Spatially preserved multi-region transcriptomic subtyping and biomarkers of chemoimmunotherapy outcome in extensive-stage small cell lung cancer.

BACKGROUND: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small-cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. PATIENTS AND METHODS: We analyzed tumor samples from 58 ES-SCLC patients enrolled in two multicenter single-arm phase IIIb studies evaluating front-line chemoimmunotherapy in Spain: n=32 from the IMfirst trial, and n=26 from the CANTABRICO trial. We utilized the GeoMxTM DSP system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). RESULTS: Subtype distribution was similar between both cohorts, except for SCLC-P, not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple co-existing transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity were not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ³12 months) contained an IFNg-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. CONCLUSIONS: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Pre-existing IFNg-driven immunity and mitochondrial metabolism seem correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.

Cyclosporine A in hospitalized COVID-19 pneumonia patients to prevent the development of interstitial lung disease: a pilot randomized clinical trial.

Post-COVID-19 interstitial lung disease (ILD) is a new entity that frequently causes pulmonary fibrosis and can become chronic. We performed a single-center parallel-group open-label pilot randomized clinical trial to investigate the efficacy and safety of cyclosporine A (CsA) in the development of ILD in the medium term among patients hospitalized with COVID-19 pneumonia. Patients were randomized 1:1 to receive CsA plus standard of care or standard of care alone. The primary composite outcome was the percentage of patients without ILD 3 months after diagnosis of pneumonia and not requiring invasive mechanical ventilation (IMV) (response without requiring IMV). The key secondary composite outcomes were the percentage of patients who achieve a response requiring IMV or irrespective of the need for IMV, and adverse events. A total of 33 patients received at least one dose of CsA plus standard of care (n = 17) or standard of care alone (n = 16). No differences were found between the groups in the percentage of patients who achieved a response without requiring IMV or a response requiring IMV. A higher percentage of patients achieved a response irrespective of the need for IMV in the CsA plus standard of care group although the RR was almost significant 2.833 (95% CI, 0.908-8.840; p = 0.057). No differences were found between the groups for adverse events. In hospitalized patients with COVID-19 pneumonia, we were unable to demonstrate that CsA achieved a significant effect in preventing the development of ILD. (EU Clinical Trials Register; EudraCT Number: 2020-002123-11; registration date: 08/05/2020).

Howl: Nightmare or REM Sleep Behavior Disorder?

Objective: Nightmare disorder consists of the appearance of unpleasant and vivid, repeated dreams, with a situation of discomfort and anguish on awakening. Its prevalence is 3%-4% in adults. They do not associate muscle mobilization during this phase. REM sleep behavior disorder (RSBD) is a rare parasomnia (0.5% of people older than 60 years of age), characterized by the presence of unpleasant dreams, with violent content, and vigorous movements of limbs (kicks and punches), reflecting a loss of muscle atony typical of the REM phase of sleep. Language (screams and words) can also be emitted. The same clinical manifestations of RSBD can appear in other sleep disorders. The diagnosis requires the performance of a polysomnography. Methods: We present the case of a 41-year-old man referred for vivid and unpleasant dreams, beginning in the last year, related to work stress. Results: The polysomnography showed the loss of atony in the REM phase and emission of a prolonged howl after which the patient continues in the REM phase. Discussion: Prolonged howling is a very rare symptom in sleep disorders, and very atypical in RSBD, so polysomnography is essential to confirm the diagnosis and rule out other parasomnias.

Anxiety and depression in patients with narcolepsy.

We analysed the co-existence of psychopathology in patients with narcolepsy at our centre. We performed an observational retrospective descriptive analysis of patients with a diagnosis of narcolepsy, with and without psychopathology, who attended our sleep disorders unit from October 2012 to October 2021. A total of 51patients with narcolepsy (mean [SD] age 41.10 [14.71] years; 23 [45.1%] males and 28 [54.90%] females) were included. In all, 27 patients (52.94%) and 24 patients (47.06%) had narcolepsy with and without cataplexy, respectively. Of the total, 18 (33.33%) had a mood disorder: 18 with anxiety disorder (33.33%). Of these patients 14 (27.45%) had major depression, two (4%) had attempted suicide, one (2%) had manic outbreak, and one (2%) had substance abuse. Of the 18 patients with anxiety and depression, 10 (55.55%) and eight (44.44%) had narcolepsy with and without cataplexy, respectively. In the comparative analysis, a statistically significant relationship was found between younger age and the presence of anxiety. The prevalence of anxiety and depression in patients with narcolepsy was triple that of the general population, especially in younger patients. Psychopathology precedes the diagnosis of narcolepsy in most patients, not being reactive to diagnosis. This high prevalence suggests a possible biological relationship between both disorders, which should be assessed with larger studies.

Seroprevalence and immunological memory against SARS-CoV-2 in lung cancer patients: the SOLID study.

BACKGROUND: At present, we did not find any articles that studied seroprevalence and its persistence several months later in lung cancer patients in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Most patients with coronavirus disease 2019 (COVID-19) go on to develop antibodies (Abs) against viral proteins. However, it is not known how long these Abs last nor whether cancer treatments could affect the duration of immune response. METHODS: This prospective, longitudinal, multicenter serological study in the setting of SARS-CoV-2 infection was carried out in 50 Spanish hospitals. Eligibility criterion was the diagnosis of any lung cancer. The determination of anti-SARS-CoV-2 IgG Abs was performed by qualitative immuno-enzymatic assay using enzyme-linked immunosorbent assay (ELISA) kit from NovaLisa whose Abs target the recombinant antigen N of the nucleocapsid of SARS-CoV-2. The first Ab determination was performed between April 21 and June 3, 2020. The second Ab determination was performed in all previously seropositive patients, between September 10 and November 20, 2020. Study objectives were to prospectively determine seroprevalence in unselected lung cancer patients during the first wave of the pandemic; the persistence of immunity; protection or lack thereof against reinfection; and the influence of treatments on maintenance or loss of immunity. RESULTS: Of 1,500 patients, 128 were seropositive, overall prevalence of 8.5% seropositivity [95% confidence interval (CI): 7.2-10.1%]. Seventy-five percent were in active cancer treatment. Forty-seven point seven percent of IgG positive participants had experienced a symptomatic illness suspected of being infected with SARS-CoV-2 (95% CI: 38.8-56.6%). A second determination was performed on average 4.5 months later [interquartile range (IQR), 4.0-5.0 months] and obtained for 104 of the initially seropositive patients (81%), it could not be obtained in 24 patients, the majority due to death caused by disease progression (73%). In the second determination, IgG was not detected in 30.8% of patients. The severity of the infection, the need for hospitalization (P=0.032) and the presence of symptoms at diagnosis (P=0.02) were associated with persistence of immunity in the second determination. No variables or treatments received were associated with Abs loss. CONCLUSIONS: Immunity against SARS-CoV-2 does not appear to be compromised by treatment and persists beyond 4 months. Neither do mortality rates appear to be particularly high in this unselected population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04407143.

Moderate obstructive sleep apnea and cardiovascular outcomes in older adults: a propensity score-matched multicenter study (CPAGE-MODE study).

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) has been associated with cardiovascular events (CVEs), although recent randomized controlled trials have not demonstrated that long-term continuous positive airway pressure (CPAP) prevents CVEs. Our objective was to determine the effect of CPAP on older adults with moderate OSA regarding CVE reduction. METHODS: An observational and multicenter study of a cohort of older adults (> 70 years of age) diagnosed with moderate OSA (apnea-hypopnea index 15.0-29.9 events/h) was conducted. Two groups were formed: (1) CPAP treatment and (2) standard of care. The primary endpoint was CVE occurrence after OSA diagnosis. Association with CPAP treatment was assessed by propensity score matching and inverse weighting probability. Secondary endpoints were incidence of CVE separately and time to first CVE. RESULTS: A total of 614 patients were included. After matching, 236 older adults (111 men, mean age 75.9 ± 4.7 years) with a follow-up of 47 months (interquartile range: 29.6-64.0 months) were considered for primary and secondary endpoint evaluations. Forty-one patients presented at least 1 CVE (17.4%): 20 were in the standard-of-care group (16.9%) and 21 were in the CPAP group (17.8%), with a relative risk of 1.05 (95% confidence interval [CI], 0.60-1.83; P = .43) for CPAP treatment. Inverse probability weighting of the initial 614 patients determined an adjusted relative risk of 1.24 (95% CI, 0.79-1.96; P = .35) for CPAP treatment. No statistical differences were found in secondary endpoint analyses. CONCLUSIONS: CPAP should not be prescribed to reduce CVE probability in older adults with moderate OSA. CITATION: López-Padilla D, Terán-Tinedo J, Cerezo-Lajas A, et al. Moderate obstructive sleep apnea and cardiovascular outcomes in older adults: a propensity score-matched multicenter study (CPAGE-MODE study). J Clin Sleep Med. 2022;18(2):553-561.

Liquid Biopsy as a Tool for the Characterisation and Early Detection of the Field Cancerization Effect in Patients with Oral Cavity Carcinoma.

Oral squamous cell carcinoma (OSCC) constitutes approximately 25% of all head and neck cancer, for which the consumption of tobacco and alcohol are the main associated risk factors. The field cancerization effect of OSCC is one of the main reasons for the poor survival rates associated with this disease. Despite some advances, its ccharacterization and early diagnosis continue to challenge modern oncology, and the goal of improving the prognosis remains to be achieved. Among new early diagnostic tools for OSCC that have been proposed, liquid biopsy appears to be an ideal candidate, as studies have shown that the analysis of blood and saliva provides promising data for the early detection of relapses or second tumours.

Consumo habitual de café y riesgo de eventos cerebrovasculares / Regular coffee consumption and stroke risk

Resumen Introducción: La enfermedad cerebrovascular es causa frecuente de morbimortalidad y, en ese sentido, el consumo de café tiene un impacto cardiovascular, por lo cual es importante evaluar la evidencia respecto a la asociación entre su consumo y la enfermedad cerebrovascular. Objetivo: Evaluar la asociación entre consumo de café y riesgo de morbimortalidad por enfermedad cerebrovascular. Método: Se realizó una búsqueda en las bases Medline, EMBASE, LILACS y Cochrane (enero de 1966 a junio de 2018) y se seleccionaron revisiones sistemáticas y metaanálisis evaluados de forma estandarizada y pareada. Se seleccionaron seis publicaciones. Resultados: Se encontró que el consumo de café en rango moderado (hasta cuatro tazas) se asocia a una reducción del riesgo de enfermedad cerebrovascular (riesgo relativo [RR] = 0.89, intervalo de confianza del 95% [IC95%]: 0.81-0.97, y RR: 0.83, IC95%: 0.75-0.91). Esta protección se mantiene en el subgrupo de mujeres, con reducciones del 13% (IC95%: 0.78-0.97) para una taza, del 16% (IC95%: 0.74-0.95) para dos tazas y 19% (RR: 0.81; IC95%: 0.70-0.93) (IC95%: 0.70-0.93) para cuatro o más tazas. Los hallazgos también son significativos para el subtipo isquémico (RR = 0.80; IC95%: 0.71-0.90). Conclusiones: El consumo de café reduce el riesgo de eventos cerebrovasculares entre un 11% y un 17%, y esto se mantiene en el subgrupo de mujeres y en el subtipo isquémico.

Abstract Introduction: Cerebrovascular disease is a frequent cause of morbidity and mortality and, in this sense, coffee consumption has a cardiovascular impact, which is why it is important to evaluate the evidence regarding the association between its consumption and cerebrovascular disease. Objective: To evaluate the association between coffee consumption and risk of morbidity and mortality due to cerebrovascular disease. Method: A search was carried out in the Medline, EMBASE, LILACS and Cochrane databases (January 1966 to June 2018), selecting systematic reviews and meta-analyzes evaluated in a standardized and paired way. Six publications were selected. Results: it was found that the consumption of coffee in a moderate range (up to 4 cups) is associated with a reduction in the risk of cerebrovascular disease (relative risk [RR] = 0.89, 95% confidence interval [95% CI]: 0.81- 0.97, and RR = 0.83, 95% CI: 0.75-0.91). This protection is maintained in the subgroup of women, with reductions of 13% (95% CI: 0.78-0.97) for a cup, 16% (95% CI: 0.74-0.95) for two cups, and RR = 0.81 (95% CI: 0.70-0.93) for four or more cups. The findings are also significant for the ischemic subtype (RR = 0.80; 95% CI: 0.71-0.90). Conclusions: Coffee consumption reduces the risk of cerebrovascular events between 11% and 17%, and this is maintained in the subgroup of women and in the ischemic subtype.

Rovalpituzumab Tesirine as a Maintenance Therapy After First-Line Platinum-Based Chemotherapy in Patients With Extensive-Stage-SCLC: Results From the Phase 3 MERU Study.

INTRODUCTION: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, an atypical Notch ligand expressed in SCLC tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive-stage-SCLC after platinum-based chemotherapy. METHODS: MERU was a phase 3 randomized, double-blinded, placebo-controlled study. Patients without disease progression after four cycles of platinum-based, front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (every 6 wk, omitted every third cycle). Primary efficacy end points were progression-free survival (PFS) evaluated by the Central Radiographic Assessment Committee and overall survival (OS) in patients with DLL3-high tumors. RESULTS: Median age of all randomized patients (N = 748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the subset with DLL3-high tumors, the hazard ratio for OS was 1.07 (95% confidence interval: 0.84-1.36) favoring the placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 mo, hazard ratio = 0.48, p < 0.001). Any-grade adverse events (≥20%) in the Rova-T arm were pleural effusion (27%), decreased appetite (27%), peripheral edema (26%), photosensitivity reaction (25%), fatigue (25%), nausea (22%), and dyspnea (21%). CONCLUSIONS: Because of the lack of survival benefit in the Rova-T arm, the study did not meet its primary end point and was terminated early. As a result, the Central Radiographic Assessment Committee evaluation of PFS was not performed. The frequency of grade greater than or equal to 3 and drug-related toxicities were higher with Rova-T versus placebo. Rova-T was associated with unique toxicities, such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the population with extensive-stage-SCLC.

Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451.

PURPOSE: In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC. METHODS: Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity. Primary end point was overall survival (OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were hierarchically tested. RESULTS: Overall, 834 patients were randomly assigned. The minimum follow-up was 8.9 months. OS was not significantly prolonged with nivolumab plus ipilimumab versus placebo (hazard ratio [HR], 0.92; 95% CI, 0.75 to 1.12; P = .37; median, 9.2 v 9.6 months). The HR for OS with nivolumab versus placebo was 0.84 (95% CI, 0.69 to 1.02); the median OS for nivolumab was 10.4 months. Progression-free survival HRs versus placebo were 0.72 for nivolumab plus ipilimumab (95% CI, 0.60 to 0.87) and 0.67 for nivolumab (95% CI, 0.56 to 0.81). A trend toward OS benefit with nivolumab plus ipilimumab was observed in patients with tumor mutational burden ≥ 13 mutations per megabase. Rates of grade 3-4 treatment-related adverse events were nivolumab plus ipilimumab (52.2%), nivolumab (11.5%), and placebo (8.4%). CONCLUSION: Maintenance therapy with nivolumab plus ipilimumab did not prolong OS for patients with ED-SCLC who did not progress on first-line chemotherapy. There were no new safety signals.

Consumo habitual de café y riesgo de enfermedad cardiovascular: una evaluación crítica de la literatura / Regular coffee drinking and cardiovascular risk: A critical review of the literature

Resumen Objetivo Analizar y sintetizar la evidencia sobre el efecto del consumo habitual de café en la aparición de enfermedad cardiovascular. Métodos Se realizó una evaluación crítica de la literatura basada en metaanálisis y revisiones sistemáticas publicadas en Medline, EMBASE, Cochrane Database of Systematic Reviews y LILACS (enero 1966 a junio 2018). La búsqueda, selección y extracción de información fue llevada a cabo por una pareja de investigadores. La calidad de los manuscritos fue evaluada con AMSTAR. Resultados Se analizaron cuatro revisiones sistemáticas que consideraron como desenlaces enfermedad coronaria, riesgo cardiovascular e infarto del miocardio; para el primer y segundo desenlace se encontró una reducción del riesgo con consumo de 3-4 tazas/día (RR=0,90; IC95% 0,84-0,9; p de heterogeneidad=0,02 y RR=0,85; IC95% 0,80-0,90; p de heterogeneidad=0,09); para 1-2 tazas/día (RR=0,89; IC95% 0,85-0,94; p de heterogeneidad=0,83 y RR=0,89; IC95% 0,84-0,94; p de heterogeneidad=0,09) respectivamente. Para infarto agudo de miocardio se reportó un aumento del riesgo en hombres con consumo de 3-4 tazas/día (OR=1,75; IC95% 1,44-2,14; p de heterogeneidad=0,005) y de ≥ 4 tazas/día (OR=2,01; IC95% 1,7-2,36; p de heterogeneidad<0,001). Conclusiones Los consumos leves y moderados de café tienen un efecto neutro o de reducción del riesgo cardiovascular y de enfermedad coronaria; en contraste, el riesgo de infarto agudo de miocardio se incrementa con consumos mayores o iguales a 3 tazas/día en hombres. Se recomienda el consumo de hasta 3 tazas de café día y se desaconsejan consumos mayores, especialmente en hombres.

Abstract Objective To analyse and summarise the evidence on the effect of regular coffee drinking on the appearance of cardiovascular disease. Methods A critical review of the literature was carried out based on a meta-analysis and systematic reviews published in MedLine, EMBASE, Cochrane Database of Systematic Reviews, and LILACS (January 1966 to June 2018). The search, selection, and extraction of the information were performed by two investigators. The quality of the manuscripts was evaluated using AMSTAR. Results An analysis was made of 4 systematic reviews that considered coronary disease, cardiovascular risk, and myocardial infarction as outcomes. For the first and second outcomes, a reduction in risk was found with consuming 3-4 cups/day (RR=0.90; 95%CI; 0.84-0.9; P=.02, and RR=0.85; IC95% CI; 0.80-0.90; P=.09); for 1-2 cups/day (RR=0.89; 95%CI; 0.85-0.94; P=.83, and RR=0.89; 95%CI; 0.84-0.94; P=.09), respectively. As regards myocardial infarction, an increase in risk was reported with consuming 3-4 cups/day (OR=1.75; 95%CI; 1.44-2.14; P=.005) and ≥ 4 cups/day (OR=2.01; IC95%CI; 1.7-2.36; P<.001). Conclusion Mild and moderate consumption of coffee has a neutral effect or a reduction in cardiovascular risk and coronary disease. On the other hand, the risk of myocardial is increased with drinking more or equal to 3 cups/day in men. The drinking of up to 3 cups of coffee/day is recommended, and it is not advised to drink more, especially in men.

Relación entre el consumo habitual de café y la mortalidad general y cardiovascular: revisión de revisiones sistemáticas de la literatura / Relationship between habitual coffee consumption and all-cause and cardiovascular mortality: systematic review of reviews

El objetivo de este estudio fue establecer la relación entre consumo habitual de café y la mortalidad general y cardiovascular. En una búsqueda sistemática en Medline, EMBASE, LILACS y Cochrane se seleccionaron y analizaron revisiones sistemáticas y meta-análisis por una pareja de investigadores. De 181 referencias, 74 fueron seleccionadas por título y resumen; luego de eliminar duplicados y según el puntaje de calidad obtenido por AMSTAR, se consideraron 5 artículos para extracción y análisis. El consumo moderado de café (3 o 4 tazas) disminuye la mortalidad general, tanto comparado con el no consumo (RR= 0,83; IC95%: 0,79-0,88; I2= 83% para 3 tazas, y RR=0,84 IC95%: 0,82-0,87; I2= 58% para 4), como con un consumo mínimo (RR= 0,88; IC95%: 0,84-0,93; I2= 68,7% para 4 tazas, y RR= 0,87; IC95%: 0,83-0,91; I2= 59,8% para consumo entre 3 y 4 tazas). La mortalidad cardiovascular se reduce si se compara con el no consumo, para 4 tazas (RR= 0,80; IC95%: 0,74-0,86; I2= 58%) y (RR= 0,83; IC95%: 0,75-0,92, I2 = 92%) y para 3 tazas (RR= 0,81; IC95%: 0,72-0,90; I2= 92%) y RR (0,79; IC95% 0.74-0.84; I2= 58%). Como conclusión, el consumo habitual de 3 y 4 tazas de café reduce la mortalidad general y cardiovascular.

The objective of this study was to establish the relationship between habitual coffee consumption and all-cause and cardiovascular mortality. A systematic review was conducted using Medline, EMBASE, LILACS and Cochrane databases. Systematic reviews and meta-analysis were selected and analyzed. From 181 systematic reviews, 74 were selected by title and summary; after eliminating duplicates. According to the quality score of the AMSTAR tool, five articles were selected for information extraction and analysis. Moderate coffee consumption (3 or 4 cups) decreased overall mortality, compared to non-consumption (RR= 0.83, 95% CI: 0.79-0.88; I2= 83% for 3 cups, and RR= 0.84, 95% CI: 0.82-0.87; I2= 58% for 4 cups) and minimum consumption (RR= 0.88, 95% CI: 0.84-0.93; I2= 68.7% for 4 cups, and RR= 0.87, 95% CI: 0.83-0.91; I2= 59.8% between 3 and 4 cups). Cardiovascular mortality was reduced when compared to non-consumption, for 4 cups (RR= 0.80, 95% CI: 0.74-0.86; I2= 58%) and (RR= 0.83, 95% CI: 0.75-0.92; I2= 92%), and for 3 cups (RR= 0.81, 95 CI: 0.72-0.90; I2= 92%; RR= 0.79, 95% CI: 0.74-0.84; I2= 58%). In conclusion, habitual coffee consumption between 3 and 4 cups reduces the risk of all-cause and cardiovascular mortality.

Oral vinorelbine versus etoposide with cisplatin and chemo-radiation as treatment in patients with stage III non-small cell lung cancer: A randomized phase II (RENO study).

OBJECTIVES: Concomitant chemo-radiation is the standard treatment for unresectable stage III non-small cell lung cancer (LA-NSCLC). The aim of this study was to assess the safety and efficacy of oral vinorelbine and cisplatin (OVP) compared with etoposide and cisplatin (EP), both in combination with radiotherapy, in this setting. MATERIAL AND METHODS: An open-label, randomized phase II trial was undertaken including 23 hospitals in Spain. Adults with untreated unresectable stage III NSCLC were randomized1:1 to receive: oral vinorelbine (days 1 and 8 with cisplatin on day 1 in 3-week cycles; 2 cycles of induction, 2 cycles in concomitance) or etoposide (days 1-5 and 29-32 with cisplatin on days 1 and 8 in 4-week cycles; 2 cycles in concomitance). Both groups received concomitant radiotherapy 2 Gy/day (66 Gy). The primary endpoint was progression free survival (PFS). RESULTS: One hundred and forty patients were enrolled. Sixty-nine patients received OVP and 71 received EP. Globally adverse events grade 3/4 per cycle were fewer in the vinorelbine arm (19.4%) than in the etoposide arm (62.6%) (p < 0.001). One patient (1.5%) in the OVP arm and 12 pts (17.6%) in the EP arm presented esophagitis grade 3/4 (p = 0.002). Median PFS was similar in both groups (10.8 [95% CI 7.7-13.8] and 9.6 months [95% CI 4.4-14.8]; p = 0.457, respectively). Preliminary median overall survival was 30 months in the OVP arm and 31.9 months in the EP arm (p = 0.688). CONCLUSIONS: Our findings show that OVP could be considered a standard combination with similar efficacy and better safety profile for the treatment of LA-NSCLC patients.

Efecto del consumo habitual de café en la salud cardiovascular: protocolo de una revisión de revisiones sistemáticas de la literatura / Effect of the Habitual Coffee Consumption in the Cardiovascular Health: A Protocol of Systematic Review of Reviews

Introducción: El café es una de las bebidas más consumidas en el mundo, aunque no están claramente establecidos sus efectos en la salud. En particular, aún hay controversia sobre sus efectos cardiovasculares. El objetivo de este trabajo es sintetizar evidencia acerca de los efectos del consumo habitual de café, en la salud cardiovascular. Métodos: Se llevó a cabo una revisión de revisiones sistemáticas de la literatura, de artículos obtenidos de las bases Medline, Embase, Cochrane y LILACS, publicados en inglés, español, francés o portugués. La búsqueda fue complementada manualmente con las referencias de las revisiones incluidas. Una pareja de investigadores seleccionó y extrajo información de manera independiente, y las discrepancias se resolvieron por consenso. Las revisiones incluidas se clasificaron según el año de publicación, desenlaces, diseño de los estudios primarios y calidad. Se utilizó el instrumento Assessing Methodological Quality for Systematic Reviews para calificar la calidad, y la información se sintetizó en formatos sistematizados. Discusión: La revisión sintetizó la evidencia del efecto del café sobre la salud cardiovascular y estimó la relación dosis-respuesta.

Introduction: Coffee is one of the most consumed beverages worldwide and its effect on health is not clearly established. There is a special controversy about its effects on the cardiovascular system. The objective of this work is to synthesize the evidence on the effects of habitual coffee consumption on the cardiovascular health. Methods: Review of systematic reviews of the literature published in English, Spanish, French or Portuguese in biomedical databases (Medline, Embase, Cochrane, and Lilacs). The search will be supplemented with hand searching of references of the included reviews. The selection and extraction of information will be done independently by two researchers resolving the disagreements by consensus. The included reviews will be grouped by publication year, outcomes, design of original studies and quality. The study will apply the Assessing Methodological Quality for Systematic Reviews checklists to assess the methodological quality of systematic reviews. Information will be synthesized in systematized formats. Discussion: The review of reviews will synthesize the evidence of the effect of coffee on cardiovascular health and estimate the dose response relationship.

Clinical management and outcome of patients with advanced NSCLC carrying EGFR mutations in Spain.

BACKGROUND: Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) over chemotherapy has been demonstrated in several clinical trials, data from clinical practice is lacking and the optimal EGFR TKI to be used remains unclear. This study aims to assess the real-life diagnostic and clinical management and outcome of patients with advanced non-small-cell lung cancer (NSCLC) carrying EGFR mutations in Spain. METHODS: All consecutive patients recently diagnosed with advanced or metastatic NSCLC from April 2010 to December 2011 in 18 Spanish hospitals and carrying EGFR mutations were retrospectively evaluated. RESULTS: Between March and November 2013, a total of 187 patients were enrolled (98.3% Caucasian, 61.9% female, 54.9% never-smokers, 89.0% adenocarcinoma). Mutation testing was mainly performed on biopsy tumour tissue specimens (69.0%) using a qPCR-based test (90%) (47.0% Therascreen EGFR PCR Kit). Common sensitising mutations were detected in 79.8% of patients: 57.1% had exon 19 deletions and 22.6% exon 21 L858R point mutations. The vast majority of patients received first-line therapy (n = 168; 92.8%). EGFR TKIs were the most commonly used first-line treatment (81.5%), while chemotherapy was more frequently administered as a second- and third-line option (51.9% and 56.0%, respectively). Of 141 patients who experienced disease progression, 79 (56.0%) received second-line treatment. After disease progression on first-line TKIs (n = 112), 33.9% received chemotherapy, 8.9% chemotherapy and a TKI, and 9.8% continued TKI therapy. Most patients received first-line gefitinib (83.0%), while erlotinib was more frequently used in the second-line setting (83.0%). Progression-free survival (PFS) and overall survival (OS) in patients harbouring common mutations were 11.1 months and 20.1 months respectively (exon 19 deletions: 12.4 and 21.4 months; L858R: 8.3 and 14.5 months), and 3.9 months and 11.1 months respectively for those with rare mutations. CONCLUSION: EGFR TKIs (gefitinib and erlotinib) are used as the preferred first-line treatment while chemotherapy is more frequently administered as a second- and third-line option in routine clinical practice in Spain. In addition, efficacy data obtained in the real-life setting seem to concur with data from EGFR TKI phase III pivotal studies in NSCLC.

Síndrome de apneas-hipopneas y narcolepsia. Descripción de una serie hospitalaria / Sleep apnoea-hypopnoea syndrome and narcolepsy. Description of a series of hospital patients

Introducción. Los trastornos del sueño son muy prevalentes en la población general; sin embargo, la asociación de síndrome de apneas-hipopneas (SAHS) en pacientes con narcolepsia se ha descrito en pocas ocasiones. Se revisan los trastornos del sueño encontrados en pacientes con narcolepsia, la prevalencia de SAHS asociado a estos pacientes y su respuesta a los tratamientos. Pacientes y métodos. Análisis descriptivo retrospectivo observacional de 25 pacientes, con diagnóstico de narcolepsia, atendidos en nuestro centro desde octubre de 2012 hasta diciembre de 2016. Resultados. De 470 pacientes valorados en la consulta monográfica de neurología, hemos diagnosticado a 25 pacientes con narcolepsia (5,31%); el 65% eran hombres, y el 35%, mujeres. Edad media en el momento del diagnóstico: 40 años. El 60% presenta otros trastornos del sueño asociados, el más frecuente es el SAHS (36%). La eficacia del tratamiento con presión aérea positiva continua nasal (CPAP) es del 66% en los pacientes con SAHS con indicación de CPAP. Conclusiones. El 60% de los pacientes con narcolepsia asocia un segundo trastorno del sueño (mayor que la incidencia de coexistencia en la población general, del 20-25% de los pacientes), y los descritos también son los más frecuentes en la población general (SAHS, síndrome de piernas inquietas, movimientos periódicos de las piernas). El 36% de los pacientes con narcolepsia asocia SAHS. De ellos, en el 78% se ha conseguido un control de eventos respiratorios adecuado; el 57% se ha controlado con CPAP y el 43% restante no ha precisado CPAP por corrección de eventos con otros métodos (AU)

Introduction. Sleep disorders are highly prevalent among the general population, although very few cases of sleep apnoea-hypopnoea syndrome (SAHS) have been reported in patients with narcolepsy. This study reviews the sleep disorders found in patients with narcolepsy, the prevalence of SAHS associated with these patients and their response to the different treatments. Patients and methods. We conducted an observation-based retrospective descriptive analysis of 25 patients diagnosed with narcolepsy, who were treated in our centre between October 2012 and December 2016. Results. Of 470 patients evaluated in the specialised neurology consultation unit, 25 patients were diagnosed with narcolepsy (5.31%); 65% were males and the remaining 35% were females; the mean age at the time of diagnosis was 40 years. 60% presented other associated sleep disorders, the most frequent being SAHS (36%). The efficacy rate of treatment with continuous positive airway pressure (CPAP) is 66% in patients with SAHS with an indication of CPAP. Conclusions. Altogether, 60% of patients with narcolepsy have a second associated sleep disorder (greater than the incidence of coexistence in the general population, of 20-25% of patients), and those reported are also the most frequent among the general population (SAHS, restless legs syndrome, periodic limb movement disorder). 36% of patients with narcolepsy have SAHS as an associated condition. Of these, 78% have reached a suitable degree of control over respiratory events; 57% have achieved control with CPAP, and the remaining 43% did not require CPAP for event correction with other methods (AU)

Spotlight on ramucirumab in the treatment of nonsmall cell lung cancer: design, development, and clinical activity.

The vascular endothelial growth factor (VEGF) and receptor is a therapeutic target because of the importance of this pathway in carcinogenesis. This pathway regulates and promotes angiogenesis as well as increases endothelial cell proliferation, permeability, and cancer survival. Ramucirumab is a new fully human monoclonal antibody that targets the VEGF receptor-2, an important key receptor implicated in angiogenesis. Ramucirumab has been approved for the treatment of second-line advanced or metastatic non-small cell lung cancer (NSCLC) in combination with the chemotherapy agent docetaxel. This was based on the result of the randomized trial REVEL of 1,253 patients with metastatic NSCLC previously treated with a platinum-based combination therapy. The authors observed a significant improvement in overall survival (OS) with an acceptable toxicities profile. In this study, patients were randomized to receive ramucirumab plus docetaxel or placebo with docetaxel. The combination of docetaxel and ramucirumab showed an improved OS (hazard ratio [HR]: 0.86; 95% CI: 0.75, 0.98). Median OS was 10.5 months in the ramucirumab arm versus 9.1 months in the placebo arm. Regarding side effects, the toxicity described on the ramucirumab arm were principally diarrhea, fatigue, and neutropenia. The most common (5%) adverse reactions of grade 3 and 4 in the ramucirumab arm were fatigue, neutropenia, febrile neutropenia, leukopenia, and hypertension. Adding ramucirumab to docetaxel improves QoL of patients, and does not impair symptoms or functioning. There are currently several trials in progress evaluating the effects of ramucirumab in combination with other drugs in patients with advanced NSCLC.

Influence of CFH, HTRA1 and ARMS2 polymorphisms in the response to intravitreal ranibizumab treatment for wet age-related macular degeneration in a Spanish population.

AIM: To determine whether gene polymorphisms of the major genetic risk loci for age-related macular degeneration (AMD): ARMS2 (rs10490923), the complement factor H (CFH) (rs1410996) and HTRA1 (rs11200638) influence the response to a treatment regimen with ranibizumab for exudative AMD. METHODS: This study included 100 patients (100 eyes) with exudative AMD. Patients underwent a treatment with ranibizumab injections monthly during three months. Reinjections were made when the best corrected visual acuity (BCVA) decrease five letters (ETDRS) or central subfield retinal thickness gained 100 µm in optical coherence tomography image. Genotypes (rs10490923, rs1410996 and rs11200638) were analyzed using TaqMan probes or polymerase chain reaction-restricted fragment length polymorphisms analysis. RESULTS: There were no statistically significant differences in allelic distribution of CFH (rs1410996), ARMS2 (rs10490923) and HTRA1 (rs11200638) polymorphisms regarding to response to ranibizumab treatment. CONCLUSION: Ranibizumab treatment response is not related to CFH (rs1410996), ARMS2 (rs10490923) and HTRA1 (rs11200638) poymorphisms.

[Afatinib in patients with squamous cell carcinoma of the lung: current context and the option of oral treatment]. / Afatinib en pacientes con carcinoma escamoso de pulmón: contexto actual y opción de un tratamiento oral.

Squamous cell carcinoma (SCC) of the lung represents 30% of non-small cell lung cancers (NSCLC). Docetaxel and the EGFR tyrosine kinase inhibitor (TKI), erlotinib, are the only two drugs approved for second-line treatment of advanced SCC. The sensitivity of SCC to TKIs can be explained by EGFR overexpression. Erlotinib demonstrated a significant benefit in terms of overall survival (OS) in successive lines in NSCLC, including squamous histology. The magnitude of this benefit is similar to that of chemotherapy. Afatinib is an irreversible inhibitor of the entire ErbB family (EGFR, HER2-4) that has recently been approved for its current indication, advanced EGFR mutation-positive NSCLC and has well-defined and manageable toxicity, mainly gastrointestinal and cutaneous. The LUX-Lung 8 study was a phase III randomized trial in patients with NSCLC with squamous histology that compared erlotinib versus afatinib as second-line treatment. A total of 795 patients were included and a significant benefit was observed for afatinib in progression-free survival (2.7 vs 1.9 months (HR 0.79 [95%CI 0.68-0.91]; p=0.0012) and in OS (7.9 vs 6.8 months (HR 0.81 [95%CI 0.69-0.95]; p=0.0077), as well as a significant improvement in OS at 12 and 18 months. More diarrhoea and stomatitis was observed with afatinib and more rash with erlotinib, but the overall proportion of toxicity was similar in each group. Afatinib offered better results in quality of life. In summary, afatinib is a second-line treatment option in squamous NSCLC based on its survival advantage over erlotinib.