Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer.

Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.

Pembrolizumab and Enzalutamide in Patients with Abiraterone Acetate-Pretreated Metastatic Castration-Resistant Prostate Cancer: Cohort C of the Phase 1b/2 KEYNOTE-365 Study.

BACKGROUND: Limited responses have been observed in patients treated with enzalutamide after disease progression on abiraterone for metastatic castration-resistant prostate cancer (mCRPC), but androgen receptor signaling impacts T-cell function. OBJECTIVE: To evaluate the efficacy and safety of pembrolizumab plus enzalutamide in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Patients in cohort C of the phase 1b/2 KEYNOTE-365 study, who received ≥4 wk of treatment with abiraterone acetate in the prechemotherapy mCRPC state and experienced treatment failure or became drug-intolerant, were included. INTERVENTION: Pembrolizumab 200 mg intravenously every 3 wk plus enzalutamide 160 mg orally once daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoints were safety, the confirmed prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 on blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) on BICR and overall survival (OS). RESULTS AND LIMITATIONS: A total of 102 patients received pembrolizumab plus enzalutamide. Median follow-up was 51 mo (interquartile range 37-56). The confirmed PSA response rate was 24% (95% confidence interval [CI] 16-33%). The confirmed ORR was 11% (95% CI 2.9-25%; 4/38 patients; two complete responses). Median rPFS was 6.0 mo (95% CI 4.1-6.3). Median OS was 20 mo (95% CI 17-24). Treatment-related adverse events (TRAEs) occurred in 94 patients (92%); grade 3-5 TRAEs occurred in 44 patients (43%). The incidence of treatment-related rash was higher with combination therapy than expected from the safety profile of each drug. One patient (1.0%) died of a TRAE (cause unknown). Study limitations include the single-arm design. CONCLUSIONS: Pembrolizumab plus enzalutamide had limited antitumor activity in patients who received prior abiraterone treatment without previous chemotherapy for mCRPC, with a safety profile consistent with the individual profiles of each agent. PATIENT SUMMARY: Pembrolizumab plus enzalutamide showed limited antitumor activity and manageable safety in patients with metastatic castration-resistant prostate cancer. The KEYNOTE-365 trial is registered on ClinicalTrials.gov as NCT02861573.

Pembrolizumab Plus Docetaxel and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort B Study.

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) frequently receive docetaxel after they develop resistance to abiraterone or enzalutamide and need more efficacious treatments. OBJECTIVE: To evaluate the efficacy and safety of pembrolizumab plus docetaxel and prednisone in patients with mCRPC. DESIGN, SETTING, AND PARTICIPANTS: The trial included patients with mCRPC in the phase 1b/2 KEYNOTE-365 cohort B study who were chemotherapy naïve and who experienced failure of or were intolerant to ≥4 wk of abiraterone or enzalutamide for mCRPC with progressive disease within 6 mo of screening. INTERVENTION: Pembrolizumab 200 mg intravenously (IV) every 3 wk (Q3W), docetaxel 75 mg/m2 IV Q3W, and prednisone 5 mg orally twice daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoints were safety, the prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included time to PSA progression; the disease control rate (DCR) and duration of response (DOR) according to RECIST v1.1 by BICR; ORR, DCR, DOR, and radiographic progression-free survival (rPFS) according to Prostate Cancer Working Group 3-modified RECIST v1.1 by BICR; and overall survival (OS). RESULTS AND LIMITATIONS: Among 104 treated patients, 52 had measurable disease. The median time from allocation to data cutoff (July 9, 2020) was 32.4 mo, during which 101 patients discontinued treatment, 81 (78%) for disease progression. The confirmed PSA response rate was 34% and the confirmed ORR (RECIST v1.1) was 23%. Median rPFS and OS were 8.5 mo and 20.2 mo, respectively. Treatment-related adverse events (TRAEs) occurred in 100 patients (96%). Grade 3-5 TRAEs occurred in 46 patients (44%). Seven AE-related deaths (6.7%) occurred (2 due to treatment-related pneumonitis). Limitations of the study include the single-arm design and small sample size. CONCLUSIONS: Pembrolizumab plus docetaxel and prednisone demonstrated antitumor activity in chemotherapy-naïve patients with mCRPC treated with abiraterone or enzalutamide for mCRPC. Safety was consistent with profiles for the individual agents. Further investigation is warranted. PATIENT SUMMARY: We evaluated the efficacy and safety of the anti-PD-1 antibody pembrolizumab combined with the chemotherapy drug docetaxel and the steroid prednisone for patients with metastatic prostate cancer resistant to androgen deprivation therapy , and who never received chemotherapy. The combination showed antitumor activity and manageable safety in this patient population. This trial is registered on ClinicalTrials.gov as NCT02861573.

Examining health care champions: a mixed-methods study exploring self and peer perspectives of champions.

Background: Champions are widely recognized as playing a key role in the successful implementation of evidence-based interventions within the health care sector; however, little is known about which characteristics and skills enable them to play that role. Furthermore, previous studies have measured only individual champions' responses to personal attributes without incorporating input from other observers. A mixed-methods study was conducted to identify, analyze, and group the behaviors and characteristics of champions who have successfully promoted the adoption of new initiatives within the health care delivery system, taking into consideration self and peer perspectives. Methods: Using a mixed-methods, cross-sectional triangulation design with a convergence model, quantitative data were collected and analyzed from health care champions (n = 30) and their colleagues (n = 58) from 11 countries using a survey. Every champion and a subset of colleagues (n = 14) also participated in in-depth interviews. Descriptive statistics were used to explore the relationship between champion and colleague responses to survey items; chi-squared tests and Kruskal-Wallis tests were used to compare the differences. Thematic content analysis of qualitative data was used to explore champion-like behaviors and features. Characteristics of champions were categorized using the Transformational Leadership Theory framework. Results: Champions exhibited characteristics that facilitated trust and encouraged motivation among their colleagues to adopt innovations, such as being intrinsically motivated, persistent, enthusiastic, and highly effective communicators. Champions were described by their colleagues as empathetic, curious, physically present, approachable, and often soliciting feedback from others. Although there was a high degree of agreement between champion and colleague survey responses, champions were more likely to underrate their skills and abilities to instigate change compared to their colleagues. Conclusion: Both champions and colleagues described key champion-like characteristics, but champions often downplayed the characteristics and behaviors that make champions uniquely effective at facilitating the adoption of evidence-based interventions. Plan language abstract: Health care champions are people who promote the adoption of new initiatives to improve the quality of patient care among their colleagues within health care settings. Champions are often viewed by organizational leaders and researchers as critical for the successful implementation of new ideas; however, little is known about what specific skills or characteristics make them effective at promoting the adoption of new ideas among their colleagues. Most studies on champions' behaviors have only included the perspectives of champions, and not perspectives from others within the organization. The goal of our study was to not only explore champions' perspectives of themselves, but also the views of champions' colleagues to understand why and how champions motivated and influenced their colleagues to try new things. Findings from this study could lead to more accurate identification of health care champions, which in turn could lead to more efficient and effective adoption of new initiatives to improve the quality of patient care.

Circulating Tumor Cell Chromosomal Instability and Neuroendocrine Phenotype by Immunomorphology and Poor Outcomes in Men with mCRPC Treated with Abiraterone or Enzalutamide.

PURPOSE: While the detection of AR-V7 in circulating tumor cells (CTC) is associated with resistance to abiraterone or enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC), it only accounts for a minority of this resistance. Neuroendocrine (NE) differentiation or chromosomal instability (CIN) may be additional mechanisms that mediate resistance. EXPERIMENTAL DESIGN: PROPHECY was a multicenter prospective study of men with high-risk mCRPC starting abiraterone or enzalutamide. A secondary objective was to assess Epic CTC CIN and NE phenotypes before abiraterone or enzalutamide and at progression. The proportional hazards (PH) model was used to investigate the prognostic importance of CIN and NE in predicting progression-free survival and overall survival (OS) adjusting for CTC number (CellSearch), AR-V7, prior therapy, and clinical risk score. The PH model was utilized to validate this association of NE with OS in an external dataset of patients treated similarly at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY). RESULTS: We enrolled 118 men with mCRPC starting on abiraterone or enzalutamide; 107 were evaluable on the Epic platform. Of these, 36.4% and 8.4% were CIN positive and NE positive, respectively. CIN and NE were independently associated with worse OS [HR, 2.2; 95% confidence interval (CI), 1.2-4.0 and HR 3.8; 95% CI, 1.2-12.3, respectively] when treated with abiraterone/enzalutamide. The prognostic significance of NE positivity for worse OS was confirmed in the MSKCC dataset (n = 173; HR, 5.7; 95% CI, 2.6-12.7). CONCLUSIONS: A high CIN and NE CTC phenotype is independently associated with worse survival in men with mCRPC treated with abiraterone/enzalutamide, warranting further prospective controlled predictive studies to inform treatment decisions.

Combination of Radiation Therapy and Short-Term Androgen Blockade With Abiraterone Acetate Plus Prednisone for Men With High- and Intermediate-Risk Localized Prostate Cancer.

PURPOSE: Long-term androgen-deprivation therapy (ADT) is the standard of care in combination with radiation therapy (RT) in high-risk prostate cancer (PC), despite substantial toxicity from the resulting hypogonadism. We hypothesized that a combination of more potent but shorter-term androgen inhibition in men with intermediate- or high-risk localized PC would synergize with definitive RT to provide short-term testosterone recovery and improve disease control. METHODS AND MATERIALS: This prospective phase 2 single-arm trial enrolled men with low-volume unfavorable intermediate or high-risk localized PC. Treatment included 6 months of ADT concurrent with abiraterone acetate plus prednisone (AAP) once daily and RT to prostate and seminal vesicles. The primary endpoint was the proportion of men with an undetectable prostate-specific antigen (PSA) at 12-months; secondary objectives included biochemical progression-free survival (PFS), testosterone recovery, toxicity, and sexual and hormonal quality of life. RESULTS: We enrolled 37 men between January 2014 and August 2016, 45% of whom were high risk. All patients had T1-2 disease and PSA < 20 ng/mL. Median follow-up is 37 months (95% confidence interval [CI], 35.7-39.1). Treatment noted 32% grade 3 toxicities related to AAP, predominantly hypertension, with no toxicities ≥G4. The rate of undetectable PSA at 12 months was 55% (95% CI, 36%-72%). With 46 months of median follow-up, 2 of 37 patients developed PSA progression (36-month PFS = 96%; 95% CI, 76%-99%), and 81% of patients recovered testosterone with a median time to recovery of 9.2 months. Hormonal or sexual function declined at 6 months with subsequent improvement by 24 months. CONCLUSIONS: The combination of RT and 6 months of ADT and AAP demonstrated acceptable toxicity and a high rate of testosterone recovery with restoration of quality of life and excellent disease control in men with low-volume, intermediate- or high-risk localized prostate cancer. Prospective comparative studies are justified.

Prospective Multicenter Study of Circulating Tumor Cell AR-V7 and Taxane Versus Hormonal Treatment Outcomes in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Androgen receptor splice variant 7 (AR-V7) detection in circulating tumor cells (CTCs) is associated with a low probability of response and short progression-free (PFS) and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide or abiraterone. However, it is unclear whether such men benefit from taxane chemotherapy. PATIENTS AND METHODS: PROPHECY is a multicenter prospective blinded study of patients with poor-risk mCRPC starting abiraterone or enzalutamide and observed through subsequent progression and taxane chemotherapy. We assessed AR-V7 status using the Johns Hopkins modified AdnaTest CTC AR-V7 messenger RNA assay and the Epic Sciences CTC nuclear-localized AR-V7 protein assay before treatment. The primary objective was to validate the independent prognostic value of CTC AR-V7 status based on radiographic/clinical PFS. OS, confirmed prostate-specific antigen (PSA), and objective radiologic responses were secondary end points. RESULTS: We enrolled 118 men with mCRPC treated with abiraterone or enzalutamide, 51 of whom received subsequent docetaxel or cabazitaxel. Pretreatment CTC AR-V7 status by the Johns Hopkins and Epic Sciences assays was independently associated with worse PFS (hazard ratio [HR], 1.7; 95% CI, 1.0 to 2.9 and HR, 2.1; 95% CI, 1.0 to 4.4, respectively) and OS (HR, 3.3; 95% CI, 1.7 to 6.3 and HR, 3.0; 95% CI, 1.4 to 6.3, respectively) and a low probability of confirmed PSA responses, ranging from 0% to 11%, during treatment with abiraterone or enzalutamide. At progression, subsequent CTC AR-V7 detection was not associated with an inferior PSA or radiographic response or worse PFS or OS with subsequent taxane chemotherapy after adjusting for CellSearch CTC enumeration and clinical prognostic factors. CONCLUSION: Detection of AR-V7 in CTCs by two different blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, but such men with AR-V7-positive disease still experience clinical benefits from taxane chemotherapy.

DCLK1-Isoform2 Alternative Splice Variant Promotes Pancreatic Tumor Immunosuppressive M2-Macrophage Polarization.

Tumor-associated M2-macrophages are one of the most abundant immunosuppressive cell types in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). However, the molecular mechanisms responsible for the generation of M2-macrophages are unclear. Here, we demonstrated that overexpression of DCLK1-isoform2 in AsPC1 and MIA PaCa2 cells resulted in the polarization of M1-macrophages toward an M2 phenotype via secreted chemokines/cytokines. These M2-macrophages enhanced parental PDAC cell migration, invasion, and self-renewal, and this was associated with increased expression of Snail and Slug. We observed distinct expression of Dclk-isoform2, marked infiltration of M2-macrophages, and a marginal increase of CD8+ T cells in 20-week-old KPCY mice pancreas compared with 5 weeks old. Utilizing an autochthonous mouse model of pancreatic adenocarcinoma, we observed distinct immunoreactive Dclk1 and arginase1 in tissues where CD8+ T-cell infiltration was low and observed a paucity of DCLK1 and arginase1 staining where CD8+ T-cell infiltration was high. Finally, we found that DCLK1-isoform2 tumor-educated M2-macrophages inhibit CD8+ T-cell proliferation and granzyme-B activation. Inhibition of DCLK1 in an organoid coculture system enhanced CD8+ T-cell activation and associated organoid death. We conclude that DCLK1-isoform2 is a novel initiator of alternate macrophage activation that contributes to the immunosuppression observed in the PDAC TME. These data suggest that tumor DCLK1-isoform2 may be an attractive target for PDAC therapy, either alone or in conjunction with immunotherapeutic strategies.

Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer.

BACKGROUND: Pembrolizumab is approved for patients with metastatic, microsatellite instability (MSI)-high or mismatch repair-deficient (dMMR) solid tumors. However, very few men with prostate cancer were included in these initial studies. METHODS: We performed a single institution retrospective review of men with metastatic castrate-resistant prostate cancer (mCRPC) who were treated with pembrolizumab. The primary objective was to describe the clinical efficacy of pembrolizumab associated with patient and genomic characteristics. RESULTS: We identified 48 men who received ≥1 cycle of pembrolizumab for mCRPC. Of these, 94% (45/48) had ≥3 prior lines of therapy for mCRPC. Somatic tumor sequencing was available in 18/48 men (38%). We found that 17% (8/48) had a ≥50% confirmed PSA decline with pembrolizumab, and 8% (4/48) had a ≥90% PSA decline with durations of response ranging from 3.1 to 16.3 months. Two of these four men had mutations in LRP1b, one of whom also had MSH2 loss and was MSI-H and TMB-high. Despite prior progression on enzalutamide, 48% (23/48) of men were treated with concurrent enzalutamide. The median PSA progression-free-survival was 1.8 months (range 0.4-13.7 months), with 31% of patients remaining on pembrolizumab therapy and 54% of men remain alive with a median follow-up of 7.1 months. CONCLUSIONS: In a heavily pretreated population of men with mCRPC, pembrolizumab was associated with a ≥50% PSA decline in 17% (8/48) of men, including a dramatic ≥90% PSA response in 8% (4/48), two of whom harbored pathogenic LRP1b mutations suggesting that LRP1b mutations may enrich for PD-1 inhibitor responsiveness in prostate cancer.

Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study.

PURPOSE: Androgen receptor splice variant 7 (AR-V7) results in a truncated receptor, which leads to ligand-independent constitutive activation that is not inhibited by anti-androgen therapies, including abiraterone or enzalutamide. Given that previous reports suggested that circulating tumor cell (CTC) AR-V7 detection is a poor prognostic indicator for the clinical efficacy of secondary hormone therapies, we conducted a prospective multicenter validation study. PATIENTS AND METHODS: PROPHECY ( ClinicalTrials.gov identifier: NCT02269982) is a multicenter, prospective-blinded study of men with high-risk mCRPC starting abiraterone acetate or enzalutamide treatment. The primary objective was to validate the prognostic significance of baseline CTC AR-V7 on the basis of radiographic or clinical progression free-survival (PFS) by using the Johns Hopkins University modified-AdnaTest CTC AR-V7 mRNA assay and the Epic Sciences CTC nuclear-specific AR-V7 protein assay. Overall survival (OS) and prostate-specific antigen responses were secondary end points. RESULTS: We enrolled 118 men with mCRPC who were starting abiraterone or enzalutamide treatment. AR-V7 detection by both the Johns Hopkins and Epic AR-V7 assays was independently associated with shorter PFS (hazard ratio, 1.9 [95% CI, 1.1 to 3.3; P = .032] and 2.4 [95% CI, 1.1 to 5.1; P = .020], respectively) and OS (hazard ratio, 4.2 [95% CI, 2.1 to 8.5] and 3.5 [95% CI, 1.6 to 8.1], respectively) after adjusting for CTC number and clinical prognostic factors. Men with AR-V7-positive mCRPC had fewer confirmed prostate-specific antigen responses (0% to 11%) or soft tissue responses (0% to 6%). The observed percentage agreement between the two AR-V7 assays was 82%. CONCLUSION: Detection of AR-V7 in CTCs by two blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, and such men with mCRPC should be offered alternative treatments.

Phase 1 study of PSMA ADC, an antibody-drug conjugate targeting prostate-specific membrane antigen, in chemotherapy-refractory prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-characterized target that is overexpressed selectively on prostate cancer cells. PSMA antibody-drug conjugate (ADC) is a fully human IgG1 monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), which is designed to specifically bind PSMA-positive cells, internalize, and then release its cytotoxic payload into the cells. PSMA ADC has demonstrated potent and selective antitumor activity in preclinical models of advanced prostate cancer. A Phase 1 study was conducted to assess the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment-refractory prostate cancer. METHODS: In this first-in-man dose-escalation study, PSMA ADC was administered by intravenous infusion every three weeks to subjects with progressive metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with docetaxel chemotherapy. The primary endpoint was to establish a maximum tolerated dose (MTD). The study also examined the pharmacokinetics of the study drug, total antibody, and free MMAE. Antitumor effects were assessed by measuring changes in serum prostate-specific antigen (PSA), circulating tumor cells (CTCs), and radiologic imaging. RESULTS: Fifty-two subjects were administered doses ranging from 0.4 to 2.8 mg/kg. Subjects had a median of two prior chemotherapy regimens and prior treatment with abiraterone and/or enzalutamide. Neutropenia and peripheral neuropathy were identified as important first-cycle and late dose-limiting toxicities, respectively. The dose of 2.5 mg/kg was determined to be the MTD. Pharmacokinetics were approximately dose-proportional with minimal drug accumulation. Reductions in PSA and CTCs in subjects treated with doses of ≥1.8 mg/kg were durable and often concurrent. CONCLUSIONS: In an extensively pretreated mCRPC population, PSMA ADC demonstrated acceptable toxicity. Antitumor activity was observed over dose ranges up to and including 2.5 mg/kg. The observed anti-tumor activity supported further evaluation of this novel agent for the treatment of advanced metastatic prostate cancer.

Quality Improvement in Ambulatory Surgery Centers: A Major National Effort Aimed at Reducing Infections and Other Surgical Complications.

BACKGROUND: Surgical volume has shifted significantly from inpatient to outpatient settings, including free-standing ambulatory surgery centers (ASCs). Approaches to quality improvement (QI) and surveillance used in hospitals are not always appropriate to the ambulatory setting. METHODS: We recruited 665 ASCs in 47 US states to participate in an intervention to improve safe practice through implementation of a surgical safety checklist and infection control practices. Areas for partner contribution included recruitment, project development, content development and delivery, clinical subject matter expertise, data analysis, and facility coaching. RESULTS: Barriers to implementation and data collection were encountered during the project, requiring revisions to the implementation plan. Project activities, such as facility recruitment, data measurement, and implementation strategies were modified to meet ASC-specific needs. Several ASC-specific tools were designed. CONCLUSIONS: The increasing number of patients being cared for in ASCs makes it essential to better understand how to implement quality improvement projects in that environment. Tailoring interventions to the ASC's unique needs is necessary.

Multisource Evaluation of Surgeon Behavior Is Associated With Malpractice Claims.

OBJECTIVE: We merged direct, multisource, and systematic assessments of surgeon behavior with malpractice claims, to analyze the relationship between surgeon 360-degree reviews and malpractice history. BACKGROUND: Previous work suggests that malpractice claims are associated with a poor physician-patient relationship, which is likely related to behaviors captured by 360-degree review. We hypothesize that 360-degree review results are associated with malpractice claims. METHODS: Surgeons from 4 academic medical centers covered by a common malpractice carrier underwent 360-degree review in 2012 to 2013 (n = 385). Matched, de-identified reviews and malpractice claims data were available for 264 surgeons from 2000 to 2015. We analyzed 23 questions, highlighting positive and negative behaviors within the domains of education, excellence, humility, openness, respect, service, and teamwork. Regression analysis with robust standard error was used to assess the potential association between 360-degree review results and malpractice claims. RESULTS: The range of claims among the 264 surgeons was 0 to 8, with 48.1% of surgeons having at least 1 claim. Multiple positive and negative behaviors were significantly associated with the risk of having malpractice claims (P < 0.05). Surgeons in the bottom decile for several items had an increased likelihood of having at least 1 claim. CONCLUSION: Surgeon behavior, as assessed by 360-degree review, is associated with malpractice claims. These findings highlight the importance of teamwork and communication in exposure to malpractice. Although the nature of malpractice claims is complex and multifactorial, the identification and modification of negative physician behaviors may mitigate malpractice risk and ultimately result in the improved quality of patient care.

Scaling Safety: The South Carolina Surgical Safety Checklist Experience.

Proven patient safety solutions such as the World Health Organization's Surgical Safety Checklist are challenging to implement at scale. A voluntary initiative was launched in South Carolina hospitals in 2010 to encourage use of the checklist in all operating rooms. Hospitals that reported completing implementation of the checklist in their operating rooms by 2017 had significantly higher levels of CEO and physician participation and engaged more in higher-touch activities such as in-person meetings and teamwork skills trainings than comparison hospitals did. Based on our experience and the participation data collected, we suggest three considerations for hospital, hospital association, state, and national policy makers: Successful programs must be designed to engage all stakeholders (CEOs, physicians, nurses, surgical technologists, and others); offering a variety of program activities-both lower-touch and higher-touch-over the duration of the program allows more hospital and individual participation; and change takes time and resources.

Phase I Study of Seviteronel, a Selective CYP17 Lyase and Androgen Receptor Inhibitor, in Men with Castration-Resistant Prostate Cancer.

Purpose: Seviteronel (INO-464) is a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor (AR) inhibitor with antitumor activity in vitro and in vivo This open-label phase I clinical study evaluated the safety, tolerability, pharmacokinetics and activity of once-daily seviteronel in male chemotherapy-naïve subjects with castration-resistant prostate cancer (CRPC).Patients and Methods: Seviteronel was administered at 600 mg once daily with dose titration (DT) and in modified 3 + 3 dose escalation once-daily cohorts at 600, 750, and 900 mg without DT. The primary objectives of this study were to establish safety, tolerability, and the MTD of seviteronel in chemotherapy-naïve subjects with or without prior treatment with FDA-approved CRPC treatments, abiraterone acetate (AA), and enzalutamide. Secondary objectives were to assess pharmacokinetics, PSA, tumor response, and endocrine results.Results: Twenty-one subjects were enrolled. No dose-limiting toxicities (DLT) were observed through 750 mg once daily. Most treatment-emergent adverse events (AE) reported at grade 1-2. The most commonly reported AEs were fatigue (71%), dizziness (52%), blurred vision (38%), and dysgeusia (33%), with most AEs improving after dose reduction or dose interruption.Conclusions: Once-daily seviteronel was generally well tolerated in this phase I study of men with CRPC, a majority of which had progressed on prior AA or enzalutamide, or both. Of the doses evaluated, 600 mg once daily was chosen as the recommended phase II dose for future studies in subjects with CRPC. Clin Cancer Res; 24(21); 5225-32. ©2018 AACR.

An evidence-based intraoperative communication tool for emergency general surgery: a pilot study.

BACKGROUND: Emergency general surgery (EGS) is characterized by high rates of morbidity and mortality. Though checklists and associated communication-based huddle strategies have improved outcomes, these tools have never been specifically examined in EGS. We hypothesized that use of an evidence-based communication tool aimed to trigger intraoperative discussion could improve communication in the EGS operating room (OR). MATERIALS AND METHODS: We designed a set of discussion prompts based on modifiable factors identified from previously published studies aimed to encourage all team members to speak up and to centralize awareness of patient disposition and intraoperative transfusion practices. This tool was pilot-tested using OR human patient simulators and was then rolled out to EGS ORs at an academic medical center. The perceived effect of our tool's implementation was evaluated through mixed-methodologic presurvey and postsurvey analysis. RESULTS: Preimplementation and postimplementation survey-based data revealed that providers reported the EGS-focused discussion prompts as improving team communication in EGS. A trend toward shared awareness of intraoperative events was observed; however, nurses described cultural impedance of discussion initiation. Providers described a need for further reinforcement of the tool and its indications during implementation. CONCLUSIONS: Use of a discussion-based communication tool is perceived as supporting team communication in the EGS OR and led to a trend toward improving a shared understanding of intraoperative events. Analyses suggest the need for enhanced reinforcement of use during implementation and improvement of team-based education regarding EGS. Furthermore work is needed to understand the full impact of this evidence-based tool on OR team dynamics and EGS patient outcomes.

Factors associated with the use of cognitive aids in operating room crises: a cross-sectional study of US hospitals and ambulatory surgical centers.

BACKGROUND: Operating room (OR) crises are high-acuity events requiring rapid, coordinated management. Medical judgment and decision-making can be compromised in stressful situations, and clinicians may not experience a crisis for many years. A cognitive aid (e.g., checklist) for the most common types of crises in the OR may improve management during unexpected and rare events. While implementation strategies for innovations such as cognitive aids for routine use are becoming better understood, cognitive aids that are rarely used are not yet well understood. We examined organizational context and implementation process factors influencing the use of cognitive aids for OR crises. METHODS: We conducted a cross-sectional study using a Web-based survey of individuals who had downloaded OR cognitive aids from the websites of Ariadne Labs or Stanford University between January 2013 and January 2016. In this paper, we report on the experience of 368 respondents from US hospitals and ambulatory surgical centers. We analyzed the relationship of more successful implementation (measured as reported regular cognitive aid use during applicable clinical events) with organizational context and with participation in a multi-step implementation process. We used multivariable logistic regression to identify significant predictors of reported, regular OR cognitive aid use during OR crises. RESULTS: In the multivariable logistic regression, small facility size was associated with a fourfold increase in the odds of a facility reporting more successful implementation (p = 0.0092). Completing more implementation steps was also significantly associated with more successful implementation; each implementation step completed was associated with just over 50% higher odds of more successful implementation (p ≤ 0.0001). More successful implementation was associated with leadership support (p < 0.0001) and dedicated time to train staff (p = 0.0189). Less successful implementation was associated with resistance among clinical providers to using cognitive aids (p < 0.0001), absence of an implementation champion (p = 0.0126), and unsatisfactory content or design of the cognitive aid (p = 0.0112). CONCLUSIONS: Successful implementation of cognitive aids in ORs was associated with a supportive organizational context and following a multi-step implementation process. Building strong organizational support and following a well-planned multi-step implementation process will likely increase the use of OR cognitive aids during intraoperative crises, which may improve patient outcomes.

Developing Process Maps as a Tool for a Surgical Infection Prevention Quality Improvement Initiative in Resource-Constrained Settings.

BACKGROUND: Surgical infections cause substantial morbidity and mortality in low-and middle-income countries (LMICs). To improve adherence to critical perioperative infection prevention standards, we developed Clean Cut, a checklist-based quality improvement program to improve compliance with best practices. We hypothesized that process mapping infection prevention activities can help clinicians identify strategies for improving surgical safety. STUDY DESIGN: We introduced Clean Cut at a tertiary hospital in Ethiopia. Infection prevention standards included skin antisepsis, ensuring a sterile field, instrument decontamination/sterilization, prophylactic antibiotic administration, routine swab/gauze counting, and use of a surgical safety checklist. Processes were mapped by a visiting surgical fellow and local operating theater staff to facilitate the development of contextually relevant solutions; processes were reassessed for improvements. RESULTS: Process mapping helped identify barriers to using alcohol-based hand solution due to skin irritation, inconsistent administration of prophylactic antibiotics due to variable delivery outside of the operating theater, inefficiencies in assuring sterility of surgical instruments through lack of confirmatory measures, and occurrences of retained surgical items through inappropriate guidelines, staffing, and training in proper routine gauze counting. Compliance with most processes improved significantly following organizational changes to align tasks with specific process goals. CONCLUSIONS: Enumerating the steps involved in surgical infection prevention using a process mapping technique helped identify opportunities for improving adherence and plotting contextually relevant solutions, resulting in superior compliance with antiseptic standards. Simplifying these process maps into an adaptable tool could be a powerful strategy for improving safe surgery delivery in LMICs.

Mortality Trends After a Voluntary Checklist-based Surgical Safety Collaborative.

OBJECTIVE: To determine whether completion of a voluntary, checklist-based surgical quality improvement program is associated with reduced 30-day postoperative mortality. BACKGROUND: Despite evidence of efficacy of team-based surgical safety checklists in improving perioperative outcomes in research trials, effective methods of population-based implementation have been lacking. The Safe Surgery 2015 South Carolina program was designed to foster state-wide engagement of hospitals in a voluntary, collaborative implementation of a checklist program. METHODS: We compared postoperative mortality rates after inpatient surgery in South Carolina utilizing state-wide all-payer discharge claims from 2008 to 2013, linked with state vital statistics, stratifying hospitals on the basis of completion of the checklist program. Changes in risk-adjusted 30-day mortality were compared between hospitals, using propensity score-adjusted difference-in-differences analysis. RESULTS: Fourteen hospitals completed the program by December 2013. Before program launch, there was no difference in mortality trends between the completion cohort and all others (P = 0.33), but postoperative mortality diverged thereafter (P = 0.021). Risk-adjusted 30-day mortality among completers was 3.38% in 2010 and 2.84% in 2013 (P < 0.00001), whereas mortality among other hospitals (n = 44) was 3.50% in 2010 and 3.71% in 2013 (P = 0.3281), reflecting a 22% difference between the groups on difference-in-differences analysis (P = 0.0021). CONCLUSIONS: Despite similar pre-existing rates and trends of postoperative mortality, hospitals in South Carolina completing a voluntary checklist-based surgical quality improvement program had a reduction in deaths after inpatient surgery over the first 3 years of the collaborative compared with other hospitals in the state. This may indicate that effective large-scale implementation of a team-based surgical safety checklist is feasible.

Relationship Between Labor and Delivery Unit Management Practices and Maternal Outcomes.

OBJECTIVE: To define, measure, and characterize key competencies of managing labor and delivery units in the United States and assess the associations between unit management and maternal outcomes. METHODS: We developed and administered a management measurement instrument using structured telephone interviews with both the primary nurse and physician managers at 53 diverse hospitals across the United States. A trained interviewer scored the managers' interview responses based on management practices that ranged from most reactive (lowest scores) to most proactive (highest scores). We established instrument validity by conducting site visits among a subsample of 11 hospitals and established reliability using interrater comparison. Using a factor analysis, we identified three themes of management competencies: management of unit culture, patient flow, and nursing. We constructed patient-level regressions to assess the independent association between these management themes and maternal outcomes. RESULTS: Proactive management of unit culture and nursing was associated with a significantly higher risk of primary cesarean delivery in low-risk patients (relative risk [RR] 1.30, 95% CI 1.02-1.66 and RR 1.47, 95% CI 1.13-1.92, respectively). Proactive management of unit culture was also associated with a significantly higher risk of prolonged length of stay (RR 4.13, 95% CI 1.98-8.64), postpartum hemorrhage (RR 2.57, 95% CI 1.58-4.18), and blood transfusion (RR 1.87, 95% CI 1.12-3.13). Proactive management of patient flow and nursing was associated with a significantly lower risk of prolonged length of stay (RR 0.23, 95% CI 0.12-0.46 and RR 0.27, 95% CI 0.11-0.62, respectively). CONCLUSION: Labor and delivery unit management varies dramatically across and within hospitals in the United States. Some proactive management practices may be associated with increased risk of primary cesarean delivery and maternal morbidity. Other proactive management practices may be associated with decreased risk of prolonged length of stay, indicating a potential opportunity to safely improve labor and delivery unit efficiency.