Double burden of malnutrition as a risk factor for overweight and obesity

OBJECTIVE To assess the longitudinal effect of double burden of malnutrition (DBM) on the risk of developing child and adolescent overweight or obesity. METHODS Analysis of the Peruvian Young Lives Study, younger cohort: baseline (2002) and 4 follow-ups (2006–2007, 2009–2010, 2013–2014, and 2016–2017). Outcomes were the incidence of overweight and obesity as defined by the World Health Organization standards. The exposure comprised a variable with 4 categories: non-stunted child with a non-overweight mother (reference group), non-stunted child with an overweight mother, stunted child with a non-overweight mother, and stunted child with an overweight mother (i.e., DBM). Poisson regression models were built to assess the association of interest, and relative risks (RR) and 95%CI were reported. RESULTS Data from 2,034 children; 50.0% were girls and the mean age was 12.0 (3.6) months at baseline. Non-stunted children with an overweight mother had greater risk (RR = 1.64; 95%CI: 1.35–1.99) of developing overweight, compared with the risk for stunted children with a non-overweight mother (RR = 1.38; 95%CI: 1.10–1.72), and for those with DBM (RR = 1.28; 95%CI: 1.02–1.61). When compared with the reference group, obesity risk was greater among non-stunted children with an overweight mother (RR = 2.33; 95%CI: 1.68–3.22), greater among stunted children with a non-overweight mother (RR = 2.59; 95%CI: 1.75–3.84), and greater among those with DBM (RR = 2.14; 95%CI: 1.39–3.28). CONCLUSIONS DBM is a risk factor for childhood overweight and obesity in Peru. Dual-duty policies tackling both undernutrition in children and overweight in mothers are needed to reduce DBM and its future effects in Peru

Clinical and molecular parameters associated to pneumonitis development in non-small-cell lung cancer patients receiving chemoimmunotherapy from NADIM trial

Background Pneumonitis (Pn) is one of the main immune-related adverse effects, having a special importance in lung cancer, since they share affected tissue. Despite its clinical relevance, Pn development remains an unpredictable treatment adverse effect, whose mechanisms are mainly unknown, being even more obscure when it is associated to chemoimmunotherapy.Methods In order to identify parameters associated to treatment related Pn, we analyzed clinical variables and molecular parameters from 46 patients with potentially resectable stage IIIA non-small-cell lung cancer treated with neoadjuvant chemoimmunotherapy included in the NADIM clinical trial (NCT03081689). Pn was defined as clinical or radiographic evidence of lung inflammation without alternative diagnoses, from treatment initiation to 180 days. Results Among 46 patients, 12 developed Pn (26.1%). Sex, age, smoking status, packs-year, histological subtype, clinical or pathological response, progression free survival, overall survival and number of nivolumab cycles, were not associated to Pn development. Regarding molecular parameters at diagnosis, Pn evelopment was not associated to programmed death ligand 1, TPS, T cell receptor repertoire parameters, or tumor mutational burden. However, patients who developed Pn had statistically significant lower blood median levels of platelet to monocyte ratio (p=0.012) and teratocarcinoma derived growth factor 1 (p=0.013; area under the curve (AUC) 0.801), but higher median percentages of natural killers (NKs) (p=0.019; AUC 0.786), monocytes (p=0.017; AUC 0.791), MSP (p=0.006; AUC 0.838), PARN (p=0.017; AUC 0.790), and E-Cadherin (p=0.022; AUC 0.788). In addition, the immune scenario of Pn after neoadjuvant treatment involves: high levels of neutrophils and NK cells, but low levels of B and T cells in peripheral blood; increased clonality of intratumoral T cells; and elevated plasma levels of several growth factors (EGF, HGF, VEGF, ANG-1, PDGF, NGF, and NT4) and inflammatory cytokines (MIF, CCL16, neutrophil gelatinase-associated lipocalin, BMP-4, and u-PAR). Conclusions Although statistically underpowered, our results shed light on the possible mechanisms behind Pn development, involving innate and adaptative immunity, and open the possibility to predict patients at high risk. If confirmed, this may allow the personalization of both, the surveillance strategy and the therapeutic approaches to manage Pn in patients receiving chemoimmunotherapy

Prognostic model of long-term advanced stage (IIIB-IV) EGFR mutated non-small cell lung cancer (NSCLC) survivors using real-life data

Background There is a lack of useful diagnostic tools to identify EGFR mutated NSCLC patients with long-term survival. This study develops a prognostic model using real world data to assist clinicians to predict survival beyond 24 months. Methods EGFR mutated stage IIIB and IV NSCLC patients diagnosed between January 2009 and December 2017 included in the Spanish Lung Cancer Group (SLCG) thoracic tumor registry. Long-term survival was defined as being alive 24 months after diagnosis. A multivariable prognostic model was carried out using binary logistic regression and internal validation through bootstrapping. A nomogram was developed to facilitate the interpretation and applicability of the model. Results 505 of the 961 EGFR mutated patients identified in the registry were included, with a median survival of 27.73 months. Factors associated with overall survival longer than 24 months were: being a woman (OR 1.78); absence of the exon 20 insertion mutation (OR 2.77); functional status (ECOG 0–1) (OR 4.92); absence of central nervous system metastases (OR 2.22), absence of liver metastases (OR 1.90) or adrenal involvement (OR 2.35) and low number of metastatic sites (OR 1.22). The model had a good internal validation with a calibration slope equal to 0.781 and discrimination (optimism corrected C-index 0.680). Conclusions Survival greater than 24 months can be predicted from six pre-treatment clinicopathological variables. The model has a good discrimination ability. We hypothesized that this model could help the selection of the best treatment sequence in EGFR mutation NSCLC patients

Double Burden of Malnutrition Workshop Facilitation Manual: Lima, Peru

This is a facilitation manual for workshops in Lima, Peru as part of the project “Addressing the double burden of malnutrition in Peru: using a community-based system dynamics approach to improve food systems”. The project is a collaboration between investigators at the Center of Excellence in Chronic Diseases (CRONICAS) at the University of Peruana Cayetano Heredia, Universidad de los Andes in Bogota, Peru, the Social System Design Lab at Washington University in St. Louis, USA and Imperial College London funded by the Biotechnology and Biological Science Research Council (Grant Ref: BB/T009004/1). It is a supplemental document associated with the paper “Mapping food system drivers of the double burden of malnutrition using community-based system dynamics: a case study in Peru by Carmen Quinteros-Reyes, Paraskevi Seferidi, Laura Guzman-Abello, Christopher Millett, Antonio Bernabé-Ortiz, Ellis Ballard

Double Burden of Malnutrition Workshop Facilitation Manual: Iquitos, Peru

This is a facilitation manual for workshops in Lima, Peru as part of the project “Addressing the double burden of malnutrition in Peru: using a community-based system dynamics approach to improve food systems”. The project is a collaboration between investigators at the Center of Excellence in Chronic Diseases (CRONICAS) at the University of Peruana Cayetano Heredia, Universidad de los Andes in Bogota, Peru, the Social System Design Lab at Washington University in St. Louis, USA and Imperial College London funded by the Biotechnology and Biological Science Research Council (Grant Ref: BB/T009004/1). It is a supplemental document associated with the paper “Mapping food system drivers of the double burden of malnutrition using community-based system dynamics: a case study in Peru by Carmen Quinteros-Reyes, Paraskevi Seferidi, Laura Guzman-Abello, Christopher Millett, Antonio Bernabé-Ortiz, Ellis Ballard

Comprehensive cross-platform comparison of methods for non-invasive EGFR mutation testing: results of the RING observational trial

Several platforms for noninvasive EGFR testing are currently used in the clinical setting with sensitivities ranging from 30% to 100%. Prospective studies evaluating agreement and sources for discordant results remain lacking. Herein, seven methodologies including two next-generation sequencing (NGS)-based methods, three high-sensitivity PCR-based platforms, and two FDA-approved methods were compared using 72 plasma samples, from EGFR-mutant non-small-cell lung cancer (NSCLC) patients progressing on a first-line tyrosine kinase inhibitor (TKI). NGS platforms as well as high-sensitivity PCR-based methodologies showed excellent agreement for EGFR-sensitizing mutations (K = 0.80–0.89) and substantial agreement for T790M testing (K = 0.77 and 0.68, respectively). Mutant allele frequencies (MAFs) obtained by different quantitative methods showed an excellent reproducibility (intraclass correlation coefficients 0.86–0.98). Among other technical factors, discordant calls mostly occurred at mutant allele frequencies (MAFs) ≤ 0.5%. Agreement significantly improved when discarding samples with MAF ≤ 0.5%. EGFR mutations were detected at significantly lower MAFs in patients with brain metastases, suggesting that these patients risk for a false-positive result. Our results support the use of liquid biopsies for noninvasive EGFR testing and highlight the need to systematically report MAFs

Addition of Immune Checkpoint Inhibitors to Chemotherapy vs Chemotherapy Alone as First-Line Treatment in Extensive-Stage Small-Cell Lung Carcinoma: A Systematic Review and Meta-Analysis

Introduction The addition of immune checkpoint inhibitors (ICIs) to conventional chemotherapy (CT) as first-line treatment improves survival in extensive-stage small-cell lung cancer (ES-SCLC). The aim of this meta-analysis was to determine the relative efficacy of first-line ICIs compared with CT in patients with ES-SCLC. Methods Two independent reviewers extracted relevant data according to PRISMA guidelines and assessed the risk of bias using the Cochrane Collaboration's risk-of-bias tool. Meta-analysis was conducted using random-effects models to calculate an average effect size for overall survival (OS), progression-free survival (PFS), and safety outcomes in the overall populations and clinically relevant subgroups. Results A literature search of PubMed and Embase was performed. Six randomized controlled clinical trials (IMpower133, CHECKMATE-451, CASPIAN, KEYNOTE-604, and phase II and III ipilimumab plus CT trials) with a total of 3757 patients were included. Compared with CT alone, ICIs plus CT showed a favourable effect on OS (hazard ratio [HR] 0.85; 95% confidence intervals [CI] 0.79–0.96) and PFS (HR 0.78; 95% CI 0.72–0.83) but a non-significant increase in the risk of experiencing any adverse event (relative risk, 1.05; 95% CI 0.99–1.11). The estimated HR for OS favoured ICI combinations in all planned subgroups according to age (< 65 years/≥ 65 years), sex (men/women), and ECOG performance status (0/1). Analysis by specific ICI revealed significant improvements in OS only for atezolizumab + CT (HR 1.36; 95% CI 1.09–1.69) and durvalumab + CT (HR 1.35; 95% CI 1.12–1.62) compared with CT alone. Conclusion Combining anti-programmed cell death ligand 1 antibodies with platinum/etoposide is a superior therapeutic approach compared to CT alone for the first-line treatment of patients with ES-SCLC

Veliparib in Combination With Platinum-Based Chemotherapy for First-Line Treatment of Advanced Squamous Cell Lung Cancer: A Randomized, Multicenter Phase III Study

PURPOSE Squamous non–small-cell lung cancer (sqNSCLC) is genetically complex with evidence of DNA damage. This phase III study investigated the efficacy and safety of poly (ADP-ribose) polymerase inhibitor veliparib in combination with conventional chemotherapy for advanced sqNSCLC (NCT02106546). PATIENTS AND METHODS Patients age ≥ 18 years with untreated, advanced sqNSCLC were randomly assigned 1:1 to carboplatin and paclitaxel with veliparib 120 mg twice daily (twice a day) or placebo twice a day for up to six cycles. The primary end point was overall survival (OS) in the veliparib arm versus the control arm in current smokers, based on phase II findings. Archival tumor samples were provided for biomarker analysis using a 52-gene expression histology classifier (LP52). RESULTS Overall, 970 patients were randomly assigned to carboplatin and paclitaxel plus either veliparib (n = 486) or placebo (n = 484); 57% were current smokers. There was no significant OS benefit with veliparib in current smokers, with median OS 11.9 versus 11.1 months (hazard ratio [HR], 0.905; 95% CI, 0.744 to 1.101; P = .266). In the overall population, OS favored veliparib; median OS was 12.2 versus 11.2 months (HR, 0.853; 95% CI, 0.747 to 0.974), with no difference in progression-free survival (median 5.6 months per arm). In patients with biomarker-evaluable tumor samples (n = 360), OS favored veliparib in the LP52-positive population (median 14.0 v 9.6 months; HR, 0.66; 95% CI, 0.49 to 0.89), but favored placebo in the LP52-negative population (median 11.0 v 14.4 months; HR, 1.33; 95% CI, 0.95 to 1.86). No new safety signals were observed in the experimental arm. CONCLUSION In current smokers with advanced sqNSCLC, there was no therapeutic benefit of adding veliparib to first-line chemotherapy. The LP52 signature may identify a subgroup of patients likely to derive benefit from veliparib with chemotherapy

First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial

Introduction: In CheckMate 227, nivolumab plus ipilimu mab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report re sults with minimum 4 years’ follow-up. Methods: Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who dis continued nivolumab plus ipilimumab due to treatment related AEs (TRAEs). Results: After 54.8 months’ median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemo therapy in patients with PD-L1 greater than or equal to 1% (hazard ratio ¼ 0.76; 95% confidence interval: 0.65–0.90) and PD-L1 less than 1% (0.64; 0.51–0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 1%); and 24% versus 10% (PD L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemo therapy was rash; most immune-mediated AEs (except endocrine events) occurred within 6 months from start of treatment and resolved within 3 months after, mainly with systemic corticosteroids. Patients who discontinued nivo lumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all randomized population. Conclusions: At more than 4 years’ minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients

Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non–Small-Cell Lung Cancer (NADIM phase II trial)

PURPOSE Neoadjuvant chemotherapy plus nivolumab has been shown to be effective in resectable non–small cell lung cancer (NSCLC) in the NADIM trial (ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS) and circulating tumor DNA (ctDNA) analysis have not been reported. METHODS This was an open-label, multicenter, single-arm, phase II trial in which patients with stage IIIA NSCLC, who were deemed to be surgically resectable, were treated with neoadjuvant paclitaxel (200 mg/m2 once a day) and carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each 21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives of the trial. RESULTS OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the per-protocol population. Neither tumor mutation burden nor programmed cell death ligand-1 staining was predictive of survival. Conversely, low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and OS (hazard ratio [HR], 0.20; 95% CI, 0.06 to 0.63, and HR, 0.07; 95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1 criteria did not predict survival outcomes. However, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and OS (HR, 0.26; 95% CI, 0.07 to 0.93, and HR, 0.04; 95% CI, 0.00 to 0.55, respectively). The C-index to predict OS for ctDNA levels after neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72). CONCLUSION The efficacy of neoadjuvant chemotherapy plus nivolumab in resectable NSCLC is supported by 3- year OS. ctDNA levels were significantly associated with OS and outperformed radiologic assessments in the prediction of survival