Bioequivalence Between a New Omalizumab Prefilled Syringe With an Autoinjector or with a Needle Safety Device Compared with the Current Prefilled Syringe: A Randomized Controlled Trial in Healthy Volunteers.

Omalizumab is an anti-IgE monoclonal antibody currently approved for the treatment of asthma, nasal polyps/chronic rhinosinusitis with nasal polyps, and chronic spontaneous urticaria. Omalizumab is available as an injection in a prefilled syringe (PFS) with a needle safety device (NSD). New product configurations were developed to reduce the number of injections per dose administration, improve patient convenience and treatment compliance. The objective of this randomized open-label 12-week study was to demonstrate pharmacokinetic bioequivalence between (1) new PFS with autoinjector (PFS-AI), (2) new PFS-NSD configuration, and (3) current PFS-NSD configuration. Each new configuration was considered bioequivalent to the current configuration if the confidence intervals (CIs) for the geometric mean ratios (GMR) were contained in the 0.80-1.25 range for maximum concentration (Cmax ), area under the concentration-time curve until the last quantifiable measurement (AUClast ), and AUC extrapolated to infinity (AUCinf ). Safety was assessed throughout the study. In total, 193 healthy volunteers were randomized at 1:1:1 ratio to omalizumab 1×300 mg/2 mL via new PFS-AI (n = 66), omalizumab 1×300 mg/2 mL via new PFS-NSD (n = 64), or omalizumab 2×150 mg/1 mL via current PFS-NSD (n = 63). Comparing new PFS-AI versus current PFS-NSD, the GMRs were: Cmax , 1.085; AUClast , 1.093; AUCinf , 1.100. Comparing new PFS-NSD versus current PFS-NSD, the GMRs were: Cmax , 1.006; AUClast , 1.016; AUCinf , 1.027. The 95% CIs for all GMR parameters were contained within the 0.80-1.25 range. Safety findings were consistent with the known safety profile of omalizumab. Single-dose omalizumab administered as the new PFS-AI or new PFS-NSD was bioequivalent to the current PFS-NSD.

Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials.

BACKGROUND: Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies. METHODS: PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete. FINDINGS: Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, -8·0 (95% CI -10·6 to -5·4; PEARL-1), -10·0 (-12·6 to -7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (-1·2 to 2·5; PEARL-1), 0·4 (-1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo -8·0 (-10·5 to -5·4; PEARL-1), -11·1 (-13·7 to -8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (-1·1 to 2·5; PEARL-1), -0·7 (-2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab. INTERPRETATION: In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies. FUNDING: Novartis Pharma.

Global prevalence of Rett syndrome: systematic review and meta-analysis.

BACKGROUND: Rett syndrome is a rare, severe neurodevelopmental disorder. Almost all cases occur in girls, in association with spontaneous (non-inherited) mutations involving the methyl-CpG-binding protein 2 gene located on the X chromosome. Diagnostic criteria for typical Rett syndrome require a period of regression, followed by recovery or stabilization, and fulfillment of all four main criteria (loss of purposeful hand skills, loss of spoken language, gait abnormalities, and stereotypic hand movements). Our objective was to estimate the prevalence of Rett syndrome in the general population, stratified by sex. METHODS: We conducted a search of PubMed, Embase, Web of Science, Cochrane Library, LILACS, and LIVIVO to retrieve studies published in English between Jan. 1, 2000, and June 30, 2021. Pooled prevalence with a 95% confidence interval (CI) was estimated using a random-effects meta-analysis based on a generalized linear mixed model with a logit link. RESULTS: Ten eligible studies were identified (all in females), with a combined sample size of 9.57 million women and 673 Rett syndrome cases. The pooled prevalence estimate (random effects) was 7.1 per 100,000 females (95% CI: 4.8, 10.5, heterogeneity p < 0.001). Despite greatly variable precision of estimation, all estimates were compatible with a prevalence range of approximately 5 to 10 cases per 100,000 females based on their respective 95% CIs. CONCLUSION: These findings may facilitate planning of therapeutic trials in this indication in terms of target sample size and accrual times.

International Country-Level Trends, Factors, and Disparities in Compassionate Use Access to Unlicensed Products for Patients With Serious Medical Conditions.

Importance: Compassionate use (CU) is a treatment option for patients with serious or life-threatening medical conditions that provides access to locally unlicensed medications (generally free of charge) when all available treatment options have been exhausted and enrollment in a clinical trial is not possible. Objective: To examine the disparity in CU access observed across countries and explore the key driving factors. Design Settings and Participants: This study analyzed all Novartis CU requests (for individual/named patients and cohort programs) received between January 1, 2018, and December 31, 2020, and investigated selected country-specific factors for association with request activity. Data analysis was performed from February 2021 to February 2022. Main Outcomes and Measures: Country-specific request activity was quantified using request counts and rates per million population and examined in stratified and multivariable analyses (negative-binomial regression) for association with the following covariates: existence of local CU regulations and their public availability, clinical trial activity, population size, and gross domestic product. Results: During the 36-month observation period, 31 711 CU requests were received from 110 countries, 23 194 (73%) of which came from only 10 high-income countries. All high-income countries combined accounted for 27 612 (87%) of all requests, while lower-middle-income and low-income countries contributed only 1021 (3%). Of all requests, 29 870 (94%) were from countries with CU regulations made publicly available on the internet, and higher request activity was demonstrated in countries conducting more clinical trials. Presence and public availability of CU regulations, population size, gross domestic product, and clinical trial activity were independently associated with the CU request activity in multivariable analysis. Conclusions and Relevance: In this cohort study analyzing Novartis CU requests over a 3-year period, existence and public availability of CU regulations and local clinical trial activity were positively associated with higher CU request rates. The analysis also identified an association between macroeconomic factors and CU request activity, despite the generally free provision of unlicensed therapeutic products. Similar analyses of other comparable experiences are needed to supplement these initial observations. Ultimately, better understanding of factors associated with CU request activity would translate into improved early access to novel lifesaving products for patients with unmet medical needs around the world.

A Review of the Unique Drug Development Strategy of Indacaterol Acetate/Glycopyrronium Bromide/Mometasone Furoate: A First-in-Class, Once-Daily, Single-Inhaler, Fixed-Dose Combination Treatment for Asthma.

A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler® device, is the first long-acting beta2-adrenergic agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS) therapy to be approved for maintenance treatment of asthma in adults inadequately controlled on LABA/ICS. The approval of IND/GLY/MF in the European Union (EU) also included an optional electronic sensor and smartphone (or other suitable device) application, making it the first "digital companion" that can be prescribed with an asthma medication. As a result, the European Medicines Agency included this approval as one of the "outstanding contributions to public health" (for Pneumology/Allergology) in their 2020 highlights report. Alongside IND/GLY/MF, an o.d. LABA/ICS FDC, IND/MF, was also developed and approved. This review outlines the unique strategy used in the accelerated development of IND/GLY/MF that combined various approaches: (1) selecting individual components with established efficacy/safety, (2) bridging doses to optimize efficacy/safety of IND/GLY/MF and IND/MF delivered via the Breezhaler® device, (3) developing IND/GLY/MF and IND/MF in parallel, and (4) submission for regulatory approval before formal completion of the pivotal phase III studies. IND/GLY/MF and IND/MF were combined in a single-development plan (PLATINUM program), which comprised four phase III studies: QUARTZ and PALLADIUM evaluated IND/MF while IRIDIUM and ARGON evaluated IND/GLY/MF. A unique feature was the inclusion of two LABA/ICS comparators in the pivotal IRIDIUM study-IND/MF as an internal comparator, and high-dose salmeterol xinafoate/fluticasone propionate (SAL/FLU) as a marketed comparator. In the ARGON study, IND/GLY/MF was compared against o.d. tiotropium (via Respimat®) plus twice-daily (b.i.d.) high-dose SAL/FLU (via Diskus®). As a result of this development strategy, the development and approval of IND/GLY/MF was accelerated by ca. 4 years as against what would be expected from a traditional approach, novel data were generated, and a unique optional digital companion was approved in the EU. A Video Abstract by Dr Dominic Brittain, Global Drug Development, Novartis. (MP4 228293 kb).

Confidence intervals for exposure-adjusted rate differences in randomized trials.

Exposure-adjusted event rate is a quantity often used in clinical trials to describe average event count per unit of person-time. The event count may represent the number of patients experiencing first (incident) event episode, or the total number of event episodes, including recurring events. For inference about difference in the exposure-adjusted rates between interventions, many methods of interval estimation rely on the assumption of Poisson distribution for the event counts. These intervals may suffer from substantial undercoverage both, asymptotically due to extra-Poisson variation, and in the settings with rare events even when the Poisson assumption is satisfied. We review asymptotically robust methods of interval estimation for the rate difference that do not depend on distributional assumptions for the event counts, and propose a modification of one of these methods. The new interval estimator has asymptotically nominal coverage for the rate difference with an arbitrary distribution of event counts, and good finite sample properties, avoiding substantial undercoverage with small samples, rare events, or over-dispersed data. The proposed method can handle covariate adjustment and can be implemented with commonly available software. The method is illustrated using real data on adverse events in a clinical trial.

Cardiovascular safety of mometasone/indacaterol and mometasone/indacaterol/glycopyrronium once-daily fixed-dose combinations in asthma: pooled analysis of phase 3 trials.

OBJECTIVE: To evaluate cardiovascular safety of two new inhaled fixed-dose combinations for treatment of asthma: (i) the inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) mometasone furoate/indacaterol acetate (MF/IND), (ii) the ICS/LABA/long-acting muscarinic antagonist (LAMA) MF/IND/glycopyrronium bromide (GLY). METHODS: Patient-level data were pooled from four randomized trials, including 52-week studies PALLADIUM (n = 2216) and IRIDIUM (n = 3092), 24-week study ARGON (n = 1426), and 12-week study QUARTZ (n = 802). Cardio-/cerebrovascular (CCV) event frequencies were examined in the following comparisons: (1) LABA effect: pooled-dose MF/IND vs. pooled-dose MF; (2) LAMA effect: pooled-dose MF/IND/GLY vs. pooled-dose MF/IND; (3) ICS-dose effects: (a) high-dose MF/IND vs. medium-dose MF/IND, (b) high-dose MF/IND/GLY vs. medium-dose MF/IND/GLY; (4) intra-class effects: (a) high-dose MF/IND vs. Fluticasone/Salmeterol (F/S), (b) high-dose MF/IND/GLY vs. F/S + Tiotropium (TIO). Risk estimates (percentage of patients with ≥1 CCV event) and risk differences (RDs) with 95% confidence intervals (CIs) were calculated for each comparison. RESULTS: The frequency of CCV events was low, without notable differences between comparison groups. Risk estimates and corresponding RDs (95% CIs) were as follows: (1) pooled-dose MF/IND = 2.35%, pooled-dose MF = 2.18%, RD = 0.17% (-1.00%, 1.34%); (2) pooled-dose MF/IND/GLY = 3.65%, pooled-dose MF/IND = 3.77%, RD = -0.12% (-1.63%, 1.39%); (3a) high-dose MF/IND = 3.69%, medium-dose MF/IND = 3.35%, RD = 0.34% (-1.25%, 1.94%); (3b) high-dose MF/IND/GLY = 2.84%, medium-dose MF/IND/GLY = 2.02%, RD = 0.82% (-0.49%, 2.13%); (4a) high-dose MF/IND = 3.69%, F/S = 2.82%, RD = 0.87% (-0.66%, 2.40%); (4b) high-dose MF/IND/GLY = 1.26%, F/S + TIO = 1.05%, RD = 0.21% (-1.26%, 1.68%). CONCLUSIONS: There was no evidence of increased cardiovascular risk attributable to the addition of IND to MF or addition of GLY to MF/IND. Similarly, no evidence of increased cardiovascular risk was observed with an increase in the ICS-dose or relative to F/S ± TIO.

Improved confidence intervals for a difference of two cause-specific cumulative incidence functions estimated in the presence of competing risks and random censoring.

A cause-specific cumulative incidence function (CIF) is the probability of failure from a specific cause as a function of time. In randomized trials, a difference of cause-specific CIFs (treatment minus control) represents a treatment effect. Cause-specific CIF in each intervention arm can be estimated based on the usual non-parametric Aalen-Johansen estimator which generalizes the Kaplan-Meier estimator of CIF in the presence of competing risks. Under random censoring, asymptotically valid Wald-type confidence intervals (CIs) for a difference of cause-specific CIFs at a specific time point can be constructed using one of the published variance estimators. Unfortunately, these intervals can suffer from substantial under-coverage when the outcome of interest is a rare event, as may be the case for example in the analysis of uncommon adverse events. We propose two new approximate interval estimators for a difference of cause-specific CIFs estimated in the presence of competing risks and random censoring. Theoretical analysis and simulations indicate that the new interval estimators are superior to the Wald CIs in the sense of avoiding substantial under-coverage with rare events, while being equivalent to the Wald CIs asymptotically. In the absence of censoring, one of the two proposed interval estimators reduces to the well-known Agresti-Caffo CI for a difference of two binomial parameters. The new methods can be easily implemented with any software package producing point and variance estimates for the Aalen-Johansen estimator, as illustrated in a real data example.

Medical Careers and Motherhood: A Cross-Sectional Study of Hispanic Female Physicians.

BACKGROUND: One factor many women consider when choosing a medical specialty is the plan to have children and the compatibility of their chosen specialty with motherhood. OBJECTIVE: We surveyed Hispanic female physicians who are mothers to collect demographic information, specialty choice, childbearing, and professional and personal life characteristics, along with respondents' suggestions for female physicians who want to start a family, and how hospitals and medical institutions could enhance their support of female medical staff members with children. METHODS: The questionnaire was fielded on an online forum for Hispanic female physicians who are mothers. We summarized data by frequency and percentages, and means and standard deviations. RESULTS: Common medical specialties of respondents included pediatrics, family medicine, and obstetrics and gynecology, and 19% did not report a medical specialty. Most respondents were married (72%), had 1 or 2 children (89%), and worked at a public hospital 5 days a week (51%). Forty-four percent reported they slept 6 or more hours a night. Differences among specialties included dermatologists, radiologists, and gynecologists reporting working more than other specialties (6 to 7 days a week), psychiatrists reporting greater use of psychiatric medications, and anesthesiologists reporting lower rates of marriage. Female surgeons and emergency medicine physicians reported the highest consumption of alcohol. CONCLUSIONS: The results offer initial insights into how medical specialty choice may affect female physicians' work-life balance and can be used to provide guidance to female learners who plan to have a family.

Power analysis for multivariable Cox regression models.

In power analysis for multivariable Cox regression models, variance of the estimated log-hazard ratio for the treatment effect is usually approximated by inverting the expected null information matrix. Because, in many typical power analysis settings, assumed true values of the hazard ratios are not necessarily close to unity, the accuracy of this approximation is not theoretically guaranteed. To address this problem, the null variance expression in power calculations can be replaced with one of the alternative expressions derived under the assumed true value of the hazard ratio for the treatment effect. This approach is explored analytically and by simulations in the present paper. We consider several alternative variance expressions and compare their performance to that of the traditional null variance expression. Theoretical analysis and simulations demonstrate that, whereas the null variance expression performs well in many nonnull settings, it can also be very inaccurate, substantially underestimating, or overestimating the true variance in a wide range of realistic scenarios, particularly those where the numbers of treated and control subjects are very different and the true hazard ratio is not close to one. The alternative variance expressions have much better theoretical properties, confirmed in simulations. The most accurate of these expressions has a relatively simple form. It is the sum of inverse expected event counts under treatment and under control scaled up by a variance inflation factor.

Exploratory Subgroup Analyses of Renal Function and Overall Survival in European Organization for Research and Treatment of Cancer randomized trial of Nephron-sparing Surgery Versus Radical Nephrectomy.

BACKGROUND: In the European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904, nephron-sparing surgery (NSS) reduced the risk of renal dysfunction compared with radical nephrectomy (RN); however, overall survival was better in the RN arm. OBJECTIVE: To determine whether treatment effect on the risk of renal dysfunction and all-cause mortality differed in magnitude across levels of baseline variables. DESIGN, SETTING, AND PARTICIPANTS: This was an exploratory subgroup analysis of EORTC 30904, a phase 3 randomized trial conducted in patients with a small (≤5cm) renal mass and normal contralateral kidney. INTERVENTION: Patients were randomized to RN (n=273) or NSS (n=268). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: End points included follow-up estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2, eGFR <45ml/min/1.73m2, eGFR <30ml/min/1.73m2, and all-cause mortality. Treatment effect was examined within baseline variables: age (<62 vs ≥62 yr), sex, chronic disease (any vs none), performance status (0 vs≥1), and serum creatinine ≤1.25 vs >1.25×upper limit of normal (ULN). Logistic and Cox regression models were used for analysis of renal dysfunction and all-cause mortality, respectively. RESULTS AND LIMITATIONS: The median follow-up periods were 6.7 yr for eGFR and 9.3 yr for survival. No variable-by-treatment interactions were significant at alpha=0.05. For patients with baseline creatinine >1.25×ULN (n=36), estimated mortality hazard ratio (HR) for NSS versus RN reversed its direction (HR=0.76, 95% confidence interval [CI]: 0.17-3.39) relative to the rest of the study cohort (HR=1.56, 95% CI: 1.06-2.29), although this reversal was not statistically significant (interaction p=0.25). This analysis was limited by low power. CONCLUSIONS: This exploratory analysis did not reveal strong evidence of treatment effect modification in EORTC 30904, but it was limited by low power. PATIENT SUMMARY: We aimed to determine whether the effect of partial versus radical nephrectomy on kidney function and overall survival depended on age, sex, and baseline health of patients enrolled in a large clinical trial. Such dependence could not be demonstrated in this analysis.

Can Disproportionality Analysis of Post-marketing Case Reports be Used for Comparison of Drug Safety Profiles?

Clinical trials usually do not have the power to detect rare adverse drug reactions. Spontaneous adverse reaction reports as for example available in post-marketing safety databases such as the FDA Adverse Event Reporting System (FAERS) are therefore a valuable source of information to detect new safety signals early. To screen such large data-volumes for safety signals, data-mining algorithms based on the concept of disproportionality have been developed. Because disproportionality analysis is based on spontaneous reports submitted for a large number of drugs and adverse event types, one might consider using these data to compare safety profiles across drugs. In fact, recent publications have promoted this practice, claiming to provide guidance on treatment decisions to healthcare decision makers. In this article we investigate the validity of this approach. We argue that disproportionality cannot be used for comparative drug safety analysis beyond basic hypothesis generation because measures of disproportionality are: (1) missing the incidence denominators, (2) subject to severe reporting bias, and (3) not adjusted for confounding. Hypotheses generated by disproportionality analyses must be investigated by more robust methods before they can be allowed to influence clinical decisions.

Asymptotically robust variance estimation for person-time incidence rates.

Person-time incidence rates are frequently used in medical research. However, standard estimation theory for this measure of event occurrence is based on the assumption of independent and identically distributed (iid) exponential event times, which implies that the hazard function remains constant over time. Under this assumption and assuming independent censoring, observed person-time incidence rate is the maximum-likelihood estimator of the constant hazard, and asymptotic variance of the log rate can be estimated consistently by the inverse of the number of events. However, in many practical applications, the assumption of constant hazard is not very plausible. In the present paper, an average rate parameter is defined as the ratio of expected event count to the expected total time at risk. This rate parameter is equal to the hazard function under constant hazard. For inference about the average rate parameter, an asymptotically robust variance estimator of the log rate is proposed. Given some very general conditions, the robust variance estimator is consistent under arbitrary iid event times, and is also consistent or asymptotically conservative when event times are independent but nonidentically distributed. In contrast, the standard maximum-likelihood estimator may become anticonservative under nonconstant hazard, producing confidence intervals with less-than-nominal asymptotic coverage. These results are derived analytically and illustrated with simulations. The two estimators are also compared in five datasets from oncology studies.

Effectiveness and safety of extended-duration prophylaxis for venous thromboembolism in major urologic oncology surgery.

PURPOSE: To examine the association between extended-duration prophylaxis (EDP), low-molecular-weight heparin prophylaxis for 28 days after surgery for urologic cancer in patients at high risk of developing a venous thromboembolism (VTE), the risk of VTE, and the complications resulting from VTE prophylaxis. MATERIALS AND METHODS: The cohort included 332 patients at high risk for VTE who were surgically treated for urologic cancer from June 2011 to June 2014. Adherence to VTE prophylaxis protocol, VTEs, and complications within 365 days from surgery were tracked. Patients were grouped as follows: (1) per protocol in-hospital prophylaxis with EDP (n = 107), (2) per protocol in-hospital prophylaxis without EDP (n = 42), (3) not per protocol in-hospital prophylaxis with EDP (n = 83), and (4) not per protocol in-hospital prophylaxis without EDP (n = 100). The risk of VTE was compared between the 4 groups using the Cox model, with adjustment for baseline risk factors. RESULTS: The rates of VTEs and median times to VTE were 7% and 58 days in group 1, 17% and 44 days in group 2, 17% and 46 days in group 3, and 21% and 15 days in group 4, respectively. Adjusted hazard ratios (HR) for VTE were HR = 0.27 (95% CI: 0.11-0.70) for groups 1 vs. 4; HR = 0.66 (95% CI: 0.25-1.60) for groups 2 vs. 4; and HR = 0.66 (95% CI: 0.29-1.26) for groups 3 vs. 4 with a trend of P = 0.002. The incidence of complications from VTE prophylaxis was not significantly different between the groups, with a rate of 8% in group 1, 17% in group 2, 6% in group 3, and 12% in group 4 (P = 0.33). CONCLUSIONS: In high-risk urologic cancer surgery patients, a clinical protocol, with perioperative and EDP, is safe and effective in reducing VTE events.

Overall Survival after Partial Versus Radical Nephrectomy for a Small Renal Mass: Systematic Review of Observational Studies.

INTRODUCTION: In EORTC trial 30904 of partial versus radical nephrectomy overall survival was significantly better in the radical nephrectomy arm. However, many observational studies reported better survival after partial than radical nephrectomy. We present an updated systematic review of observational studies of overall survival after partial versus radical nephrectomy with assessment of quality of evidence. METHODS: The literature search was performed until December 31, 2013, and all studies reporting overall survival after partial vs radical nephrectomy were included in the initial review. Further inclusion criteria for complete review were malignant tumors 7 cm or smaller, or benign tumors of any size, and survival analysis performed with adjustment for confounding variables. Studies not meeting these criteria were excluded from full review because of selection bias in favor of patients treated with partial nephrectomy who were younger and with less advanced tumors. RESULTS: A total of 34 studies were included in the initial review and 13 were included in the full review. The 13 studies were based on the SEER database (6) or on institutional cohorts (7). In 8 of the 13 studies the estimated hazard ratios were significantly below 1, indicating better overall survival after partial nephrectomy, while in the remaining 5 studies estimated HR was not significantly different from 1. Median HR was 0.80 (interquartile range 0.57 to 0.96, absolute range 0.40 to 1.10). CONCLUSIONS: In most observational studies overall survival was better after partial than after radical nephrectomy. However, because residual confounding could be present despite adjustment for measured covariates, another randomized trial of partial vs radical nephrectomy may be needed to confirm or refute the findings of EORTC 30904.

Sex differences in incidence and mortality of bladder and kidney cancers: national estimates from 49 countries.

OBJECTIVES: In the United States, among patients diagnosed with bladder cancer (BC), women have increased disease-specific mortality compared with men. The main objective of this study was to determine whether this pattern is also present in other countries. For comparison, similar analyses were performed for kidney cancer (KC). METHODS AND MATERIALS: Data for this study were obtained from the GLOBOCAN 2008 database. A total of 49 countries with available information on BC and KC incidence and mortality were included in the analysis, representing all major geographic regions except Africa. For each country, we computed the sex-specific ratio of the total number of deaths from a given cancer to the total number of diagnoses in the year 2008 (the mortality-to-incidence ratio [MIR]). The relative MIR was computed for each country as a ratio of MIR in women to MIR in men. A relative MIR of more than 1 would indicate that the number of cancer-specific deaths relative to the number of cancer-specific diagnoses is greater in women than in men. RESULTS: For BC, the relative MIRs were significantly more than 1 in 26 countries (53%), significantly less than 1 in 2 countries (4%), and not significantly different from 1 in 21 countries (43%). The median relative MIR was 1.21 (interquartile range: 1.04-1.41). For KC, the relative MIRs were significantly more than 1 in 4 countries (8%), significantly less than 1 in 3 countries (6%), and not significantly different from 1 in 42 countries (86%). The median relative MIR was 1.00 (interquartile range: 0.94-1.06). CONCLUSION: Among BC patients, increased disease-specific mortality in women compared with men appears to be a common (although not a universal) phenomenon. This pattern may potentially be explained by differences between the sexes in the biology of disease, time to diagnosis, treatment decisions, and other factors. In contrast, among KC patients, no significant differences in disease-specific mortality were seen between the 2 sexes in the overwhelming majority of the countries.

Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904.

BACKGROUND: In the European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904, nephron-sparing surgery (NSS) was associated with reduced overall survival compared with radical nephrectomy (RN) over a median follow-up of 9.3 yr (hazard ratio: 1.50; 95% confidence interval [CI], 1.03-2.16). OBJECTIVE: To examine the impact of NSS relative to RN on kidney function in EORTC 30904. DESIGN, SETTING, AND PARTICIPANTS: This phase 3 international randomized trial was conducted in patients with a small (≤5 cm) renal mass and normal contralateral kidney who were enrolled from March 1992 to January 2003. INTERVENTION: Patients were randomized to RN (n=273) or NSS (n=268). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Follow-up estimated glomerular filtration rates (eGFR; milliliters per minute per 1.73 m(2)) were recorded for 259 subjects in the RN arm and 255 subjects in the NSS arm. Percentages of subjects developing at least moderate renal dysfunction (eGFR <60), advanced kidney disease (eGFR <30), or kidney failure (eGFR <15) were calculated for each treatment arm based on the lowest recorded follow-up eGFR (intent-to-treat analysis). RESULTS AND LIMITATIONS: With a median follow-up of 6.7 yr, eGFR <60 was reached by 85.7% with RN and 64.7% with NSS, with a difference of 21.0% (95% CI, 13.8-28.3); eGFR <30 was reached by 10.0% with RN and 6.3% with NSS, with a difference of 3.7% (95% CI, -1.0 to 8.5); and eGFR <15 was reached by 1.5% with RN and 1.6% with NSS, with a difference of -0.1% (95% CI, -2.2 to 2.1). Lack of longer follow-up for eGFR is a limitation of these analyses. CONCLUSIONS: Compared with RN, NSS substantially reduced the incidence of at least moderate renal dysfunction (eGFR <60), although with available follow-up the incidence of advanced kidney disease (eGFR <30) was relatively similar in the two treatment arms, and the incidence of kidney failure (eGFR <15) was nearly identical. The beneficial impact of NSS on eGFR did not result in improved survival in this study population. REGISTRATION: EORTC trial 30904; ClinicalTrials.gov identifier NCT00002473.

Bladder cancer incidence and mortality in patients treated with radiation for uterine cancer.

OBJECTIVE: To estimate the effect of radiation therapy (RT) administered for uterine cancer (UtC) on bladder cancer (BC) incidence, tumour characteristics at presentation, and mortality. PATIENTS AND METHODS: In this retrospective cohort study, records of 56 681 patients diagnosed with UtC as their first primary malignancy during 1980-2005 were obtained from the Surveillance, Epidemiology and End-Results (SEER) database. Follow-up for incident BC ended on 31 December 2008. Occurrences of BC diagnoses and BC deaths in patients with UtC managed with or without RT were summarised with counts and person-time incidence rates (counts divided by person-years of observation). Age adjustment of rates was performed by direct standardisation. Incident BC cases were described in terms of histological types, grades and stages. RESULTS: With a mean follow-up of 15 years, BC was diagnosed in 146 (0.93%) of 15 726 patients with UtC managed with RT, and in 197 (0.48%) of 40 955 patients with UtC managed without RT, with an age-adjusted rate ratio of 2.0 (95% confidence interval [CI] 1.6-2.5). Fatal BC occurred in 39 (0.25%) and 36 (0.09%) of patients with UtC managed with vs without RT, respectively, with an age-adjusted rate ratio of 2.9 (95% CI 1.8-4.6). Incident BC cases diagnosed in patients with UtC managed with vs without RT had similar distributions of histological types, grades, and stages. CONCLUSIONS: Use of RT for UtC is associated with increased BC incidence and mortality later in life. Heightened awareness should help identify women with new voiding symptoms or haematuria, all of which should be fully evaluated.

A randomized trial of 2% lidocaine gel versus plain lubricating gel for minimizing pain in men undergoing flexible cystoscopy.

This article presents findings from a randomized trial of intra-urethral lidocaine versus a plain lubricating gel for pain reduction in men undergoing flexible cystoscopy. Compared with the plain gel, use of lidocaine resulted in significantly less pain during the procedure.