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.

Contemporary Outcomes of Patients with Nonmuscle-Invasive Bladder Cancer Treated with bacillus Calmette-Guérin: Implications for Clinical Trial Design.

PURPOSE: Recurrent disease after bacillus Calmette-Guérin treatment presents a therapeutic challenge. To aid trial development, the U.S. Food and Drug Administration defined "adequate bacillus Calmette-Guérin" therapy and adopted the "bacillus Calmette-Guérin unresponsive" disease state. Available data for efficacy benchmark comparison are outdated, leading to concerns about appropriate control arms and sample size calculations. We describe a contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with intravesical bacillus Calmette-Guérin, and provide benchmark outcomes data. MATERIALS AND METHODS: We retrospectively reviewed patients receiving adequate bacillus Calmette-Guérin therapy at a tertiary cancer center between January 2004 and August 2018. Unadjusted univariable analysis was conducted using the Pearson chi-square test. Kaplan-Meier estimates for recurrence-free survival-high grade, progression-free survival-muscle-invasive bladder cancer and overall survival were used to create survival curves and compared using the log-rank test. RESULTS: Of the 542 patients who received adequate bacillus Calmette-Guérin, 518 (90%) had European Association Urology high risk disease, with carcinoma in situ present in 175 (32%). With a median followup of 47.8 months, freedom from high grade recurrence at 1, 3 and 5 years was 81%, 76% and 74%, respectively, and progression-free survival was 97%, 93% and 92%. Progression to muscle invasion at 5 years was exclusively seen in patients with high risk disease (progression-free survival 91%; log-rank test, p=0.024). CONCLUSIONS: A contemporary cohort of patients with nonmuscle-invasive bladder cancer treated with adequate bacillus Calmette-Guérin demonstrated markedly better outcomes than seen in prior studies. These data could be used in the design of clinical trials, to guide power calculations, as well as serve as benchmarks for comparison to evaluate nonrandomized studies.

The obesity paradox: defining the impact of body mass index and diabetes mellitus for patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin.

OBJECTIVES: To evaluate if the obesity paradox, wherein obesity portends worse overall prognosis for a disease but improved outcomes for patients receiving immunotherapy, exists for patients receiving bacillus Calmette-Guérin (BCG) in a contemporary cohort. PATIENTS AND METHODS: We performed an Institutional Review Board-approved database review to identify patients with non-muscle-invasive bladder cancer (NMIBC) completing at least an induction course of BCG. Clinicopathological variables collected included: body mass index (BMI), medications, and diabetes mellitus (DM). Outcomes of interest included: recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Univariate and multivariate modelling were used to evaluate the association between outcomes and clinical factors. RESULTS: A total of 579 patients (median follow-up 4.6 years) received BCG induction for NMIBC; 90% had high-grade disease (47.2% clinical stage T1). In all, 75.7% of patients were overweight or obese and 18% had DM. Aspirin, statins, metformin and ß-blockers were used in 34%, 42%, 11%, and 29% of patients, respectively. Overweight and obese patients had improved PFS, CSS and OS. DM was associated with worse RFS. Medications of interest had no association with outcomes. CONCLUSION: Elevated BMI is associated with improved outcomes in patients with NMIBC treated with BCG immunotherapy. Patients with DM are at increased risk of recurrence. These findings support a potential obesity paradox in bladder cancer. Evaluation of the underlying mechanism and the role of global patient assessment, counselling, and risk factor modification are warranted.

Risk-adapted management of low-grade bladder tumours: recommendations from the International Bladder Cancer Group (IBCG).

OBJECTIVE: To provide a contemporary update and recommendations for the diagnosis and management of low-grade non-muscle-invasive bladder cancer (BCa) based on current literature and expert consensus of the International Bladder Cancer Group. METHODS: We reviewed published trials, guidelines, meta-analyses and reviews (up to March 2019) and provide recommendations on baseline evaluations, treatment, endpoints, study design and surveillance protocols. RESULTS: Low-grade Ta BCa poses minimal risk to patients in terms of progression and disease-specific survival. Thus, to minimize patient morbidity, this entity should be managed appropriately. After initial diagnosis of low-grade Ta tumour, subsequent stable, low-grade-appearing recurrences can be managed conservatively with office cystoscopy and fulguration or even followed using an active surveillance protocol. Intravesical therapy other than single-dose peri-operative chemotherapy instillation should be used judiciously, and only after assigning appropriate risk points. Routine use of urinary cytology - other than at initial risk stratification, or for patients on active surveillance without therapy - is not recommended; and surveillance cystoscopy may be discontinued after 5 years. Clinical studies in this group of patients should focus on recurrence rates, and time to recurrence, rather than progression events. CONCLUSIONS: The International Bladder Cancer Group has developed formal recommendations regarding the diagnosis, treatment and surveillance of low-grade non-muscle-invasive BCa to minimize morbidity and encourage uniformity among studies in this disease.

Clinical and Genomic Considerations for Variant Histology in Bladder Cancer.

PURPOSE OF REVIEW: Urothelial carcinoma demonstrates remarkable plasticity in its ability to differentiate into divergent histologic subtypes in both a pure and mixed form. This review presents the most current data pertaining to bladder cancer with variant histology. RECENT FINDINGS: Recognition of bladder cancer variants has increased profoundly in the past two decades with their inclusion in the pathologic guidelines and increased awareness among pathologists and urologists. Most of the available literature consists of small single-institutional studies, but there is compelling evidence to support deviation from the normal urothelial carcinoma management pathways for certain subtypes. While traditionally diagnosed by microscopic appearance, next-generation sequencing and molecular profiling have enabled identification of genomic markers associated with specific variants that exist in tumors lacking classic histologic hallmarks. This genomic information holds promise for predicting response to specific treatments or even in the development of novel targeted therapies. Combining increased awareness of variant histology, its impact on clinical outcomes, and genomic data will result in a more nuanced treatment approach to reduce morbidity and optimize oncologic outcomes for our patients.

Conservative Management Following Complete Clinical Response to Neoadjuvant Chemotherapy of Muscle Invasive Bladder Cancer: Contemporary Outcomes of a Multi-Institutional Cohort Study.

PURPOSE: We report the outcomes in patients with muscle invasive bladder cancer from 2 institutions who experienced a clinically complete response to neoadjuvant platinum based chemotherapy and elected active surveillance. It was unknown whether conservative treatment could be safely implemented in these patients. MATERIALS AND METHODS: We retrospectively reviewed the records of patients with muscle invasive bladder cancer at our institutions who elected surveillance following a clinically complete response to transurethral resection of bladder tumors and neoadjuvant chemotherapy from 2001 to 2017. A clinically complete response was defined as absent tumor on post-chemotherapy transurethral resection of bladder tumor, negative cytology and normal cross-sectional imaging. RESULTS: In the 148 patients followed a median of 55 months (range 5 to 145) the 5-year disease specific, overall, cystectomy-free and recurrence-free survival rates were 90%, 86%, 76% and 64%, respectively. Of the patients 71 (48%) experienced recurrence in the bladder, including 16 (11%) with muscle invasive disease and 55 (37%) with noninvasive disease. Salvage radical cystectomy prevented cancer specific death in 9 of 12 patients (75%) who underwent cystectomy after muscle invasive relapse and in 13 of 14 (93%) after noninvasive relapse. CONCLUSIONS: We observed high rates of overall and disease specific survival with bladder preservation in patients who achieved a clinically complete response to neoadjuvant chemotherapy. These outcomes support the safety of active surveillance in carefully selected, closely monitored patients with muscle invasive bladder cancer. Future studies should aim to improve patient selection by identifying biomarkers predicting invasive relapse and developing novel imaging methods of early detection.

Discordance between Ureteroscopic Biopsy and Final Pathology for Upper Tract Urothelial Carcinoma.

PURPOSE: We evaluated the discordance between ureteroscopic biopsy and surgical pathology findings for grading and staging upper tract urothelial carcinoma. We also sought to establish preoperative predictors of aggressive tumors. MATERIALS AND METHODS: We retrospectively reviewed the records of 314 patients who underwent ureteroscopic biopsy followed by surgical management of upper tract urothelial carcinoma from 2000 to 2016 at a total of 3 institutions. Our primary outcomes were muscle invasive (pT2 or greater) disease at surgical pathology and upgrading of clinical low grade tumors to pathological high grade. RESULTS: At biopsy 61% of the patients had clinical high grade tumors and 21% had subepithelial connective tissue invasion (cT1+). On final pathology 79% of the patients had pathological high grade tumors and 45% had stage pT2 or greater. On multivariate analysis advanced patient age, clinical high grade and cT1+ were independently associated with pT2 or greater. The combined presence of clinical high grade and cT1+ had 86% positive predictive value for muscle invasion while the combined absence of clinical high grade and cT1+ had 80% negative predictive value. The likelihood of missing invasion on biopsy in patients with muscle invasive disease was increased when biopsy fragments were limited to 1 mm or less. Of clinical low grade cases on biopsy 51% were upgraded at surgery. The presence of positive urine cytology was associated with an increased risk of upgrading but this was not statistically significant. CONCLUSIONS: Clinical high grade, cT1+ on biopsy and advanced patient age are independent risk factors for muscle invasive upper tract urothelial carcinoma. There is a significant risk of upgrading in patients with clinical low grade tumors on biopsy, especially when urine cytology is positive. The predictive value of biopsy can likely be improved by more extensive ureteroscopic sampling.

Contemporary treatment patterns and outcomes of sarcomatoid bladder cancer.

PURPOSE: To characterize the treatment patterns and survival outcomes of sarcomatoid bladder cancer, a rare urothelial variant histology using a large population level cancer database. METHODS: The National Cancer Database was queried for all cases of sarcomatoid bladder cancer using International Classification of Disease-O-3 morphologic code 8122 between 2004 and 2014. Primary outcome was overall survival. RESULTS: A total of 489 patients met our inclusion criteria and were included in our analysis. Average age at diagnosis was 70.4 years. The majority of the population was male (61.8%) and Caucasian (92.2%). Tumor characteristics included 23.7% cT1, 41.1% cT2 and 15.3% cT3 or above. Median overall survival was 18.4 months (95% CI 13.3-23.6). On multivariate Cox proportional analysis, radical cystectomy alone or with multimodal therapy (chemotherapy or radiotherapy) resulted in a statistically significant reduction in the risk of death as compared to bladder preservation surgery alone. Survival in the radical cystectomy group did not differ between radical cystectomy alone and those receiving either neoadjuvant or adjuvant chemotherapy. CONCLUSIONS: Sarcomatoid bladder cancer has poor prognosis with 18.4-month median overall survival. While our data suggest that aggressive treatment improves outcomes, the role of multimodal therapy is unclear. Future study should continue to focus on multi-institutional collaboration to determine the most effective therapy.

Vesicovaginal fistulas in the developed world: An analysis of disease characteristics, treatments, and complications of surgical repair using the ACS-NSQIP database.

AIMS: To analyze patient characteristics, complications, and surgical trends in vesicovaginal fistulas (VVF) from a national database. METHODS: Current Procedural Terminology was used to identify patients undergoing VVF repair from the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) database. Characteristics and treatments were identified. Logistic regression was used to identify characteristics associated with complications. RESULTS: From 2006 to 2013, 200 patients underwent VVF repair. Mean age was 50.3 ± 12.3 years. A large proportion of patients were overweight (72%) and recent smokers (30%). Predominant comorbidities were heart disease (29%) and type 2 diabetes (9.5%). Of all VVF repairs, 65% were repaired vaginally. Concomitant procedures included hysterectomy (n = 6), reconstructive flaps (n = 13), and slings (n = 2). Post-operative complications occurred in 15% of patients. The most common complication was urinary tract infection (8%) followed by blood transfusion (3%). Compared to the vaginal approach, abdominal VVF repairs had higher overall morbidity (22% vs 7% P = 0.003), longer length of stay (3.5 ± 2.3 vs 1.6 ± 2 days P = 0.00) and were more likely to be associated with sepsis (4.3% vs 0% P = 0.02), blood transfusion (7.1% vs 0.8% P = 0.017), and readmission (10.1% vs 0.8% P = 0.003). In multivariate analysis, abdominal approach was a significant predictor of complications within 30 days (P = 0.03, P = 0.02). CONCLUSIONS: In the US VVF remains a rare entity. Over half of VVFs were repaired vaginally. The occurrence of serious complications is low. A vaginal approach appears to be associated with fewer complications.

Radical Prostatectomy for High-risk Localized or Node-Positive Prostate Cancer: Removing the Primary.

PURPOSE OF REVIEW: We reviewed the literature to determine what role, if any, radical prostatectomy should play in the treatment of high-risk and/or node-positive prostate cancer. RECENT FINDINGS: The AUA, NCCN, and EAU all include radical prostatectomy as a treatment option for high-risk prostate cancer based on evidence that has shown improvements in biochemical-free and disease-specific survival. Lymph node-positive patients may also derive benefit from radical prostatectomy with lymph node dissection, however, only retrospective studies with high risk of selection bias have been published to date. High-risk prostate cancer is a heterogeneous disease representing a wide range of disease characteristics. Radical surgery, historically avoided in such patients, may now be considered a valid treatment option for select cases. The adverse effects of surgery using modern techniques lead to similar quality of life outcomes as radiation therapy, and treatment of the primary tumor is likely beneficial when compared to ADT alone.

Predictors of biochemical recurrence in pT3b prostate cancer after radical prostatectomy without adjuvant radiotherapy.

BACKGROUND: Men with pathologic evidence of seminal vesicle invasion (SVI) at radical prostatectomy (RP) have higher rates of biochemical recurrence (BCR) and mortality. Adjuvant radiotherapy (XRT) has been shown to increase freedom from BCR, but its impact on overall survival is controversial and it may represent overtreatment for some. The present study, therefore, sought to identify men with SVI at higher risk for BCR after RP in the absence of adjuvant XRT. METHODS: We identified 180 patients in our institutional database who underwent RP from 1990 to 2011 who had pT3bN0-1 disease. The Kaplan-Meier method was used to estimate freedom from BCR for the overall cohort and substratified by Gleason score, PSA, surgical margin status, and lymph node positivity. Cox Proportional Hazards models were used to determine demographic and histopathological factors predictive of BCR. Time-dependent ROC curve analysis was conducted to assess the ability of the UCSF-CAPRA score to predict BCR. RESULTS: Median age was 64 years, and 52.8% of patients were preoperative D'Amico high risk. At RP, 41.4% had a positive surgical margin (PSM), and 12.2% had positive lymph nodes (LN). The most common sites of PSM were the peripheral zone (56.8%) and the apex (32.4%). Positive bladder neck margin (HR = 7.01, P = 0.035) and PSA 10-20 versus ≤10 (HR = 1.63, P = 0.047) predicted higher BCR in multivariable analyses. Median follow-up was 26 months, and 2-, 3-, and 5-year BCR-free rates were 56.1%, 49.0%, and 39.5%. Log rank tests showed that freedom from BCR was significantly less for Gleason 9-10, PSA >20, PSM, and N1 patients. The area under curve (AUC) for CAPRA in predicting BCR was 0.713 at 2 years, 0.692 at 3 years, and 0.641 at 5 years. Increasing CAPRA score was associated with an increased risk of BCR (HR = 1.33, P < 0.001). CONCLUSIONS: pT3b prostate cancer is a heterogeneous disease commonly associated with several high-risk features. Stratifying men with SVI by prognostic features (i.e., Gleason, PSA, node status, surgical margin status) and using these features to augment the CAPRA score will improve identification of those at higher risk for BCR that should be strongly considered for adjuvant XRT.

Perioperative blood transfusion predicts short term morbidity after nephrectomy.

INTRODUCTION: To assess 30-day morbidity and mortality following partial nephrectomy (PN) and radical nephrectomy (RN) with relation to the administration of perioperative blood transfusions PBT). MATERIALS AND METHODS: The National Surgical Quality Improvement Program was queried for patients with malignant renal tumors (International Classification of Diseases Ninth Revision codes 189-189.2) who underwent RN (Current Procedure Terminology codes 50220, 50225, 50230, 50234, 50236, 50545, 50546, 50548) or PN (50240, 50543) between 2005-2013. Patients were stratified by transfusion status and assessed for postoperative outcomes both separately and in composite, including morbidity, mortality, infectious complications, and pulmonary complications. Univariate and multivariate analyses were performed to identify significant independent predictors of these composite outcomes. RESULTS: The overall transfusion rates were 15.8% and 8.2% for RN and PN, respectively. On multivariate analysis, PBT was associated with increased morbidity (RN: OR 2.147, 95% CI 1.687-2.733; PN: OR 2.081, 95% CI 1.434-3.022), mortality (RN: OR 2.308, 95% CI 1.159-4.598; PN: OR 5.166, 95% CI 1.207-22.12), infectious complications (RN: OR 1.656, 95% CI 1.151-2.383; PN: OR 1.945, 95% CI 1.128-3.354) and pulmonary complications (RN: OR 3.040, 95% CI 2.125-4.349; OR 3.771, 95% CI 2.108-6.746). CONCLUSIONS: For patients undergoing RN or PN there is a significant association between receipt of PBT and 30-day postoperative outcomes, specifically overall morbidity, mortality, infectious complications, and pulmonary complications. The mechanism that underlies these effects has not been elucidated, but it most likely involves immunomodulation and acute lung injury. Future research should focus on formulating comprehensive transfusion guidelines for oncologic-related nephrectomies.

Perioperative blood transfusion in radical cystectomy: Analysis of the National Surgical Quality Improvement Program database.

OBJECTIVES: To determine whether perioperative blood transfusion is associated with worse 30-day postoperative outcomes in radical cystectomy patients. METHODS: Utilizing the National Surgical Quality Improvement Program database, we identified 2934 patients diagnosed with bladder cancer (International Classification of Diseases Ninth Revision codes 188-188.9) who underwent radical cystectomy (Current Procedure Terminology codes 51570, 51575, 51580, 51585, 51590, 51595, 51596) between 2005 and 2013. Patients were stratified by transfusion status and assessed based on four composite postoperative outcomes: morbidity, surgical site infection, mortality and readmission. Multivariate regression models were used to determine significant independent predictors of the composite outcomes. RESULTS: Overall, 40.1% of patients received a transfusion, and there were significant differences in baseline variables such as age, sex, body mass index, smoking history and comorbidities. Transfusion was associated with increased morbidity, surgical site infection, readmission, operative time and length of stay on unadjusted analyses. On multivariate regression, transfusion was associated with increased morbidity (OR 1.361, 95% CI 1.131-1.638) and surgical site infection (OR 1.371, 95% CI 1.070-1.757). CONCLUSIONS: Perioperative blood transfusion is associated with increased risk of postoperative infection and morbidity. Previous work in this area has focused on negative long-term oncological outcomes, but this is the first study to examine short-term postoperative outcomes. Future research should focus on the immunosuppressive mechanism of perioperative blood transfusion and on restrictive transfusion guidelines for oncology patients.

Predicting Renal Parenchymal Loss after Nephron Sparing Surgery.

PURPOSE: We analyze the relationship among various patient, operative and tumor characteristics to determine which factors correlate with renal parenchymal volume loss after nephron sparing surgery using a novel 3-dimensional volume assessment. MATERIALS AND METHODS: We conducted a retrospective review of an institutional database of patients who underwent nephron sparing surgery from 1992 to 2014 for a localized renal mass. Tumors were classified according to the R.E.N.A.L. nephrometry system. Using 3-dimensional reconstruction imaging software, preoperative and postoperative renal parenchymal volume was calculated for the ipsilateral and contralateral kidney. RESULTS: A total of 158 patients were analyzed. Mean patient age was 58.7 years and mean followup was 40.1 months. Mean preoperative tumor volume was 34.0 cc and mean tumor dimension was 3.4 cm. Mean R.E.N.A.L. nephrometry score was 6.2, with 60.1%, 34.2% and 5.7% of tumors classified as low, medium and high complexity, respectively. Mean change in renal parenchymal volume after nephron sparing surgery was -15.3% for the ipsilateral kidney and -6.8% for total kidney volume. On univariate analysis ischemia time, tumor size, R.E.N.A.L. nephrometry score, complexity grouping and the individual nephrometry components of tumor size, percent exophytic, anterior/posterior, depth and tumor proximity to the renal artery or vein were associated with greater renal parenchymal volume loss. On multivariate analysis only ischemia time, tumor size, posterior location and percent exophytic were independently associated with more renal parenchymal volume loss. CONCLUSIONS: Using precise 3-dimensional volumetric analysis we found that ischemia time, tumor size and endophytic/exophytic properties of a localized renal mass are the most important determinants of renal parenchymal volume loss.

It's complicated: The relationship of non-narcotic medications and postoperative opioid use in radical cystectomy patients.

INTRODUCTION: The effect of individual non-narcotic analgesics in cystectomy enhanced recovery after surgery (ERAS) is unknown. Additionally, many non-narcotic medications are associated with side effects pertinent to the cystectomy population. To better understand the actual use and utility of these medications, we sought to characterize the association between non-narcotic medications and milligram morphine equivalent (MME) narcotic score during the postoperative inpatient stay. METHODS: We reviewed 260 consecutive ERAS cystectomy patients. The MME impact of non-narcotic compliance and cumulative dose of medication received was evaluated separately with general linear models. We also assessed relationship of non-narcotic compliance to patient reported pain score, length of stay (LOS), and time to return of bowel function (ROBF) and performed manual review of postoperative documentation to identify reasons for medication noncompliance. RESULTS: Compliance with postoperative acetaminophen, gabapentin, and ketorolac was low. There was an inverse relationship between ketorolac dose and MME on postoperative day 1 (-0.026 MME/mg; P = 0.004) and postoperative day 2 (-0.33 MME/mg; P < 0.001). Compliance with ketorolac was associated with lower MME on postoperative day 1 (26.1 MME v. 33.6 MME; P = 0.023). There were no such associations identified with gabapentin or acetaminophen. Gabapentin compliance was associated with earlier ROBF (3.7 days v. 4.3 days; P = 0.006). Ketorolac compliance was associated with lower pain score on POD1 (3.25 VAS v. 4.07 VAS; P = 0.019) and POD2 (3.05 VAS v. 3.85 VAS; P = 0.040) There was no association between medication compliance and LOS. The most common reasons identified for non-compliance with gabapentin and ketorolac were renal function concerns (38% and 40% respectively), bleeding concerns with ketorolac (20%) and concerns for neurologic adverse effect with gabapentin (16%). CONCLUSION: Compliance with non-narcotic medications in our ERAS cystectomy protocol was poor. There was a modest association with ketorolac and postoperative MME but no association with gabapentin or acetaminophen. Further study will clarify the role of these medications for cystectomy patients. Component specific analysis of protocolized care is valuable and may alter care pathways.

Impact of Socioeconomic Status on Patient Adherence in Managing Renal Masses.

INTRODUCTION: Previous literature suggests socioeconomic status and racial disparities impact management decisions for patients with small renal masses. We aim to build upon these findings and examine how these modalities impact patient adherence to their management plan. METHODS: This retrospective study analyzed our Kidney Tumor Program database (n = 1476) containing patients from 2000 to 2020. Socioeconomic status was estimated using 2 modalities: Area Deprivation Index and household income. Patients were then evaluated for differences in adherence, nonadherence, and loss to follow-up. Adherent patients completed all recommended appointments within 6 months of their initial follow-up. Nonadherent patients did not complete all recommended appointments within 6 months of their originally scheduled follow-up but eventually did. Patients lost to follow-up were recommended to follow up but never did. RESULTS: Patient adherence was not significantly different across sex or primary treatment method but differed with respect to race/ethnicity. Black patients were significantly more likely to be nonadherent (P = .021) and lost to follow-up (P = .008). After adjusting for race/ethnicity, Area Deprivation Index and income bracket were significantly associated with adherence and loss to follow-up. Patients with a high socioeconomic status had significantly higher rates of adherence (ADI, quartile [Q] 1 vs Q4, P = .038; income, >$120,000 vs $30,000-$59,999, P < .003) and decreased loss to follow-up (ADI, Q1 vs Q4, P = .03; income, >$120,000 vs $30,000-$59,999, P = .002). CONCLUSIONS: Our results demonstrate that Black race and low socioeconomic status are associated with decreased adherence and increased loss to follow-up. Possible strategies to target these disparities include financial assistance programming, social determinants of health screening, and nurse navigator programs.

Low co-expression of PD-L1 and oncogenic receptor tyrosine kinases HER2 and cMET in urothelial carcinoma is associated with discordant expression between primary and metastatic sites.

OBJECTIVES: Novel regimens targeting immune checkpoints and the cMET or HER2 pathways are under investigation in metastatic urothelial carcinoma (mUC) though co-expression of these molecular targets has not been defined. We sought to characterize the protein co-expression rates of PD-L1, cMET and HER2 in primary and metastatic mUC lesions and agreement rates in paired biopsies. MATERIALS AND METHODS: We assessed PD-L1, cMET and HER2 protein expression by immunohistochemistry (IHC) in archival mUC samples identified from an institutional database (n = 143). Correlation of expression between primary and metastatic biopsies was performed in patients with available paired biopsies (n = 79). Protein expression levels by predefined thresholds were measured, and Cohen's kappa statistics (κ) were utilized to assess the agreement in expression between paired primary and metastatic samples. RESULTS: In primary tumors (n = 85), high expression of PD-L1, cMET, and HER2 was observed in 14.1%, 34.1%, and 12.9%, respectively. In metastatic samples (n = 143), high expression of PD-L1, cMET and HER2 was detected in 9.8%, 41.3%, and 9.8%, respectively. Expression agreement rates between paired specimens (n = 79) were PD-L1: 79.7% (κ = 0.09), cMET: 69.6% (κ = 0.35), HER2: 84.8% (κ = 0.17). High PD-L1/cMET co-expression was observed in only 5.1% (n = 4) of primary and 4.9% (n = 7) of metastatic specimens. High co-expression of PD-L1/HER2 occurred in 3.8% (n = 3) of primary samples and no metastatic samples. The overall co-expression agreement between paired samples was 55.7% (κ = 0.22) for PD-L1/cMET and 67.1% (κ = 0.06) for PD-L1/HER2, but agreement for high co-expression between paired samples was very low (2.5% for PD-L1/cMET and 0% for PD-L1/HER2). CONCLUSIONS: Tumor co-expression of high cMET or HER2 and PD-L1 is low in this cohort. Agreement of high co-expression between primary and metastatic sites is rare. Biomarker-based strategies used in selection of patients for contemporary trials testing combinations of immune checkpoint inhibitors with either cMET or HER2-targeted agents should account for discordant biomarker expression between primary and metastatic sites.

Persistent opioid and benzodiazepine use after radical cystectomy in enhanced recovery after surgery (ERAS) patients.

OBJECTIVES: Opioid use, misuse, and diversion is of paramount concern in the United States. Radical cystectomy is typically managed with some component of opioid pain control. We evaluated persistent opioid and benzodiazepine use after radical cystectomy and assessed the impact of their preoperative use on this outcome. We also explored associations between preoperative use and perioperative outcomes. METHODS AND MATERIALS: We used prospectively maintained data from our enhanced recovery after surgery (ERAS) cystectomy database and the Prescription Reporting with Immediate Medication Utilization Mapping (PRIMUM) database to identify controlled substance prescriptions for radical cystectomy patients. We separated patients by frequency of preoperative opioid and/or benzodiazepine prescriptions (0, 1, 2+) and used these cohorts to explore persistent use (prescription 3-12 months after surgery) alongside perioperative outcomes. RESULTS: Our cohort included 257 patients undergoing cystectomy at a single institution from 2017 to 2021. Preoperative opioid and benzodiazepine prescriptions were documented for 120 (46.7%) and 26 (10.1%) patients, respectively. Persistent opioid use was observed in 20 (14.6%) of opioid-naive patients (no prescriptions in 9 months prior to surgery) while 13 (19.7%) patients with 1 preoperative prescription and 28 (51.9%) patients with 2 or more preoperative prescriptions demonstrated persistent use. New persistent benzodiazepine use occurred in 6 (2.6%) patients. Overall persistent benzodiazepine use was present in 11 (4.3%) patients. In a multivariable model, preoperative opioid and benzodiazepine prescriptions were associated with persistent opioid use (P < 0.001; P = 0.027 respectively). No association was identified between preoperative opioid or benzodiazepine usage and perioperative outcomes including length of stay, return of bowel function, inpatient opioid usage, inpatient or discharge complications, readmissions, or emergency department visits. Inpatient pain scores were noted to be higher in patients with ≥ 2 preoperative opioid prescriptions (P = 0.037). CONCLUSIONS: Persistent opioid use was present in 23.7% of patients, with a new persistent use rate of 14.6%. Benzodiazepine use was less frequent than opioids, with a small number demonstrating new persistent use. Preoperative opioid and benzodiazepine use is associated with persistent opioid use postoperatively. Preoperative opioid and benzodiazepine use did not affect perioperative outcomes in our cohort.

Prognostic value of galectin-1 and galectin-3 expression in localized urothelial bladder cancer.

Background: Galectin-1 (Gal-1) and Galectin-3 (Gal-3) are carbohydrate binding proteins with a wide range of biological activity, including regulation of cellular adhesion, proliferation, and apoptosis in solid tumors. Prior small studies have reported that Gal-3 expression is associated with progression of disease in urothelial carcinoma (UC), from non-muscle invasive UC progression to muscle invasive UC. We assessed Gal-1 and Gal-3 protein expression H-score utilizing a tissue microarray (TMA) created from 301 cystectomy specimens. Methods: Immunohistochemistry for Gal-1 and Gal-3 was performed on TMA generated from tumor blocks from chemotherapy naïve cystectomy specimens. The variable of interest, H-score, was defined as the product of the percentage of cells staining positive (0-100) and intensity score (0-3) scored by a single pathologist. Survival end points were analyzed using Kaplan-Meier and Cox Proportional Hazards methods. Clinical data including Charlson Comorbidity Index (CCI), pathologic tumor (T) stage, tumor size, node stage, and surgical margins, were included in multivariable analysis. Results: We found that Gal-1 and Gal-3 expression correlated with intratumoral T stage (median Gal-1 H-score was 0 across non-invasive tissue types and 200 in invasive, P<0.01 and median Gal-3 score was 270 across non-invasive tissue types and 70 in invasive, P<0.01). However, the highest intratumoral H-score per cystectomy core did not independently predict for recurrence-free survival (RFS) (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.65) or OS (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.72) in this cohort. Significant intratumoral heterogeneity was present for both Gal-1 and Gal-3, with an average difference between the highest and lowest H score was 95 for Gal-1 and 109 for Gal-3 for cystectomy specimens with more than one biopsy. Conclusions: Gal-1 and Gal-3 H-score per bladder did not independently predict for RFS or OS. Intra-tumoral Gal-1/Gal-3 heterogeneity complicates the use of Gal-1 and Gal-3 expression as a prognostic biomarker. Future studies should consider the evaluation of serum and urinary galectins as an approach to mitigate tumor heterogeneity.