Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer.

Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.

Oncologic outcomes among Black and White men with grade group 4 or 5 (Gleason score 8-10) prostate cancer treated primarily by radical prostatectomy.

BACKGROUND: The aim of this study was to describe pathologic and short-term oncologic outcomes among Black and White men with grade group 4 or 5 prostate cancer managed primarily by radical prostatectomy. METHODS: This was a multi-institutional, observational study (2005-2015) evaluating radical prostatectomy outcomes by self-identified race. Descriptive analysis was performed via nonparametric statistical testing to compare baseline clinicopathologic data. Univariable and multivariable time-to-event analyses were performed to assess biochemical recurrence (BCR), metastasis, cancer-specific mortality (CSM), and overall survival between Black and White men. RESULTS: In total, 1662 men were identified with grade group 4 or 5 prostate cancer initially managed by radical prostatectomy. Black men represented 11.3% of the cohort (n = 188). Black men were younger, demonstrated a longer time from diagnosis to surgery, and were at a lower clinical stage (all P < .05). Black men had lower rates of pT3/4 disease (49.5% vs 63.5%; P < .05) but higher rates of positive surgical margins (31.6% vs 26.5%; P = .14) on pathologic evaluation. There was no difference in BCR, CSM, or overall survival over a median follow-up of 40.7 months. Black men had a lower 5-year cumulative incidence of metastasis-free survival (93.6%; 95% confidence interval [CI], 86.5%-97.0%) in comparison with White men (85.8%; 95% CI, 83.1%-88.0%), which did not persist in an age-adjusted analysis. CONCLUSIONS: Black and White men with high-grade prostate cancer at diagnosis demonstrated similar oncologic outcomes when they were managed by primary radical prostatectomy. Our findings suggest that racial disparities in prostate cancer mortality are not related to differences in the efficacy of extirpative therapy.

Racial and ethnic representation in primary research contributing to pelvic organ prolapse treatment guidelines.

INTRODUCTION AND HYPOTHESIS: To evaluate whether the studies contributing to the national treatment guidelines on pelvic organ prolapse adequately represent the racial and/or ethnic makeup of the American population. METHODS: This analysis examines the racial and ethnic makeup of all primary study cohorts contributing to the American College of Obstetricians and Gynecologists/American Urogynecologic Society Practice Bulletin No. 214 on pelvic organ prolapse. References were excluded if they lacked a primary patient population or were from outside the US. Mean proportional representation of racial/ethnic groups was compared to the 2018 United States Census data on race/ethnicity. The representation quotient was also calculated to evaluate for relative representation of each group. Descriptive statistics were used. RESULTS: Of the 110 references, 53 primary studies were included in the final analysis with 30 studies reporting on race/ethnicity. On average, 82% (SD = 15%) of study populations were White, while Blacks, Hispanics, and Asians represented 67% (SD = 7%), 4% (SD = 8%), and < 1% (SD = 1%), respectively, differing significantly from the 2018 US Census (p < 0.01.) The representation quotients for White women was 1.36, demonstrating a 36% overrepresentation, while Black, Hispanic, and Asian women were underrepresented among studies of all evidence levels, with representative quotients of 0.50, 0.23, and 0.09, respectively. CONCLUSIONS: Our study demonstrates a significant underrepresentation of non-White populations in primary cohorts of studies contributing to the ACOG/AUGS Practice Bulletin No. 214 on POP. This analysis reinforces that more efforts are required to include and report on racial and ethnically diverse cohorts to better serve all patients.

Small Bowel Diverticulosis: Pathogenesis, Clinical Management, and New Concepts.

PURPOSE OF REVIEW: Small bowel diverticulosis is a well-known clinical entity whose diagnosis and management has evolved in recent years. This review covers pathophysiology, incidence, and prevalence, and it also provides an update on modern diagnosis and management. Meckel's diverticula are covered elsewhere in this volume. RECENT FINDINGS: CT scan and MRI have largely supplanted barium follow-through for diagnosis. No intervention is needed in asymptomatic individuals. Endoscopic management is playing an increasing role for both bleeding and resection of intraduodenal diverticula, but surgical intervention remains the only definitive intervention for other complications like diverticulitis and small bowel obstruction. Small bowel diverticulosis is an uncommon condition which is associated with numerous possible complications. While endoscopy is playing an increasingly large role in management, surgical resection remains the treatment of choice for most complications. A high index of suspicion is needed in order to diagnose this entity.

The Timing of Radical Cystectomy for bacillus Calmette-Guérin Failure: Comparison of Outcomes and Risk Factors for Prognosis.

PURPOSE: We compared the pathological and survival outcomes of patients who underwent radical cystectomy soon after bacillus Calmette-Guérin failure with those of patients who received additional salvage intravesical chemotherapy before cystectomy for nonmuscle invasive bladder cancer. We also identified predictors of prognosis in the entire cohort. MATERIALS AND METHODS: We retrospectively analyzed the records of 117 patients who underwent radical cystectomy for recurrent nonmuscle invasive bladder cancer at our institution from 1990 to 2012. The cohort was divided into group 1 of 61 patients treated only with bacillus Calmette-Guérin with or without interferon-α and group 2 of 56 who received at least 1 additional salvage intravesical chemotherapy after bacillus Calmette-Guérin. RESULTS: Final pathology and survival outcomes did not differ significantly between the groups. Five-year overall and cancer specific survival was similar in groups 1 and 2 at 80% and 85%, respectively, at approximately equivalent followups. Median bladder retention was 1.7 years longer in group 2 (p <0.001). On multivariate Cox regression analysis delayed cystectomy in group 2 did not convey a significant hazard for all cause mortality after cystectomy (HR 1.08, p = 0.808). Only up-staging to cT1 (HR 1.88, p = 0.045), lymph node invasion (HR 2.58, p = 0.023) and prostatic urethra involvement (HR 1.95, p = 0.029) achieved significance. CONCLUSIONS: With appropriate selection for salvage intravesical chemotherapy patients who elect bladder sparing treatment instead of earlier radical cystectomy after bacillus Calmette-Guérin fails do not sacrifice positive pathological or oncologic outcomes while retaining bladder function for a significantly longer duration.

Epicardial adipocyte hypertrophy: Association with M1-polarization and toll-like receptor pathways in coronary artery disease patients.

BACKGROUND AND AIMS: In coronary artery disease (CAD) epicardial adipose tissue (EAT) shows an elevated inflammatory infiltrate. Toll-like receptors (TLRs) are important mediators of adipose tissue inflammation and they are able to recognize endogenous products released by damaged cells. Because adipocyte death may be driven by hypertrophy, our aim was to investigate in CAD and non-CAD patients the association between EAT adipocyte size, macrophage infiltration/polarization and TLR-2 and TLR-4 expression. METHODS AND RESULTS: EAT biopsies were collected from CAD and non-CAD patients. The adipocyte size was determined by morphometric analysis. Microarray technology was used for gene expression analysis; macrophage phenotype and TLRs expression were analyzed by immunofluorescence and immunohistochemical techniques. Inflammatory mediator levels were determined by immunoassays. EAT adipocytes were larger in CAD than non-CAD patients and do not express perilipin A, a marker of lipid droplet integrity. In CAD, EAT is more infiltrated by CD68-positive cells which are polarized toward an M1 state (CD11c positive) and presents an increased pro-inflammatory profile. Both TLR-2 and TLR-4 expression is higher in EAT from CAD and observed on all the CD68-positive cells. CONCLUSIONS: Our findings suggested that EAT hypertrophy in CAD promotes adipocyte degeneration and drives local inflammation through increased infiltration of macrophages which are mainly polarized towards an M1 state and express both TLR-2 and TLR-4.

Phase II trial of intravesical nanoparticle albumin bound paclitaxel for the treatment of nonmuscle invasive urothelial carcinoma of the bladder after bacillus Calmette-Guérin treatment failure.

PURPOSE: Response rates to current second line intravesical therapies for recurrent nonmuscle invasive bladder cancer range between 10% and 30%. Nanoparticle albumin bound (nab-)paclitaxel has increased solubility and lower toxicity compared to other taxanes. Results of the phase I intravesical trial of this compound demonstrated minimal toxicity during dose escalation. We now report the results of a phase II trial to assess efficacy. MATERIALS AND METHODS: This study was an investigator initiated, single center, single arm, phase II trial investigating the use of nab-paclitaxel in patients with recurrent Tis, T1 and Ta urothelial carcinoma in whom at least 1 prior regimen of intravesical bacillus Calmette-Guérin failed. Patients received 500 mg/100 ml nab-paclitaxel administered in 6 weekly intravesical instillations. Efficacy was evaluated with cystoscopy, biopsy, cytology and imaging. If complete response was achieved, patients were treated with full dose monthly maintenance treatments for 6 months. RESULTS: A total of 28 patients were enrolled in the study. Of these patients 10 (35.7%) exhibited a complete response after initial treatment. At 1 year all of these responses remained durable after maintenance therapy. At a mean followup of 21 months (range 5 to 47) 19 of 28 (67.8%) patients retained their bladders without progression or distant metastases. A single patient had progression to muscle invasive disease at radical cystectomy. Treatment related adverse events were noted in 9 of 28 (32.1%) patients and were limited to grade 1 or 2. CONCLUSIONS: Intravesical nab-paclitaxel has minimal toxicity and a 35.7% response rate in patients with nonmuscle invasive bladder cancer and previous bacillus Calmette-Guérin failure. Complete response remained durable at 1 year followup in this heavily pretreated patient population.

Long-term survival outcomes with intravesical docetaxel for recurrent nonmuscle invasive bladder cancer after previous bacillus Calmette-Guérin therapy.

PURPOSE: Docetaxel is a safe agent for intravesical therapy. Adding monthly maintenance treatments can extend response durability. We report our cumulative experience with intravesical docetaxel in a larger cohort with extended followup. MATERIALS AND METHODS: A total of 54 patients received salvage intravesical docetaxel for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer between 2003 and 2012, including 18 treated during the original phase I trial. All patients received 6 weekly instillations of intravesical docetaxel. After the phase I trial, those with a complete response to induction treatment were offered single dose monthly maintenance treatments for a total of up to 12 months of docetaxel therapy. Recurrence was defined as positive biopsy or urine cytology. Recurrence-free, disease specific and overall survival was determined by Kaplan-Meier analysis. RESULTS: Median followup was 39.1 months. Of the 54 patients 32 (59%) had a complete initial response after induction therapy, including 18 who received additional monthly maintenance treatments. Median time to recurrence in initial responders treated with vs without docetaxel maintenance was 39.3 vs 19.0 months. One and 3-year recurrence-free survival rates for the entire cohort were 40% and 25%, respectively. Of the 54 patients 17 (24%) underwent radical cystectomy at a median of 24 months of followup. Five-year disease specific and overall survival rates were 85% and 71%, respectively. CONCLUSIONS: Intravesical docetaxel appears to be a promising agent with significant efficacy and durability for bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer. Adding maintenance treatments may increase the duration of recurrence-free survival.

Experience with newer intravesical chemotherapy for high-risk non-muscle-invasive bladder cancer.

The definitive treatment for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) who fail to respond to intravesical bacillus Calmette-Guérin (BCG) is cystectomy. However, many patients who experience recurrence after BCG are either poor operative candidates or refuse surgery due to the long-term impact on their quality of life. In the last decade, there has been an increased interest in alternative intravesical therapies, and several novel chemotherapeutics have emerged as promising agents for high-risk NMIBC patients unable or unwilling to undergo cystectomy. Additionally, extended treatment regimens with combined induction and maintenance therapy have been investigated, and may increase the durability of response to these new agents, as has been shown for conventional intravesical therapy.

Unexpected discovery of massive liver echinococcosis. A clinical, morphological, and functional diagnosis.

We report a case of symptomatic massive liver echinococcosis due to Echinococcus granulosus, unexpectedly found in a 34 year old woman living in Apulia, Italy. Based on size (max diameter 18 cm), clinical presentation, geographical area, and natural history of echinococcosis, we estimate that the initial infection should have occurred 9-20 yrs before. Presenting symptoms were those of typical mass effect with RUQ pain, pruritus, malaise, and recent weight loss. Abdominal ultrasound diagnosis of probable echinococcal cyst was subsequentely confirmed by positive serology and further detailed by radiological imaging. The cyst was massively occupying subdiaphragmatic liver segments and extending to the omentum and the stomach. The characteristics of the lesion were compatible with the WHO 2003 classification type CE2l, indicating a large active fertile cyst with daughter cysts. The cyst was successfully treated with medical therapy followed by surgery. The prevalence, diagnostic workup, management, and costs of echinococcosis are discussed in this case presentation.

A comparison of the outcomes of neoadjuvant and adjuvant chemotherapy for clinical T2-T4aN0-N2M0 bladder cancer.

BACKGROUND: Despite evidence supporting perioperative chemotherapy, few randomized studies compare neoadjuvant and adjuvant chemotherapy for bladder cancer. Consequently, the standard of care regarding the timing of chemotherapy for locally advanced bladder cancer remains controversial. We compared patient outcomes following neoadjuvant or adjuvant systemic chemotherapy for cT2-T4aN0-N2M0 bladder cancer. METHODS: In a retrospective review of a single institutional database from 1988 through 2009, we identified patients receiving neoadjuvant or adjuvant multiagent platinum-based systemic chemotherapy for locally advanced bladder cancer. Survival analysis was performed comparing disease-specific survival (DSS) and overall survival (OS). RESULTS: A total of 146 patients received systemic perioperative chemotherapy (73 neoadjuvant, 73 adjuvant). Of these, 84% (122/146) received cisplatin-based chemotherapy compared with carboplatin-based chemotherapy (24/146, 16.4%). Most patients receiving cisplatin-based chemotherapy were treated with methotrexate/vinblastine/adriamycin/cisplatin (79/122, 64.8%), whereas the remaining patients received gemcitabine/cisplatin (GC) (43/122, 35.2%). In multivariable analysis, there was no significant difference in DSS (P = .46) or OS (P = .76) between neoadjuvant or adjuvant chemotherapy groups. There was statistically significant improvement in DSS when patients received neoadjuvant GC rather than adjuvant GC (P = .049, hazard ratio, 10.6; 95% confidence interval, 1.01-112.2). CONCLUSION: In this study, there was no statistically significant difference in OS and DSS between patients receiving neoadjuvant versus adjuvant systemic platinum-based chemotherapy for locally advanced bladder cancer. In addition, there was no significant difference between neoadjuvant and adjuvant cisplatin- or carboplatin-based chemotherapy. Chemotherapy sequence relative to surgery appeared less important than whether or not a patient actually received perioperative chemotherapy.

Editorial: not so nosocomial anymore: the growing threat of community-acquired Clostridium difficile.

Clostridium difficile infection is widely accepted to be the leading cause of nosocomial infection-related morbidity and mortality, outpacing both antibiotic-resistant staphylococcus and enterococcus. The existence and prevalence of community-acquired Clostridium difficile infection, on the other hand, is much less well appreciated. Growing evidence now suggests that community-acquired Clostridium difficile infection may account for more than a third of Clostridium difficile-associated diarrhea overall. Similar to nosocomial Clostridium difficile infection, community-acquired cases appear to be increasing in incidence, and although associated mortality is lower than in nosocomial cases, morbidity including hospitalization and recurrence are high. Further, traditional risk factors for Clostridium difficile infection including antibiotic exposure appear to be less important in community-acquired cases and common routes of exposure and infection in the community are yet to be elucidated. In this issue of the American Journal of Gastroenterology, Khanna et al. provide important epidemiological data on the growing threat of community-acquired Clostridium difficile infection.

Adenoma detection rates vary minimally with time of day and case rank: a prospective study of 2139 first screening colonoscopies.

BACKGROUND: Adenoma detection rate is an important measure of colonoscopy quality; however, factors including procedure order that contribute to adenoma detection are incompletely understood. OBJECTIVE: The aim of this study was to prospectively evaluate factors associated with adenoma detection rate. DESIGN: Prospective cohort study. Data were collected on patient and physician characteristics, trainee participation, time of day, and case rank. SETTING: Outpatient tertiary-care center. PATIENTS: This study involved consecutive patients presenting for first screening colonoscopies. MAIN OUTCOME MEASUREMENTS: Adenoma and polyp detection rates (proportion of cases with one or more lesion detected) and ratios (mean number of lesions detected per case). RESULTS: A total of 2139 colonoscopies were performed by 32 gastroenterologists. Detection rates were 42.7% for all polyps, 25.4% for adenomas, and 5.0% for advanced adenomas. Adenoma detection was associated with male sex and increasing age on multivariate analysis. In the overall study cohort, time of day and case rank were not significantly associated with detection rates. In post hoc analysis, polyp and adenoma detection rates appeared lower after the fifth case of the day for endoscopists with low volumes of cases and after the tenth case of the day for endoscopists with high volumes of cases. LIMITATION: Single center. CONCLUSION: Overall, time of day and case rank did not influence adenoma detection rate. We observed a small but significant decrease in detection rates in later procedures, which was dependent on physician typical procedure volume. These findings imply that colonoscopy quality in general is stable throughout the day; however, there may be a novel "stamina effect" for some endoscopists, and interventions aimed at improving colonoscopy quality need to take individual physician practice styles into consideration.

A phase I trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of bacillus Calmette-Guérin refractory nonmuscle invasive bladder cancer.

PURPOSE: Up to 50% of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence. Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary. Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use. Nanoparticle albumin-bound paclitaxel (Abraxane®, ABI-007) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy. Thus, we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel. MATERIALS AND METHODS: Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intravesical regimen failed. Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved. The primary end point was dose limiting toxicity and the secondary end point was response rate. RESULTS: A total of 18 patients were enrolled in the study. One patient demonstrated measurable systemic absorption after 1 infusion. Grade 1 local toxicities were experienced by 10 (56%) patients with dysuria being the most common, and no grade 2, 3 or 4 drug related local toxicities were encountered. Of the 18 patients 5 (28%) had no evidence of disease at posttreatment evaluation. CONCLUSIONS: Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge. A larger phase II study has begun to formally evaluate the activity of this regimen.