalidade por todas as causas e mortalidade cardiovascular ao final do período de acompanhamento. Resultados: Foram incluídos 435 pacientes. Desses, 352 (80,9%) e 182 (41,8%) apresentaram pontuações no STOP-Bang ≥ 3 e ≥ 5, respectivamente. Quando comparados com o grupo com pontuação no STOP-Bang de 0-2, os outros dois grupos apresentaram prevalências mais elevadas de obesidade, hipertensão, diabetes e dislipidemia. A análise multivariada mostrou uma associação independente entre mortalidade cardiovascular e pontuação no STOP-Bang ≥ 5 (razão de risco ajustada = 3,12 [IC95%, 1,39-7,03]; p = 0,01). Além disso, doença coronariana prévia também foi associada à mortalidade cardiovascular. Conclusões: Nesta coorte de pacientes hospitalizados, pontuações no STOP-Bang ≥ 5 foram capazes de identificar pacientes com risco aumentado de mortalidade cardiovascular três anos após a alta.

Inhibition of 5-lipoxygenase induces cell growth arrest and apoptosis in rat Kupffer cells: implications for liver fibrosis.

The existence of an increased number of Kupffer cells is recognized as critical in the initiation of the inflammatory cascade leading to liver fibrosis. Because 5-lipoxygenase (5-LO) is a key regulator of cell growth and survival, in the current investigation we assessed whether inhibition of the 5-LO pathway would reduce the excessive number of Kupffer cells and attenuate inflammation and fibrosis in experimental liver disease. Kupffer cells were the only liver cell type endowed with a metabolically active 5-LO pathway (i.e., expressed mRNAs for 5-LO, 5-LO-activating protein [FLAP], and leukotriene [LT] C4 synthase and generated LTB4 and cysteinyl-LTs). Both the selective 5-LO inhibitor AA861 and the FLAP inhibitor BAY-X-1005 markedly reduced the number of Kupffer cells in culture. The antiproliferative properties of AA861 and BAY-X-1005 were associated with the occurrence of condensed nuclei, fragmented DNA, and changes in DNA content and cell cycle frequency distribution consistent with an apoptotic process. In vivo, in carbon tetrachloride-treated rats, BAY-X-1005 had a significant antifibrotic effect and reduced liver damage and the hepatic content of hydroxyproline. Together, these findings indicate a novel mechanism by which inactivation of the 5-LO pathway could disrupt the sequence of events leading to liver inflammation and fibrosis.

Short-term transdermal estradiol enhances nitric oxide synthase III and estrogen receptor mRNA expression in arteries of women with coronary artery disease.

OBJECTIVE: To analyze the short-term effects of estradiol (E2) on the expression of nitric oxide synthase (NOS III) and estrogen receptors (ER) alpha and beta. METHODS: We studied 20 post-menopausal women with coronary artery disease (CAD) undergoing CABG surgery with left internal mammary artery (LIMA) grafting. Ten women received treatment with transdermal E2 prior to surgery (48-72 h) and 10 did not. The distal segment of the LIMA was excised and processed to determine mRNA expression of NOS III and ER alpha and beta (RT-PCR). Expression of NOS III and ER alpha and beta was measured in arbitrary densitometric units (ADUs) relative to GPdH expression, constitutively expressed in human vessels. RESULTS: NOS III and ER alpha and beta mRNA expression was enhanced in women treated with E2 as compared to the control group (NOS III: 1.69+/-0.61 versus 1.14+/-0.48 ADUs, p=0.04; ER alpha: 6.52+/-6.80 versus 1.83+/-1.22 ADUs, p=0.04; ER beta: 4.20+/-3.42 versus 1.56+/-0.59 ADUs, p=0.03). ER alpha, but not ER beta expression, correlated with NOS III expression (r=0.70, p<0.001). CONCLUSIONS: After treatment with E2, NOS III, ER alpha, and ER beta mRNA expression was enhanced in arterial vessels of postmenopausal women with CAD. NOS III mRNA expression was only correlated to ER alpha expression, suggesting that NOS III activation could be more mediated by ER alpha.

Cyclooxygenase-1 derived prostaglandins are involved in the maintenance of renal function in rats with cirrhosis and ascites.

1. The maintenance of renal function in decompensated cirrhosis is highly dependent on prostaglandins (PGs). Since PG synthesis is mediated by cyclooxygenase-1 and -2 (COX-1 and COX-2), the present study was designed to examine which COX isoform is involved in this phenomenon. 2. Renal COX-1 and COX-2 protein expression and distribution were analysed by Western blot and immunohistochemistry in nine rats with carbon tetrachloride-induced cirrhosis and ascites and 10 control animals. The effects of placebo and selective COX-1 (SC-560) and COX-2 (celecoxib) inhibitors on urine flow (V), urinary excretion of sodium (U(Na)V) and PGE(2) (U(PGE2)V), glomerular filtration rate (GFR), renal plasma flow (RPF), the diuretic and natriuretic responses to furosemide and renal water metabolism were assessed in 88 rats with cirrhosis and ascites. 3. COX-1 protein levels were found to be unchanged in kidneys from cirrhotic rats. In contrast, these animals showed enhanced renal COX-2 protein expression which was focally increased in the corticomedullary region. Although U(PGE2)V was equally reduced by SC-560 and celecoxib, only SC-560 produced a significant decrease in U(Na)V, GFR and RPF and a pronounced impairment in the diuretic and natriuretic responses to furosemide in rats with cirrhosis and ascites. Neither SC-560 nor celecoxib affected renal water metabolism in cirrhotic rats. 4. These results indicate that despite abundant renal COX-2 protein expression, the maintenance of renal function in cirrhotic rats is mainly dependent on COX-1-derived prostaglandins.

Binge drinking: conductas sexuales de riesgo y drogas facilitadoras del asalto sexual en jóvenes españoles / Binge drinking: Risky sexual behaviors and drug facilitated sexual assault in spanish youths

El uso de drogas -alcohol incluido- como facilitadoras del asalto sexual y las conductas sexuales de riesgo son dos fenómenos relevantes desde una perspectiva sociosanitaria. El objetivo de la presente investigación es comparar las actitudes hacia estas variables en una muestra de 164 jóvenes en condiciones de intoxicación etílica frente a sobriedad. La muestra está compuesta por 82 varones y 82 mujeres. Su media de edad era 27.50 ± 63.72. Contestaron un cuestionario en el que se recogen datos sociodemográficos, información del consumo de drogas y la Escala de Conductas Sexuales; además, se emplearon varios etilómetros Digital Zaphir Deluxe para determinar la alcoholemia. Se trata de un estudio cuasiexperimental realizado sobre un diseño intraindividual. El muestreo es no probabilístico de tipo "bola de nieve". Los resultados muestran unas actitudes más positivas y una mayor intencionalidad hacia el empleo de drogas como facilitadoras del asalto sexual y hacia las conductas sexuales de riesgo de los sujetos que se encuentran bajo el efecto del alcohol en contextos recreativos, independientemente del sexo de la muestra. Se destaca, por un lado, la importancia de investigar sobre el uso de drogas como facilitadoras del asalto sexual (tema ampliamente ignorado en España) y se profundiza en cómo el consumo de drogas afecta al uso de métodos anticonceptivos, y por otro, la necesidad de incluir información en los programas preventivos sobre cómo el consumo de alcohol (y otras drogas) está relacionado con la actividad sexual.

Drug use (alcohol included) as a sexual-assault facilitator and risky sexual behavior are two important issues from a social and health perspective. This study aims to compare the attitudes towards these variables in a sample of 164 young people in conditions of intoxication vs sobriety. The sample consisted of 82 men and 82 women. Their mean age was 27.50 (SD = 3.72). Participants answered a sociodemographic questionnaire, a drug information questionnaire, and the Sexual Behaviors Scale. and moreover, Several Zaphir Deluxe Digital breathalyzers were also used to monitor alcohol level. This is a quasiexperimental study conducted using a within-subject design. Non-probabilistic snowball sampling was used. The results showed more positive attitudes and greater intentions towards the use of drugs as facilitators of sexual assault and risky sexual behaviors in those who are under the influence of alcohol in recreational contexts, regardless of the sex of the sample. These results showed, on the one hand, the importance of studies into the use of drug facilitated sexual assault -a largely ignored issue in Spain- and to determine how drug use affects the use of contraceptive methods. On the other hand, the results show the need to include information in preventive programs about the way alcohol (and other drugs) use is related to sexual activity.

Home intervention improves cognitive and social-emotional scores in iron-deficient anemic infants.

BACKGROUND: Iron-deficiency anemia (IDA) is associated with alterations in infant behavior and development that may not be corrected with iron therapy. OBJECTIVE: To determine if a home-based intervention to foster child development improves behavior and development of infants with IDA. METHODS: Infants with IDA and nonanemic infants aged 6 and 12 months were treated with oral iron and randomly assigned to a year of surveillance or intervention. Infants in the surveillance group were visited weekly, and information on iron intake, feeding, and health were recorded. Infants in the intervention were visited weekly, and the home visits included an hour-long program to foster child development by providing support to the mother-infant relationship. The number of infants enrolled was 128 (66 who received intervention) and 149 (70 intervention) at 6 and 12 months, respectively. Psychologists who were unaware of iron status and intervention assignment assessed infants' cognitive, motor, and social-emotional development (Bayley Scales) at the beginning, midpoint, and end of the year; 116 6-month-olds and 134 12-month-olds had at least 2 assessments. Hierarchical linear modeling was used to analyze change over time. RESULTS: Infants with IDA, regardless of enrollment age, were rated as less positive in social-emotional behavior at baseline. There were significant interactions between iron status and intervention associated with change in cognitive performance and positive social-emotional behavior. Infants with IDA who received intervention had developmental trajectories comparable to those of nonanemic infants in the intervention and surveillance groups, but these infants did not catch up in social-emotional behavior. Infants with IDA who received surveillance showed less increase in cognitive scores and had declines in positive social-emotional ratings. CONCLUSIONS: Home-based intervention to foster child development improved cognitive and social-emotional scores in infants with IDA, but social-emotional differences remained between infants with IDA and those without IDA.