Implementation of entrustable professional activities in multiple surgical residencies: A quality improvement approach.

BACKGROUND: The COVID-19 pandemic decreased the operative case volume for surgical residents. Our institution implemented Entrustable Professional Activities (EPAs) in all core surgical training programs to document the competency of graduating residents. Continuation of this project aimed to improve implementation. METHODS: This project occurred at a large academic center with eight surgical specialties during the 2020-21 (Year 1) and 2021-22 (Year 2) academic years. Each specialty chose five EPAs, and residents were asked to obtain three micro-assessments per EPA. After the initial pilot year, program directors were surveyed regarding perceptions of EPA utility and barriers to implementation. RESULTS: Seventy senior residents completed 732/906 (80.8%) micro-assessments. Of these, 99.6% were deemed practice ready. Total micro-assessment completion rates in four specialties, four specific EPAs (including one EPA identified "at risk" due to the COVID-19 pandemic), and overall were significantly higher in Year 2 than Year 1 (p â€‹< â€‹0.05) CONCLUSIONS: Implementing EPAs in all core surgical specialties at an institution is achievable, though expectedly initially imperfect. An ongoing quality collaborative initiative focused on barriers to implementation can improve completion rates.

Veterans Affairs Cooperative Studies Program Study #553: Chemotherapy After Prostatectomy for High-risk Prostate Carcinoma: A Phase III Randomized Study.

BACKGROUND: The Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy. OBJECTIVE: To test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS). DESIGN, SETTING, AND PARTICIPANTS: Eligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was PFS. Secondary endpoints included overall, prostate cancer-specific, and metastasis-free survival, and time to androgen deprivation therapy. RESULTS AND LIMITATIONS: A total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2-103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p=0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58-1.11; p=0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32-0.92; p=0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43-0.99; p=0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%. CONCLUSIONS: Adjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage≥pT3b (ClinicalTrials.gov number NCT00132301). PATIENT SUMMARY: In this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit.

Microbiome diversity in carriers of fluoroquinolone resistant Escherichia coli.

Purpose: Fluoroquinolone-resistant (FQR) Escherichia coli causes transrectal prostate biopsy infections. In order to reduce colonization of these bacteria in carriers, we would like to understand the surrounding microbiome to determine targets for decolonization. Materials and Methods: We perform an observational study to investigate the microbiome differences in men with and without FQR organisms found on rectal culture. A rectal swab with two culturettes was performed on men before an upcoming prostate biopsy procedure as standard of care to perform "targeted prophylaxis." Detection of FQR was performed by the standard microbiology lab inoculates the swab onto MacConkey agar containing ciprofloxacin. The extra swab was sent for 16S rRNA amplicon sequencing (MiSeq paired-end) using the V1V2 primer. Alpha and beta-diversity analysis were performed using QIIME. We used PERMANOVA to evaluate the statistical significance of beta-diversity distances within and between groups of interest. Results: We collected 116 rectal swab samples before biopsy for 16S rRNA amplicon sequencing. We identified 18 isolates (15.5%, 18/116) that were positive and had relative reduced diversity profiles (p<0.05). Enterobacteriaceae were significantly over-represented in the FQR subjects (adjusted p=0.03). Conclusions: Microbiome analysis determined that men colonized with FQR bacteria have less diverse bacterial communities (dysbiosis), higher levels of Enterobacteriaceae and reduced levels of Prevotella disiens. These results may have implications in pre/probiotic intervention studies.

Local Antibiogram Predicts Appropriate Antibiotic Selection for Prostate Biopsy Prophylaxis.

INTRODUCTION: We evaluated our local antibiogram to determine the accuracy of its use in antibiotic augmentation before transrectal prostate biopsy. METHODS: We analyzed pre-transrectal prostate biopsy rectal swabs from January 2016 to September 2017 at the South Texas Veterans Health Care System (STVHCS). A query was run on pre-procedure rectal swabs positive for fluoroquinolone resistance in men undergoing transrectal prostate biopsy during this time. Culture results and antibiotic resistance profiles were recorded and compared to the proportion of antibiotic resistance in the STVHCS 2016 antibiogram. RESULTS: We identified 611 patients who underwent rectal culture before transrectal prostate biopsy, of which 98 were ciprofloxacin resistant Escherichia coli isolates. Our cohort demonstrated 80% sensitivity to ciprofloxacin compared to the STVHCS antibiogram sensitivity of 65% (p <0.001). Gentamicin demonstrated similar sensitivities between the antibiogram and cohort (90% and 88%, respectively). There were no statistically significant differences between the STVHCS antibiogram and the sensitivity profiles of our rectal swab cohort except for ampicillin/sulbactam, which was 57% in the antibiogram and 32% in our cohort (p=0.019). Of the ciprofloxacin resistant E. coli identified 4% (4 of 98) were considered extended spectrum beta-lactamase producers. CONCLUSIONS: Overall, resistance patterns in ciprofloxacin resistant E. coli isolates from our study population are consistent with the STVHCS antibiogram. Therefore, a local antibiogram may be used in an implementation strategy for targeted antibiotics or augmentation of fluoroquinolone prophylaxis for transrectal prostate biopsy.

Metabolic Biosynthesis Pathways Identified from Fecal Microbiome Associated with Prostate Cancer.

BACKGROUND: The fecal microbiome is associated with prostate cancer risk factors (obesity, inflammation) and can metabolize and produce various products that may influence cancer but have yet to be defined in prostate cancer. OBJECTIVE: To investigate gut bacterial diversity, identify specific metabolic pathways associated with disease, and develop a microbiome risk profile for prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: After prospective collection of 133 rectal swab samples 2 wk before the transrectal prostate biopsy, we perform 16S rRNA amplicon sequencing on 105 samples (64 with cancer, 41 without cancer). Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was applied to infer functional categories associated with taxonomic composition. The p values were adjusted using the false discovery rate. The α- and ß-diversity analyses were performed using QIIME. The Mann-Whitney U test was employed to evaluate the statistical significance of ß-diversity distances within and between groups of interest, and least absolute shrinkage and selection operator (LASSO) regression analysis was used to determine pathway significance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The detection of prostate cancer on transrectal prostate needle biopsy and 16s microbiome profile. RESULTS AND LIMITATIONS: We identified significant associations between total community composition and cancer/non-cancer status (Bray-Curtis distance metric, p<0.01). We identified significant differences in enrichments of Bacteroides and Streptococcus species in cancer (all p<0.04). Folate (LDA 3.8) and arginine (LDA 4.1) were the most significantly altered pathways. We formed a novel microbiome-derived risk factor for prostate cancer based on 10 aberrant metabolic pathways (area under curve=0.64, p=0.02). CONCLUSIONS: Microbiome analyses on men undergoing prostate biopsy noted mostly similar bacterial species diversity among men diagnosed with and without prostate cancer. The microbiome may have subtle influences on prostate cancer but are likely patient-specific and would require paired analysis and precise manipulation, such as improvement of natural bacterial folate production. PATIENT SUMMARY: Microbiome evaluation may provide patients with personalized data regarding the presence or absence of particular bacteria that have metabolic functions and implications regarding prostate cancer risk. The study provides a basis to investigate the manipulation of aberrant microbiomes to reduce prostate cancer risk.

Suppression of ribosomal protein RPS6KB1 by Nexrutine increases sensitivity of prostate tumors to radiation.

Radiation therapy (XRT) is a standard treatment for prostate cancer (PCa). Although dose escalation increases local control, toxicity hampers further escalation. Broader improvement will be possible by the addition of adjuvant therapies, which can synergize with radiation and thus improve efficacy. We have identified a natural compound (Nexrutine, Nx) that inhibits the survival and growth of PCa cells in combination with radiation. Combination studies demonstrated strong interaction between Nx and radiation both in vitro in multiple PCa cell lines and in the Transgenic adenocarcinoma of mouse prostate (TRAMP) model. Nx potentiated growth inhibitory effects of IR by down regulating ribosomal protein S6K (RPS6KB1), CyclinD1, Chk1 and HIF-1 α and prolonging G2/M checkpoint block. RPS6KB1 is upregulated in prostate cancers and its expression is correlated with tumor grade. Knockdown of RPS6KB1 in PCa cells increased their sensitivity toward radiation-induced survival inhibition. Overall, we provide scientific evidence (i) in support of Nx as an adjuvant in PCa patients receiving XRT (ii) suggesting that RPS6KB1 is an important player in Nx-mediated combinatorial benefits and emphasizes that RPS6KB1 is a novel target for PCa treatment. These data underscore the need to test the agent in additional preclinical models to validate these observations.

Improving risk stratification among veterans diagnosed with prostate cancer: impact of the 17-gene prostate score assay.

BACKGROUND: Active surveillance (AS) has been widely implemented within Veterans Affairs' medical centers (VAMCs) as a standard of care for low-risk prostate cancer (PCa). Patient characteristics such as age, race, and Agent Orange (AO) exposure may influence advisability of AS in veterans. The 17-gene assay may improve risk stratification and management selection. OBJECTIVES: To compare management strategies for PCa at 6 VAMCs before and after introduction of the Oncotype DX Genomic Prostate Score (GPS) assay. STUDY DESIGN: We reviewed records of patients diagnosed with PCa between 2013 and 2014 to identify management patterns in an untested cohort. From 2015 to 2016, these patients received GPS testing in a prospective study. Charts from 6 months post biopsy were reviewed for both cohorts to compare management received in the untested and tested cohorts. SUBJECTS: Men who just received their diagnosis and have National Comprehensive Cancer Network (NCCN) very low-, low-, and select cases of intermediate-risk PCa. RESULTS: Patient characteristics were generally similar in the untested and tested cohorts. AS utilization was 12% higher in the tested cohort compared with the untested cohort. In men younger than 60 years, utilization of AS in tested men was 33% higher than in untested men. AS in tested men was higher across all NCCN risk groups and races, particular in low-risk men (72% vs 90% for untested vs tested, respectively). Tested veterans exposed to AO received less AS than untested veterans. Tested nonexposed veterans received 19% more AS than untested veterans. Median GPS results did not significantly differ as a factor of race or AO exposure. CONCLUSIONS: Men who receive GPS testing are more likely to utilize AS within the year post diagnosis, regardless of age, race, and NCCN risk group. Median GPS was similar across racial groups and AO exposure groups, suggesting similar biology across these groups. The GPS assay may be a useful tool to refine risk assessment of PCa and increase rates of AS among clinically and biologically low-risk patients, which is in line with guideline-based care.

Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer.

BACKGROUND: In the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride. METHODS: From 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5mg finasteride or placebo daily in a double-blind study during the 4-6weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERß, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers. FINDINGS: We found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups. INTERPRETATION: We showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT.

Tolerance of Phellodendron amurense bark extract (Nexrutine®) in patients with human prostate cancer.

Phellodendron amurense bark extract (Nexrutine®) has shown a favorable effect on prostate cancer in vivo and in vitro. We evaluated its tolerance in patients undergoing surgery or radiation for prostate cancer. Patients received Nexrutine® orally (500 mg tid) either 1 to 2 months preoperatively or 1 to 2 months prior to and with radiation therapy. Common Terminology Criteria for Adverse Events were used to measure tolerance. In total, 21 patients (9 surgery and 12 radiation) underwent treatment. During the Nexrutine® alone component, there were two transient grade 3 toxicities (hypokalemia and urinary incontinence). There was no grade 4 toxicity. For the combined Nexrutine® and radiation component, no additional patients suffered a grade 3 toxicity. All the toxicities were transient. By the end of the neoadjuvant treatment, 81% of the patients had a decline in prostate-specific antigen. This is the first report of patients with prostate cancer being treated with P. amurense bark extract, and it was very well tolerated. Toxicities were minimal and self-limited. This compound can be safely used in further evaluation of a treatment effect on cancer.

Alvimopan for prevention of postoperative paralytic ileus in radical cystectomy patients: a cost-effectiveness analysis.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: No cost-effectiveness studies exist in patients after radical cystectomy for the routine use of alvimopan for the prevention of postoperative ileus. The present study provides a reasonable estimate of the cost-effectiveness of alvimopan for the prevention of postoperative ileus in the patient after radical cystectomy. OBJECTIVE: To determine if the cost of administering alvimopan, to help restore bowel function after abdominal surgery, to all patients undergoing radical cystectomy (RC) is cost prohibitive. PATIENTS AND METHODS: A cost-effective analysis was conducted from a healthcare payer perspective using a decision-tree model that incorporated direct healthcare costs and probabilities associated with the possible events and outcomes. Sensitivity analyses were conducted on the influence of the cost and effectiveness of the drug, the probability of POI in RC patients, and the extended length of stay (LOS) as a result of POI. Precision in estimates was determined using probabilistic sensitivity analyses with 5000 Monte-Carlo simulations. RESULTS: Under the base case assumption, the additional cost of a patient's LOS related to POI was $10 246 per person. Under the assumption that 15.6% of patients will have POI, the mean cost associated with POI in a cohort of patients not treated with alvimopan was $1597 (90% confidence interval [CI] $1335-1875) per patient. Conversely, the routine use of alvimopan for all patients undergoing RC was associated with a mean POI-associated cost of $1495(90% CI $1312-1696) per person, which represents the cost of alvimopan ($700 per hospitalisation) and a 50% reduction in the rate of POI. Sensitivity analyses revealed that there is a cost savings with the routine use of alvimopan under the following conditions: the POI results in extending LOS by ≥3.5 days, POI occurs in ≥14% of patients undergoing RC, or the drug results in a relative risk reduction of ≥44%. CONCLUSIONS: Routine use of perioperative alvimopan may not be cost prohibitive because of its influence on POI rate and associated costs. The cost-effectiveness of alvimopan is influenced by the POI incidence and the degree to which the drug can decrease the LOS.

High-grade prostate cancer: favorable results in the modern era regardless of initial treatment.

Purpose. We performed a retrospective study to determine the outcome of a modern cohort of patients with high-grade (Gleason score ≥ 8) prostate cancer treated with radical prostatectomy, radiation therapy, or hormone therapy. Methods. We identified 404 patients in the South Texas Veteran's Healthcare System Tumor Registry diagnosed with high grade prostate cancer between 1998 and 2008. Mean follow-up was 4.62 ± 2.61 years. End points were biochemical failure-free survival, overall survival, metastasis-free survival, and cancer-specific survival. Results. 5-year overall survival for patients undergoing radical prostatectomy, radiation therapy, and hormone therapy was 88.9%, 76.3%, and 58.9%, respectively. 5-year metastasis-free survival for patients undergoing radical prostatectomy, radiation therapy, and hormone therapy was 96.8%, 96.6%, and 88.4%, respectively, and 5-year cancer-specific survival was 97.2%, 100%, and 89.9%, respectively. Patients with a Gleason score of 10 and pretreatment prostate-specific antigen > 20 ng/mL had decreased 5-year biochemical failure-free and cancer-specific survival. Patients with a pretreatment prostate-specific antigen > 20 ng/mL had decreased 5-year overall survival. Discussion. Even for patients with high-grade disease, the outcome is not as dire in the modern era regardless of primary treatment modality chosen. While there is room for improvement, we should not have a nihilistic impression of how these patients will respond to treatment.

Intraductal carcinoma of the prostate in the ejaculatory duct.

Intraductal carcinoma of the prostate (IDCP) involving prostatic ducts and acini is a well-known phenomenon typically seen in a background of high-grade invasive prostatic adenocarcinoma. The current case of prostatic adenocarcinoma with Gleason score of 9 (4 + 5) invades the ejaculatory ducts, left seminal vesicle, and extraprostatic tissue. The tumor involving the left ejaculatory duct spans the lumen with preservation of native duct architecture, including basal cells, similar features described in IDCP involving prostatic ducts and acini.

Prognostic factors for failure after prostatectomy.

Several randomized studies have been completed in prostate cancer that show a benefit to immediate postoperative treatment in patients undergoing prostatectomy. In one of the studies, there was even a survival advantage. In spite of those positive findings, there has been some reluctance to uniformly offer adjuvant treatment to patients. The perception is that the risk is not really high enough to warrant the risk of toxicity that comes with treatment. There are clearly factors that can help predict who is at the highest risk. Our purpose is to review those factors and identify patients that have a high enough risk justifying immediate treatment.

Evaluation of mechanical bowel preparation methods in urinary diversion surgery.

OBJECTIVES: We performed the first prospective, randomized, multi-center comparison of overall quality and patient tolerability of polyethylene glycol (PEG) and sodium phosphate (NaP) solution for mechanical bowel preparation prior to urinary diversion surgery. METHODS: Between 2001 and 2003, 36 patients at six institutions underwent major urological reconstructive surgery incorporating small intestine (35 radical cystectomy with urinary diversion and 1 bladder augmentation). Patients were prospectively randomized to receive either oral polyethylene glycol (group 1, n = 16) or sodium phosphate (group 2, n = 20) for mechanical bowel preparation prior to surgery, according to our multi-institutional IRB-approved protocol. All patients completed a questionnaire the morning of surgery to assess the tolerability and side effects of each agent. Quality of the bowel preparation was recorded based on intraoperative findings of the attending surgeon, who was blinded to the preparation method. RESULTS: Both bowel cleansing regimens were safe and well tolerated. Patient-reported ease of use and subjective incidence of side effects were statistically similar in the two groups, and a statistically non-significant trend to more bloating in the PEG group was also noted (p = 0.085). Surgeon-scored overall quality of preparation adequacy revealed no significant differences between oral sodium phosphate and polyethylene glycol solutions (p = 0.555). Postoperative complications were rare for each bowel preparation agent. CONCLUSIONS: Performance characteristics of oral sodium phosphate and polyethylene glycol bowel preparations appear to be similar. Each method is safe, efficacious, and well-tolerated when used prior to urinary diversion surgery. The cost for the NaP preparation was $1.40 versus $19.70 for the PEG bowel preparation. Sodium phosphate may have a slight advantage because of its convenience and economic advantage.

Metastatic prostate cancer-does treatment of the primary tumor matter?

PURPOSE: In recent years there has been increased interest in adjuvant therapy for prostate cancer. This trend has engendered a tendency toward overlooking the issue of therapy to the primary tumor in advanced disease. We reviewed the effect of treating the principal disease bulk on overall treatment outcome in patients with advanced and metastatic cancer. Specifically we evaluated the role of surgical tumor cytoreduction. MATERIALS AND METHODS: We performed a comprehensive literature review to evaluate the role of surgical debulking on the outcome of advanced cancer, including any published evidence supporting a benefit of this therapy for prostate cancer. RESULTS: Even in cancers for which adjuvant chemotherapy and radiation are used liberally there is a clear benefit to optimal surgical debulking for local control and survival. The beneficial role of maximal surgical cytoreduction has been clearly demonstrated in advanced ovarian cancer and gastrointestinal carcinomatosis. Maximal debulking of brain, liver and lung metastasis has translated into longer survival. Removal of the primary tumor has been proved to increase survival in randomized trials of metastatic renal cell cancer. It appears that patients with node positive and possibly metastatic prostate cancer have a better response to androgen ablation with surgical removal of the gland. CONCLUSIONS: Surgical cytoreduction of cancer results in a more favorable and durable response to systemic therapy. It is reasonable to explore aggressive surgical therapy for advanced prostate cancer.

Current status of lymph node-positive prostate cancer: Incidence and predictors of outcome.

In early surgical series, the incidence of positive lymph nodes in patients with prostate cancer was approximately 40%. In the modern era of screening and improved patient selection, the incidence is now <10%, although most series excluded patients with higher risk disease. The risk of having positive lymph nodes is influenced by disease stage, prostate-specific antigen level, and tumor grade and by the aggressiveness of lymph node dissection. Many of the same factors predict the outcome of these patients. Although the percentage of patients with positive lymph nodes has declined, there remain significant numbers of patients with lymph node-positive prostate cancer, and it remains a therapeutic dilemma.

Treatment options in lymph node-positive prostate cancer.

With improved awareness and screening, the incidence of lymph node-positive prostate cancer has declined dramatically over the last 50 years. Stage of cancer, prostate-specific antigen, and grade are risk factors for positive lymph nodes; and those factors, along with the number of involved lymph nodes, are prognostic factors for outcome. Although the numbers have declined, the number of men with lymph node-positive prostate cancer remains significant, and the current challenge is how best to treat these patients. Commonly used treatments include any combination of androgen ablation, surgery, and radiation. There have been a few studies with chemotherapy, and no treatment has been proven superior to the others. Consequently, there remain several reasonable alternatives to treatment, and long-term survival is not unusual.