Adrian V. Hernandez

Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials

Background Programmed death 1 (PD‐1) programmed death‐ligand 1 (PD‐L1) inhibitors show significant clinical activity in non‐small cell lung carcinoma (NSCLC). However, they are often associated with potentially fatal immune‐mediated pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis with PD‐1 and PD‐L1 inhibitors. We sought to determine the overall incidence of pneumonitis and differences according to type of inhibitors and prior chemotherapy use. Methods MEDLINE, Embase, and Scopus databases were searched up to November 2016. Rates of pneumonitis of any grade and grade ≥ 3 from all clinical trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab as single agents in NSCLC were collected. The incidence of pneumonitis across trials was calculated using DerSimonian‐Laird random effects models. We compared incidences between PD‐1 and PD‐L1 inhibitors and between treatment naive and previously treated patients. Results Nineteen trials (12 with PD‐1 inhibitors [n = 3,232] and 7 with PD‐L1 inhibitors [n = 1,806]) were identified. PD‐1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis compared with PD‐L1 inhibitors (3.6%; 95% CI, 2.4%‐4.9% vs 1.3%; 95% CI, 0.8%‐1.9%, respectively; P = .001). PD‐1 inhibitors were also associated with higher incidence of grade 3 or 4 pneumonitis (1.1%; 95% CI, 0.6%‐1.7% vs 0.4%; 95% CI, 0%‐0.8%; P = .02). Treatment naive patients had higher incidence of grade 1 through 4 pneumonitis compared with previously treated patients (4.3%; 95% CI, 2.4%‐6.3% vs 2.8%; 95% CI, 1.7%‐ 4%; P = .03). Conclusions There was a higher incidence of pneumonitis with use of PD‐1 inhibitors compared with PD‐L1 inhibitors. Higher rate of pneumonitis was more common in treatment naive patients.

Incidence of pneumonitis with use of PD-1 and PD-L1 inhibitors in non-small cell lung cancer: A Systematic Review and Meta-analysis of trials

Background Programmed death 1 (PD‐1) programmed death‐ligand 1 (PD‐L1) inhibitors show significant clinical activity in non‐small cell lung carcinoma (NSCLC). However, they are often associated with potentially fatal immune‐mediated pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis with PD‐1 and PD‐L1 inhibitors. We sought to determine the overall incidence of pneumonitis and differences according to type of inhibitors and prior chemotherapy use. Methods MEDLINE, Embase, and Scopus databases were searched up to November 2016. Rates of pneumonitis of any grade and grade ≥ 3 from all clinical trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab as single agents in NSCLC were collected. The incidence of pneumonitis across trials was calculated using DerSimonian‐Laird random effects models. We compared incidences between PD‐1 and PD‐L1 inhibitors and between treatment naive and previously treated patients. Results Nineteen trials (12 with PD‐1 inhibitors [n = 3,232] and 7 with PD‐L1 inhibitors [n = 1,806]) were identified. PD‐1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis compared with PD‐L1 inhibitors (3.6%; 95% CI, 2.4%‐4.9% vs 1.3%; 95% CI, 0.8%‐1.9%, respectively; P = .001). PD‐1 inhibitors were also associated with higher incidence of grade 3 or 4 pneumonitis (1.1%; 95% CI, 0.6%‐1.7% vs 0.4%; 95% CI, 0%‐0.8%; P = .02). Treatment naive patients had higher incidence of grade 1 through 4 pneumonitis compared with previously treated patients (4.3%; 95% CI, 2.4%‐6.3% vs 2.8%; 95% CI, 1.7%‐ 4%; P = .03). Conclusions There was a higher incidence of pneumonitis with use of PD‐1 inhibitors compared with PD‐L1 inhibitors. Higher rate of pneumonitis was more common in treatment naive patients.

Systematic review and meta-analysis of the effect of metformin treatment on overall mortality rates in women with endometrial cancer and type 2 diabetes mellitus

BACKGROUND Obesity, insulin resistance and type 2 diabetes mellitus (T2DM) have been associated with endometrial cancer (EC). In this systematic review and meta-analysis we evaluated the effect of metformin on clinical outcomes in patients with EC and insulin resistance or T2DM. METHODS Four research databases were searched for original articles published in all languages up to 30 October 2016. Outcomes of interest were overall mortality (OM), cancer-specific mortality, disease progression, and metastases. We performed a random effect meta-analysis of adjusted effects expressed as hazard ratios (HR); heterogeneity among studies was described with the I2 statistic. RESULTS Of the 290 retrieved citations, 6 retrospective cohort studies in women with EC (n=4723) met the inclusion criteria, and 8.9% to 23.8% were treated with metformin; OM data was available from 5 studies. In 4 studies of EC patients (n=4132), metformin use was associated with a significant reduction in OM in comparison with not using metformin (adjusted HR [aHR] 0.64, 95% CI 0.45-0.89, p=0.009). In three studies evaluating patients with EC and T2DM (n=2637), metformin use was associated with a significant reduction in OM (aHR 0.50, 95%CI 0.34-0.74, p=0.0006). There was low to moderate heterogeneity of adjusted effects across studies. There was no information about the effect of metformin on cancer-specific mortality, disease progression, or metastases. CONCLUSIONS Metformin treatment is associated with a significant reduction in OM irrespective of diabetes status in patients with EC. The survival benefit suggests that diabetes screening and maintenance of good glycemic control may improve outcomes in EC.

Safety and Efficacy of PD-1/PD-L1 Inhibitors in Treatment-Naive and Chemotherapy-Refractory Patients With Non–Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

Micro‐Abstract Programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibitors are a significant advance in the treatment of patients with non–small‐cell lung cancer. In this study we investigated the comparative safety and efficacy of these agents when used in patients who are chemotherapy‐naive vs. patients previously treated with chemotherapy. We found that PD‐1/PD‐L1 inhibitors have greater clinical efficacy in chemotherapy‐naive patients compared with patients who were previously treated with chemotherapy. Introduction Programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibitors show significant clinical activity in non–small‐cell lung carcinoma (NSCLC). However, there is a relative lack of data on comparative efficacy of these drugs in the first‐line setting versus chemotherapy‐treated patients. We compared the efficacy and toxicity of these drugs in these 2 distinct groups of patients. Materials and Methods Electronic databases (PubMed‐Medline, EMBASE, Scopus) and major conference proceedings were systematically searched for all phase I to III clinical trials in NSCLC using PD‐1/PD‐L1 inhibitors. Objective response rate (ORR) and progression‐free survival (PFS) data were collected and combined using DerSimonian and Laird random effects model meta‐analysis. The I2 statistic was used to assess heterogeneity. Results Seventeen distinct trials (8 with treatment‐naive patients [n = 937]; 14 with chemotherapy‐treated patients [n = 3620]; 5 with separate treatment‐naive and previously treated arms) were included. Treatment‐naive patients had a statistically significant higher ORR (30.2%; 95% confidence interval [CI], 22.70‐38.2) than patients previously treated with chemotherapy (ORR, 20.1%; 95% CI, 17.5‐22.9; P = .02). No significant differences in PFS were observed between the 2 groups. Treatment‐naive patients had statistically significant higher rates of all grade pneumonitis compared with previously treated patients (4.9%; 95% CI, 3.4‐6.7 vs. 3.0%; 95% CI, 2.0‐4.1; P = .04); however, no significant differences in any other immune‐related adverse events were observed. Conclusion PD‐1/PD‐L1 inhibitor therapy for advanced NSCLC has a significantly higher ORR and a higher rate of immune‐mediated pneumonitis when used in the first‐line setting compared with chemotherapy treated patients.

Association Between Endometriosis and Preterm Birth in Women With Spontaneous Conception or Using Assisted Reproductive Technology: A Systematic Review and Meta-Analysis of Cohort Studies:

Objective: To perform a systematic review and meta-analysis to estimate the effect of endometriosis on preterm birth (PB) risk. Methods: Searches were conducted in PubMed–MEDLINE, Embase, Scopus, Web of Science, Cochrane Library, Google Scholar, and SciELO for studies published in all languages from inception through April 2017. We included cohort studies evaluating pregnant women with and without endometriosis and conception either by spontaneous conception (SC) or with assisted reproductive technology (ART). Primary outcome was PB (<37 weeks), and secondary outcomes were intrauterine growth restriction (IUGR), low birthweight, small for gestational age (SGA), and birthweight. Pooled odds ratios (ORs) and its 95% confidence interval (CI) were calculated as effects, and random-effects models were used for meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa Scale, and heterogeneity of effects among studies was described with the I2 statistic. Results: We identified 9 cohort studies including a total of 1 496 715 pregnancies (13 798 with endometriosis diagnosis). In women with endometriosis, the PB risk was significantly increased in both SC (OR: 1.59; 95% CI: 1.32-1.90) and ART (OR: 1.43; 95% CI: 1.14-1.79). The SGA risk was increased in women with endometriosis (OR: 1.16; 95% CI: 1.05-1.28), while the IUGR and low birthweight risks and birthweight were not affected by endometriosis. Conclusion: Endometriosis is associated with increased PB risk in both SC and women who obtained pregnancy using ART. Prospective studies evaluating relevant outcomes are needed to confirm these results.

Uterine or paracervical lidocaine application for pain control during intrauterine contraceptive device insertion: a meta-analysis of randomised controlled trials

Abstract Objective: Systematic review and meta-analysis to assess the effects of uterine or paracervical lidocaine application on pain control during IUD insertion. Methods: PubMed and five other electronic research databases were searched through 15 November 2017 for RCTs comparing lidocaine treatment vs. a control (placebo or no-intervention) to prevent pain during IUD insertion. Searched terms included ‘IUD insertion’, ‘lidocaine’ and ‘randomised controlled trial’. RCTs evaluating lidocaine treatment before IUD insertion without restriction of language, age and IUD type. Pain measured by visual pain scales at tenaculum placement, IUD insertion and immediate post-IUD insertion. Results of random effects meta-analyses were reported as mean differences (MDs) of visual pain scale (VPS) scores and their 95% confidence intervals (CIs). Results: Eleven RCTs (n = 1458 women) reporting paracervical lidocaine block or uterine mucosa lidocaine application before IUD insertion. Lidocaine produced lower VPS scores during tenaculum placement (MD −0.99, 95% CI: −1.73 to −0.26), IUD insertion (MD −1.26, 95% CI: −2.23 to −0.29) and immediate post-IUD insertion period (MD −1.25, 95% CI: −2.17 to −0.33). Conclusion: Lidocaine treatment was associated with modest reduction of pain during tenaculum placement and after IUD insertion.

Effect of exercise alone or combined with dietary supplements on anthropometric and physical performance measures in community-dwelling elderly people with sarcopenic obesity: A meta-analysis of randomized controlled trials

OBJECTIVE To evaluate the effect of exercise (EXE) alone or exercise combined with dietary supplements (EXE-SUPPL) on body composition and physical performance in subjects 60 years and older with sarcopenic obesity. METHODS A systematic review was carried out of studies identified through five search engines up to April 15, 2018. We searched for randomized controlled trials (RCTs) evaluating EXE or EXE-SUPPL in elderly individuals with sarcopenic obesity for at least six weeks. Primary outcomes were percentage of body fat mass, appendicular skeletal muscle mass, and hand grip strength. Random effects meta-analyses with the inverse variance method were used to evaluate the effects of interventions on outcomes. Effects were expressed as mean differences (MD) and their 95% confidence intervals (CI). Risk of bias was assessed with the Cochrane tool. RESULTS Nine papers reporting seven RCTs (with a total of 558 participants) were included in the review. EXE alone and EXE-SUPPL increased grip strength (MD 1.30 kg; 95% CI 0.58-2.01), gait speed (MD 0.05 m/s; 95% CI 0.03-0.07) and appendicular skeletal muscle mass (MD 0.40 kg; 95% CI 0.18-0.63). EXE alone and EXE-SUPPL reduced waist circumference (MD -1,40 cm; 95% CI -1.99 to -0.81), total fat mass (MD -1,77 kg; 95% CI -2.49 to -1.04), and trunk fat mass (MD -0.82 kg; 95% CI -1.22 to -0.42). CONCLUSION EXE alone and EXE-SUPPL improved muscle-related outcomes and reduced fat-related outcomes in subjects with sarcopenic obesity. There is a need for better-designed RCTs with systematic assessment of both different exercise regimes and dietary supplements in sarcopenic obese subjects.

Predictive Value of Stress Testing, Revised Cardiac Risk Index, and Functional Status in Patients Undergoing Non Cardiac Surgery

OBJECTIVE Patients undergoing noncardiac surgery are at risk for postoperative cardiovascular complications. Literature regarding the ability of the Revised Cardiac Risk Index (RCRI), functional capacity, and stress testing to predict perioperative cardiac events is scarce. The authors examined the association of these parameters with perioperative cardiac events and their additive ability to predict these outcomes. DESIGN This was a single-center retrospective study conducted at the Cleveland Clinic. SETTING Hospital. PARTICIPANTS Patients undergoing noncardiac surgery. INTERVENTION Patients underwent stress testing. MEASUREMENTS AND MAIN RESULTS The primary outcome of interest was major adverse cardiac events (MACE). The study cohort included 509 patients with a predominantly good functional status, as defined by estimated metabolic equivalents (METSe), which was ≥4 in 83% of the patients. The addition of preoperative stress testing, when indicated based on the RCRI and functional class limitation, only modestly improved discrimination of risk for postoperative outcomes (METSe + RCRI + positive stress test-C statistic 0.77 for MACE; 0.84 for 1-year mortality) compared with the combination of functional capacity (METSe) and RCRI (C statistic 0.70 for MACE; 0.79 for 1-year mortality). A surprisingly high prevalence of false negative stress tests (negative stress tests in patients who later had presence of obstructive coronary disease on angiography) was noted, but the C statistic for MACE remained unchanged, even when no false negative results were assumed. CONCLUSIONS In a cohort of patients with predominantly good functional status and intermediate-to-high RCRI scores, addition of a preoperative stress test was of only moderate value in predicting postoperative cardiovascular outcomes compared with a combination of functional class and RCRI.

Effects of intermittent versus continuous dieting on weight and body composition in obese and overweight people: a systematic review and meta-analysis of randomized controlled trials

BackgroundIntermittent dieting may be an alternative to continuous dieting for weight reduction.ObjectiveTo evaluate the effect of intermittent dieting versus continuous dieting on weight and body composition in overweight or obese adults.DesignA systematic review and meta-analysis of randomized controlled trials (RCTs). Five databases were searched until February 2018 for RCTs comparing intermittent versus continuous dieting. Intermittent dieting consisted of two types: regular intermittent was caloric restriction interspersed with days of weight maintenance or ad libitum eating; intensified intermittent was caloric restriction interspersed with days of even lower caloric restriction. Continuous was continual caloric restriction. Primary outcomes were weight, body fat, lean mass, waist circumference, hip circumference, and energy expenditure. Data were pooled by the inverse variance method using random-effects models and expressed as mean differences (MD) and their 95% confidence intervals (CI).ResultsNine trials met the inclusion criteria (n = 782), six comparing regular intermittent vs continuous (n = 553), and three comparing intensified intermittent vs continuous (n = 229). Populations were heterogeneous: obese only in five studies, and overweight or obese (mixed) in four studies. Lean mass was significantly lower in regular intermittent vs continuous (MD −0.86 kg; 95% CI −1.62 to −0.10; p = 0.03). No differences were found for the remaining outcomes for both comparisons (regular intermittent or intensified intermittent vs continuous). There was low heterogeneity of effects across trials. Subgroup effects by time to follow-up, gender, per-protocol versus intention-to-treat, enforced exercise, and diabetes were similar to main analyses.ConclusionsThis systematic review in obese and overweight individuals showed that regular intermittent dieting decreased lean mass compared to continuous dieting. There were no differences in effects for either intermittent vs continuous interventions across all other outcomes. In contrast to previous systematic reviews, this study suggested that lean mass is better preserved in continuous dieting compared to regular intermittent dieting.

Effect of Citalopram for the Treatment of Neurocardiogenic Syncope.

Background: Neurocardiogenic syncope (NCS) is a common form of syncope. Although selective serotonin reuptake inhibitors and other medications have been used to treat NCS with variable success, there is no consensus regarding a first-line therapy. Study Question: To assess the effects of citalopram in NCS and to examine the effect of diagnostic use of the head-up tilt table (HUTT) versus empirical diagnosis on patient outcome. Study Design: A retrospective case series of 1000 consecutive patients who were diagnosed with NCS and treated with citalopram. Measures and Outcomes: The primary outcome measure was well-being score (WS) recorded at each outpatient visit. Results: After excluding patients who had other comorbidities, were taking daily medication, or did not attend a follow-up visit within 1 month after treatment initiation, data from 186 patients were included. Thirty-five patients were diagnosed empirically, and 151 patients were diagnosed with the HUTT. All 186 patients were followed up within 1 month (early follow-up); of these, 92 patients attended a second follow-up after 1 month (late follow-up). The early follow-up group showed a significant improvement in mean WS (7.35 vs. 4.46, P < 0.001) and only 5 patients discontinued therapy because of intolerability. The late follow-up group also showed significant improvements in mean WS at the early follow-up (7.42 vs. 4.43, P < 0.001) and late follow-up (7.42 vs. 4.26, P < 0.001). Of 186 patients who were treated with citalopram, only 11 reported the development of undesirable side effects. There was no significant difference in the outcome of patients who were diagnosed empirically versus those who were diagnosed with the HUTT. Conclusions: Citalopram seems to have desirable effects on NCS and patient well-being. Diagnostic use of the HUTT is useful for confirming diagnoses of NCS but is not likely to improve patient outcome.