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Background Pneumococcal conjugate vaccines (PCVs) have greatly reduced the incidence of pneumococcal disease, yet unmet medical need remains due to increased disease caused by non-vaccine serotypes (STs). V114 (VAXNEUVANCETM, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA) is a 15-valent PCV containing 13 serotypes in licensed PCV13 and 2 additional serotypes (22F, 33F) which significantly contribute to pneumococcal disease burden. This phase 3 trial compared safety, tolerability, and immunogenicity of V114 to PCV13 in adults ≥50 years of age. Methods Adults were randomized 1:1 to receive a single dose of V114 or PCV13; randomization was stratified by age (50–64 years, 65–74 years, and ≥75 years). Adverse events (AEs) were collected following vaccination. Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were measured prior to and 30 days after vaccination (Day 30). Primary objectives included assessing noninferiority of V114 to PCV13 for the 13 shared serotypes and superiority of V114 to PCV13 for the two unique serotypes. Superiority of V114 to PCV13 for shared serotype 3 was assessed as a secondary objective. Results Overall, 1,202 participants were vaccinated (V114 N = 602, PCV13 N = 600). The most commonly reported AEs across both groups were injection-site pain, fatigue, and myalgia. V114 met noninferiority criteria compared to PCV13 for the 13 shared serotypes (using a 2-fold non-inferiority margin for the ratio of OPA geometric mean titers [GMTs] [V114/PCV13] at Day 30) and met superiority for the 2 unique serotypes (using a 2-fold super-superiority margin for the ratio of OPA GMTs [V114/PCV13] at Day 30 and a 0.10 super-superiority margin for the difference in proportions of participants with ≥4-fold rise from prevaccination to Day 30). V114 met superiority criteria compared to PCV13 for serotype 3 (based on a super-superiority margin of 1.2 for the ratio of the OPA GMTs [V114/PCV13] and a superiority margin of 0 for the difference in proportions of participants with ≥4-fold rise). [NCT03950622, EudraCT#2018-004316-22, Japic-CTI#194845].

Purpose: To date, studies regarding the use of prophylactic cranial irradiation (PCI) versus standard of care (SoC) for patients with non-small cell lung cancer (NSCLC) have not shown a significant effect in terms of overall survival (OS). Additionally, the effect of PCI among high-risk patients has been scarcely studied. The objective of this randomized phase 2 study was to evaluate the role of PCI in a population of patients at high risk for development of brain metastases (BM). Methods and Materials: Eligible patients had histologically confirmed NSCLC without baseline BM, harboring epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or elevated carcinoembryonic antigen levels at the time of diagnosis. Participants received systemic therapy according to molecular status, those without progressive disease were then assigned to receive SoC or SoC thorn PCI (25 Gy in 10 fractions). The primary outcome was cumulative incidence of brain metastases (CBM). The secondary endpoints included progression-free survival and OS. Quality of life and neurocognitive function are discussed in a separate article (Clinicaltrials.gov: NCT01603849). Results: From May 2012 to December 2017, 84 patients were enrolled in the study, with 41 patients allocated to receive PCI and 43 received SoC. Patients allocated to receive PCI had a CBM at 24 months of 7% versus 38% in those allocated to the SoC arm. PCI was associated with a hazard ratio of 0.12 (95% confidence interval, 0.035-0.42) for developing BM. A benefit in OS was also observed (64.5 vs 19.8 months; hazard ratio: 0.41 (95% confidence interval, 0.22-0.78; P = .007). Conclusions: Among a selected population at high risk for developing BM, PCI significantly decreased CBM in addition to increasing progression-free survival and OS. To our knowledge, this is the first study to evaluate PCI in epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or elevated carcinoembryonic antigen levels in patients with NSCLC, showing a significant improvement in CBM. This relevant information should be of particular importance in the context of patients without access to third-generation targeted agents. Further studies are warranted to ascertain this effect. (C) 2021 Elsevier Inc. All rights reserved.

Introduction Brain metastases (BM) are frequent among lung cancer patients, affecting prognosis and quality of life. The International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS) lung adenocarcinoma (LADC) classification (IASLC/ATS/ERS) has prognostic impact in early-stage disease; however, its role in the advanced setting is not precise. This study aims to determine the correlation between the predominant histological subtype and the risk of developing brain metastases (BM) in locally advanced and metastatic (stages IIIB-IV) LADC. Methods A total of 710 patients with LADC were treated at our institution from January 2010 to December 2017. After excluding patients with brain metastases at diagnoses (n = 151), they were categorized according to the IASLC/ATS/ERS LADC classification to estimate the risk of developing brain metastases. A competing risk analysis was employed, considering death a competing risk event. Results From 559 patients, the mean age was 59 ± 13.2 years, women (52.4 %), and clinical-stage IV (79.2 %). LADC subtypes distribution was lepidic (11.6 %), acinar (37.9 %), papillary (10.2 %), micropapillary (6.8 %), and solid (33.5 %). A total of 27.0 % of patients developed BM, 32.9 % died without brain affection, and 40.0 % did not progress. The predominantly solid subtype showed the greatest probability of all subtypes for developing BM [HR 4.0; 95 % CI (1.80−8.91), p = 0.0006], followed by micropapillary [HR1.11; 95 % CI (0.36−3.39), p = 0.85). The solid subtype, moderately differentiated tumors, age, and ECOG PS (>2) were associated with increased hazards in the multivariate analysis. CONCLUSION According to the IASLC/ATS/ERS classification, the predominantly solid pattern was significantly associated with an increased risk of developing BM in patients with locally advanced and metastatic LADC. Its prognostic value might help explore novel clinical approaches, modify monitoring for earlier detection, prevent complications, and reduce morbidity.

Background: Mutations in STK11 (STK11(Mut)) and, frequently co-occurring, KEAP1 mutations (KEAP1(Mut)) are associated with poor survival in metastatic Non-small Cell Lung Cancer (mNSCLC) patients treated with immunotherapy. However, there are limited data regarding the prognostic or predictive significance of these genomic alterations among Hispanics. Methods: This retrospective study analyzed a cohort of Hispanic patients (N = 103) diagnosed with mNSCLC from the US and seven Latin American countries (LATAM) treated with immune checkpoint inhibitors (ICI) alone or in combination as first-line (Cohort A). All cases were treated in routine care between January 2016 and December 2021. The main objectives were to determine the association of mutations in STK11 or KEAP1 in these patients' tumors with overall (OS) and progression-free survival (PFS), presence of KRAS mutations, tumor mutational burden (TMB), and other relevant clinical variables. To compare outcomes with a STK11(Wt)/KEAP1(Wt) population, historical data from a cohort of Hispanic patients (N = 101) treated with first-line ICI was used, matching both groups by country of origin, gender, and Programed Death-ligand 1 (PD-L1) expression level (Cohort B). Results: Most tumors had mutations only in STK11 or KEAP1 (45.6%) without KRAS co-mutation or any other genomic alteration. Besides, 35%, 8.7%, 6.8%, and 3.9% were KRAS(Mut) + STK11(Mut), KRAS(Mut) + STK11(Mut) + KEAP1(Mut), STK11(Mut) + KEAP1(Mut), and KRAS(Mut) + KEAP1(Mut), respectively. Based on KRAS status, STK11 alterations were associated with significantly lower PD-L1 expression among those with KRAS(Wt) (p = 0.023), whereas KEAP1 mutations were predominantly associated with lower PD-L1 expression among KRAS(Mut) cases (p = 0.047). Tumors with KRAS(Mut) + KEAP1(Mut) had significantly higher median TMB when compared to other tumors (p = 0.040). For Cohort A, median PFS was 4.9 months (95%CI 4.3-5.4), slightly longer in those with KEAP1(mut) 6.1 months versus STK11(Mut) 4.7 months (p = 0.38). In the same cohort, PD-L1 expression and TMB did not influence PFS. OS was significantly longer among patients with tumors with PD-L1 >= 50% (30.9 months), and different from those with PD-L1 1-49% (22.0 months), and PD-L1 < 1% (12.0 months) (p = 0.0001). When we compared the cohorts A and B, OS was significantly shorter for patients carrying STK1 [STK11(Mut) 14.2 months versus STK11(Wt) 27.0 months (p = 0.0001)] or KEAP1 [KEAP1(Mut) 12.0 months versus KEAP1(Wt) 24.4 months (p = 0.005)] mutations. PD-L1 expression significantly affected OS independently of the presence of mutations in STK11, KEAP1, or KRAS. TMB-H favored better OS. Conclusions: This is the first large Hispanic cohort to study the impact of STK11 and KEAP1 mutations in NSCLC patient treated with ICI. Our data suggest that mutations in the above-mentioned genes are associated with PD-L1 expression levels and poor OS.

Co-occurring genomic alterations identified downstream main oncogenic drivers have become more evident since the introduction of next-generation sequencing (NGS) analyses at diagnosis and progression. Emerging evidence has stated that co-occurring genomic alterations at diagnosis might represent de novo and primary resistance mechanisms to tyrosine kinase inhibitors (TKIs) in advanced EGFR-mutant (EGFRm) non-small lung cancer (NSCLC). In this study, we assessed the prognostic role of co-occurring genomic alterations in advanced EGFRm NSCLC.A cohort of 111 patients with advanced NSCLC harboring EGFR-sensitive mutations detected by PCR was analyzed in 5 Latin American oncological centers from January 2019 to December 2020. All eligible patients received upfront therapy with EGFR-TKI. Co-occurring genomic alterations were determined at diagnosis in every patient by the NGS (FoundationOneCDx) comprehensive platform, which evaluates 324 known cancer-related genes.EGFR exon19 deletion was the most frequent oncogenic driver mutation (60.4 %) detected by NGS. According to the NGS assay, 31 % and 68.3 % of patients had 1-2 and ≥ 3 co-occurring genomic alterations, respectively. The most frequent co-occurring genomic alterations were TP53 mutations (64.9 %) followed by CDKN2AB alterations (13.6 %), BRCA2 (13.6 %), and PTEN (12.7 %) mutations. Baseline central nervous system disease was present in 42.7 % of patients. First- or second-generation EGFR TKIs (gefitinib, afatinib, or erlotinib) were the most common treatment in 67.5 % of patients, while osimertinib was administered in 27.9 % of cases. The median PFS in all evaluated patients was 13.63 months (95 %CI: 11.79-15.52). Using ≥ 3 co-occurring alterations as the cut-off point, patients with ≥ 3 co-occurring genomic alterations showed a median PFS, of 12.7 months (95 %CI: 9.92-15.5) vs 21.3 months (95 %CI: 13.93-NR) in patients with 2 or less co-occurring genomic alterations [HR 3.06, (95 %CI: 1.55-5.48) p = 0.0001]. Also, patients with a TP53 mutation had a shorter PFS, 13.6 (95 %CI: 10.7-15.5) vs 19.2 months (95 %CI: 12.8-NR); in wild type TP53 [HR 2.01 (95 %CI: 1.18-3.74) p = 0.12]. In the multivariate analysis, the number (≥3) of concurrent genomic alterations and ECOG PS of 2 or more were related to a significant risk factor for progression [HR 2.79 (95 %CI: 1.49-5.23) p = 0.001 and HR 2.42 (95 %CI: 1.22-4.80) p = 0.011 respectively].EGFR-mutant NSCLC is not a single oncogene-driven disease in the majority of cases, harboring a higher number of co-occurring genomic alterations. This study finds the number of co-occurring genomic alterations and the presence of TP53 mutations as negative prognostic biomarkers, which confers potentially earlier resistance mechanisms to target therapy.

The general equation of state employed in direct form, and for the first time presented in Part I of this series, is extended to correlate and predict the viscosity of binary mixtures of ionic liquids. The extension, also done for the first time, considers the classical mixing and combining rules commonly used in studies on pressure-temperature-volume equations of state, including two cases: (i) with no-interaction parameter (predictive model); and (ii) with one adjustable interaction parameter (correlating model). Data on viscosity of binary mixtures of ionic liquids have been gathered from the literature, analyzed, and selected, to finally construct a database of consistent data to obtain a general model that relates viscosity with pressure, temperature and concentration. A total of 2520 data points distributed on 344 isotherms, for 32 mixtures were considered for analysis, with average absolute relative deviations below 6%. If no interaction parameter is used, the model is still capable of predicting the viscosity of a mixture using only properties of the pure components. Results show that the model is accurate enough, being simpler and more accurate than sophisticated multiparametric models.

A generalized viscosity equation of state including a single adjustable parameter for correlating and estimating the viscosity of ionic liquids at different temperatures and pressures is proposed. The similar shape and form of the curves (isotherms and saturation lines) observed in a density-pressure-temperature plot and in a viscosity-pressure-temperature plot (ρTP and μTP plots), known as geometrical similitude, is the basis of the proposed model. Viscosity data available in the literature has been gathered, analyzed, and selected to finally construct a database of consistent data to obtain a general model. The generalized equation of state model includes a number of parameters that are determined by fitting the model using the selected experimental viscosity data of different types of ionic liquids. In total, 3857 viscosity data for 187 ionic liquids in the temperature range of 253–573 K and pressures from 1.0 up to 1500 bar have been considered. The generalized viscosity model has been compared with other existing approaches and results show that the new viscosity cubic equation of state model provides accurate and consistent results taking in account the simplicity of the generalized expressions, which contains only one adjustable parameter for each ionic liquid.

To compare the intraocular pressure (IOP)-lowering efficacy and safety of netarsudil once daily (QD) and timolol twice daily (BID).Double-masked, randomized, phase 3, noninferiority study.Patients with open-angle glaucoma or ocular hypertension (unmedicated baseline IOP20 to30 mm Hg at 8:00 AM) were randomized to netarsudil ophthalmic solution 0.02% QD (PM) or timolol ophthalmic solution 0.5% BID. The primary endpoint was mean IOP at 8:00 AM, 10:00 AM, and 4:00 PM at week 2, week 6, and month 3 in patients with baseline IOP25 mm Hg (per-protocol population). Safety was recorded over the 6-month treatment period.A total of 186 patients from each treatment arm were included in the primary efficacy analysis. Netarsudil QD met the criteria for noninferiority to timolol BID. Mean treated IOP ranged from 16.3 to 17.9 mm Hg for netarsudil and 16.7 to 17.6 for timolol, with mean reductions from baseline of 3.9 to 4.7 mm Hg and 3.8 to 5.2 mm Hg, respectively. In prespecified secondary analyses, netarsudil demonstrated noninferiority to timolol in patients with baseline IOP27 mm Hg and30 mm Hg. The IOP-lowering effects of netarsudil were sustained over 6 months of treatment. No treatment-related serious adverse event (AE) was reported for either study drug. However, statistically significant reductions in mean heart rate were recorded at all study visits for the timolol group. The most frequent ocular AE among netarsudil-treated patients was conjunctival hyperemia (47.9%), which was predominately mild.Netarsudil QD (PM), a first-in-class IOP-lowering medication, was noninferior to timolol BID and was associated with tolerable ocular AEs.

Introduction Epidermal growth factor receptor (EGFR) pathway deregulation promotes the acquisition of stemlike properties in non–small-cell lung cancer. EGFR inhibition through NOTCH enriches lung cancer stem cells (CSCs). Src through Yes-associated protein 1 (YAP1) activates NOTCH. Signal transduction and activator of transcription 3 (STAT3) activation occurs upon EGFR blockade and regulates the generation of CSCs. Patients and Methods Using the Aldefluor assay kit, we investigated the enrichment of aldehyde dehydrogenase (ALDH)-positive cells in EGFR-mutation–positive cells treated with gefitinib, afatinib, and osimertinib. Western blot analysis was performed to evaluate changes in CSC marker expression upon EGFR blockade. We performed gene expression analysis in a cohort of EGFR-mutation–positive non–small-cell lung cancer patients. We evaluated the association of gene expression with treatment outcomes. Results The cell subpopulation surviving EGFR inhibition had high ALDH activity and elevated CSC marker expression. Concurrent inhibition of EGFR, STAT3, and Src diminished the CSC subpopulation in an EGFR-mutation–positive cellular model. In a cohort of 64 EGFR-mutation–positive patients, 2 ALDH1 isoforms and the NOTCH target hairy and enhancer of split 1 (HES1), when highly expressed, were predictive of worse outcome to EGFR blockade. The gene expression of B-cell–specific Moloney murine leukemia virus integration site 1 (Bmi-1) that maintains the self-renewal of stem cells was also related to treatment outcome. Conclusion Single EGFR inhibitors increase the population of CSCs. Combinatory therapy targeting STAT3 and Src may be of potential benefit. ALDH1, HES1, and Bmi-1 are essential biomarkers in the initial assessment of EGFR-mutation–positive patients.

A new coronavirus, named severe acute respiratory syndrome-coronavirus-2 by the WHO, has rapidly spread around the world since its first reported case in late December of 2019 from Wuhan, the People's Republic of China. As of mid-April 2020, this virus has affected more than 180 countries and territories, infecting more than 1,650,000 individuals and causing over 100,000 deaths. With approximately 20 million new cases globally per year, cancer affects a substantial portion of the population. Individuals affected by cancer are more susceptible to infections owing to coexisting chronic diseases (cardiovascular, pulmonary, and diabetes), overall poor health status, and systemic immunosuppressive states caused by both cancer and the anticancer treatment. As a consequence, patients with malignancies, especially those with lung cancer who develop coronavirus disease 2019, experience more difficult outcomes. A recent multicenter study carried out by the Hubei Anti-Cancer Association has also documented that patients with lung cancer had an increased risk of death, intensive care unit requirement, risk of presenting severe or critical symptoms, and use of invasive mechanical ventilation. Here, we present two representative cases of patients with lung cancer and coronavirus disease 2019 without respiratory compromise and with atypical and severe skin manifestations-findings that could be influenced by the long-term use of anti-programmed cell death protein 1 antibody.

The world currently faces a pandemic due to SARS-CoV-2. Relevant information has emerged regarding the higher risk of poor outcomes in lung cancer patients. As such, lung cancer patients must be prioritized in terms of prevention, detection and treatment. On May 7th, 45 experts in thoracic cancers from 11 different countries were invited to participate. A core panel of experts regarding thoracic oncology care amidst the pandemic gathered virtually, and a total of 60 initial recommendations were drafted based on available evidence, 2 questions were deleted due to conflicting evidence. By May 16th, 44 experts had agreed to participate, and voted on each of the 58 recommendation using a Delphi panel on a live voting event. Consensus was reached regarding the recommendations (>66 % strongly agree/agree) for 56 questions. Strong consensus (>80 % strongly agree/agree) was reached for 44 questions. Patients with lung cancer represent a particularly vulnerable population during this time. Special care must be taken to maintain treatment while avoiding exposure.

Here we report a case of a young, never-smoker Hispanic woman with a hereditary familial overlap syndrome (Li-Fraumeni plus CDH1). The patient developed multiple synchronous primary lung adenocarcinomas related to Intra-Alveolar Tumor Spread (STAS) several years after the diagnosis of a locally advanced lower limb osteosarcoma. Comprehensive genomic profiling by next generation sequencing (NGS) was performed on 90 cancer-related genes over each lung lesion (including two nodules of acinar adenocarcinoma, one lepidic spread tumor and in the STAS area). Likewise, the broad genomic analysis was performed on archival tissue from the previous bone tumor. Lung tumors were found to harbor PIK3CA (invasive lesions) and a rare in-frame insertion of nucleotides in exon 19 of EGFR (lepidic tumor). STAS area showed KRAS and BRAF mutations in two different segments, and osteosarcoma tested positive for well known PIK3CA, KRAS and CDH1 alterations. This unique case raises practical questions as to the challenges of molecular testing and highlights the potential association of germline TP53 and CDH1 mutations with concurrent somatic alterations that elucidate the basis of tumor heterogeneity.

The frontal lobes are one of the most complex brain structures involved in both domain-general and specific functions. The goal of this work was to assess the anatomical and cognitive affectations from a unique case with massive bilateral frontal affectation. We report the case of GC, an eight-year old child with nearly complete affectation of bilateral frontal structures and spared temporal, parietal, occipital, and cerebellar regions. We performed behavioral, neuropsychological, and imaging (MRI, DTI, fMRI) evaluations. Neurological and neuropsychological examinations revealed a mixed pattern of affected (executive control/abstraction capacity) and considerably preserved (consciousness, language, memory, spatial orientation, and socio-emotional) functions. Both structural (DTI) and functional (fMRI) connectivity evidenced abnormal anterior connections of the amygdala and parietal networks. In addition, brain structural connectivity analysis revealed almost complete loss of frontal connections, with atypical temporo-posterior pathways. Similarly, functional connectivity showed an aberrant frontoparietal network and relative preservation of the posterior part of the default mode network and the visual network. We discuss this multilevel pattern of behavioral, structural, and functional connectivity results. With its unique pattern of compromised and preserved structures and functions, this exceptional case offers new constraints and challenges for neurocognitive theories. Fil: Ibanez Barassi, Agustin Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencias Cognitivas y Traslacional; Argentina. Universidad Adolfo Ibañez; Chile. Australian Research Council; Australia Fil: Zimerman, Máximo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencias Cognitivas y Traslacional; Argentina Fil: Sedeño, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencias Cognitivas y Traslacional; Argentina Fil: Lori, Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencias Cognitivas y Traslacional; Argentina Fil: Rapacioli, Melina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencias Cognitivas y Traslacional; Argentina Fil: Cardona Londoño, Juan Felipe. Universidad del Valle; Colombia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Suarez, Diana M. A.. Universidad del Valle; Colombia Fil: Herrera, Eduar. Universidad Icesi; Colombia Fil: García, Adolfo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencias Cognitivas y Traslacional; Argentina. Universidad Nacional de Cuyo; Argentina Fil: Manes, Facundo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencias Cognitivas y Traslacional; Argentina

The group contribution concept is used and a simple and general method is proposed for estimating phase change properties of ionic liquids. The proposal includes some especial characteristics, such as: (i) the model considers the well-known relation between the melting temperature, the heat of melting, and the entropy of melting; (ii) the model considers that a given group has a contribution value if the group occurs in the cation and another different value if it occurs in the anion; and (iii) the correlation process considers experimental data of melting temperature and heat of melting. Despite its simplicity, the proposed model provides deviations that are similar to other more sophisticated, multiparametric models. The literature analysis and our own results indicate that there are still some unknown facts that determine phase transitions and that models have not been able to include and quantify. All this indicates that the goal of having the most general and accurate model for predicting the melting temperature and melting enthalpy of ionic liquids is still far away. However, the present proposal represents a new attempt for contributing to this interesting puzzle of getting good and reasonable estimates for the melting properties which could help in choosing the appropriate ionic liquid for an existing or new application.

Background A proportion of patients with NSCLC is diagnosed at 40 years or younger. These patients tend to be never-smokers, usually present with stage IV adenocarcinoma, and have somatic genomic alterations. Few studies have documented and analyzed epidemiological characteristics of this population. Materials and methods We performed an international epidemiological analysis of 389 young patients with NSCLC. Data was collected from centers participating in the Latin American Consortium for Lung Cancer Research (AduJov-CLICaP). Patients were identified and data was retrospectively collected from different Latin American countries and Canada (Argentina = 6, Canada = 19, Colombia = 29, Costa Rica = 9, Mexico = 219, Nicaragua = 2, Panama = 19, Peru = 76 and Venezuela = 10). The period of study was from 2012 to 2017. Inclusion criteria were: age 40 years or less and a histologically confirmed NSCLC. Clinical data was obtained, and EGFR mutation status and EML4-ALK translocation were collected. Results NSCLC patients aged 40 years or less accounted for approximately 4% of the total NSCLC population. Female patients accounted for 54.5%, while median age was of 37 years. Adenocarcinoma accounted for 86.1% (n = 335/389), 72.5% (n = 282/389; unknown = 5) of patients were non-smokers, and 90.3% (n = 351/389) had stage IV disease. Site of metastasis was obtained from 260/351 (unknown = 91) stage IV patients (lung metastasis = 40.0%, CNS metastasis = 35.7%, and bone metastasis = 31.5%). OS for the total population was 17.3 months (95%CI = 13.9-20.7). OS for EGFRm(+) = 31.4 months (95%CI = 11.6-51.3), EGFRm(−) = 14.5 months (95%CI = 11.0–17.9) (p = 0.005). OS for alk(+) = 9.8 months (95%CI = 3.1-16.5) and alk(−) = 5.6months (95%CI = 3.9–7.3) (p = 0.315). Conclusions Patients aged 40 years or less account for a small but important proportion of NSCLC cases. Younger patients may have different characteristics compared to the older population. EGFRm and EML4-alk translocation frequency is higher than that of the general population.

The current lung cancer classification from the Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society has considerably changed the pathologic diagnosis of lung invasive adenocarcinoma, identifying disease subtypes with substantial implications for medical practice, such as clinical, radiological, molecular, and prognostic differences. We analyzed the differences in the genetic expression of adenocarcinoma subtypes according to the new classification. Microarray gene expression analysis was performed on a cohort of 29 adenocarcinoma patients treated at the Instituto Nacional de Cancerologia of Mexico from 2008 to 2011. All patients had an available biopsy sample and were classified into 4 different subtypes of adenocarcinoma (2015 World Health Organization classification). Lepidic-predominant adenocarcinoma was the only pattern that exhibited a marked gene expression difference compared with other predominant histologic patterns, revealing genes with significant expression (P < .01). Moreover, we identified 13 genes with specific differential expression in the lepidic-predominant adenocarcinoma that could be used as a gene signature. The lepidic-predominant histologic pattern has a differential gene expression profile compared with all predominant histologic patterns. Additionally, we identified a gene expression signature of 13 genes that have a unique behavior in the lepidic histologic pattern; these 13 genes are candidates for follow-up studies for their potential use as biomarkers or therapeutic targets. Results from this study highlight the importance of the new Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification and exemplify the potential clinical implications of correlating histopathology with exclusive molecular beacons.

Lung cancer, the deadliest cancer worldwide, is of particular concern in Latin America. The rising incidence poses a myriad of challenges for the region, which struggles with limited resources to meet the health care needs of its low- and middle-income populations. In this environment, we are concerned that governments are relatively unaware of the pressing need to implement effective strategies for screening, diagnosis, and treatment of lung cancer. The region has also been slow in adopting molecularly-based therapies in the treatment of advanced disease: testing for epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements are not routine, and access to targeted agents such as monoclonal antibodies and tyrosine kinase inhibitors is problematic. In this paper, we review the current situation in the management of lung cancer in Latin America, hoping that this initiative will help physicians, patient associations, industry, governments, and other stakeholders better face this epidemic in the near future.

The general equation of state based on the concept of geometric similarity presented in Part 1 of this series is extended to correlate and predict the thermal conductivity and the speed of sound of binary water + ionic liquid mixtures. The extension considers the classical mixing and combining rules commonly used in studies and applications of pressure-temperature-volume equations of state. Data on thermal conductivity and speed of sound of binary water + ionic liquids mixtures were gathered from the literature in the temperature range from 278 K to 343 K at atmospheric pressure. A total of 77 data for the thermal conductivity and 1560 data for the speed of sound for 28 binary mixtures are included in the study. The results of the extension to mixtures show that the empirical equation of state model provides adequate and consistent values using pure component data only, proving its good predictive capability.

A model based on the geometric similitude concept recently proposed by the authors is extended to calculate the thermal conductivity and the speed of sound of ionic liquids. Experimental data for these properties are employed to determine the constants and the parameters of the proposed general model. The experimental data are taken from ionic liquid database provided by the National Institute of Standards and Technology (NIST). In total, 320 thermal conductivity data (40 ionic liquids) and 2572 speed of sound data (61 ionic liquids), at the temperature range of 263.15 K to 390.15 K and pressure from 0.86 up to 2000 bar have been considered. The proposed empirical equation of state model contains only one adjustable parameter for each ionic liquid, parameter that can be determined using a single experimental data or can be generalized in terms of other available properties, as proposed in this work. The results show that the equation of state model provides acceptable results for the correlation and prediction of the thermal conductivity and the speed of sound for the studied pure ionic liquids.

Background: The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-1 inked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogenactivated protein kinase (MAPK) pathway activation. Methods: We analyzed tumor ILK,13-receptor subunit glycoprotein 130 (gp130), SHP2, and stromal hepatocyte growth factor (HGF) and interleukin-6 (IL-6) mRNA expression in baseline tumor specimens of advanced EGFR-mutation positive NSCLC patients treated with EGFR TKIs. Results: ILK, when highly expressed, was an independent poor prognostic factor for the progression-free survival of the patients, both in the univariate (hazard ratio [HR for disease progression, 2.49; 95% Cl, 1.37-452; P .0020]) and in the multivariate (HR 3.74; 95% Cl, 1.33-10.56; P.0126) Cox regression model. Patients with high SHP2 expression had an almost 13-month shorter progression-free survival (P.0094) and an 18 month shorter overall survival (P.0182) in comparison to those with low SHP2 mRNA expression. Interpretation: The levels of ILK and SHP2 could be predictive for upfront combinatory therapy of EGFR TKIs plus SHP2 or ILK inhibitors. Fund: A grant from La Caixa Foundation, an Institute de Salud Carlos III grant (RESPONSE, PIE16/00011), an Institute de Salud Carlos III grant (PI14/01678), a Marie Sklodowska-Curie Innovative Training Networks European Grant (ELBA No 765492) and a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE). (C) 2018 The Authors. Published by Elsevier B.V.

Background: Cancer is a global problem. Estimates for 2018 expect around 18.1 million new cases and 9.6 related deaths worldwide. Interestingly, there is significant geographical variation in cancer research that has an inverse correlation with cancer-specific mortality. In Latin America (LATAM), the percentage of gross domestic product (GDP) invested in research is below 1% in the majority of countries. The region has been a participant in only 4.6% of clinical trials in cancer worldwide and produced only 4% of all scientific publications. Methods: This study, a bibliometric analysis of cancer-related publications in LATAM establishes the relationship between sociodemographic factors and countries, taking into account authors and their networking efforts. We implemented a high sensitivity search strategy for cancer publications between 2000 and 2018 using the Scopus database, limited to LATAM nations. We constructed collaboration networks for both authors and citations for LATAM and each country in the region, calculated correlations between the number of included publications, author and national indicators. Findings: The search included 8528 articles across 9 countries. Brazil was the most productive nation with 41.8% of the included references. Mexico (16.6%), Argentina (12.9%), and Chile (9.7%) followed. LATAM experienced a 9% growth in publications. Peru had the greatest percentage growth (23%). Number of publications by country highly correlated with author network size (r = 0.75, p = 0.019). Percentage of invested GDP in research and development correlated positively with the number of publications for most nations. Interpretation: LATAM has experienced a significant growth in cancer related publications. Furthermore, it highlights the importance of scientific networking as a strategy for increasing scientific productivity. Hopefully, these results will serve to bolster oncology related publications in the region, further contributing with cancer research and leading to progress in the scientific field. Funding Statement: This study was self-funded. Declaration of Interests: The authors declare no potential conflict of interest related to this article. Ethics Approval Statement: Due to the nature of the study, no approval of an institutional Ethics and Research board was required.

Lung cancer (LC), the leading cause of cancer-related deaths worldwide, is a complex and highly heterogeneous disease. Additional to its biological complexity, LC patients are often confronted with a high degree of stigma, mostly from the association of the disease with tobacco. Nonetheless, a proportion of LC patients are never-smokers, a population which we are beginning to comprehensively explore. Several risk factors have been linked to LC in never-smokers. Studies have consistently shown that radon exposure and domestic fuel smoke increase LC risk. Additionally, infections such as Mycobacterium tuberculosis, and Human Papilloma Virus are also risk factors. Other less conclusive associations include inflammatory diseases such as asthma and sarcoidosis. Moreover, we are now aware that molecular characteristics of LC vary widely according to smoking history, with important therapeutic implications. This review comprehensively assesses the current knowledge in terms of risk factors and disease characteristics in the never-smoker lung cancer population.

Several studies have recently shown that basal ganglia (BG) deterioration leads to distinctive impairments in the domains of syntax, action verbs, and action semantics. In particular, such disruptions have been repeatedly observed in Parkinson's disease (PD) patients. However, it remains unclear whether these deficits are language-specific and whether they are equally dissociable from other reported disturbances -viz., processing of object semantics. To address these issues, we administered linguistic, semantic, and executive function (EFs) tasks to two groups of non-demented PD patients, with and without mild cognitive impairment (PD-MCI and PD-nMCI, respectively). We compared these two groups with each other and with matched samples of healthy controls. Our results showed that PD patients exhibited linguistic and semantic deficits even in the absence of MCI. However, not all domains were equally related to EFs and MCI across samples. Whereas EFs predicted disturbances of syntax and object semantics in both PD-nMCI and PD-MCI, they had no impact on action-verb and action-semantic impairments in either group. Critically, patients showed disruptions of action-verb production and action semantics in the absence of MCI and without any executive influence, suggesting a sui generis deficit present since early stages of the disease. These findings indicate that varied language domains are differentially related to the BG, contradicting popular approaches to neurolinguistics. Fil: Bocanegra, Yamile. Universidad de San Buenaventura; Colombia. Universidad de Antioquia; Colombia Fil: García, Adolfo Martín. Universidad Diego Portales; Chile. Instituto de Neurología Cognitiva. Laboratorio de Psicología Experimental y Neurociencia; Argentina. Universidad Nacional de Cuyo. Facultad de Educación Elemental y Especial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pineda, David. Universidad de Antioquia; Colombia Fil: Buriticá, Omar. Universidad de Antioquia; Colombia. Hospital Pablo Tobón Uribe; Colombia Fil: Villegas, Andrés. Universidad de Antioquia; Colombia Fil: Lopera, Francisco. Universidad de Antioquia; Colombia Fil: Gómez, Diana. Universidad de Antioquia; Colombia Fil: Gómez Arias, Catalina. Universidad de San Buenaventura; Colombia Fil: Cardona Londoño, Juan Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad del Valle; Colombia Fil: Trujillo, Natalia. Universidad de Antioquia; Colombia Fil: Ibáñez Barassi, Agustín Mariano. Universidad Autónoma Del Caribe; Colombia. Universidad Diego Portales; Chile. Instituto de Neurología Cognitiva. Laboratorio de Psicología Experimental y Neurociencia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Antioquia; Colombia

HighlightsWe implemented a modelling tool for product conceptualization over the real context.We carried out a test with 21 users to prove our tool against a traditional CAD tool.Total time for product conceptualization using our tool was smaller in most cases.The users made less use of measurements tool during the sessions with our tool. Augmented reality (AR) technologies are just being used as interface in CAD tools allowing the user to perceive 3D models over a real environment. The influence of the use of AR in the conceptualization of products whose configuration, shape and dimensions depend mainly on the context remains unexplored. We aimed to prove that modelling in AR environments allows to use the context in real-time as an information input for making the iterative design process more efficient. In order to prove that, we developed a tool called AIR-MODELLING in which the designer is able to create virtual conceptual products by hand gestures meanwhile he/she is interacting directly with the real scenario. We conducted a test for comparing designers' performance using AIR-MODELLING and a traditional CAD system. We obtained an average reduction of 44% on the modeling time in 76% of the cases. We found that modelling in AR environments using the hands as interface allows the designer to quickly and efficiently conceptualize potential solutions using the spatial restrictions of the context as an information input in real-time. Additionally, modelling in a natural scale, directly over the real scene, prevents the designer from drawing his/her attention on dimensional details and allows him/her to focus on the product itself and its relation with the environment.

Objective To determine the prevalence of trial registration in randomized controlled trials (RCTs) published in 2010 (PUBMED/LILACS) from Latin America and the Caribbean’s (LAC) and to compare methodological characteristics between registered and nonregistered RCTs. Study Design and Setting A search for detecting RCTs in which at least the first/contact author had a LAC’s affiliation was made. We determined if RCTs were registered in the International Clinical Trial Registry Platform (ICTRP). Data were independently extracted by two authors. The risk of bias (RoB) was assessed in all registered RCTs (n = 89) and in a sample of nonregistered RCTs (n = 237). Results The search identified 1,695 references; 526 RCTs from 19 countries were included. 16.9% (89/526) of RCTs were registered in the ICTRP; however, only 21 (4.0%) were prospectively registered. A significant difference was found in the overall assessment of the RoB between registered and nonregistered RCTs. Overall, registered RCTs were multinational, had larger sample size and longer follow-up, and reported more frequently information on funding, conflict of interests, and ethic issues. No significant differences were found when analyzing prospectively registered RCTs. Conclusion This study shows that trial registration rates are still low in LAC and the quality of reporting needs to be improved.

Introduction: Frequency of mutations in EGFR and KRAS in non-small cell lung cancer (NSCLC) is different between ethnic groups; however, there is no information in Latin-American population. Methods: A total of 1150 biopsies of NSCLC patients from Latin America (Argentina, Colombia, Peru, and Mexico) were used extracting genomic DNA to perform direct sequencing of EGFR gene (exons 18 and 21) and KRAS gene in 650 samples. In Mexico, Scorpions ARMS was also used to obtain a genetic profile. Results: We report the frequency of mutations in EGFR and KRAS genes in four Latin-American countries (n = 1150). Frequency of EGFR mutations in NSCLC was 33.2% (95% confidence interval [CI] 30.5-35.9) (Argentina 19.3%, Colombia 24.8%, Mexico 31.2%, and Peru 67%). The frequency of KRAS mutations was 16.6% (95% CI 13.8-19.4). EGFR mutations were independently associated with adenocarcinoma histology, older age, nonsmokers, and absence of KRAS mutations. Overall response rate to tyrosine kinase inhibitors in EGFR-mutated patients (n = 56) was 62.5% (95% CI 50-75) with a median overall survival of 16.5 months (95% CI 12.4-20.6). Conclusions: Our findings suggest that the frequency of EGFR mutations in Latin America lies between that of Asian and Caucasian populations and therefore support the genetic heterogeneity of NSCLC around the world. Copyright © 2011 by the International Association for the Study of Lung Cancer.

We are all aware of the recent rapid changes in cancer management mostly achieved with emerging new data regarding tumor biology. Currently, research in oncology is mainly focused on identifying the unique molecular characteristics of neoplasms and developing new targeted drugs to treat them. Although some tumors have specific genetic alterations that set off a cause-and-effect process after targeted treatment, those who work in the lung cancer field recognize that this is a more complex disease in which various genetic disorders carry its distinctive aggressiveness. At this time, the efforts of the scientific community are directed toward the identification of predictive markers to customize treatment based on specific genomic or protein expression profiles of individual tumors. This report provides a review on the breast cancer susceptibility gene 1, a promising gene determinant of response to different types of chemotherapy and its potential applications as a new molecular marker in lung cancer.

Background and Objective A large number of trials remain difficult to locate or unpublished for systematic reviews. The objective of this article was to determine the usefulness of making e-mail contact with authors of clinical trials and literature reviews found in MEDLINE to identify unpublished or difficult to locate Randomized Controlled Trials (RCTs). Materials and Methods A structured search for detecting RCTs in MEDLINE was made from January 1999 to June 2003; a questionnaire was sent to a random sample of 525 author's mails. Those RCTs obtained were sought in MEDLINE, EMBASE, the Cochrane Controlled Trials Register, LILACS, and ongoing registers. Results 40 (7.6%) replies were received; 10 previously undescribed and unpublished RCTs and 21 unregistered ongoing RCTs were found. The most frequently given reasons for not publishing were: lack of time for finalizing the statistical analysis and preparing the manuscript, contractual obligations with the pharmaceutical industry, methodologic errors in designing, and editorial rejection. Conclusions Using the e-mails of authors detected by the search in electronic databases could contribute toward detecting potentially relevant ongoing or unpublished RCTs enabling rapid, straightforward, low-cost systematic review; in addition, the results of this study support the need of universal registration of all studies at their inception.