Adjunctive Systemic Corticosteroids for Pulmonary Exacerbations of Cystic Fibrosis.

RATIONALE: Pulmonary exacerbations (PEx) remain the most common cause of morbidity, recurrent hospitalization and diminished survival in people with CF (PWCF), and are characterized by excess inflammation. Corticosteroids are potent, widely available anti-inflammatory drugs. However, corticosteroid efficacy data from randomized controlled trials (RCTs) in PWCF are limited. OBJECTIVES: To determine whether adjunctive systemic corticosteroid therapy is associated with improved outcomes in acute CF PEx. METHODS: We performed a secondary analysis of STOP2, a large multicenter RCT of antimicrobial treatment durations for adult PWCF presenting with PEx, that included the use of corticosteroids as a stratification criterion in its randomization protocol. Corticosteroid treatment effects were determined after propensity score-matching for covariates including age, sex, baseline FEV1, genotype and randomization arm. The primary outcome measure was the change in percent predicted FEV1 (ppFEV1). Symptoms, time to next PEx and the incidence of adverse events (AEs) and serious adverse events (SAEs) were assessed as secondary endpoints. Phenotypic factors associated with the clinical decision to prescribe steroids were also investigated. RESULTS: Corticosteroids were prescribed for 168 of 982 PEx events in STOP2 (17%). Steroid prescription was associated with decreased baseline ppFEV1, increased age, and female sex. Co-treatment with corticosteroids was independent of treatment arm allocation, and did not result in greater mean ppFEV1 response, longer median time to next PEx or more substantial symptomatic improvement compared to propensity-matched PWCF receiving antibiotics alone. AEs were not increased in corticosteroid-treated PWCF. The total number of SAEs - but not the number of corticosteroid-related or PEx-ralated SAEs - was higher among patients receiving corticosteroids. CONCLUSION: Empiric, physician-directed treatment with systemic corticosteroids, while common, is not associated with improved clinical outcomes in PWCF receiving antibiotics for PEx.

Impact of lumacaftor/ivacaftor and tezacaftor/ivacaftor on treatment response in pulmonary exacerbations of F508del/F508del cystic fibrosis.

BACKGROUND: Pulmonary exacerbations (PEx) remain a major cause of morbidity and mortality in people with cystic fibrosis (PWCF). Although the combination cystic fibrosis transmembrane conductance regulator (CFTR) modulators lumacaftor/ivacaftor and tezacaftor/ivacaftor have been shown to reduce PEx frequency, their influence on clinical and biochemical responses to acute PEx treatment is unknown. METHODS: We performed a secondary analysis of STOP2, a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx. Propensity score matching was used to compare outcomes in antibiotic-treated F508del/F508del PWCF receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor with those observed in antibiotic-treated F508del/F508del controls not receiving CFTR modulator therapy. The primary outcome measure was the change in percent predicted FEV1 (ppFEV1) following completion of intravenous (IV) antibiotics, with post-antibiotic changes in symptoms, serum C-reactive protein (CRP) concentrations and weight included as secondary endpoints. RESULTS: Among 982 PEx events in randomized PWCF, 480 were homozygous for F508del, of whom 289 were receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor at initiation of antibiotic therapy. Modulator-treated F508del/F508del PWCF did not demonstrate greater improvements in ppFEV1, symptoms, serum CRP or weight following antibiotic treatment compared to modulator-naïve controls matched for age, sex, baseline ppFEV1, genotype, body mass index, initial CRP, initial symptoms, exacerbation history, diabetic status, randomization arm and concomitant medical therapy. CONCLUSION: In the acute setting, CFTR modulator therapy with lumacaftor/ivacaftor or tezacaftor/ivacaftor does not convey additional clinical or biochemical advantage above standardized PEx treatment in F508del/F508del PWCF.

Discontinuation versus continuation of hypertonic saline or dornase alfa in modulator treated people with cystic fibrosis (SIMPLIFY): results from two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials.

BACKGROUND: Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI). METHODS: The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEV1 (ppFEV1) of 70% or more, or those aged 18 years or older with ppFEV1 of 60% or more, if they had been taking ETI and either (or both) mucoactive therapies (≥3% hypertonic saline or dornase alfa) for at least 90 days before screening. Participants on both hypertonic saline and dornase alfa were randomly assigned to one of the two trials, and those on a single therapy were assigned to the applicable trial. All participants were then randomly assigned 1:1 to continue or discontinue therapy for 6 weeks using permuted blocks of varying size, stratified by baseline ppFEV1 (week 0; ≥90% or <90%), single or concurrent use of hypertonic saline and dornase alfa, previous SIMPLIFY study participation (yes or no), and age (≥18 or <18 years). For participants randomly assigned to continue their therapy during a given trial, this therapy was instructed to be taken at least once daily according to each participant's pre-existing, clinically prescribed regimen. Hypertonic saline concentration was required to be at least 3%. The primary objective for each trial was to determine whether discontinuing was non-inferior to continuing, measured by the 6-week change in ppFEV1 in the per-protocol population. We established a non-inferiority margin of -3% for the difference between groups in the 6-week change in ppFEV1. Safety outcomes were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT04378153. FINDINGS: From Aug 25, 2020, to May 25, 2022, a total of 672 unique participants were screened for eligibility for one or both trials, resulting in 847 total random assignments across both trials with 594 unique participants. 370 participants were randomly assigned in the hypertonic saline trial and 477 in the dornase alfa trial. Participants across both trials had an average ppFEV1 of 96·9%. Discontinuing treatment was non-inferior to continuing treatment with respect to the absolute 6-week change in ppFEV1 in both the hypertonic saline trial (-0·19% [95% CI -0·85 to 0·48] in the discontinuation group [n=133] vs 0·14% [-0·51 to 0·78] in the continuation group [n=140]; between-group difference -0·32% [-1·25 to 0·60]) and dornase alfa trial (0·18% [-0·38 to 0·74] in the discontinuation group [n=199] vs -0·16% [-0·73 to 0·41] in the continuation group [n=193]; between-group difference 0·35% [-0·45 to 1·14]), with consistent results in the intention-to-treat populations. In the hypertonic saline trial, 64 (35%) of 184 in the discontinuation group versus 44 (24%) of 186 participants in the continuation group and, in the dornase alfa trial, 89 (37%) of 240 in the discontinuation group versus 55 (23%) of 237 in the continuation group had at least one adverse event. INTERPRETATION: In individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment.

Measuring the impact of CFTR modulation on sweat chloride in cystic fibrosis: Rationale and design of the CHEC-SC study.

BACKGROUND: The Characterizing CFTR Modulated Changes in Sweat Chloride and their Association with Clinical Outcomes (CHEC-SC) study is a large epidemiologic study designed to determine the relationship between sweat chloride response and clinical outcomes in people with cystic fibrosis (CF) on commercially approved CFTR modulators. A challenge to study feasibility was capturing sweat chloride measurements before modulator initiation. We tested the hypothesis that historic sweat chloride approximated contemporary pre-modulator values to estimate CFTR modulator-induced changes, allowing a single-visit study design. METHODS: GOAL and PROSPECT were multi-center prospective studies of individuals initiating ivacaftor or lumacaftor-ivacaftor. At enrollment, pre-modulator sweat chloride was measured and historic results recorded. Post-modulator sweat chloride was measured at 1, 3 and 6 months. For this analysis, differences between historic and pre-modulator sweat chloride were estimated. CFTR modulator-induced sweat chloride mean changes were compared using historic and pre-modulator sweat chloride. RESULTS: Paired historic and pre-modulator sweat chloride (n=406 participants) revealed a non-significant mean change of -1.0 mmol/L (95% CI: -2.71, 0.66) over an average of 17.2 years. Calculating sweat response to ivacaftor or lumacaftor-ivacaftor using historic or pre-modulator values resulted in similar estimates of modulator response. Based on these results, the CHEC-SC study was designed with a single, post-modulator sweat chloride measurement. CONCLUSIONS: Historic sweat chloride values provide a reliable estimate of pre-modulator sweat chloride for people starting on modulator therapy. The CHEC-SC study anticipates capturing approximately 5,000 sweat chloride values, providing an unprecedented understanding of sweat chloride across the CF population in the era of CFTR modulators.

Evaluating the Impact of Stopping Chronic Therapies after Modulator Drug Therapy in Cystic Fibrosis: The SIMPLIFY Clinical Trial Study Design.

The care for individuals with cystic fibrosis (CF) with at least one F508del mutation will greatly change as a result of the unparalleled clinical benefits observed with the new triple-combination CFTR (CF transmembrane regulator)-modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). Incorporating ETI into the standard of care creates new motivation and opportunity to consider reductions in overall treatment burden and evaluate whether other chronic medications can now be safely discontinued without loss of clinical benefit. SIMPLIFY is a master protocol poised to test the impact of discontinuing versus continuing two commonly used chronic therapies in people with CF who are at least 12 years of age or older and stable on ETI therapy. The protocol is composed of two concurrent randomized controlled trials designed to evaluate the independent short-term effects of discontinuing hypertonic saline or dornase alfa, enabling individuals on both therapies to participate in one or both trials. The primary objective for each trial is to determine whether discontinuing treatment is noninferior to continuing treatment after establishment of ETI, as measured by the 6-week absolute change in the percent-predicted forced expiratory volume in 1 second. Developing this study required a balance between ideal study-design principles and feasibility. SIMPLIFY will be the largest multicenter, randomized, controlled medication-withdrawal study in CF. This study is uniquely positioned to provide timely evidence on whether the daily treatment burden can be reduced among individuals on CFTR-modulator therapy. Clinical trial registered with www.clinicaltrials.gov (NCT04378153).

Practice Patterns for Women With Overactive Bladder Syndrome: Time Between Medications and Third-Line Treatments.

OBJECTIVE: The aims of this study are to determine how long it takes female patients with overactive bladder (OAB) to receive third-line treatment after starting OAB medications and identify factors associated with increased time. METHODS: This was a retrospective observational cohort study of adult female patients with OAB who received third-line treatment between 2013 and 2015 using insurance claims databases. Primary outcome was time between first OAB medication and first third-line treatment. Additional variables were patient demographics, diagnostic tests, and medical comorbidities. RESULTS: Of 3232 patients included in this study, 48.8% underwent sacral neuromodulation, 31.6% percutaneous tibial nerve stimulation, and 23% intradetrusor onabotulinumtoxin A injections. Twenty-one percent of patients filled medication prescriptions for 3 or more antimuscarinic medications, 30.4% took mirabegron, and 32.3% had advanced diagnostic tests suggestive of a specialist evaluation prior to starting medications. Median time to third-line treatment was 37.7 (interquartile range, 14.9, 16.3) months. Adjusted linear regression model revealed 2 predominant predictors of time to third-line treatments: each antimuscarinic medication trial was associated with 5.3 (95% confidence interval, 4.4-6.3) more months before third-line treatment (P < 0.001), and advanced diagnostic evaluations prior to starting medications were associated with 28.2 (95% confidence interval, 21-35) fewer months before third-line treatment (P < 0.001). CONCLUSIONS: Women with OAB who undergo third-line therapy do so on average more than 3 years after starting medications. Time to third-line treatment is largely driven by the number of antimuscarinic medications tried and timing of diagnostic evaluation by a specialist. Based on these results, we suggest providers consider limiting antimuscarinic trials to 2 medications prior to moving on to other treatment options.

Pulmonary Outcomes Associated with Long-Term Azithromycin Therapy in Cystic Fibrosis.

Rationale: Chronic azithromycin is commonly used in cystic fibrosis based on short controlled clinical trials showing reductions in pulmonary exacerbations and improved FEV1. Long-term effects are unknown.Objectives: Examine pulmonary outcomes among chronic azithromycin users compared with matched controls over years of use and consider combined azithromycin use in cohorts using chronic inhaled tobramycin or aztreonam.Methods: This retrospective cohort study used the U.S. cystic fibrosis Foundation Patient Registry. Incident chronic azithromycin users were compared with matched controls by FEV1% predicted rate of decline and rates of intravenous antibiotic use to treat pulmonary exacerbations. Propensity score methods were utilized to address confounding by indication. Predefined sensitivity analyses based on lung function, Pseudomonas aeruginosa (PA) status, and follow-up time intervals were conducted.Measurements and Main Results: Across 3 years, FEV1% predicted per-year decline was nearly 40% less in those with PA using azithromycin compared with matched controls (slopes, -1.53 versus -2.41% predicted per yr; difference: 0.88; 95% confidence interval [CI], 0.30-1.47). This rate of decline did not differ based on azithromycin use in those without PA. Among all cohorts, use of intravenous antibiotics was no different between azithromycin users and controls. Users of inhaled tobramycin and azithromycin had FEV1% predicted per-year decline of -0.16 versus nonusers (95% CI, -0.44 to 0.13), whereas users of inhaled aztreonam lysine and azithromycin experienced a mean 0.49% predicted per year slower decline than matched controls (95% CI, -0.11 to 1.10).Conclusions: Results from this study provide additional rationale for chronic azithromycin use in PA-positive patients to reduce lung function decline.

Assessing noninferiority: Evaluating efficacy of a new treatment without complete data.

The FDA released the final guidance on noninferiority trials in November 2016. In noninferiority trials, validity of the assessment of the efficacy of the test treatment depends on the control treatment's efficacy. Therefore, it is critically important that there be a reliable estimate of the control treatment effect-which is generally obtained from historical trials, and often assumed to hold in the current setting (the assay constancy assumption). Validating the constancy assumption requires clinical data, which are typically lacking. The guidance acknowledges that "lack of constancy can occur for many reasons." We clarify the objectives of noninferiority trials. We conclude that correction for bias, rather than assay constancy, is critical to conducting valid noninferiority trials. We propose that assay constancy not be assumed and discounting or thresholds be used to address concern about loss of historical efficacy. Examples are provided for illustration.

Prediction Model for Nodal Disease Among Patients With Non-Small Cell Lung Cancer.

BACKGROUND: We characterized the performance characteristics of guideline-recommended invasive mediastinal staging (IMS) for lung cancer and developed a prediction model for nodal disease as a potential alternative approach to staging. METHODS: We conducted a prospective cohort study of adults with suspected/confirmed non-small cell lung cancer without evidence of distant metastatic disease (by computed tomography/positron emission tomography) who underwent nodal evaluation by IMS and/or at the time of resection. The true-positive rate was the proportion of patients with true nodal disease selected to undergo IMS based on guideline recommendations, and the false-positive rate was the proportion of patients without true nodal disease selected to undergo IMS. Logistic regression was used to predict nodal disease using radiographic predictors. RESULTS: Among 123 eligible subjects, 31 (25%) had pathologically confirmed nodal disease. A guideline-recommended invasive staging strategy had a true-positive rate and false-positive rate of 100% and 65%, respectively. The prediction model fit the data well (goodness-of-fit test, p = 0.55) and had excellent discrimination (optimism corrected c-statistic, 0.78; 95% confidence interval, 0.72 to 0.89). Exploratory analysis revealed that use of the prediction model could achieve a false-positive rate of 44% and a true-positive rate of 97%. CONCLUSIONS: A guideline-recommended strategy for IMS selects all patients with true nodal disease and most patients without nodal disease for IMS. Our prediction model appears to maintain (within a margin of error) the sensitivity of a guideline-recommended invasive staging strategy and has the potential to reduce the use of invasive procedures.

Role of bleeding recognition and evaluation in Black-White disparities in endometrial cancer.

BACKGROUND: Advanced stage at diagnosis is an independent, unexplained contributor to racial disparity in endometrial cancer. OBJECTIVE: We sought to investigate whether, prior to diagnosis, provider recognition of the cardinal symptom of endometrial cancer, postmenopausal bleeding, differs by patient race. STUDY DESIGN: Black and White women diagnosed with endometrial cancer (2001 through 2011) from Surveillance, Epidemiology, and End Results-Medicare who had at least 2 years of claims prior to diagnosis were identified. Bleeding diagnoses along with procedures done prior to diagnosis were captured via claims data. Multinomial logistic regression was used to evaluate the association of race with diagnostic workup and multivariate models built to determine the association of appropriate diagnostic procedures with stage at diagnosis. RESULTS: In all, 4354 White and 537 Black women diagnosed with endometrial cancer were included. Compared to White women, Black women were less likely to have guideline-concordant care: postmenopausal bleeding and appropriate diagnostic evaluation (70% vs 79%, P < .001), with adjusted relative risk ratios of 1.12-1.73 for different nonguideline-concordant pathways: bleeding without diagnostic procedures, alternative bleeding descriptions, and neither bleeding nor procedures. These pathways were associated with higher odds of advanced stage at diagnosis (adjusted odds ratio, 1.90-2.88). CONCLUSION: The lack of recognition and evaluation of postmenopausal bleeding is associated with advanced stage at diagnosis in endometrial cancer. Older Black women are at highest risk for the most aggressive histology types, yet they are less likely to have guideline-concordant evaluation of vaginal bleeding. Efforts aimed at improving recognition-among patients and providers-of postmenopausal bleeding in Black women could substantially reduce disparities in endometrial cancer.

Challenges in Predicting Recurrence After Resection of Node-Negative Non-Small Cell Lung Cancer.

BACKGROUND: One in 5 patients with completely resected early-stage non-small cell lung cancer will recur within 2 years. Risk stratification may facilitate a personalized approach to the use of adjuvant therapy and surveillance imaging. We developed a prediction model for recurrence based on five clinical variables (tumor size and grade, visceral pleural and lymphovascular invasion, and sublobar resection), and tested the hypothesis that the addition of several new molecular markers of poor long-term outcome (vascular endothelial growth factor C; microRNA precursors 486 and 30d) would enhance prediction. METHODS: We performed a retrospective cohort study of patients with completely resected, node-negative non-small cell lung cancer from 2011 to 2014 (follow-up through 2016) using the Lung Cancer Biospecimen Resource Network. Cox regression was used to estimate the 2-year risk of recurrence. Our primary measure of model performance was the optimism-corrected C statistic. RESULTS: Among 173 patients (mean tumor size, 3.6 cm; 12% sublobar resection, 32% poorly differentiated, 16% lymphovascular invasion, 26% visceral pleural invasion), the 2-year recurrence rate was 23% (95% confidence interval, 17% to 31%). A prediction model using five known risk factors for recurrence performed only slightly better than chance in predicting recurrence (optimism-corrected C statistic, 0.54; 95% confidence interval, 0.51 to 0.68). The addition of biomarkers did not improve the model's ability to predict recurrence (corrected C statistic, 0.55; 95% confidence interval, 0.52 to 0.71). CONCLUSIONS: We were unable to predict lung cancer recurrence using a risk-prediction model based on five well-known clinical risk factors and several biomarkers. Further research should consider novel predictors of recurrence to stratify patients with completely resected early-stage non-small cell lung cancer according to their risk of recurrence.

Bioactive lipids accumulate in stored red blood cells despite leukoreduction: a targeted metabolomics study.

BACKGROUND: Accumulation of bioactive lipids during red blood cell (RBC) storage has been identified as a potential source of posttransfusion sequelae in vulnerable populations. Typically, white blood cells (WBCs) have been implicated in the generation of bioactive lipids, and leukoreduction has been seen as a solution to this issue. STUDY DESIGN AND METHODS: We developed a targeted metabolomics approach with isotope dilution to quantify a panel of bioactive lipids in both leukoreduced (LR) and nonleukoreduced (NLR) RBC units over the course of storage. RESULTS: Leukoreduction greatly attenuated the production of 12-hydroxyeicosatetraenoic acid (HETE), 12-hydroxyeicosapentaenoic acid, and 14-hydroxydocosahexaenoic acid (HDoHE), all three of which are mediated by 12-lipoxygenase present in WBCs and platelets. However, despite leukoreduction, micromolar levels of linoleic acid (LA), arachidonic acid (AA), and docosahexaenoic acid (DHA) were observed in the RBC units stored for 42 days. These major polyunsaturated fatty acids (PUFAs) and their oxidation products (oxylipins) also significantly increased with storage time, including 5-, 8-, 9-, 11-, 12-, and 15- HETEs from AA; 9- and 13-hydroxyoctadecadienoic acid (HODE); 9-, 10-, and 12,13-dihydroxyoctadecenoic acids from LA; and 14-, 16-, and 17-HDoHEs from DHA. The majority of PUFAs and oxylipins accumulated in the supernatant fraction. Large donor-to-donor variations were observed in both LR-RBC and NLR-RBC units. CONCLUSION: While the exact role the accumulation of PUFAs and oxylipins plays in RBC unit quality and transfusion medical outcomes remains undetermined, the analytes of interest in this study may serve as biomarkers for lipid degradation and oxidation during storage and may induce changes in human physiology upon transfusion.

Metabolites in stored platelets associated with platelet recoveries and survivals.

BACKGROUND: Transfusion of platelets (PLTs) is a common therapy in a number of clinical settings. However, it is well understood that there is substantial donor-to-donor variation in how well PLTs store and thus the quality of the products that are transfused. The basis of such variation is poorly understood, and there are limited metrics by which units of PLTs can be assessed for their posttransfusion performance. It has repeatedly been demonstrated that myriad biologic changes take place during PLT storage; however, which of the changes correlate with quality of the stored PLTs and/or are mechanistically involved in PLT function remains undetermined. STUDY DESIGN AND METHODS: The current study tested stored PLTs from 21 normal subjects, combining high-resolution metabolomics of stored PLTs with in vivo PLT recoveries and survivals. Both individual analytes and metabolic pathways that correlate with posttransfusion PLT viability were identified. RESULTS: Caffeine metabolites were associated with poor PLT recovery; caffeine metabolism was not ongoing in the PLT bag and remained at prestorage levels. Acylcarnitines, particular fatty acid metabolites, and oxidized fatty acids were associated with poor PLT survivals. Of the myriad metabolic changes during PLT storage, these are the first reported metabolic findings to begin distinguishing which changes are of functional importance regarding posttransfusion PLT performance. CONCLUSIONS: Together, these findings provide novel mechanistic insights into the functional biology of the PLT storage lesion as well as identifying potential targets for modifying donor environment (e.g., caffeine consumption) and also metrics of quality assessment for stored human PLTs.

Patterns of Care and Survival Outcomes for Malignant Sex Cord Stromal Testicular Cancer: Results from the National Cancer Data Base.

PURPOSE: Sex cord stromal tumors of the testis comprise less than 5% of testicular neoplasms. Consequently, data regarding patterns of care and survival are sparse. Using a large national database, we sought to provide a more definitive analysis of outcomes and management of these malignancies. MATERIALS AND METHODS: Data were obtained from the National Cancer Data Base. Patients diagnosed from 1998 to 2011 with 2 of the most frequent sex cord stromal tumors of the testis, including Leydig and Sertoli cell tumors, were selected for study. Overall survival estimates were assessed by the Kaplan-Meier method. RESULTS: Of the 79,120 cases of testicular cancer between 1998 and 2011, 315 (0.39%) were primary malignant Leydig or Sertoli cell tumors. Median patient age was 43 years for both tumors. Of the 315 patients 250 (79%) had malignant Leydig cell tumors and 65 (21%) had malignant Sertoli cell tumors, of which 94% and 78%, respectively, were stage I. Overall survival at 1 and 5 years for stage I Leydig cell tumors was 98% (95% CI 96-100) and 91% (95% CI 85-96), and for stage I Sertoli cell tumors overall survival was 93% (95% CI 83-100) and 77% (95% CI 62-95), respectively (p = 0.015). Of patients with stage I Leydig and Sertoli cell tumors 94% and 84%, respectively, received no further treatment following orchiectomy. CONCLUSIONS: Five-year survival estimates of stage I Leydig and Sertoli cell tumors are significantly lower compared to those of stage I germ cell tumors with Sertoli cell tumors significantly worse than Leydig cell tumors. These differences in the survival of sex cord stromal tumors indicate the importance of large databases to evaluate the efficacy of treatment for rare neoplasms.

Prospective Quality of Life in Men Choosing Active Surveillance Compared to Those Biopsied but not Diagnosed with Prostate Cancer.

PURPOSE: Active surveillance is an important alternative to definitive therapy for men with low risk prostate cancer. However, the impact of active surveillance on health related quality of life compared to that in men without cancer remains unknown. In this study we evaluated health related quality of life outcomes in men on active surveillance compared to men followed after negative prostate needle biopsy. MATERIALS AND METHODS: A prospective study was conducted on men who were enrolled into the Center for Prostate Disease Research Multicenter National Database and underwent prostate needle biopsy for suspicion of prostate cancer between 2007 and 2014. Health related quality of life was assessed at biopsy (baseline) and annually for up to 3 years using SF-36 and EPIC questionnaires. Health related quality of life scores were modeled using generalized estimating equations, adjusting for baseline health related quality of life, and demographic and clinical characteristics. RESULTS: Of the 1,204 men who met the initial eligibility criteria 420 had a negative prostate needle biopsy (noncancer comparison group). Among the 411 men diagnosed with low risk prostate cancer 89 were on active surveillance. Longitudinal analysis revealed that for most health related quality of life subscales there were no significant differences between the groups in adjusted health related quality of life score trends over time. CONCLUSIONS: In this study most health related quality of life outcomes in patients with low risk prostate cancer on active surveillance did not differ significantly from those of men without prostate cancer. A comparison group of men with a similar risk of prostate cancer detection is critical to clarify the psychological and physical impact of active surveillance.

Changes in Vaginal Microbiota and Immune Mediators in HIV-1-Seronegative Kenyan Women Initiating Depot Medroxyprogesterone Acetate.

BACKGROUND: Depot medroxyprogesterone acetate (DMPA) is associated with HIV acquisition. We studied changes in vaginal microbiota and inflammatory milieu after DMPA initiation. METHODS: In a cohort of HIV-negative Kenyan women, we collected monthly vaginal swabs over 1 year before and after DMPA. Using quantitative polymerase chain reaction, we compared quantities of Lactobacillus crispatus, Lactobacillus jensenii, Lactobacillus iners, Gardnerella vaginalis, and total bacterial load (16S ribosomal RNA gene levels). Six vaginal immune mediators were measured with enzyme-linked immunosorbent assay. Trends in the detection and quantity of bacteria were estimated by logistic and linear mixed-effects regression. RESULTS: From 2010 to 2012, 15 HIV-seronegative women initiated DMPA, contributing 85 visits (median, 6 visits/woman; range, 3-8 visits/woman). The median time of DMPA-exposed follow-up was 8.4 months (range, 1.5-11.6 months). Seven women (46%) had bacterial vaginosis within 70 days before DMPA start. L. iners was detected in 13 women (87%) before DMPA start, but other lactobacilli were rarely detected. Gardnerella vaginalis decreased by 0.21 log10 copies per swab per month after DMPA exposure (P = 0.01). Total bacterial load decreased by 0.08 log10 copies per swab per month of DMPA (P = 0.02). Sustained decreases in interleukin (IL)-6 (P = 0.03), IL-8 (P = 0.04), and IL-1 receptor antagonist (P < 0.001) were also noted. Nine women (60%) had L. crispatus detected post-DMPA, which significantly correlated with reduced IL-6 (P < 0.01) and IL-8 (P = 0.02). CONCLUSIONS: Initiation of DMPA led to sustained shifts in vaginal bacterial concentrations and levels of inflammatory mediators. Further studies are warranted to outline components of the vaginal microbiota influenced by DMPA use and impact on HIV susceptibility.

Maternal Neutralization-Resistant Virus Variants Do Not Predict Infant HIV Infection Risk.

UNLABELLED: Mother-to-child transmission (MTCT) of HIV provides a setting for studying immune correlates of protection. Neutralizing antibodies (NAbs) are suggested to contribute to a viral bottleneck during MTCT, but their role in blocking transmission is unclear, as studies comparing the NAb sensitivities of maternal viruses have yielded disparate results. We sought to determine whether transmitting mothers differ from nontransmitting mothers in the ability to neutralize individual autologous virus variants present at transmission. Ten transmitting and 10 nontransmitting HIV-infected mothers at high risk of MTCT were included in this study. Full-length HIV envelope genes (n = 100) were cloned from peripheral blood mononuclear cells obtained near transmission from transmitting mothers and at similar time points from nontransmitting mothers. Envelope clones were tested as pseudoviruses against contemporaneous, autologous maternal plasma in neutralization assays. The association between transmission and the log2 50% inhibitory concentration (IC50) for multiple virus variants per mother was estimated by using logistic regression with clustered standard errors. t tests were used to compare proportions of neutralization-resistant viruses. Overall, transmitting mothers had a median IC50 of 317 (interquartile range [IQR], 202 to 521), and nontransmitting mothers had a median IC50 of 243 (IQR, 95 to 594). Transmission risk was not significantly associated with autologous NAb activity (odds ratio, 1.25; P = 0.3). Compared to nontransmitting mothers, transmitting mothers had similar numbers of or fewer neutralization-resistant virus variants, depending on the IC50 neutralization resistance cutoff. In conclusion, HIV-infected mothers harbor mostly neutralization-sensitive viruses, although resistant variants were detected in both transmitting and nontransmitting mothers. These results suggest that MTCT during the breastfeeding period is not driven solely by the presence of maternal neutralization escape variants. IMPORTANCE: There are limited data demonstrating whether NAbs can prevent HIV transmission and infection in humans, and for this reason, NAbs have been studied in MTCT, where maternal antibodies are present at the time of transmission. Results of these studies have varied, perhaps because of differences in methods. Importantly, studies often used cultured viruses and samples from time points outside the window of transmission, which could confound findings. Here, we considered the role of maternal NAbs against individual maternal virus variants near the time of transmission. We found no evidence that NAbs are associated with protection from infection. In fact, depending on the cutoff used to define neutralization resistance, we found evidence that nontransmitting mothers have more neutralization-resistant virus variants. These results suggest that lack of virus transmission in the early breastfeeding period is not simply due to an absence of maternal neutralization escape variants and likely includes multiple factors.

Metabolic pathways that correlate with post-transfusion circulation of stored murine red blood cells.

Transfusion of red blood cells is a very common inpatient procedure, with more than 1 in 70 people in the USA receiving a red blood cell transfusion annually. However, stored red blood cells are a non-uniform product, based upon donor-to-donor variation in red blood cell storage biology. While thousands of biological parameters change in red blood cells over storage, it has remained unclear which changes correlate with function of the red blood cells, as opposed to being co-incidental changes. In the current report, a murine model of red blood cell storage/transfusion is applied across 13 genetically distinct mouse strains and combined with high resolution metabolomics to identify metabolic changes that correlated with red blood cell circulation post storage. Oxidation in general, and peroxidation of lipids in particular, emerged as changes that correlated with extreme statistical significance, including generation of dicarboxylic acids and monohydroxy fatty acids. In addition, differences in anti-oxidant pathways known to regulate oxidative stress on lipid membranes were identified. Finally, metabolites were identified that differed at the time the blood was harvested, and predict how the red blood cells perform after storage, allowing the potential to screen donors at time of collection. Together, these findings map out a new landscape in understanding metabolic changes during red blood cell storage as they relate to red blood cell circulation.