Impact of KRASG12D subtype and concurrent pathogenic mutations on advanced non-small cell lung cancer outcomes / Impacto del subtipo KRASG12D y mutaciones patogénicas concurrentes en los resultados del cáncer de pulmón de células no pequeñas avanzado

Purpose: Mutations in the Kirsten rat sarcoma viral (KRAS) oncogene constitute a significant driver of lung adenocarcinoma, present in 10–40% of patients, which exhibit heterogeneous clinical outcomes, mainly driven by concurrent genetic alterations. However, characterization of KRAS mutational subtypes and their impact on clinical outcomes in Latin America is limited. Methods: A cohort study was conducted at the National Cancer Institute (INCan) of Mexico. Individuals with advance-staged of adenocarcinoma and KRAS mutations, detected by next-generation sequencing, having undergone at least one line of therapy were included for analysis. Clinical and pathological characteristics were retrieved from institutional database from June 2014 to March 2023. Results: KRAS was identified in fifty-four (15.6%) of 346 patients, among which 50 cases were included for analysis. KRASG12D (n = 16, 32%) and KRASG12C (n = 16, 32%) represented the most prevalent subtypes. KRASG12D mutations were associated with female (p = 0.018), never smokers (p = 0.108), and concurrences with EGFR (25.0% vs. 17.6%, p = 0.124) and CDKN2A (18.8% vs. 14.7%, p = 0.157). KRASG12D patients showed a better ORR (66.6% vs. 30.0%; OR 4.66, 95% CI 1.23–17.60, p = 0.023) and on multivariate analysis was significantly associated with better PFS (HR 0.36, 95% CI 0.16–0.80; p = 0.012) and OS (HR 0.24, 95% CI 0.08–0.70; p = 0.009). Conclusions: To our knowledge, this study represents the first effort to comprehensively characterize the molecular heterogeneity of KRAS-mutant NSCLC in Latin American patients. Our data reinforce the current view that KRAS-mutated NSCLC is not a single oncogene-driven disease and emphasizes the prognostic impact of diverse molecular profiles in this genomically defined subset of NSCLC. Further validation is warranted in larger multicenter Latin American cohorts to confirm our findings.(AU)

Impact of KRASG12D subtype and concurrent pathogenic mutations on advanced non-small cell lung cancer outcomes.

PURPOSE: Mutations in the Kirsten rat sarcoma viral (KRAS) oncogene constitute a significant driver of lung adenocarcinoma, present in 10-40% of patients, which exhibit heterogeneous clinical outcomes, mainly driven by concurrent genetic alterations. However, characterization of KRAS mutational subtypes and their impact on clinical outcomes in Latin America is limited. METHODS: A cohort study was conducted at the National Cancer Institute (INCan) of Mexico. Individuals with advance-staged of adenocarcinoma and KRAS mutations, detected by next-generation sequencing, having undergone at least one line of therapy were included for analysis. Clinical and pathological characteristics were retrieved from institutional database from June 2014 to March 2023. RESULTS: KRAS was identified in fifty-four (15.6%) of 346 patients, among which 50 cases were included for analysis. KRASG12D (n = 16, 32%) and KRASG12C (n = 16, 32%) represented the most prevalent subtypes. KRASG12D mutations were associated with female (p = 0.018), never smokers (p = 0.108), and concurrences with EGFR (25.0% vs. 17.6%, p = 0.124) and CDKN2A (18.8% vs. 14.7%, p = 0.157). KRASG12D patients showed a better ORR (66.6% vs. 30.0%; OR 4.66, 95% CI 1.23-17.60, p = 0.023) and on multivariate analysis was significantly associated with better PFS (HR 0.36, 95% CI 0.16-0.80; p = 0.012) and OS (HR 0.24, 95% CI 0.08-0.70; p = 0.009). CONCLUSIONS: To our knowledge, this study represents the first effort to comprehensively characterize the molecular heterogeneity of KRAS-mutant NSCLC in Latin American patients. Our data reinforce the current view that KRAS-mutated NSCLC is not a single oncogene-driven disease and emphasizes the prognostic impact of diverse molecular profiles in this genomically defined subset of NSCLC. Further validation is warranted in larger multicenter Latin American cohorts to confirm our findings.

Impact of Tyrosine Kinase Inhibitors on the Immune Response to SARS-CoV-2 Vaccination in Patients with Non-Small Cell Lung Cancer.

Immune dysregulation and cancer treatment may affect SARS-CoV-2 vaccination protection. Antibody production by B-cells play a vital role in the control and clearance of the SARS-CoV-2 virus. This study prospectively explores B-cell seroconversion following SARS-CoV-2 immunization in healthy individuals and non-small cell lung cancer (NSCLC) patients undergoing oncological treatment. 92 NSCLC patients and 27 healthy individuals' blood samples were collected after receiving any COVID-19 vaccine. Serum and mononuclear cells were isolated, and a serum surrogate virus neutralization test kit evaluated SARS-CoV-2 antibodies. B-cell subpopulations on mononuclear cells were characterized by flow cytometry. Patients were compared based on vaccination specifications and target mutation oncological treatment. A higher percentage of healthy individuals developed more SARS-CoV-2 neutralizing antibodies than NSCLC patients (63% vs. 54.3%; p = 0.03). NSCLC patients receiving chemotherapy (CTX) or tyrosine kinase inhibitors (TKIs) developed antibodies in 45.2% and 53.7%, of cases, respectively, showing an impaired antibody generation. CTX patients exhibited trends towards lower median antibody production than TKIs (1.0, IQR 83 vs. 38.23, IQR 89.22; p = 0.069). Patients receiving immunotherapy did not generate antibodies. A sub-analysis revealed that those with ALK mutations exhibited non-significant trends towards higher antibody titers (63.02, IQR 76.58 vs. 21.78, IQR 93.5; p = 0.1742) and B-cells quantification (10.80, IQR 7.52 vs. 7.22, IQR 3.32; p = 0.1382) against the SARS-CoV-2 spike protein than EGFR patients; nonetheless, these differences were not statistically significant. This study shows that antibodies against SARS-CoV-2 may be impaired in patients with NSCLC secondary to EGFR-targeted TKIs compared to ALK-directed treatment.

A Novel Combination of Sotorasib and Metformin Enhances Cytotoxicity and Apoptosis in KRAS-Mutated Non-Small Cell Lung Cancer Cell Lines through MAPK and P70S6K Inhibition.

Novel inhibitors of KRAS with G12C mutation (sotorasib) have demonstrated short-lasting responses due to resistance mediated by the AKT-mTOR-P70S6K pathway. In this context, metformin is a promising candidate to break this resistance by inhibiting mTOR and P70S6K. Therefore, this project aimed to explore the effects of the combination of sotorasib and metformin on cytotoxicity, apoptosis, and the activity of the MAPK and mTOR pathways. We created dose-effect curves to determine the IC50 concentration of sotorasib, and IC10 of metformin in three lung cancer cell lines; A549 (KRAS G12S), H522 (wild-type KRAS), and H23 (KRAS G12C). Cellular cytotoxicity was evaluated by an MTT assay, apoptosis induction through flow cytometry, and MAPK and mTOR pathways were assessed by Western blot. Our results showed a sensitizing effect of metformin on sotorasib effect in cells with KRAS mutations and a slight sensitizing effect in cells without K-RAS mutations. Furthermore, we observed a synergic effect on cytotoxicity and apoptosis induction, as well as a notable inhibition of the MAPK and AKT-mTOR pathways after treatment with the combination, predominantly in KRAS-mutated cells (H23 and A549). The combination of metformin with sotorasib synergistically enhanced cytotoxicity and apoptosis induction in lung cancer cells, regardless of KRAS mutational status.

Nitroglycerin Plus Whole Intracranial Radiation Therapy for Brain Metastases in Patients With Non-Small Cell Lung Cancer: A Randomized, Open-Label, Phase 2 Clinical Trial.

PURPOSE: Hypoxia has been associated with chemoradioresistance secondary to vascular endothelial growth factor receptor induced by hypoxia-induced factor (HIF). Nitroglycerin (NTG) can reduce HIF-1 in tissues, and this may have antiangiogenic, proapoptotic, and antiefflux effects. Particularly, epidermal growth factor-mutated (EGFRm) tumor cell lines have been shown to overexpress both vascular endothelial growth factor and HIF. In this phase 2 study, we evaluated the effect of transdermal NTG plus whole brain radiation therapy (WBRT) in patients with non-small cell lung cancer (NSCLC) with brain metastases (BM). METHODS: This was an open-label, phase 2 clinical trial with 96 patients with NSCLC and BM. Patients were randomized 1:1 to receive NTG plus WBRT (30 Gy in 10 fractions) or WBRT alone. The primary endpoint was intracranial objective response rate (iORR) evaluated 3 months posttreatment. NTG was administered using a transdermal 36-mg patch from Monday through Friday throughout WBRT administration (10 days). The protocol was retrospectively registered at ClinicalTrials.gov (NCT04338867). RESULTS: Fifty patients were allocated to the control group, and 46 were allocated to the experimental group (NTG); among these, 26 (52%) had EGFRm in the control group and 21 (45.7%) had EGFRm in the NTG arm. In terms of the iORR, patients in the NTG group had a significantly higher response compared with controls (56.5% [n = 26/46 evaluable patients] vs 32.7% [n = 16/49 evaluable patients]; relative risk, 1.73; 95% confidence interval [CI], 1.08-2.78; P = .024). Additionally, patients who received NTG + WBRT had an independently prolonged intracranial progression-free survival (ICPFS) compared with those who received WBRT alone (27.7 vs 9.6; hazard ratio [HR], 0.5; 95% CI, 0.2-0.9; P = .020); this positively affected overall progression-free survival among patients who received systemic therapy (n = 88; HR, 0.5; 95% CI, 0.2-0.9; P = .043). The benefit of ICPFS (HR, 0.4; 95% CI, 0.2-0.9; P = .030) was significant in the EGFRm patient subgroup. No differences were observed in overall survival. A significantly higher rate of vomiting presented in the NTG arm of the study (P = .016). CONCLUSIONS: The concurrent administration of NTG and radiation therapy improves iORR and ICPFS among patients with NSCLC with BM. The benefit in ICPFS is significant in the EGFRm patient subgroup.

Will We Unlock the Benefit of Metformin for Patients with Lung Cancer? Lessons from Current Evidence and New Hypotheses.

Metformin has been under basic and clinical study as an oncological repurposing pharmacological agent for several years, stemming from observational studies which consistently evidenced that subjects who were treated with metformin had a reduced risk for development of cancer throughout their lives, as well as improved survival outcomes when diagnosed with neoplastic diseases. As a result, several basic science studies have attempted to dissect the relationship between metformin's metabolic mechanism of action and antineoplastic cellular signaling pathways. Evidence in this regard was compelling enough that a myriad of randomized clinical trials was planned and conducted in order to establish the effect of metformin treatment for patients with diverse neoplasms, including lung cancer. As with most novel antineoplastic agents, early results from these studies have been mostly discouraging, though a recent analysis that incorporated body mass index may provide significant information regarding which patient subgroups might derive the most benefit from the addition of metformin to their anticancer treatment. Much in line with the current pipeline for anticancer agents, it appears that the benefit of metformin may be circumscribed to a specific patient subgroup. If so, addition of metformin to antineoplastic agents could prove one of the most cost-effective interventions proposed in the context of precision oncology. Currently published reviews mostly rely on a widely questioned mechanism of action by metformin, which fails to consider the differential effects of the drug in lean vs. obese subjects. In this review, we analyze the pre-clinical and clinical information available to date regarding the use of metformin in various subtypes of lung cancer and, further, we present evidence as to the differential metabolic effects of metformin in lean and obese subjects where, paradoxically, the obese subjects have reported more benefit with the addition of metformin treatment. The novel mechanisms of action described for this biguanide may explain the different results observed in clinical trials published in the last decade. Lastly, we present novel hypothesis regarding potential biomarkers to identify who might reap benefit from this intervention, including the role of prolyl hydroxylase domain 3 (PHD3) expression to modify metabolic phenotypes in malignant diseases.

Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial-Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells.

The combination of metformin and TKIs for non-small cell lung cancer has been proposed as a strategy to overcome resistance of neoplastic cells induced by several molecular mechanisms. This study sought to investigate the effects of a second generation TKI afatinib, metformin, or their combination on three adenocarcinoma lung cancer cell lines with different EGFRmutation status. A549, H1975, and HCC827 cell lines were treated with afatinib, metformin, and their combination for 72 h. Afterwards, several parameters were assessed including cytotoxicity, interactions, apoptosis, and EGFR protein levels at the cell membrane and several glycolytic, oxidative phosphorylation (OXPHOS), and EMT expression markers. All cell lines showed additive to synergic interactions for the induction of cytotoxicity caused by the tested combination, as well as an improved pro-apoptotic effect. This effect was accompanied by downregulation of glycolytic, EMT markers, a significant decrease in glucose uptake, extracellular lactate, and a tendency towards increased OXPHOS subunits expression. Interestingly, we observed a better response to the combined therapy in lung cancer cell lines A549 and H1975, which normally have low affinity for TKI treatment. Findings from this study suggest a sensitization to afatinib therapy by metformin in TKI-resistant lung cancer cells, as well as a reduction in cellular glycolytic phenotype.

Tumor filodes: experiencia de 12 años en la Unidad de Oncología del Hospital General de Puebla / Phyllodes tumor: A 12-year experience at Oncology Unit of the Hospital General de Puebla

Resumen OBJETIVO: Exponer la experiencia de 12 años de la Unidad de Oncología del Hospital General de Puebla Eduardo Vázquez N en el tratamiento de pacientes con tumor filodes. MATERIALES Y MÉTODOS: Estudio longitudinal, retrospectivo, observacional y clínico efectuado en pacientes con diagnóstico histopatológico de tumor filodes atendidas entre los meses de enero de 2009 a diciembre de 2021 en la Unidad de Oncología del Hospital General de Puebla. Variables de estudio: incidencia, edad al momento del diagnóstico, localización y técnica quirúrgica aplicada. Para determinar las variables entre grupos independientes se aplicaron medidas paramétricas. RESULTADOS: Se revisaron 37 expedientes de pacientes con diagnóstico de tumor filodes. Se obtuvo una incidencia institucional de 1.4%, de la que 18.9% correspondió a tumor maligno. La edad promedio de las pacientes fue de 39.4 (límites 13 a 61 años). En dos casos se encontró asociación con el embarazo. En términos generales el tratamiento fue quirúrgico, con mastectomía simple y tumorectomía, con recurrencia en seis casos. CONCLUSIONES: Si bien la incidencia del tumor filodes es baja, siempre es importante considerar su existencia como alternativa para el diagnóstico de tumores de mama. El tratamiento quirúrgico con mastectomía simple ha reportado buena respuesta, con bajas tasas de recurrencia.

Abstract OBJECTIVE: To present the 12-year experience of the Oncology Unit of the General Hospital of Puebla Eduardo Vázquez N in the treatment of patients with phyllodes tumor. MATERIALS AND METHODS: Longitudinal, restrospective, observational and clinical study carried out in patients with histopathological diagnosis of phyllodes tumor attended from January 2009 to December 2021 in the Oncology Unit of the General Hospital of Puebla. Study variables: incidence, age at diagnosis, location and surgical technique applied. Parametric measures were applied to determine the variables between independent groups. RESULTS: Thirty-seven files of patients with a diagnosis of phyllodes tumor were reviewed. An institutional incidence of 1.4% was obtained, of which 18.9% corresponded to malignant tumor. The mean age of the patients was 39.4 (limits 13 to 61 years). In two cases an association with pregnancy was found. In general terms, treatment was surgical, with simple mastectomy and lumpectomy, with recurrence in six cases. CONCLUSIONS: Although the incidence of phyllodes tumor is low, it is always important to consider its existence as an alternative for the diagnosis of breast tumors. Surgical treatment with simple mastectomy has seemed to have a good response, with low recurrence rates.

Documenting Paintings with Gigapixel Photography.

Digital photographic capture of pictorial artworks with gigapixel resolution (around 1000 megapixels or greater) is a novel technique that is beginning to be used by some important international museums as a means of documentation, analysis, and dissemination of their masterpieces. This line of research is extremely interesting, not only for art curators and scholars but also for the general public. The results can be disseminated through online virtual museum displays, offering a detailed interactive visualization. These virtual visualizations allow the viewer to delve into the artwork in such a way that it is possible to zoom in and observe those details, which would be negligible to the naked eye in a real visit. Therefore, this kind of virtual visualization using gigapixel images has become an essential tool to enhance cultural heritage and to make it accessible to everyone. Since today's professional digital cameras provide images of around 40 megapixels, obtaining gigapixel images requires some special capture and editing techniques. This article describes a series of photographic methodologies and equipment, developed by the team of researchers, that have been put into practice to achieve a very high level of detail and chromatic fidelity, in the documentation and dissemination of pictorial artworks. The result of this research work consisted in the gigapixel documentation of several masterpieces of the Museo de Bellas Artes of Valencia, one of the main art galleries in Spain. The results will be disseminated through the Internet, as will be shown with some examples.

Clinicopathological and Prognostic Significance of CD47 Expression in Lung Neuroendocrine Tumors.

BACKGROUND: Lung neuroendocrine tumors account for approximately 15% of all lung cancer cases. LNET are subdivided into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small-cell lung cancer (SCLC). The Ki-67 index has been used for decades to evaluate mitotic counts however, the role of Ki-67 as a biomarker for assessing prognosis and guiding therapy in metastatic LNET still lacks feasible clinical validation. Recent clinical trials have indicated that inhibition of CD47 with anti-CD47 antibodies exerts a promising antitumor effect against several human malignancies, including NSCLC, melanoma, and hematologic malignancies. However, the clinical relevance of CD47 expression in LNET has remained unclear. METHODS: We performed a retrospective study in which we analyzed tumor biopsies from 51 patients with a confirmed diagnosis of LNET that received treatment at our hospital. Then, we analyzed if there was any correlation between CD47 expression with any clinical or pathological characteristic. We also analyzed the prognostic significance of CD47, assessed as progression-free survival and overall survival. RESULTS: A total of 51 patients with LNET were enrolled in our study. The mean age at diagnosis was 57.6 (±11.6) years; 30 patients were women (59%). 27.5% of patients were positive for CD47 expression, and 72.5% of patients showed a CD47 expression of less than 1% and were considered as negatives. In patients with high-grade tumors (this time defined as Ki-67 > 40%), the positive expression of CD47 was strongly associated with an increased PFS. Albeit, these differences did not reach statistical significance when analyzing OS. CONCLUSION: Contrary to what happens in a wide range of hematologic and solid tumors, a higher expression of CD47 in patients with LNET is associated with a better progression-free survival, especially in patients with a Ki-67 ≥ 40%. This "paradox" remains to be confirmed and explained by larger studies.

S-allylcysteine induces cytotoxic effects in two human lung cancer cell lines via induction of oxidative damage, downregulation of Nrf2 and NF-κB, and apoptosis.

In this study, we investigated the putative cytotoxic effect elicited by the garlic-derived compound S-allylcysteine (SAC) in two human cancer cell lines (HCC827 and NCI-H1975) in order to develop an experimental approach to the therapeutic potential of this molecule for lung cancer. Cells were incubated for 24, 48 and 72 h in the presence of SAC (10 or 20 mM), which resulted in a concentration- and time-dependent decrease in cell viability and culture confluence in both cell lines. These effects were contrasted with - and validated through - those observed in an immortalized but nontumorigenic epithelial cell line from human bronchial epithelium (BEAS-2B, negative control) and an adenocarcinoma human alveolar basal epithelial cell line (A549, positive control). SAC (20 mM at 72 h) also increased the oxidative damage to lipids, augmented apoptosis, and decreased the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) and the nuclear factor kappa B (NF-κB) proteins in HCC827 and NCI-H1975 cells. Our results establish the efficacy of SAC in reducing malignant growth and proliferation of lung tumor cells. This effect is mediated by the induction of oxidative damage associated with the downregulation of Nrf2 and NF-κB and their corresponding signaling pathways.

Association between CD47 expression, clinical characteristics and prognosis in patients with advanced non-small cell lung cancer.

OBJECTIVE: CD47 is an antiphagocytic molecule that contributes to tumor cell resistance in host immune surveillance. CD47 overexpression correlated with tumor progression and shorter survival in lung cancer. However, the expression and functional significance of CD47 in Non-Small Cell Lung Cancer (NSCLC) has not been completely understood. MATERIALS AND METHODS: In this retrospective study, CD47 expression was immunohistochemically examined in tumor biopsies from 169 NSCLC patients. The association of CD47 levels (H-score) with clinicopathological characteristics and survival outcomes was evaluated. RESULTS: CD47 protein was detected in 84% of patients with a median expression of 80% (0-100). Tumor CD47 levels above 1% and 50% were found in 84% and 65.7% of patients, respectively. While, median CD47 staining index was 160 (0-300). Patients were divided into two groups according to CD47 expression (high or low), using a cutoff value of 150. High CD47 expression was associated with wood smoke exposure (71.1% vs 28.9%, P = .013) and presence of EGFR (+) mutations (66.7% vs 33.3%, P = .04). Survival analysis carried out in the whole population did not show any association of CD47 expression and survival outcome. However, in patients with EGFR (+) mutations, CD47 expression was associated with higher progression-free survival (PFS) (12.2 vs. 4.4 months, P = .032). When the survival analysis was performed according to CD47 levels (cut off value: 150), both, PFS and overall survival (OS) were shortened in patients with a high expression of CD47 (10.7 vs. NR, P = .156) and (29.2 vs. NR months P = .023), respectively. CONCLUSIONS: CD47 overexpression is not a prognostic factor for PFS and OS in NSCLC patients. However, the presence of EGFR mutations and high expression of CD47 were associated with shortened PFS and OS. Coexpression of these markers represents a potential biomarker and characterizes a therapeutic niche for lung cancer.

In-kind incentives and health worker performance: Experimental evidence from El Salvador.

We experimentally evaluated the effects of in-kind team incentives on health worker performance in El Salvador, with 38 out of 75 community health teams randomly assigned to performance incentives over a 12-month period. All teams received monitoring, performance feedback and recognition for their achievements allowing us to isolate the effect of the incentive. While both treatment and control groups exhibit improvements in performance measures over time, the in-kind incentives generated significant improvements in community outreach, quality of care, timeliness of care, and utilization of maternal and child health services after 12 months. Gains were largest for teams at the bottom and top of the baseline performance distribution. We find no evidence of results being driven by changes in reporting or by shifting away effort from non-contracted outcomes. These results suggest that in-kind team incentives may be a viable alternative to monetary or individual incentives in certain contexts.

Effect of Metformin Plus Tyrosine Kinase Inhibitors Compared With Tyrosine Kinase Inhibitors Alone in Patients With Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Metformin hydrochloride is emerging as a repurposed anticancer drug. Preclinical and retrospective studies have shown that it improves outcomes across a wide variety of neoplasms, including lung cancer. Particularly, evidence is accumulating regarding the synergistic association between metformin and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). OBJECTIVE: To assess the progression-free survival (PFS) in patients with advanced lung adenocarcinoma who received treatment with EGFR-TKIs plus metformin compared with those who received EGFR-TKIs alone. DESIGN, SETTING, AND PARTICIPANTS: Open-label, randomized, phase 2 trial conducted at the Instituto Nacional de Cancerología (INCan), Mexico City, Mexico. Eligible patients were 18 years or older, had histologically confirmed stage IIIB-IV lung adenocarcinoma with an activating EGFR mutation. INTERVENTIONS: Patients were randomly allocated to receive EGFR-TKIs (erlotinib hydrochloride, afatinib dimaleate, or gefitinib at standard dosage) plus metformin hydrochloride (500 mg twice a day) or EGFR-TKIs alone. Treatment was continued until occurrence of intolerable toxic effects or withdrawal of consent. MAIN OUTCOMES AND MEASURES: The primary outcome was PFS in the intent-to-treat population. Secondary outcomes included objective response rate, disease control rate, overall survival (OS), and safety. RESULTS: Between March 31, 2016, and December 31, 2017, a total of 139 patients (mean [SD] age, 59.4 [12.0] years; 65.5% female) were randomly assigned to receive EGFR-TKIs (n = 70) or EGFR-TKIs plus metformin (n = 69). The median PFS was significantly longer in the EGFR-TKIs plus metformin group (13.1; 95% CI, 9.8-16.3 months) compared with the EGFR-TKIs group (9.9; 95% CI, 7.5-12.2 months) (hazard ratio, 0.60; 95% CI, 0.40-0.94; P = .03). The median OS was also significantly longer for patients receiving the combination therapy (31.7; 95% CI, 20.5-42.8 vs 17.5; 95% CI, 11.4-23.7 months; P = .02). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first study to prospectively show that the addition of metformin to standard EGFR-TKIs therapy in patients with advanced lung adenocarcinoma significantly improves PFS. These results justify the design of a phase 3, placebo-controlled study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03071705.

Partial molar volumes and isentropic compressions of sugar alcohols in aqueous solutions from 15 °C to 40 °C at atmospheric pressure.

Densities and sound speeds of aqueous solutions of Erythritol, Xylitol, Sorbitol, and Maltitol were measured at 15 °C, 25 °C, 40 °C, and 45 °C using a density and sound velocity meter (DSA 5000M). The results were used to calculate the apparent and standard molar volumes and compressions, the specific volumes and compressions, as well as the hydration numbers and their temperature dependence. The volumetric results are used to characterize the hydration of sugar alcohols and are related to sweet taste chemoreception.

Targeted next generation sequencing identified a high frequency genetic mutated profile in wood smoke exposure-related lung adenocarcinoma patients.

BACKGROUND: Wood smoke exposure (WSE) has been associated with an increased risk of lung cancer development. WSE has been related with high frequency of EGFR mutations and low frequency of KRAS mutations. The aim of this study was to evaluate large scale genomic alterations in lung adenocarcinomas associated with WSE using targeted next generation sequencing. METHODS: DNA multi-targeted sequencing was performed in 42 fresh-frozen samples of advanced lung adenocarcinomas. The TruSeQ Cancer Panel (Illumina) was used for genomic library construction and sequencing assays. RESULTS: WSE rate was higher in women (p=0.037) and non-smokers (p=0.001). WSE correlated with mutations in the genes SMARCB1 (p=0.002), Ataxia telangiectasia mutated (p=0.004), Kinase Insert Domain Receptor (p=0.006), and were borderline significant in RET and EGFR exon. Genomic alterations significantly co-occurred in the tumor suppressor gene ATM with the following genes: SMARCB1, EGFR exon 7, RET and KDR. Clinical factors associated with poor prognosis were ECOG ≥ 2 (p= 0.014), mutations in KDR (p= 0.004) and APC genes (p < 0.001). CONCLUSIONS: Lung adenocarcinoma patients with WSE showed a distinctive mutated profile for the SMARCB1, ATM, EGFR exon 7, RET and KDR genes. ECOG status and KDR gene mutations were significantly associated with poor prognosis.

Interplay between Cellular and Molecular Inflammatory Mediators in Lung Cancer.

Inflammation is a component of the tumor microenvironment and represents the 7th hallmark of cancer. Chronic inflammation plays a critical role in tumorigenesis. Tumor infiltrating inflammatory cells mediate processes associated with progression, immune suppression, promotion of neoangiogenesis and lymphangiogenesis, remodeling of extracellular matrix, invasion and metastasis, and, lastly, the inhibition of vaccine-induced antitumor T cell response. Accumulating evidence indicates a critical role of myeloid cells in the pathophysiology of human cancers. In contrast to the well-characterized tumor-associated macrophages (TAMs), the significance of granulocytes in cancer has only recently begun to emerge with the characterization of tumor-associated neutrophils (TANs). Recent studies show the importance of CD47 in the interaction with macrophages inhibiting phagocytosis and promoting the migration of neutrophils, increasing inflammation which can lead to recurrence and progression in lung cancer. Currently, therapies are targeted towards blocking CD47 and enhancing macrophage-mediated phagocytosis. However, antibody-based therapies may have adverse effects that limit its use.

Predicciones de la entropía proporcional en la dinámica cardíaca / Predictions of proportional entropy in cardiac dynamics / Previsões de entropia proporcional na dinâmica cardíaca

Antecedentes: A partir de la teoría de sistemas dinámicos se desarrolló una metodología que permite diferenciar dinámicas cardíacas normales, en distintos niveles de enfermedad y en evolución entre estos estados. Esto se hizo cuantificando en el espacio de fases, mediante la entropía y sus proporciones, la probabilidad de parejas ordenadas de frecuencias cardiacas. Objetivo: Aplicar clínicamente la metodología desarrollada a 400 dinámicas cardíacas para establecer su efectividad comparándola con el diagnóstico clínico convencional. Método: Se tomaron Holters de 400 individuos; 50 diagnosticados como normales y 350 con diferentes patologías. Para cada uno se construyó un atractor en el mapa de retardo y se evaluó, mediante la entropía y sus proporciones, la probabilidad de ocupación de pares ordenados de frecuencias cardíacas durante 18 horas. Se compararon las medidas obtenidas con los valores de normalidad y enfermedad establecidos previamente para obtener el diagnóstico de cada Holter. Las conclusiones del Holter y los antecedentes clínicos sólo fueron desenmascarados luego de haber aplicado la metodología físico-matemática para calcular sensibilidad, especificidad y coeficiente Kappa respecto al Gold-Estándar. Resultados: con las proporciones de la entropía de los atractores se diferenciaron dinámicas cardíacas agudas, crónicas, normales, y evolución normalidad-enfermedad. Se confirmó la aplicabilidad clínica de la metodología predictiva desarrollada para el Holter, que mostró una sensibilidad y especificidad del 100%. La concordancia entre el Gold-Estándar y el diagnóstico físicomatemático fue 1. Conclusiones: La aplicación de la metodología permitió establecer cuantitativamente estados de normalidad y enfermedad de la dinámica cardíaca, evidenciando una auto-organización del atractor dinámico geométrico que constituye un método de ayuda diagnóstica aplicable a la clínica.

Based on dynamic systems theory, a methodology that allows to differentiate normal cardiac dynamics, different levels of abnormality and evolution between these states, was developed. This was done by quantifying the probability of ordered pairs of heart rates in the phase space, through entropy and its proportions. To apply in a clinical setting the developed methodology to 400 cardiac dynamics in order to establish its effectiveness by comparing it with the conventional diagnosis. Holters from 400 individuals were tested for a minimum of 18 hours; 50 with normal diagnosis and 350 with different pathologies. An attractor was built for each one of them in the delay map, and the occupation probability of ordered pairs of heart rates was evaluated through entropy and its proportions. Afterwards, results were compared with values of normality and disease previously established to obtain the diagnosis for each Holter. The findings of Holter and medical history were only revealed after applying the physical-mathematical methodology, in order to calculate sensitivity, specificity and Kappa coefficient regarding to the Gold-Standard. With the entropy proportions of the attractors, acute cardiac dynamics were differentiated from chronic and normal ones, as well as the evolution between normality and disease. A clinical application of the predictive methodology for Holter was developed. Sensitivity and specificity were both 100% and the correlation between the Gold-Standard and the physical-mathematical diagnosis was 1. The application of the methodology allowed establishing quantitatively states of normality and disease of the cardiac dynamic, showing a self-organization of the geometrical dynamic attractor.

Antecedentes: A partir da teoria de sistemas dinâmicos se desarrolho uma metodologia que permite diferenciar dinâmicas cardíacas normais, em distintos niveles de doença e na evolução entre estes estados, o qual foi realizado quantificando no espaço de fases a probabilidade de pares ordenados de frequências cardíacas, através da entropia e as suas proporções. Objetivo: Aplicar clinicamente a metodologia desenvolvida a 400 dinâmicas cardíacas para estabelecer sua eficácia comparada com o diagnóstico clínico convencional. Método: Se tiraram Holters de 400 pessoas, 50 deles foram diagnosticados como normais e 350 têm diferentes patologias. Um atractor no mapa de retardos foi construído para cada um deles e, através da entropia e as suas proporções, a probabilidades de ocupação de pares ordenados de frequências cardíacas durante 18 horas foi avaliada. Além disso, as medidas obtidas foram comparadas com os valores de normalidade e doenças estabelecidas previamente para obter o diagnostico de cada Holter. As conclusões do Holter e os antecedentes clínicos somente foram descobertos logo de aplicar a metodologia físico-matemática para calcular a sensibilidade, especificidade y coeficiente Kappa acerca do Padrão-Ouro (Gold-Standard). Resultados: As dinâmicas cardíacas agudas, crônicas, normais y a evolução da normalidade e as doenças foram diferenciadas pelas proporções da entropia dos atractores. Confirmou-se a aplicabilidade clínica da metodologia preditiva desenvolvida para o Holter, a qual demonstrou uma sensibilidade e especificidade de 100%. O acordo entre o Padrão-Ouro (Gold-Standard) e o diagnóstico físico-matemático foi 1. Conclusões: A aplicabilidade da metodologia permitiu estabelecer quantitativamente estado de normalidade e doenças da dinâmica cardíaca, mostrando uma auto-organização do atrator dinâmico geométrico que constitui um método de ajuda diagnostica aplicável à clínica.

[Tubal obstruction with an implant inserted by hysteroscopy: a report of 50 cases]. / Obstrucción tubaria con un implante insertado mediante histeroscopia: reporte de 50 casos.

BACKGROUND: The Essure contraceptive device consists of a titanium and nickel coiled spring containing Dacron fibers. It is placed under hysteroscopic visualizaron in the proximal section of the Fallopian tube. The microinsert acts by inducing a tissue reaction that permanently blocks the tube within three months. OBJECTIVE: Show our experience in the use and insertion of the Essure device, in a private office. METHODS: We reviewed insertion procedure, complications, degree of tolerance and acceptance by user. Between June 2008 and May 2013 fifty cases with Essure placement were made in our office. RESULTS: The average age was 36 years, as for the average number of pregnancies was two. The procedure time average was 6 minutes 25 seconds, no intraoperative complication was reported. All patients expressed very good tolerance and high degree of satisfaction with the procedure. A simple abdominal radiography was performed three months after the hysteroscopy to dem6nstrate the correct placement and position of the device, in all patients. CONCLUSION: [corrected] The number of patients is enough to show the advantages of the method and the possibility of performing it in an ambulatory environment, as it can be a private office with the correct equipment to do it.