Resistance to BRAF inhibition explored through single circulating tumour cell molecular profiling in BRAF-mutant non-small-cell lung cancer.

BACKGROUND: Resistance mechanisms to combination therapy with dabrafenib plus trametinib remain poorly understood in patients with BRAFV600E-mutant advanced non-small-cell lung cancer (NSCLC). We examined resistance to BRAF inhibition by single CTC sequencing in BRAFV600E-mutant NSCLC. METHODS: CTCs and cfDNA were examined in seven BRAFV600E-mutant NSCLC patients at failure to treatment. Matched tumour tissue was available for four patients. Single CTCs were isolated by fluorescence-activated cell sorting following enrichment and immunofluorescence (Hoechst 33342/CD45/pan-cytokeratins) and sequenced for mutation and copy number-alteration (CNA) analyses. RESULTS: BRAFV600E was found in 4/4 tumour biopsies and 5/7 cfDNA samples. CTC mutations were mostly found in MAPK-independent pathways and only 1/26 CTCs were BRAFV600E mutated. CTC profiles encompassed the majority of matched tumour biopsy CNAs but 72.5% to 84.5% of CTC CNAs were exclusive to CTCs. Extensive diversity, involving MAPK, MAPK-related, cell cycle, DNA repair and immune response pathways, was observed in CTCs and missed by analyses on tumour biopsies and cfDNA. Driver alterations in clinically relevant genes were recurrent in CTCs. CONCLUSIONS: Resistance was not driven by BRAFV600E-mutant CTCs. Extensive tumour genomic heterogeneity was found in CTCs compared to tumour biopsies and cfDNA at failure to BRAF inhibition, in BRAFV600E-mutant NSCLC, including relevant alterations that may represent potential treatment opportunities.

Incidental pathogenic germline alterations detected through liquid biopsy in patients with solid tumors: prevalence, clinical utility and implications.

Liquid biopsy, a minimally invasive approach for detecting tumor biomarkers in blood, has emerged as a leading-edge technique in cancer precision medicine. New evidence has shown that liquid biopsies can incidentally detect pathogenic germline variants (PGVs) associated with cancer predisposition, including in patients with a cancer for which genetic testing is not recommended. The ability to detect these incidental PGV in cancer patients through liquid biopsy raises important questions regarding the management of this information and its clinical implications. This incidental identification of PGVs raises concerns about cancer predisposition and the potential impact on patient management, not only in terms of providing access to treatment based on the tumor molecular profiling, but also the management of revealing genetic predisposition in patients and families. Understanding how to interpret this information is essential to ensure proper decision-making and to optimize cancer treatment and prevention strategies. In this review we provide a comprehensive summary of current evidence of incidental PGVs in cancer predisposition genes identified by liquid biopsy in patients with cancer. We critically review the methodological considerations of liquid biopsy as a tool for germline diagnosis, clinical utility and potential implications for cancer prevention, treatment, and research.

Determinants of activity and efficacy of anti-PD1/PD-L1 therapy in patients with advanced solid tumors recruited in a clinical trials unit: a longitudinal prospective biomarker-based study.

Immune-checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of cancer. However, optimal patient selection is still an unmet need. One-hundred-forty-six patients with metastatic cancer candidates to ICI at the Hospital Clinic of Barcelona Clinical Trials Unit were prospectively recruited in this observational study. Blood samples were collected at different timepoints, baseline LIPI score calculated and pre-ICI archived tissues retrieved to evaluate PD-L1, tumor-infiltrating lymphocytes (TILs) and PD1 mRNA levels. Tumor assessments were centrally reviewed by RECIST 1.1 criteria. Associations with overall response rates (ORR), durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) were performed with univariable/multivariable logistic and Cox regressions, where appropriate. At a median follow-up of 26.9 months, median PFS and OS were 2.7 and 12.9 months. Response rates were 17.8% with duration of response (DOR) of 4.4 months. LIPI score was independently associated with PFS (p = 0.025) and OS (p < 0.001). Immunotherapy-naïve status was independently associated with better PFS (p = 0.005). Time-to-best response (TTBR) and ORR (p < 0.001 both) were associated with better OS at univariate analysis. PFS and DOR were moderately correlated with OS (p < 0.001 both). A PD-L1 10% cut-off detected worse/best responders in terms of ORR (univariate p = 0.011, multivariate p = 0.028) and DCB (univariate p = 0.043). PD1 mRNA levels were strikingly associated to complete responses (p = 0.021). To resume, in our prospective observational pan-cancer study, baseline LIPI score, immunotherapy-naïve status, cancer type and RT before starting ICI were the most relevant clinical factors independently correlated with immunotherapy outcomes. Longer TTBR seemed to associate with better survival, while PD1 mRNA and PD-L1 protein levels might be tumor-agnostic predictive factors of response to ICI and should be furtherly explored.

Childhood Traumatic Experiences and Negative Alcohol-Related Consequences in Adulthood: A Cross-Cultural Examination of Distress Tolerance and Drinking to Cope.

Background: Prior research has established that Adverse Childhood Experiences (ACEs) predict harmful alcohol use outcomes. However, underlying mechanisms that could explain these associations are less clear. The present study examined if ACEs are indirectly related to alcohol negative consequences through their associations with distress tolerance and drinking to cope. Method: A sample of 3,763 (71.9% female) college students who drink alcohol from seven countries (U.S., Argentina, Canada, Uruguay, Spain, South Africa, and England) completed online surveys. Path analysis was performed within the whole sample testing the serial unique associations between ACEs→distress tolerance→drinking to cope→negative alcohol-related consequences. Multi-group analysis was performed to determine if the proposed pathways were invariant across gender and countries. Results: Both distress tolerance and drinking to cope uniquely accounted for the relationship between ACEs and negative alcohol-related consequences. Additionally, a significant double-mediation effect was found illustrating that a higher endorsement of ACEs was associated with lower distress tolerance, which in turn was associated with higher drinking to cope, which in turn was associated with more negative alcohol-related consequences. These effects were invariant across countries and gender groups. Conclusions: These findings provide support for the relevance of distress tolerance and coping motives as potential factors in linking ACEs to problematic alcohol use across nations. Our data are consistent with the idea that intervening on distress tolerance and drinking motives could mitigate downstream alcohol-related consequences related to ACEs in college student populations around the world.

Utility of the Brief Young Adult Alcohol Consequences Questionnaire to Identify College Students At-Risk for Alcohol Related Problems: Relative Operating Characteristics across Seven Countries.

Background: It is important to identify students who would benefit from early interventions to reduce harmful drinking patterns and associated consequences. the Brief Young Adult Alcohol Consequences Questionnaire (B-YAACQ) could be particularly useful as a screening tool in university settings. Objectives. The present study examined the utility of the B-YAACQ to distinguish among students at-risk for problematic alcohol use as measured by the AUDIT. Objectives: The present study examined the utility of the B-YAACQ to distinguish among students at-risk for problematic alcohol use as measured by the AUDIT. Methods: A sample of 6382 students (mean age=20.28, SD=3.75, 72.2% females) from seven countries (i.e., U.S., Canada, South-Africa, Spain, Argentina, Uruguay, England) completed the B-YAACQ, the AUDIT and different measures of alcohol use. Results: ROC analyses suggested that a cutoff score of 5 maximized the YAACQ's discrimination utility to differentiate between students at low versus moderate/high risk in the total sample and across countries (except in Canada, where the cutoff was 4). In addition, a cutoff of 7 differentiated between students at low/moderate versus high risk in the total sample, while cutoffs of 10, 9, 8 and 7 differentiate between students at low/moderate versus high risk in Uruguay, U.S and Spain (10), Argentina (9), England (8), and Canada and South-Africa (7), respectively. Students classified at the three risk levels (i.e., low, moderate and high) differed in age (i.e., a younger age was associated with higher risk) and drinking patters (i.e., higher drinking frequency, quantity, binge drinking and AUDIT and B-YAACQ scores in the higher risk groups). Conclusions: This study suggest that the B-YAACQ is a useful tool to identify college students at-risk for experiencing problematic patterns of alcohol use.

Biological Rationale for Peripheral Blood Cell-Derived Inflammatory Indices and Related Prognostic Scores in Patients with Advanced Non-Small-Cell Lung Cancer.

PURPOSE OF REVIEW: To describe the biological rationale of peripheral blood cells (PBC)-derived inflammatory indexes and assess the related prognostic scores for patients with advanced non-small cell lung cancer (aNSCLC) treated with immune-checkpoint inhibitors (ICI). RECENT FINDINGS: Inflammatory indexes based on PBC may indicate a pro-inflammatory condition affecting the immune response to cancer. The lung immune prognostic index (LIPI), consisting of derived neutrophils-to-lymphocyte ratio (NLR) and lactate dehydrogenase, is a validated prognostic tool, especially for pretreated aNSCLC patients, where the combination of NLR and PD-L1 tumour expression might also be predictive of immunotherapy benefit. In untreated high-PD-L1 aNSCLC patients, the Lung-Immune-Prognostic score (LIPS), including NLR, ECOG PS and concomitant steroids, is prognostic, and its modified version might indicate patients with favourable outcomes despite an ECOG PS of 2. NLR times platelets (i.e., SII), included in the NHS-Lung score, might improve the prognostication for combined chemoimmunotherapy. PBC-derived inflammatory indexes and related scores represent accurate, reproducible and non-expensive prognostic tools with clinical and research utility.

Effects of spatial variation in dose delivery: what can we learn from radon-related lung cancer studies?

Exposure to radon progeny results in heterogeneous dose distributions in many different spatial scales. The aim of this review is to provide an overview on the state of the art in epidemiology, clinical observations, cell biology, dosimetry, and modelling related to radon exposure and its association with lung cancer, along with priorities for future research. Particular attention is paid on the effects of spatial variation in dose delivery within the organs, a factor not considered in radiation protection. It is concluded that a multidisciplinary approach is required to improve risk assessment and mechanistic understanding of carcinogenesis related to radon exposure. To achieve these goals, important steps would be to clarify whether radon can cause other diseases than lung cancer, and to investigate radon-related health risks in children or persons at young ages. Also, a better understanding of the combined effects of radon and smoking is needed, which can be achieved by integrating epidemiological, clinical, pathological, and molecular oncology data to obtain a radon-associated signature. While in vitro models derived from primary human bronchial epithelial cells can help to identify new and corroborate existing biomarkers, they also allow to study the effects of heterogeneous dose distributions including the effects of locally high doses. These novel approaches can provide valuable input and validation data for mathematical models for risk assessment. These models can be applied to quantitatively translate the knowledge obtained from radon exposure to other exposures resulting in heterogeneous dose distributions within an organ to support radiation protection in general.

A cross-national examination of cannabis protective behavioral strategies' role in the relationship between Big Five personality traits and cannabis outcomes.

Background: Problematic cannabis use is common among young adults across the world. However, limited research has examined whether etiological models predicting negative consequences are universal.Objective: The present study examined whether the Five-Factor Model of personality (openness, conscientiousness, extraversion, agreeableness, and neuroticism) relates to cannabis outcomes via use of cannabis protective behavioral strategies (PBS) in a cross-national sample of college student cannabis users (i.e., used cannabis in the last 30 days).Method: Participants were 1175 university students (63.27% female) across five countries (United States, Argentina, Spain, Uruguay, and the Netherlands) recruited to complete an online survey.Results: PBS use mediated the associations between personality traits and cannabis consequences, such that higher conscientiousness (ß = .20), agreeableness (ß = .11), and lower emotional stability [i.e., higher neuroticism] (ß = -.14) were associated with more PBS use. Higher PBS use was, in turn, associated with lower frequency of cannabis use (ß = -.32); lower frequency of use was then associated with fewer cannabis consequences (ß = .34). This sequential pathway was invariant across sex, but not countries. Notably, there were a number of differences in links between PBS and cannabis outcomes when comparing countries (e.g., negative associations in the US sample, but positive associations in the Argentina sample).Conclusions: Cannabis PBS mediates the relationship between personality traits and cannabis outcomes, but there are nuanced differences across countries (i.e., relationship between PBS and cannabis outcomes). Overall, students that are low in conscientiousness, agreeableness, and neuroticism and/or report low rates of PBS use may benefit from cannabis PBS-focused interventions that promote utilization of PBS.

The role of personality on disordered gaming and game genre preferences in adolescence: Gender differences and person-environment transactions. / El papel de la personalidad en el juego problemático y en las preferencias de géneros de videojuegos en adolescentes.

Playing video games is one of the world's most popular leisure activities, especially for teenagers. The main aim of the present study was to examine additive and moderation effects of gender and personality to explain individual differences in problematic gaming and video game genre preferences in adolescence. 776 Spanish high school students (mean age = 14.29 years, SD = 1.59, 50.64% girls) completed the questionnaires of the Five-Factor Model of personality, frequency of video gaming, disordered use, and the video games they mostly played.Gender differences were observed for gaming behaviors: boys played more and presented much more disordered gaming than girls. Boys preferred competitive genres; for example, action-shooters, sport, fight and strategy games. Girls preferred nonviolent and ocasional game genres; for example, social simulation, and brain and skill games. Gender moderated the association between personality and disordered gaming: disordered gaming was associated with low agreeableness and low conscientiousness in boys, and with low extraversion and low conscientiousness in girls. Low consciousnness moderated the association between gaming frequency and problematic use of video games: playing more video games led to disordered gaming, mainly in irresponsible and impulsive individuals. Though small, significant associations were found among all of the personality domains and video game genre preferences. These findings highlight the relevance of gender and personality for gaming behaviors in adolescence, and suggest paying more attention to gender-dependent differences and person-environment transactional processes when studying gaming-related behaviors.

Jugar a videojuegos es una de las actividades de ocio más populares en adolescentes. El principal objetivo de este estudio fue examinar los efectos aditivos y de moderación del género y la personalidad en el juego problemático y en la preferencia en géneros de videojuegos durante la adolescencia. 776 estudiantes españoles (media de edad = 14,29; DT = 1,59; 50,64% chicas) cumplimentaron cuestionarios del Modelo de los cinco grandes de personalidad y de conductas relacionadas con videojuegos. Se observaron diferencias de género en conductas relacionadas con videojuegos: los chicos jugaban más y presentaron mucho más uso problemático que las chicas. Ellos prefirieron géneros competitivos; por ejemplo, juegos de acción-shooters, deportes, lucha y estrategia. Las chicas prefirieron géneros no violentos y ocasionales; por ejemplo, simulación social, y juegos de habilidad y lógica. El género moderó las asociaciones entre personalidad y juego problemático: el juego problemático se asoció a baja amabilidad y baja responsabilidad en chicos, y a baja extraversión y baja responsabilidad en chicas. La baja responsabilidad moderó las asociaciones entre frecuencia de juego y uso problemático: jugar más a videojuegos conducía a un uso problemático de éstos, principalmente en individuos irresponsables e impulsivos. Se encontraron asociaciones pequeñas pero significativas entre la personalidad y preferencias en géneros de videojuegos. Estos hallazgos destacan la relevancia del género y la personalidad en las conductas relacionadas con videojuegos durante la adolescencia, y animan a prestar más atención a las diferencias dependientes del género y a las transacciones persona-ambiente al estudiar estas conductas.

Association of the prognostic model iSEND with PD-1/L1 monotherapy outcome in non-small-cell lung cancer.

BACKGROUND: Accessible biomarkers are needed for immunotherapy in advanced non-small-cell lung cancer (NSCLC). We previously described a multivariate risk prediction model, the iSEND, which categorises advanced NSCLC patients treated with nivolumab into Good, Intermediate or Poor groups. This model was developed by using only clinical and analytical variables (sex, ECOG-performance status, neutrophil-to-lymphocyte ratio [NLR] and post-treatment delta NLR). METHODS: An international database of 439 patients who received post-platinum PD-1/L1 monotherapies was collected for validation. Performance of the iSEND to different PD-L1 groups was compared by using time-dependent positive predictive value (PPV) for their mortality events. RESULTS: Median follow-up was 18.2 months (95% CI: 15.9-19.6). The overall survival of the iSEND Good (HR = 0.31, 95% CI: 0.22-0.43, p < 0.0001) was superior to the iSEND Poor. Time-dependent PPV for mortality of iSEND Poor was superior to PD-L1 = 0% group at 12 (75 vs. 53%, p = 0.01) and 18 months (85 vs. 46%, p = 0.03). However, female gender did not independently associate with better outcome in the validation cohort. CONCLUSION: The iSEND model is associated with the outcome of post-platinum PD-1/L1 monotherapy in advanced NSCLC patients. The iSEND Poor demonstrated a superior performance to PD-L1 = 0% in negative prognostication. Prospective investigation and modelling with other significant parameters in a larger cohort are warranted.

Baseline metabolic tumor burden on FDG PET/CT scans predicts outcome in advanced NSCLC patients treated with immune checkpoint inhibitors.

PURPOSE: We aimed to evaluate if imaging biomarkers on FDG PET are associated with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). METHODS: In this retrospective monocentric study, we included 109 patients with advanced NSCLC who underwent baseline FDG PET/CT before ICI initiation between July 2013 and September 2018. Clinical, biological (including dNLR = neutrophils/[leukocytes minus neutrophils]), pathological and PET parameters (tumor SUVmax, total metabolic tumor volume [TMTV]) were evaluated. A multivariate prediction model was developed using Cox models for progression-free survival (PFS) and overall survival (OS). The association between biomarkers on FDG PET/CT and disease clinical benefit (DCB) was tested using logistic regression. RESULTS: Eighty patients were eligible. Median follow-up was 11.6 months (95%CI 7.7-15.5). Sixty-four and 52 patients experienced progression and death, respectively. DCB was 40%. In multivariate analyses, TMTV > 75 cm3 and dNLR > 3 were associated with shorter OS (HR 2.5, 95%CI 1.3-4.7 and HR 3.3, 95%CI 1.6-6.4) and absence of DCB (OR 0.3, 95%CI 0.1-0.9 and OR 0.4, 95%CI 0.2-0.9). Unlike TMTV, dNLR was a significant prognostic factor for PFS (HR 1.9, 95%CI 1.1-3.3) along with anemia (HR 1.9, 95%CI 1.2-3.8). No association was observed between tumor SUVmax and PFS or OS. CONCLUSION: Baseline tumor burden (TMTV) on FDG PET/CT scans and inflammatory status (dNLR) were associated with poor OS and absence of DCB for ICI treatment in advanced NSCLC patients, unlike tumor SUVmax, and may be used together to improve the selection of appropriate candidates.

Association of metastatic pattern and molecular status in stage IV non-small cell lung cancer adenocarcinoma.

OBJECTIVES: The aim of our study was to investigate the association between driver oncogene alterations and metastatic patterns on imaging assessment, in a large cohort of metastatic lung adenocarcinoma patients. METHODS: From January 2010 to May 2017, 550 patients with stage IV lung adenocarcinoma with molecular analysis were studied retrospectively including 135 EGFR-mutated, 81 ALK-rearrangement, 47 BRAF-mutated, 141 KRAS-mutated, and 146 negative tumors for these 4 mutations (4N). After review of the complete imaging report by two radiologists (junior and senior) to identify metastatic sites, univariate correlation analyzes were performed. RESULTS: We found differences in metastatic tropism depending on the molecular alteration type when compared with the non-mutated 4N group: in the EGFR group, pleural metastases were more frequent (32% versus 20%; p = 0.021), and adrenal and node metastases less common (6% versus 23%; p < 0.001 and 11% versus 23%; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% versus 29%; p = 0.043 and 37% versus 24%; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (respectively 47% versus 20%; p < 0.001 and 11% versus 3%; p = 0.04) and bone metastases were rarer (21% versus 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK, and BRAF groups (respectively 6%, 7%, and 15% versus 1%); p = 0.016; p = 0.009; and p < 0.001. CONCLUSION: The application of these correlations between molecular status and metastatic tropism in clinical practice may lead to earlier and more accurate identification of patients for targeted therapy. KEY POINTS: • Bone and brain metastasis are the most common organs involved in lung adenocarcinoma but the relative incidence of each metastatic site depends on the molecular alteration. • EGFR-mutated tumors preferentially spread to the pleura and less commonly to adrenals, ALK-rearrangement tumors usually spread to the brain and the lungs, whereas BRAF-mutated tumors are unlikely to spread to bones and have a serous (pericardial ad pleural) tropism. • These correlations could help in the clinical management of patients with metastatic lung adenocarcinoma.

The LIPI score and inflammatory biomarkers for selection of patients with solid tumors treated with checkpoint inhibitors.

Over the last decade, immune checkpoint inhibitors (ICI) have completely changed the treatment strategy and the prognosis of several solid cancer types. There is a lack of biomarkers to differ between responders and non-responders to these therapies. The development of biomarkers for immunotherapy has been mainly focused on tumor-related factors. The role of PD-L1 expression or tumor mutational burden (TMB) as potential predictive biomarkers for ICI efficacy is not universal and remains controversial. Moreover, leukocyte and neutrophil counts in blood samples have been used to develop clinical indicators of systemic inflammation like the neutrophil to lymphocyte ratio (NLR) and derived neutrophil to lymphocyte ratio (dNLR) based on the host immunologic status to respond against cancer cells by the immune-effectors. The Lung Immune Prognostic Index (LIPI) score have been developed as a reliable tool to assess the risk stratification of patients with cancer and to guide treatment decisions in the era of personalized cancer treatments. We review the clinical evidence supporting the use of the LIPI index as a clinically valuable biomarker for patients with NSCLC and other solid tumor types, treated with immunotherapy.

Development and Validation of the Marijuana Motives Measure Short Form. / Desarrollo y validación de la versión breve del cuestionario de motivos de consumo de marihuana (MMM SF).

Marijuana motives are a proximal variable to marijuana use. This research aimed to adapt and validate the short form of the Marijuana Motives Measure (MMM; Simons, Correia, Carey, y Borsari, 1998), the MMM SF, in Spanish.  The sample comprised 232 participants (mean age = 25.11 (7.58), 50.43% males) who had tried marijuana at least once in their lifetime. Item and Rasch analyses were performed to choose the final pool of 15 items. Confirmatory Factor Analysis (CFA) showed an adequate 5-factor structure (S-BX2(80) = 121.30, p = .002; NNFI = .944; CFI = .958; IFI = .959; MFI = .915; RMSEA = .047(0.029, 0.063); AIC = -38.70), and the multi-group CFA between males and females showed acceptable fit indices (S-BX2(160) = 230.01, p = .000; NNFI = .900; CFI = .924; IFI = .927; MFI = .860; RMSEA = .062(.043, .078); AIC = -89.99). The questionnaire indicated metric (S-BX2diff (15) = 13.61, p = .556)), scalar (S-BX2diff (15) = 23.15, p = .081)) and error measurement invariance (S-BX2diff (15) = 8.65, p = .895)) between gender groups. The internal consistencies and ordinal omega of the scales were between .79 and .90. In the regression analysis, enhancement, coping and low conformity motives predicted frequency and quantity of marijuana smoked. The best predictor of frequency and quantity consumed during the heaviest smoking period was enhancement, while coping and, to a lesser extent, low conformity, were the only predictors of cannabis-related problems when marijuana frequency and quantity were controlled for.  The MMM SF shows adequate psychometric properties and is a suitable instrument to assess marijuana motives, especially during time-limited sessions.

Los motivos de consumo son una variable proximal al uso de marihuana. Este estudio pretende adaptar y validar la versión española breve del Marijuana Motives Measure (MMM; Simons, Correia, Carey, y Borsari, 1998), el MMM SF. La muestra estaba compuesta por 232 participantes (edad media = 25,11 (7,58), 50,43% hombres) que habían probado la marihuana al menos una vez. Se realizaron análisis de los ítems y de Rasch para seleccionar los 15 ítems. El Análisis Factorial Confirmatorio (AFC) mostró una estructura de cinco factores adecuada (S-BX2(80) = 121,30, p = ,002; NNFI = 0,944; CFI = 0,958; IFI = 0,959; MFI = 0,915; RMSEA = 0,047(0,029, 0,063); AIC = -38,70), y el AFC multigrupo entre hombres y mujeres mostró índices de ajuste aceptables (S-BX2(160) = 230,01, p = ,000; NNFI = 0,900; CFI = 0,924; IFI = 0,927; MFI = 0,860; RMSEA = 0,062(0,043, 0,078); AIC = -89,99). El cuestionario mostró invarianza métrica (S-BX2dif (15) = 13,61, p = ,556)), escalar (S-BX2dif (15) = 23,15, p = ,081)) y de los errores de medida (S-BX2dif (15) = 8,65, p = ,895)) entre grupos de género. Los alfas de Cronbach y omega ordinal de las escalas fueron de 0,79 a 0,90. Los motivos de animación, afrontamiento y bajos motivos de conformidad predijeron el consumo de marihuana. El mejor predictor durante la época de mayor consumo fueron los motivos de animación, mientras que los motivos de afrontamiento, y en menor medida los bajos motivos de conformidad, fueron los mejores predictores de los problemas derivados una vez se controló el efecto de frecuencia y cantidad fumada.  El MMM SF presenta unas propiedades psicométricas adecuadas y es una medida útil para evaluar los motivos de consumo de marihuana, especialmente durante sesiones de evaluación con tiempo limitado.

Effects of Social Attitude Change on Smoking Heritability.

Societal attitudes and norms to female smoking changed in Spain in the mid-twentieth century from a restrictive to a tolerant, and an even pro-smoking, posture, while social attitudes remained stable for males. We explored whether this difference in gender-related social norms influenced the heritability of two tobacco use measures: lifetime smoking and number of years smoking. We used a population-based sample of 2285 twins (mean age = 55.78; SD = 7.45; 58% females) whose adolescence began between the mid-1950s and the early 1980s. After modeling the effect of sex and year of birth on the variance components, we observed that the impact of the genetic and shared environmental factors varied differently by birth cohort between males and females. For females, shared environment explained a higher proportion of variance than the genetic factors in older cohorts. However, this situation was inverted in the younger female cohorts. In contrast, no birth cohort effect was observed for males, where the impact of the genetic and environmental factors remained constant throughout the study period. These results suggest that heritability is larger in a permissive social environment, whereas shared-environmental factors are more relevant in a society that is less tolerant to smoking.

Durvalumab in non-small-cell lung cancer patients: current developments.

Immune checkpoint inhibitors (ICIs) are a key component of treating advanced cancer patients, principally antibodies against CTLA-4 and PD-1 or PD-L1. Durvalumab (MEDI4736) is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1, which binds to PD-1 and CD80, but not to PD-L2. Single-agent durvalumab showed clinical efficacy and a manageable safety profile in advanced non-small-cell lung cancer, particularly the ≥25% PD-L1+ population. Durvalumab is under evaluation in early, locally advanced and advanced disease as monotherapy and combined with ICIs, targeted therapies, chemotherapy and radiotherapy. Impressive activity has been recently reported after chemoradiation in locally advanced patients; promising activity was observed with other ICI combinations, and potentially with other drugs including platinum-based chemotherapy. In contrast, early data reveal lower response rates in EGFR and ALK-positive patients.

Development and validation of the alcohol Expectancy Questionnaire Short Form (EQ-SF). / Desarrollo y validación de la versión corta del cuestionario sobre expectativas de los efectos del alcohol (EQ-SF).

Alcohol expectancies are proximal variables to alcohol use and misuse. In recent decades, different measures have been developed to assess this construct. One of the most frequently used and recommended instruments is the Expectancy Questionnaire (EQ; Leigh y Stacy, 1993). Our aim is to develop a short version of the EQ (EQ-SF) for suitable use in time-limited administrations. Two samples, adolescents (N = 514, 57.20% females) and adults (N = 548, 61.50% females), completed the EQ together with alcohol-use measures. Different item selection strategies were applied to select the 24 items. The EQ-SF structure was explored using confirmatory factor analysis, and measurement invariance was tested running a multi-group analysis comparing groups by sex and age. Reliability was tested using Cronbach's alpha and omega coefficients. Concurrent validity was investigated with regression analyses. The EQ-SF showed acceptable between-groups measurement invariance. Alphas and omegas ranged from .77 to .93. Positive expectancies predicted both alcohol use and alcohol-related problems. Negative expectancies predicted alcohol-related problems. Sex and age moderated these associations. Males with high positive alcohol expectancies showed higher alcohol consumption than females, while adults with high negative alcohol expectancies showed greater alcohol-related problems than adolescents. Different evidence on the validity and reliability of the EQ-SF suggest that it is a suitable instrument to assess alcohol expectancies in the Spanish population.

Las expectativas sobre los efectos del alcohol son una variable proximal al consumo de alcohol. Uno de los instrumentos más usados y recomendados para evaluar este constructo es el Expectancy Questionnaire (EQ; Leigh y Stacy, 1993). El objetivo es desarrollar una versión corta del EQ (EQ-SF) útil para administraciones en las que el tiempo de evaluación es reducido. Dos muestras, una de adolescentes (N = 514, 57,20% mujeres) y una de adultos (N = 548, 61,50% mujeres), completaron el EQ y diversas medidas sobre consumo de alcohol. Se utilizaron diversas estrategias para seleccionar los 24 ítems. Se exploró la estructura del EQ-SF mediante análisis factoriales confirmatorios y la invarianza de medida entre sexos y grupos de edad realizando análisis multigrupo. Se calculó la fiabilidad de las escalas mediante el alfa de Cronbach y el coeficiente omega, y la validez concurrente a través de análisis de regresión. La invariancia entre grupos fue aceptable. Los coeficientes alfa y omega iban de ,77 a ,93. Las expectativas positivas predijeron la cantidad de alcohol consumida y los problemas derivados del consumo, mientras que las negativas predijeron los problemas derivados. Sexo y edad moderaron estas asociaciones. Los hombres con elevadas expectativas positivas bebían más que las mujeres, mientras que los adultos con elevadas expectativas negativas mostraron mayores problemas derivados del consumo que los adolescentes. Las diferentes fuentes de evidencia sobre la validez y fiabilidad del EQ-SF sugieren que es un instrumento adecuado para evaluar las expectativas sobre los efectos del alcohol en población española.

Stressful life events during adolescence and risk for externalizing and internalizing psychopathology: a meta-analysis.

The main objective of the present research was to analyze the relations between stressful life events and the externalizing and internalizing spectra of psychopathology using meta-analytical procedures. After removing the duplicates, a total of 373 papers were found in a literature search using several bibliographic databases, such as the PsycINFO, Medline, Scopus, and Web of Science. Twenty-seven studies were selected for the meta-analytical analysis after applying different inclusion and exclusion criteria in different phases. The statistical procedure was performed using a random/mixed-effects model based on the correlations found in the studies. Significant positive correlations were found in cross-sectional and longitudinal studies. A transactional effect was then found in the present study. Stressful life events could be a cause, but also a consequence, of psychopathological spectra. The level of controllability of the life events did not affect the results. Special attention should be given to the usage of stressful life events in gene-environment interaction and correlation studies, and also for clinical purposes.