Pathological response in resectable non-small cell lung cancer: a systematic literature review and meta-analysis.

BACKGROUND: Surrogate endpoints for overall survival in patients with resectable non-small cell lung cancer receiving neoadjuvant therapy are needed to provide earlier treatment outcome indicators and accelerate drug approval. This study's main objectives were to investigate the association among pathological complete response, major pathological response, event-free survival and overall survival and to determine whether treatment effects on pathological complete response and event-free survival correlate with treatment effects on overall survival. METHODS: A comprehensive systematic literature review was conducted to identify neoadjuvant studies in resectable non-small cell lung cancer. Analysis at the patient level using frequentist and Bayesian random effects (hazard ratio [HR] for overall survival or event-free survival by pathological complete response or major pathological response status, yes vs no) and at the trial level using weighted least squares regressions (hazard ratio for overall survival or event-free survival vs pathological complete response, by treatment arm) were performed. RESULTS: In both meta-analyses, pathological complete response yielded favorable overall survival compared with no pathological complete response (frequentist, 20 studies and 6530 patients: HR = 0.49, 95% confidence interval = 0.42 to 0.57; Bayesian, 19 studies and 5988 patients: HR = 0.48, 95% probability interval = 0.43 to 0.55) and similarly for major pathological response (frequentist, 12 studies and 1193 patients: HR = 0.36, 95% confidence interval = 0.29 to 0.44; Bayesian, 11 studies and 1018 patients: HR = 0.33, 95% probability interval = 0.26 to 0.42). Across subgroups, estimates consistently showed better overall survival or event-free survival in pathological complete response or major pathological response compared with no pathological complete response or no major pathological response. Trial-level analyses showed a moderate to strong correlation between event-free survival and overall survival hazard ratios (R2 = 0.7159) but did not show a correlation between treatment effects on pathological complete response and overall survival or event-free survival. CONCLUSION: There was a strong and consistent association between pathological response and survival and a moderate to strong correlation between event-free survival and overall survival following neoadjuvant therapy for patients with resectable non-small cell lung cancer.

Long-term comparative efficacy and safety of nivolumab plus ipilimumab relative to other first-line therapies for advanced non-small-cell lung cancer: A systematic literature review and network meta-analysis.

OBJECTIVES: To quantify the long-term comparative efficacy and safety of nivolumab in combination with ipilimumab (NIVO + IPI) relative to other immunotherapy (IO)-based regimens and chemotherapy in patients with first-line advanced non-small cell lung cancer (aNSCLC). METHODS: Phase 3 randomized controlled-trials (RCTs) with minimum 3-year follow-up evaluating IO-based regimens approved for first-line aNSCLC were identified via systematic literature review. Analytic populations were defined by levels of PD-L1 expression and histology. Due to presence of proportional hazards violations, time-varying hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were estimated via Bayesian fractional polynomial network meta-analysis. For safety endpoints, odds ratios (ORs) were estimated using indirect treatment comparisons (ITCs). RESULTS: CheckMate 227, KEYNOTE-189, KEYNOTE-407, KEYNOTE-024, KEYNOTE-042, and IMpower150 were included in the base case analysis. For OS and PFS, HRs of NIVO + IPI relative to other IO-based regimens trended downward over time across analytic populations. The 36-month OS HRs of NIVO + IPI versus comparators were: 0.69 (95 % credible interval: 0.47, 1.00) versus pembrolizumab + chemotherapy and 0.65 (0.45, 0.93) versus atezolizumab + bevacizumab + chemotherapy in the non-squamous and PD-L1 all-comers population; 0.73 (0.53, 1.02) versus pembrolizumab + chemotherapy in the squamous and PD-L1 all-comers population; and 1.05 (0.83, 1.32) versus pembrolizumab in the mixed histology and PD-L1 ≥ 50 % population. For PFS, 36-month HR point estimates ranged from 0.46 to 0.85 (only statistically significant versus pembrolizumab + chemotherapy in the squamous population; 0.46 [0.31, 0.69]). Adverse events (AEs) leading to discontinuation were not statistically significantly different between NIVO + IPI and pembrolizumab + chemotherapy, nor between NIVO + IPI and pembrolizumab monotherapy, although treatment-related grade ≥ 3 AEs were higher with NIVO + IPI than pembrolizumab monotherapy (OR = 2.21 [1.30, 3.75]). CONCLUSIONS: This study indicates trends towards long-term benefit with NIVO + IPI compared with other IO-based combinations, with manageable toxicities.

Correlations between objective response rate and survival-based endpoints in first-line advanced non-small cell lung Cancer: A systematic review and meta-analysis.

INTRODUCTION: The study objective was to estimate the relationship between objective response and survival-based endpoints by drug class, in first-line advanced non-small cell lung cancer (aNSCLC). MATERIALS AND METHODS: A systematic literature review identified randomized controlled trials (RCTs) of first-line aNSCLC therapies reporting overall survival (OS), progression-free survival (PFS), and/or objective response rate (ORR). Trial-level and arm-level linear regression models were fit, accounting for inclusion of immunotherapy (IO)-based or chemotherapy-only RCT arms. Weighted least squares-based R2 were calculated along with 95% confidence intervals (CIs). For the main trial-level analysis of OS vs. ORR, the surrogate threshold effect was estimated. Exploratory analyses involved further stratification by: IO monotherapy vs. chemotherapy, dual-IO therapy vs. chemotherapy, and IO + chemotherapy vs. chemotherapy. RESULTS: From 17,040 records, 57 RCTs were included. In the main analysis, trial-level associations between OS and ORR were statistically significant in both the IO-based and chemotherapy-only strata, with R2 estimates of 0.54 (95% CI: 0.26-0.81) and 0.34 (0.05-0.63), respectively. OS gains associated with a given ORR benefit were statistically significantly larger within IO vs. chemotherapy comparisons compared to chemotherapy vs. chemotherapy comparisons (p < 0.001). Exploratory analysis suggested a trend by IO type: for a given change in ORR, 'pure' IO (IO monotherapy and dual-IO) vs. chemotherapy RCTs tended to have a larger OS benefit than IO + chemotherapy vs. chemotherapy RCTs. For ORR vs. PFS, trial-level correlations were strong in the IO-based vs. chemotherapy (R2 = 0.84; 0.72-0.95), and chemotherapy vs. chemotherapy strata (R2 = 0.69; 0.49-0.88). For OS vs. PFS, correlations were moderate in both strata (R2 = 0.49; 0.20-0.78 and R2 = 0.49; 0.23-0.76). CONCLUSION: The larger OS benefit per unit of ORR benefit in IO-based RCTs compared to chemotherapy-only RCTs provides an important addition to the established knowledge regarding the durability and depth of response in IO-based treatments.

Second-line treatments in advanced biliary tract cancer: systematic literature review of efficacy, effectiveness and safety.

Background: A systematic review was conducted to understand clinical, economic and health-related quality-of-life outcomes in second-line biliary tract cancer. Materials & methods: The review followed established recommendations. The feasibility of network meta-analysis revealed limited networks, thus synthesis was limited to a summary of reported ranges, percentiles and medians. Results: The review included 62 trials and observational studies highly variable with respect to key baseline characteristics. Commonly evaluated second-line treatments included fluoropyrimidine-, gemcitabine- and S-1-based regimens. Across active treatment arms, median overall survival ranged from 3.5 to 15.0 months (median: 6.9), median progression-free survival from 1.4 to 6.5 months (median: 2.9) and objective response from 0 to 36.4%. Outcomes were similar between study types, with a few notable outliers. Treatment-related/emergent adverse events were infrequently reported; no studies reported economic or health-related quality-of-life outcomes. Conclusions: Biliary tract cancer is a difficult-to-treat disease with poor prognosis. Despite evolving treatment landscapes, more recent studies did not show clinical outcome improvement, highlighting an unmet need among advanced/metastatic patients.

A systematic review of published literature was undertaken to understand the clinical, economic and health-related quality-of-life impact of second-line biliary tract cancer (BTC). A total of 62 relevant studies were identified. The patient populations included across these studies were highly variable with respect to key patient characteristics (i.e., age, sex, physical functioning and tumor type). Commonly evaluated treatments included fluoropyrimidine-, gemcitabine- and S-1-based regimens. Reported values for key outcomes varied substantially, somewhat explained by a few outlier studies. Median overall survival ranged from 3.5 to 15.0 months, median progression-free survival from 1.4 to 6.5 months and objective response from 0 to 36.4%. Treatment-related/emergent adverse events were infrequently reported; no studies reported economic or health-related quality-of-life outcomes. The results demonstrate that BTC is a difficult-to-treat disease with poor prognosis. Despite evolving treatment landscapes, more recent studies did not show clinical outcome improvement, highlighting an unmet need among advanced/metastatic second-line BTC patients.

Real-world treatment patterns in resectable (stages I-III) non-small-cell lung cancer: a systematic literature review.

Aim: The aim of this systematic literature review was to describe treatment patterns in nonmetastatic non-small-cell lung cancer. Methods: A search was conducted in MEDLINE and EMBASE. Eligible studies were multicentered (>50 patients) and conducted after 2000 in North America, Europe and Asia. Results: Twenty studies met the eligibility criteria. Based on US and Canadian studies in the resectable population, the proportion of patients who received neoadjuvant chemotherapy/chemoradiotherapy and adjuvant chemotherapy/chemoradiotherapy increased with increasing stage (i.e., from <3% in stage I to about 40% in stage III and from 15% in stage I to 30% in stage III, respectively). Within the resectable population, the breakdown between bimodal and trimodal therapy was variable, suggesting that clinical practice is not uniform. Conclusion: Overall, studies were heterogeneous, precluding data extrapolation across regions. Despite heterogeneity and limited evidence, this review suggested an increase in neoadjuvant and adjuvant chemotherapy with increasing stage, generally in line with treatment guidelines.

This literature review aimed to describe the treatment patterns in nonmetastatic non-small-cell lung cancer. This review was performed according to the highest methodological standards and searched published and unpublished records of stages I­III non-small-cell lung cancer treatment in North America, Europe and Asia. A limited number of studies were identified showing that in North America treatment with neoadjuvant and adjuvant chemotherapy (with or without radiotherapy) increased with stage. Identified studies in all regions showed that the treatment received, such as bimodal with surgery and chemotherapy compared with trimodal with surgery, chemotherapy and radiotherapy, was quite variable and that practice was not uniform. Overall, the studies were heterogeneous and data could not be extrapolated to practice across all regions. However, the studies suggested an increase in neoadjuvant and adjuvant usage with increasing stage, which is generally in line with treatment guidelines.

Comparative effectiveness of nivolumab versus clinical practice for advanced gastric or gastroesophageal junction cancer.

Aim: To determine the effectiveness of nivolumab compared with routine clinical practice (RCP) for patients with gastric or gastroesophageal cancer refractory to, or intolerant of, two or more previous regimens, using real-world electronic patient records from a US population, a single-arm trial (CheckMate 032) and a randomized controlled trial in an Asian setting (ATTRACTION-2). Materials & methods: A simulated treatment comparison was conducted to predict overall survival for patients treated with nivolumab compared with RCP in the USA. Results: Results of the indirect simulated treatment comparison suggest that nivolumab is associated with a 50% reduction in the risk of all-cause mortality relative to RCP (Hazard ratio: 0.50; 95% CI: 0.36, 0.68). Conclusion: The survival benefit of nivolumab may extend more generally to the USA.

A Comparison of National Guidelines for Network Meta-Analysis.

BACKGROUND: Network meta-analysis (NMA) techniques allow the comparison of a complete set of interventions for patient groups. These meta-analysis techniques may be the only source of evidence to underpin estimates of comparative efficacy. Reimbursement agencies around the world are increasingly reliant upon meta-analysis techniques and assess their design and conduct with growing sophistication. OBJECTIVE: Our objective is to create a superset of requirements collated from available national guidelines for the conduct of network meta-analysis such that a single analysis may be conducted to satisfy all reimbursement bodies that have specified requirements in sufficient detail. METHODS: Published and draft guidelines documents from reimbursement bodies and health technology appraisal agencies were examined for their stipulations as to the conduct and design of network meta-analysis and measures to be taken to reduce bias and increase validity. RESULTS: Guidelines from 41 countries were reviewed, yielding a sample size of 13 countries' guideline documents: Australia, Belgium, Canada, China, Ireland, England and Wales, France, Germany, Scotland, South Africa, South Korea, Spain, Thailand, and a guideline document from the European Network of Health Technology Assessment, which contained explicit recommendations or requirements for conduct of NMA. CONCLUSION: This study expands the range of previous work that reviewed the guidelines for the use of indirect evidence from multiple national jurisdictions. These aggregate guidelines do not include requirements that are mutually prohibitive. It is possible to perform a single NMA for submission to an expanded list of national jurisdictions.

Efficacy and safety of first-line carboplatin-versus cisplatin-based chemotherapy for non-small cell lung cancer: A meta-analysis.

OBJECTIVES: Platinum-based chemotherapy is the mainstay of first-line (1L) therapy for advanced non-small cell cancer (NSCLC). The objective of this study was to evaluate the relative efficacy, safety, and health-related quality of life (HRQoL) of carboplatin- versus cisplatin-based chemotherapy in 1L NSCLC. MATERIALS AND METHODS: A meta-analysis by the Cochrane group (2013) was updated. Systematic searches of CENTRAL, Medline, Embase, Latin American and Caribbean Health Sciences database, clinicaltrials.gov and conference proceedings were conducted to include randomized controlled trials (RCTs) published between 2013-January 2018 which compared carboplatin and cisplatin combined with: gemcitabine, vinorelbine, docetaxel, paclitaxel, irinotecan, or pemetrexed. Endpoints included overall survival (OS), one-year OS, objective response rate (ORR), grade 3/4 drug-related toxicities, and HRQoL. RESULTS: Twelve RCTs (2,048 patients) were identified from 4,139 records for inclusion in the meta-analysis. There were no significant differences in OS (hazards ratio [HR]: 1.08, 95% confidence interval [CI]: 0.96, 1.21) and one-year OS (relative risk [RR]: 0.97, CI: 0.89, 1.07) between carboplatin- and cisplatin-based chemotherapy. A small effect on ORR favouring cisplatin was detected (RR = 0.88; CI: 0.78, 0.99). Differences in drug-related toxicities were observed between carboplatin- and cisplatin-based chemotherapy for thrombocytopenia, anaemia, neurotoxicity, and the risk of nausea/vomiting. Three RCTs comparing HRQoL between carboplatin- and cisplatin-based chemotherapy found no significant differences. CONCLUSIONS: This updated evidence base corroborates findings of previous meta-analyses showing no difference in OS between carboplatin- and cisplatin-based chemotherapy, despite a slight benefit in ORR for cisplatin. Toxicity profiles should be considered alongside patients' comorbidities in the choice of therapy.

Characteristics of non-randomised studies using comparisons with external controls submitted for regulatory approval in the USA and Europe: a systematic review.

OBJECTIVES: Non-randomised clinical trial designs involving comparisons against external controls or specific standards can be used to support regulatory submissions for indications in diseases that are rare, with high unmet need, without approved therapies and/or where placebo is considered unethical. The objective of this review was to summarise the characteristics of non-randomised trials submitted to the European Medicines Agency (EMA) or Food and Drug Administration (FDA) for indications in haematological cancers, haematological non-malignant conditions, stem cell transplants or rare metabolic diseases. METHODS: We conducted systematic searches of EMA databases of conditional approvals, exceptional circumstances, or orphan drug designations and FDA inventories of orphan drug designations, accelerated approvals, breakthrough therapy, fast-track and priority approvals. Products were included if reviewed by at least one agency between 2005 and 2017, the primary evidence base was non-randomised trial(s) and the indication was for haematological cancers, stem cell transplantation, haematological conditions or rare metabolic conditions. RESULTS: We identified 43 eligible indication-specific products using non-randomised study designs involving comparisons with external controls, submitted to the EMA (n=34) and/or FDA (n=41). Of the 43 indication-specific products, 4 involved matching external controls to the population of a non-randomised interventional study using individual patient-level data (IPD), 12 referred to external controls without IPD and 27 did not explicitly reference external controls. The FDA approved 98% of submissions, with 56% accelerated approvals; most required postapproval confirmatory randomised controlled trials (RCT). The EMA approved 79% of submissions, with a quarter of approvals conditional on completion of a postapproval RCT or additional non-randomised trials. CONCLUSIONS: There has been a large increase in submissions to the EMA and FDA using non-randomised study designs involving comparisons with external controls in recent years. This study demonstrated that regulators may be willing to approve such submissions, although approvals are often conditional on further confirmatory evidence from postapproval studies.

Patient and physician preferences for first-line treatment of classical Hodgkin lymphoma in Germany, France and the United Kingdom.

First-line treatments for classical Hodgkin lymphoma (HL) include ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and BEACOPPescalated (escalated dose bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone). To further improve overall outcomes, positron emission tomography-driven strategies and ABVD or BEACOPP variants incorporating the antibody-drug conjugate brentuximab vedotin (BV) or anti-PD1 antibodies are under investigation in advanced-stage patients. The present study aimed to elicit preferences for attributes associated with ABVD, BEACOPPescalated and BV-AVD (BV, adriamycin, vinblastine and dacarbazine) among patients and physicians. Cross-sectional online discrete choice experiments were administered to HL patients (n = 381) and haematologists/oncologists (n = 357) in France, Germany and the United Kingdom. Included attributes were progression-free survival (PFS), overall survival (OS), and the risk of neuropathy, lung damage, infertility and hospitalisation due to adverse events. Whereas 5-year PFS and OS were the most important treatment attributes to patients, the relative importance of each attribute and preference weights for each level varied among physicians according to the description of the hypothetical patient for whom treatment was recommended. PFS and OS most strongly influenced physicians' recommendations when considering young female patients who did not want children or young male patients. Infertility was more important to physicians' treatment decision than PFS when considering young women with unknown fertility preferences, whereas hospitalisations due to adverse events played the largest role in treatment decisions for older patients.

Treatment Decisions for Advanced Non-Squamous Non-Small Cell Lung Cancer: Patient and Physician Perspectives on Maintenance Therapy.

INTRODUCTION: Advanced non-small cell lung cancer (NSCLC) is a severe disease with burdensome symptoms and traditionally poor outcomes. The treatment of advance disease is based on chemotherapy, with the recent addition of immunotherapy. Patients who respond to initial treatment can opt to receive maintenance therapy (MT). It is important to understand why patients with advanced NSCLC choose to accept or refuse therapy, and how physician recommendations play into this decision-making process. This study characterized patient and physician decision-making regarding treatment for patients with advanced non-squamous NSCLC in the USA using the example of MT. METHODS AND MATERIALS: This study employed multiple approaches: patient interviews, a patient survey, and a physician survey. Qualitative interviews were conducted among patients who had been offered MT to identify factors influencing treatment decision-making. The patient survey explored the decision-making process and quantified challenges and motivators for receiving MT. The physician survey included a discrete choice experiment to understand the relationship between physician treatment recommendations and patient characteristics. RESULTS: Interviewed patients (n = 10) were motivated to receive MT in the hope of extending their lives and being proactive against their cancer, and they anticipated reduced adverse effects compared with first-line therapy. Surveyed patients (n = 77) described several deterrents to receiving therapy; the most prominent was severity of adverse effects, which was an influencing factor for 34% of patients. The major motivator for receiving therapy was the potential to extend life, which influenced 97% of patients. A total of 100 oncologists participated in the physician survey. Patients' lack of treatment motivation/inconvenience, disease progression, presence of severe renal co-morbidities, and older age decreased the likelihood of physicians recommending the use of MT. CONCLUSION: This study identified challenges and motivators influencing advanced NSCLC patients' decisions to accept or refuse therapy, as well as patient and disease characteristics associated with physician's treatment recommendations for MT.

Effects of calcimimetics on long-term outcomes in dialysis patients: literature review and Bayesian meta-analysis.

AIM: Randomized controlled trials (RCTs) with clinical outcomes are considered the gold standard for regulatory approval. However, by design they are only able to answer a small number of clinical questions. Other high-quality studies are required for clinical decision-making. The EVOLVE was the largest RCT, evaluating the effects of cinacalcet on clinical outcomes among adult patients receiving maintenance dialysis suffering from secondary hyperparathyroidism. While the EVOLVE trial did not reach its primary end point, imbalance in subjects' age at randomization and discontinuation rates are two of the reasons that the lack of mortality benefit is in question. We undertook a systematic literature review and Bayesian meta-analysis combining randomized and observational studies on the estimated effects of the oral calcimimetic cinacalcet on clinical outcomes including all-cause mortality, cardiovascular-related mortality, hospitalization for cardiovascular events, fracture and parathyroidectomy among patients on maintenance dialysis. METHODS: Data sources included MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases. RCTs and observational studies were included. Data extraction was completed by two authors independently and in duplicate determined the methodological quality of the studies and extracted data. RESULTS: Of 564 unique citations identified, 16 studies were included: six observational studies and ten RCTs. Four high-quality studies (two observational and two RCTs) were deemed suitable for meta-analysis. Results indicated a statistically significant reduction in the risk of death associated with cinacalcet (hazard ratio: 0.83; 95% credible interval: 0.78-0.89). CONCLUSION: The results of this meta-analysis indicate that treatment of secondary hyperparathyroidism with calcimimetic therapy may in fact reduce mortality among patients receiving maintenance dialysis. This finding provides justification for a well-designed and adequately powered randomized trial to definitively address the question.

Understanding the Early Presentation of Mucopolysaccharidoses Disorders: Results of a Systematic Literature Review and Physician Survey

Abstract As therapies are developed for rare disorders, challenges of early diagnosis become particularly relevant. This article focuses on clinical recognition of mucopolysaccharidoses (MPS), a group of rare genetic diseases related to abnormalities in lysosomal function. As quality of outcomes with current therapies is impacted by timing of intervention, minimizing time to diagnosis is critical. The objective of this study was to characterize how, when, and to whom patients with MPS first present and develop tools to stimulate earlier recognition of MPS. A tripartite approach was used, including a systematic literature review yielding 194 studies, an online physician survey completed by 209 physicians who described

Network meta-analysis of disconnected networks: How dangerous are random baseline treatment effects?

In network meta-analysis, the use of fixed baseline treatment effects (a priori independent) in a contrast-based approach is regularly preferred to the use of random baseline treatment effects (a priori dependent). That is because, often, there is not a need to model baseline treatment effects, which carry the risk of model misspecification. However, in disconnected networks, fixed baseline treatment effects do not work (unless extra assumptions are made), as there is not enough information in the data to update the prior distribution on the contrasts between disconnected treatments. In this paper, we investigate to what extent the use of random baseline treatment effects is dangerous in disconnected networks. We take 2 publicly available datasets of connected networks and disconnect them in multiple ways. We then compare the results of treatment comparisons obtained from a Bayesian contrast-based analysis of each disconnected network using random normally distributed and exchangeable baseline treatment effects to those obtained from a Bayesian contrast-based analysis of their initial connected network using fixed baseline treatment effects. For the 2 datasets considered, we found that the use of random baseline treatment effects in disconnected networks was appropriate. Because those datasets were not cherry-picked, there should be other disconnected networks that would benefit from being analyzed using random baseline treatment effects. However, there is also a risk for the normality and exchangeability assumption to be inappropriate in other datasets even though we have not observed this situation in our case study. We provide code, so other datasets can be investigated.

A network meta-analysis of the efficacy of belatacept, cyclosporine and tacrolimus for immunosuppression therapy in adult renal transplant recipients.

Belatacept is a first in-class co-stimulation blocker developed for primary maintenance immunosuppression following renal transplantation. The objective of this study was to estimate the efficacy of belatacept relative to tacrolimus and cyclosporine among adults receiving a single kidney transplant. A systematic review was conducted of randomized clinical trials (RCTs) published between January 1990 and December 2013 using EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials, and unpublished study reports from two belatacept RCTs. Bayesian network meta-analysis (NMA) methods were used to compare the efficacy measures, mortality, graft loss, acute rejection and glomerular filtration rate (GFR). Heterogeneity was quantified using statistical metrics and potential sources were evaluated using meta-regression and subgroup analysis. A total of 28 RCTs comparing tacrolimus with cyclosporine, and three comparing belatacept with cyclosporine, were identified. All three agents provided comparable graft and patient survival, despite a higher risk of acute rejection associated with belatacept and cyclosporine. Belatacept was associated with significant improvement in GFR versus cyclosporine. Compared with tacrolimus, this difference was clinically meaningful yet statistically non-significant. The probability of being the best treatment was highest for belatacept for graft survival (68%), patient survival (97%) and renal function (89%), and highest for tacrolimus for acute rejection (99%).Variability in donor, recipient, and trial characteristics was present in the included RCTs; however, minimal statistical heterogeneity was detected in the analysis of acute rejection, graft or patient survival, and none of the characteristics were found to be significantly associated with relative effect. Although the direction of effect of immunosuppressants on GFR was consistent across RCTs, precise estimation of its magnitude was limited by a small number of RCTs and heterogeneity in relative effect sizes. Clinicians often seek an alternative to CNIs due to their nephrotoxic effects. The results of this indirect comparison indicate that belatacept is an effective immunosuppressive agent in renal transplantation among adults.

Gender and the diagnosis, management, and surveillance of chronic obstructive pulmonary disease.

Following in the footsteps of cardiovascular researchers and clinicians, the pulmonary scientific community is beginning to explore how gender may impact the diagnosis, treatment, and surveillance of chronic obstructive pulmonary disease (COPD). Investigators and clinicians in this field are tackling the complex questions surrounding how differences in male/female biology may interact with gender differences in environmental, societal, cultural, and behavioral determinants of health to influence outcomes in COPD. In this article, issues such as gender differences in symptoms, gender diagnostic bias, differential impact of therapies, including smoking cessation and pharmacologic management, as well as the impact of these issues on COPD surveillance, are discussed. Current knowledge from the literature coupled with discussions from a 1-day symposium on gender and COPD diagnosis, management, and surveillance are detailed, including recommendations on where future research endeavors may be targeted.