Association between RCT methodology and disease indication with mineralocorticoid-related toxicity for patients receiving abiraterone acetate for advanced prostate cancer: A meta-analysis of RCTs.

INTRODUCTION: While abiraterone acetate (AA) has demonstrated survival benefit in advanced prostate cancer (APC), meaningful cardiotoxicity is observed. It is unclear whether the magnitude differs based on disease indication and concurrent steroid administration. METHODS: We performed a systematic review and meta-analysis of phase II/III RCTs of AA in APC published as of August 11, 2020. Primary outcomes examined were all- and high-grade (grade ≥ 3) hypokalemia and fluid retention, and secondary outcomes included hypertension and cardiac events. We performed random effects meta-analysis comparing intervention (AA + steroid) and control (placebo ± steroid), stratified by treatment indication and whether patients received steroids. RESULTS: Among 2,739 abstracts, we included 6 relevant studies encompassing 5901 patients. Hypokalemia and fluid retention were observed more frequently among patients receiving AA (odds ratio [OR] 3.10 [95% CI 1.69-5.67] and 1.41 [95% CI 1.19-1.66]). This was modified by whether patients in the control received steroids: trials where control patients did not demonstrated a larger association between AA and hypokalemia (OR 6.88 [95% CI 1.48-2.36] versus OR 1.86 [95% CI 4.97-9.54], P < .0001) and hypertension (OR 2.53 [95% CI 1.91-3.36] vs. OR 1.55 [95% CI 1.17-2.04], P = .1) than those where steroids were administered. We observed heterogeneity due to indication: there were greater effects on hypokalemia (P < 0001), hypertension (P = .03), and cardiac disorders (P = .01) among patients treated for mHSPC than mCRPC. CONCLUSIONS: The magnitude of cardiotoxicity with AA differs based on trial design and disease indication. These data are valuable in treatment decisions and highlight utilization of appropriate data for counseling.

Contrast solution properties and scan parameters influence the apparent diffusivity of computed tomography contrast agents in articular cartilage.

The inability to detect early degenerative changes to the articular cartilage surface that commonly precede bulk osteoarthritic degradation is an obstacle to early disease detection for research or clinical diagnosis. Leveraging a known artefact that blurs tissue boundaries in clinical arthrograms, contrast agent (CA) diffusivity can be derived from computed tomography arthrography (CTa) scans. We combined experimental and computational approaches to study protocol variations that may alter the CTa-derived apparent diffusivity. In experimental studies on bovine cartilage explants, we examined how CA dilution and transport direction (absorption versus desorption) influence the apparent diffusivity of untreated and enzymatically digested cartilage. Using multiphysics simulations, we examined mechanisms underlying experimental observations and the effects of image resolution, scan interval and early scan termination. The apparent diffusivity during absorption decreased with increasing CA concentration by an amount similar to the increase induced by tissue digestion. Models indicated that osmotically-induced fluid efflux strongly contributed to the concentration effect. Simulated changes to spatial resolution, scan spacing and total scan time all influenced the apparent diffusivity, indicating the importance of consistent protocols. With careful control of imaging protocols and interpretations guided by transport models, CTa-derived diffusivity offers promise as a biomarker for early degenerative changes.

Validation of watershed-based segmentation of the cartilage surface from sequential CT arthrography scans.

BACKGROUND: This study investigated the utility of a 2-dimensional watershed algorithm for identifying the cartilage surface in computed tomography (CT) arthrograms of the knee up to 33 minutes after an intra-articular iohexol injection as boundary blurring increased. METHODS: A 2D watershed algorithm was applied to CT arthrograms of 3 bovine stifle joints taken 3, 8, 18, and 33 minutes after iohexol injection and used to segment tibial cartilage. Thickness measurements were compared to a reference standard thickness measurement and the 3-minute time point scan. RESULTS: 77.2% of cartilage thickness measurements were within 0.2 mm (1 voxel) of the thickness calculated in the reference scan at the 3-minute time point. 42% fewer voxels could be segmented from the 33-minute scan than the 3-minute scan due to diffusion of the contrast agent out of the joint space and into the cartilage, leading to blurring of the cartilage boundary. The traced watershed lines were closer to the location of the cartilage surface in areas where tissues were in direct contact with each other (cartilage-cartilage or cartilage-meniscus contact). CONCLUSIONS: The use of watershed dam lines to guide cartilage segmentation shows promise for identifying cartilage boundaries from CT arthrograms in areas where soft tissues are in direct contact with each other.

Association between prior nephrectomy and efficacy of immune checkpoint inhibitor therapy in metastatic renal cell carcinoma - A systematic review and meta-analysis.

BACKGROUND: Immune checkpoint-inhibitor (ICI)-based therapy is the standard of care for first-line treatment of metastatic renal cell carcinoma (mRCC). It is unclear whether prior removal of the primary tumor influences the efficacy of these treatments. We performed a systematic review and meta-analysis of studies of first-line ICI in mRCC to determine whether the efficacy of ICI-therapy, compared to sunitinib, is altered based on receipt of prior nephrectomy. METHODS: We systematically reviewed studies indexed in MEDLINE (PubMed), Embase, and Scopus and conference abstracts from relevant medical societies as of August 2020 to identify randomized clinical trials assessing first-line immunotherapy-based regimes in mRCC. Studies were included if overall survival (OS) and progression-free survival (PFS) outcomes were reported with data stratified by nephrectomy status. We pooled hazard ratios (HRs) stratified by nephrectomy status and performed random effects meta-analysis to assess the null hypothesis of no difference in the survival advantage of immunotherapy-based regimes based on nephrectomy status, while accounting for study level correlations. RESULTS: Among 6 randomized clinical trials involving 5,121 patients, 3,968 (77%) had undergone prior nephrectomy. We found an overall survival benefit for immunotherapy-based regimes, compared to sunitinib, among both patients who had undergone nephrectomy (HR 0.75, 95% CI 0.63 -0.88) and those who had not (HR 0.74, 95% CI 0.59 -0.92), without evidence of difference based on nephrectomy history (P = 0.70; I2 = 36%). Results assessing PFS were similar (P = 0.45, I2 = 0%). CONCLUSIONS: These clinical data suggest that prior nephrectomy does not affect the efficacy of ICI-based regimens in mRCC relative to sunitinib.

Association Between Surgical Volume and Survival Among Patients With Variant Histologies of Bladder Cancer.

OBJECTIVE: To examine the relationship between hospital volume and the management of bladder cancer variant histology. Variant histologies of bladder cancer are rare which limits the ability for providers to develop expertise however there is a clear hospital and/or surgeon-volume relationship for management of rare or complex surgical and/or medical diseases. METHODS: We queried the National Cancer Database from 2004-2016 for all cases of bladder cancer, identifying cases of variant histology. Our primary outcome was overall survival while secondary outcomes included identifying treatment patterns. Hospitals were stratified into those that managed ≤2, >2-4, >4-6, and ≥6 cases per year of variant histology. RESULTS: We identified 23,284 patients with bladder cancer of variant histology who were treated at 1301 hospitals. Few institutions had high volume experience with this disease: 18.5% (n = 241) treated >2 patients annually and 5.7% (n = 76) treated >4 cases annually. Hospital volume positively correlated with utilization of early radical cystectomy (RC) in non-muscle invasive disease and neoadjuvant chemotherapy in muscle-invasive disease. On multivariable analysis, increased hospital volume was associated with improved survival. After stratifying by sub-type, hospital volume continued to be associated with improved survival for squamous, small cell, and sarcomatoid cancers. CONCLUSION: Management of variant histology urothelial carcinoma at high-volume centers is associated with improved overall survival. The mechanisms of this are multifactorial, and future research should focus on improvement opportunities for low-volume hospitals, centralization of care, and/or increased access to care at high-volume centers.

Assessment of gender representation in clinical trials leading to FDA approval for oncology therapeutics between 2014 and 2019: A systematic review-based cohort study.

BACKGROUND: Ensuring representative data accrual in clinical trials is important to safeguard the generalizability of results and to minimize disparities in care. This study's goal was to evaluate differences in gender representation in trials leading to US Food and Drug Administration (FDA) cancer drug approvals. METHODS: An observational study was conducted from January 2014 to April 2019 using PubMed and the National Institutes of Health trials registry for primary trial reports. The National Cancer Institute's Surveillance, Epidemiology, and End Results program and US Census were consulted for national cancer incidence. The outcome was an enrollment incidence disparity (EID), which was calculated as the difference between male and female trial enrollment and national incidence, with positive values representing male overrepresentation. RESULTS: There were 149 clinical trials with 59,988 participants-60.3% and 39.7% were male and female, respectively-leading to 127 oncology drug approvals. The US incidence rates were 55.4% for men versus 44.6% for women. Gender representation varied by specific tumor type. Most notably, women were underrepresented in thyroid cancer (EID, +27.4%), whereas men were underrepresented in soft tissue cancer (EID, -26.1%). Overall, women were underrepresented when compared with expected incidence (EID, +4.9%; 42% of trials). CONCLUSIONS: For many specific tumor types, women are underrepresented in clinical trials leading to FDA oncology drug approvals. It is critical to better align clinical trial cohort demographics and the populations to which these data will be extrapolated. LAY SUMMARY: This study assesses whether gender disparities exist in clinical trials leading to US Food and Drug Administration (FDA) cancer drug approvals. From January 2014 to April 2019, 149 clinical trials leading to FDA oncology drug approvals showed 60.3% and 39.7% of the enrollees were male and female, respectively. Gender representation varied by specific tumor when compared with the expected incidence rate of cancer in the United States, although women were more often underrepresented. Increased efforts are needed with regard to ensuring equitable representation in oncology clinical trials.

Association between cytoreductive nephrectomy and survival among patients with metastatic renal cell carcinoma receiving modern therapies: a systematic review and meta-analysis examining effect modification according to systemic therapy approach.

PURPOSE: Cytoreductive nephrectomy (CN) has played a role in treatment of metastatic renal cell carcinoma (mRCC) since trials demonstrated a survival benefit in patients receiving CN with interferon. With the publication of CARMENA, it became clear that the value of CN may depend on the co-therapy administered. We sought to assess the benefit of CN in the era of modern immunotherapy (IO). METHODS: We performed a systematic review to identify studies assessing CN in patients receiving TT or IO. We extracted multivariable-adjusted hazard ratios for the association between CN and overall survival (OS) and performed random effects meta-analysis. We tested for effect modification by systemic therapy approach on the association between CN and OS by pooling the difference in logHR associated with CN for patients treated with TT versus IO. RESULTS: We identified three comparisons assessing CN in patients receiving TT or IO. Pooled analysis indicated improved survival with CN in both the TT (2 cohorts, pooled HR: 0.52, 95% CI 0.46-0.59; I2 = 80%) and IO era (2 cohorts; pooled HR: 0.28, 95% CI 0.16-0.49; I2 = 21%), with a stronger association in the IO era (p = 0.01; I2 = 0%). CONCLUSION: In observational datasets, we observed a larger survival benefit to CN in patients treated with IO-based regimens versus those treated with TT-based regimens. While the role of CN for patients receiving TT has recently been questioned, this suggests that the results of CARMENA do not necessarily preclude a benefit to CN when combined with IO-based regimens.

Women as Authors of Randomized Controlled Trials of Minimally Invasive Surgery: Systematic Review and Meta-Analysis of 3 Decades of Trials.

BACKGROUND: Female authorship opportunities have lagged behind those of their male counterparts, with gender disparities most prominent in surgical specialties. Our objective was to determine trends of female first, last, and first or last authorships across time and surgical specialties and whether female first or last authorship was associated with journal impact factor. STUDY DESIGN: A systematic review of EMBASE (OvidSP), MEDLINE (OvidSP), and Cochrane (Wiley) databases from inception to December 22, 2017 was performed to identify all randomized controlled trials evaluating minimally invasive surgery vs classical surgical techniques. The primary end point was female first, last, and first or last authorship, with gender determined via an online search strategy and verified via Genderize.io. Secondary end point was journal impact factor, recorded from Clarivate Analytics InCites. RESULTS: There were 9,321 articles identified and 489 met our inclusion/exclusion criteria. Sixty-eight (13.9%) first and 60 (12.3%) last female authors were identified. A positive linear trend for female first (R2 = 0.35, Cochran-Armitage test for trend, p < 0.001), last (R2 = 0.30, p < 0.001), and first or last authorships (R2 = 0.40, p < 0.001) over time was identified. This trend was observed across surgical specialties except for orthopaedics. The highest calculated percentages of female first, last, and first or last authorships by the year 2017 were seen in obstetrics and gynecology (33.8%, 32.0%, and 43.8%, respectively), all significantly lower than the corresponding percentage of the female obstetrics and gynecology workforce in 2017 (57.0%). Neither female first nor last authorship positions were associated with journal impact factor. CONCLUSIONS: A significant increase in female first and last authorship in randomized controlled trials of minimally invasive surgical techniques in the last 3 decades has been observed, but continued efforts to bridge this gender gap are sorely needed.

Metastatic Hormone-sensitive Prostate Cancer: Current Perspective on the Evolving Therapeutic Landscape.

INTRODUCTION: The treatment landscape for patients with metastatic hormone-sensitive prostate cancer (mHSPC) has changed dramatically in the past five years, despite little change in the preceding 20 years. Such rapid change can make it difficult for clinicians to remain abreast of the current literature and synthesize the relevant data to inform evidence-based treatment decisions. METHODOLOGY: We performed a narrative, comprehensive review of treatment options for patients with mHSPC as of December 31, 2019. Specifically, we focused on phase II and III randomized controlled trials assessing the role of chemotherapy, novel androgen axis targeting agents, local-(prostate) directed therapy, and metastasis-directed therapy. RESULTS: The data support a survival benefit with the addition of four different agents to androgen deprivation among men with newly diagnosed prostate cancer-docetaxel, abiraterone acetate, enzalutamide, and apalutamide. While not directly compared, the efficacy of these agents appears similar. That said, there are differences in their toxicity profiles and notable differences in cost between agents. Although analyses encompassing men with low- and high-volume metastases failed to demonstrate a significant survival benefit for radiotherapy treatment to the prostate, new data demonstrates a benefit for men with low-volume metastatic disease. Ongoing trials will assess whether this applies to local surgical treatment. Similarly, metastasis-directed therapy appears beneficial among carefully selected patients. CONCLUSION: Treatment options for patients with mHSPC are rapidly changing following years of stagnation. A number of systemic therapies offer benefit without significant clinical differences between them. The role for local treatment of the prostate as well as metastatic sites continues to evolve.

A Holistic Approach to Chronic Disease Prevention: Good Health and Wellness in Indian Country.

The National Center for Chronic Disease Prevention and Health Promotion at the Centers for Disease Control and Prevention funds the agency's largest investment in Indian Country, Good Health and Wellness in Indian Country. This 5-year program, launched in 2014, supports American Indian and Alaska Native communities and tribal organizations to address chronic diseases and risk factors simultaneously and in coordination. This article describes the development, funding, and implementation of the program. Dialogue with tribal members and leaders helped shape the program, and unlike previous programs that funded a small number of tribes to work on specific diseases, this program funds multiple tribal entities to reach widely into Indian Country. Implementation included culturally developed and adapted practices and opportunities for peer sharing and problem solving. This program identified approaches useful for the Centers for Disease Control and Prevention, other federal agencies, or other organizations working with American Indians and Alaska Natives.

Results of surgical excision of urethral prolapse in symptomatic patients.

AIM: Here, we present the clinical presentation and surgical outcomes of women with symptomatic urethral prolapse presenting to our institution over 20 years, and seek to provide treatment recommendations for management of symptomatic urethral prolapse and caruncle. METHODS: A retrospective review of medical records from female patients who underwent surgery for symptomatic urethral prolapse from June 1995 to August 2015 was performed. Surgical technique consisted of a four-quadrant excisional approach for repair of urethral prolapse. RESULTS: A total of 26 patients were identified with a mean age of 38.8 years (range 3-81). The most common presentations were vaginal bleeding, hematuria, pain, and dysuria. All patients underwent surgical excision of urethral prolapse via a standard approach. Follow-up data was available in 24 patients. Six patients experienced temporary postoperative bleeding, and one patient required placement of a Foley catheter for tamponade. One patient experienced temporary postoperative urinary retention requiring Foley catheter placement. Three patients had visible recurrence of urethral prolapse, for which one later underwent re-excision. CONCLUSION: Surgical excision of urethral prolapse is a reasonable treatment option in patients who have tried conservative management without relief, as well as in those who present with severe symptoms. Possible complications following excision include postoperative bleeding and recurrence, and patients must be counseled accordingly. In this work, we propose a treatment algorithm for symptomatic urethral prolapse.

Operative risks associated with contralateral prophylactic mastectomy: a single institution experience.

BACKGROUND: The purpose of this study was to determine if newly diagnosed breast cancer patients undergoing contralateral prophylactic mastectomy (CPM) experience more complications than patients undergoing unilateral mastectomy (UM). METHODS: A total of 600 patients underwent either UM or CPM between January 2009 and March 2012 for unilateral breast cancer. Operative complications were classified as minor (aspirations, infection requiring antibiotics, partial flap and nipple necrosis, minor bleeding, delayed wound healing) or major (hematoma or seroma requiring operation, infection requiring rehospitalization, blood product transfusion, total flap or nipple loss, implant removal), mixed (both minor and major complications), or multiple. Chi-square and multivariate logistic regressions were used for the analysis. RESULTS: Of the 600 patients, 391 (65 %) underwent UM and 209 (35 %) underwent CPM. Across all complication groups, there were significantly more complications in the CPM group versus the UM group (41.6 vs. 28.6 %, p = 0.001). Major complications alone were significantly greater in the CPM versus the UM group (13.9 vs. 4.1 %, p < 0.001). When adjusting for age, body mass index, smoking and diabetes history, AJCC stage, reconstruction, previous radiation therapy, and adjuvant therapy, CPM patients were 1.5 times more likely to have any complication (odds ratio [OR] 1.53; 95 % CI 1.04-2.25, p = 0.029) and 2.7 times more likely to have a major complication compared with UM patients (OR 2.66; 95 % CI 1.37-5.19, p = 0.004). CONCLUSIONS: CPM patients have an increased risk of complications, especially major complications requiring rehospitalization or reoperation. These complications may influence patient and physician decisions to choose CPM.