Natural History and Genomic Landscape of Chemotherapy-Resistant Muscle-Invasive Bladder Cancer.

PURPOSE: Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials. METHODS: Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients. RESULTS: Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors. CONCLUSION: Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

Evaluation of sarcopenia in patients receiving intravesical Bacillus Calmette-Guérin for non-muscle invasive bladder cancer.

BACKGROUND: Sarcopenia is associated with adverse outcomes for patients with muscle invasive bladder cancer (MIBC), but less is known about its impact in the setting of non-muscle invasive bladder cancer (NMIBC). Sarcopenia, skeletal muscle density, and adipose tissue area have been studied as markers of malnutrition and can be determined radiographically. The purpose of this study is to characterize the prevalence of sarcopenia in patients with NMIBC receiving intravesical Bacillus Calmette-Guérin (BCG). METHODS: Following institutional review board approval, patients with NMIBC having received intravesical BCG were identified using institutional pharmacy records. Patients having undergone computed tomography (CT) of the abdomen and pelvis within 90 days of treatment were included in the analysis. Using sliceOmatic 5.0 software, skeletal muscle area (cm2) was measured at the L3 level to calculate skeletal muscle index (SMI), a marker of sarcopenia. Subcutaneous, visceral, and intramuscular adipose tissue areas in addition to skeletal muscle density were also measured. Frailty was evaluated as a secondary aim using the 5-Item Modified Frailty Index (mFI-5). Using predefined cutoffs, the prevalence of sarcopenia was determined. Descriptive statistics were used to characterize frailty and secondary body composition characteristics. Statistical analysis was performed to evaluate the impact of sarcopenia on recurrence rate and progression. RESULTS: A total of 308 patients having received BCG between 2015 and 2020 were identified, of which 90 met criteria for analysis. Nearly all (94%) patients completed at least 5 out of 6 BCG induction instillations. Median body mass index (kg/m2) was 27.64 (IQR 24.9, 30.5) for females and 27.7 (IQR 24.9, 30.66) for males. Median SMI (cm2/m2) was 49.44 (IQR 39.39, 55.17) for females and 49.58 (IQR 40.25, 55.58) for males. A majority (61%) of patients were found to be sarcopenic. High-risk frailty was identified 36% of patients. There was no association between sarcopenia and recurrence rate or progression. CONCLUSIONS: Sarcopenia and frailty are highly prevalent amongst patients with NMIBC. A diagnosis of NMIBC represents a window of opportunity to identify and intervene on modifiable risk factors such as sarcopenia and frailty, which are associated with adverse outcomes in more advanced disease states.

Infertility Counseling and Misattributed Paternity: When Should Physicians Become Involved in Family Affairs?

Infertility specialists may be confronted with the ethical dilemma of whether to disclose misattributed paternity (MP). Physicians should be prepared for instances when an assumed father's evaluation reveals a condition known for lifelong infertility, for example, congenital bilateral absence of vas deferens (CBAVD). When there is doubt regarding a patient's comprehension of his diagnosis, physicians must consider whether further disclosure is warranted. This article describes a case of MP with ethics analysis that concludes that limited nondisclosure is most consistent with a physician's principled duties to inform, to respect patients' autonomy, and to employ nonmaleficence (including the avoidance of psychosocial harms).

Effect of prior radiation on stage, differentiation, and survival in bladder cancer.

PURPOSE: Clinically significant differences in radiation-related bladder tumors are not well-characterized, and survival analyses are needed. In this study, we aimed to utilize a national cancer database to evaluate the effect of prior radiation on tumor characteristics and survival in bladder cancer patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) 9 database was queried to identify patients diagnosed with bladder cancer as a second malignancy. Patients having undergone radiation prior to developing bladder cancer were selected for comparative analysis. Logistic regression was used to generate odds ratios to evaluate differences in differentiation, stage, grade, and tumor size. Kaplan-Meier analysis and Cox non-proportional hazards regression models were used to assess the association between previous radiation and bladder cancer survival. RESULTS: A total of 25,408 patients were identified, of which 14,570 patients had sufficient data for analysis. Of these, 5968 (41.0%) received radiation for their primary malignancy. Prior radiation conferred a lower risk of developing moderately- or poorly-differentiated bladder tumors and muscle invasive or node-positive disease. An increased risk of squamous cell carcinoma was noted (OR 1.43, CI 1.06-1.93). Prior radiation led to an increased risk of bladder cancer-specific (HR 1.13, CI 1.03-1.24) mortality at 5 years. The greatest effect of prior radiation was an increased risk of bladder cancer-specific mortality for carcinoma in situ at 5 years (OR 2.37, CI 1.45-3.86). CONCLUSION: Prior radiation is associated with lower grade and stage of bladder tumors in addition to worse cancer-specific survival.

Genitourinary complications in orthopaedic surgery.

Genitourinary complications following orthopaedic intervention are uncommon but well-described occurrences and exist on a spectrum of severity. These complications vary depending on the anatomic location and surgical approach, with surgery of the spine, hip, and pelvis of particular concern. Injuries to the urinary tract may present acutely with urinary retention or hematuria. However, they often have a delayed presentation with severe complications such as urinary fistula and recurrent infection. Delayed presentations may place the onus of timely and proper diagnosis on the orthopaedic provider, who may serve as the patient's primary source of long-term follow-up. Detailed knowledge of anatomy and at-risk structures is key to both preventing and identifying injury. Although iatrogenic injury is not always avoidable, early identification can help to facilitate timely evaluation and management to prevent long-term complications such as bladder dysfunction, obstructive renal injury, sexual dysfunction, and chronic pain.  Keywords: urologic injury, bladder injury, genitourinary injury, hip arthroplasty, pelvic ring injuries, spine surgery.

Patient Preferences Regarding Chaperone Use for Sensitive Examinations.

INTRODUCTION: Chaperones are often employed during sensitive patient encounters and have been assumed to be mutually beneficial to the patient and provider. The aim of this study is to characterize patient preferences regarding the use of chaperones. METHODS: Following Institutional Review Board Approval, a questionnaire designed to evaluate preferences regarding chaperone use from a patient perspective was distributed electronically through the ResearchMatch platform as well as to patients in an outpatient urology clinic. Descriptive statistics were used to assess responder demographics, clinical experiences and preferences. Multiple regression analysis was used to determine factors associated with a preference for having a chaperone present during health care visits. RESULTS: A total of 913 individuals completed the survey. Over half (52.9%) reported they would not want a chaperone for any part of a health care visit. Although rectal and genital/pelvic examinations were considered sensitive by 76.3% and 85% of responders, respectively, only 25.4% and 15.7% preferred a chaperone during these encounters. Reasons for not wanting a chaperone included trust in the provider (80%) and comfort with examinations (70.4%). Male responders were less likely to report a preference for a chaperone (OR 0.28, 95% CI 0.19-0.39) or consider provider gender as a significant factor in preferring a chaperone (OR 0.28, 95% CI 0.09-0.66). CONCLUSIONS: Preference regarding the use of a chaperone is primarily influenced by gender of both the patient and the provider. For sensitive examinations commonly performed in the field of urology, most individuals would not prefer a chaperone be present.

Impact of Fellowship-Trained Andrology and Sexual Medicine Specialists on Performance on the Annual American Urological Association In-Service Examination.

OBJECTIVE: To demonstrate the distribution and impact of fellowship-trained andrology and/or sexual medicine urological specialists (FTAUS) on resident in-service examination (ISE) performance. METHODS: Residency program websites were accessed to create a database of FTAUS in the United States between 2007 and 2017. This database was reviewed by three separate FTAUS and cross referenced with membership lists to the Sexual Medicine of North America Society and the Society for the Study of Male Reproduction. De-identified ISE scores were obtained from the American Urological Association from 2007-2017 and scores from trainees at programs with a FTAUS were identified for comparison. Resident performance was analyzed using a linear model of the effect of a resident being at a program with an FTAUS, adjusting for post-graduate year. RESULTS: ISE data from 13,757 residents were obtained for the years 2007-2017. The number of FTAUS in the United States increased from 40-102 during this study period. Mean raw scores on the "Sexual Dysfunction, Endocrinopathy, Fertility Problems" (SDEFP) section of the ISE ranged from 52.1% ± 17.7% to 65.7% ± 16% (mean ± SD). Throughout the study period, there was no difference in performance within the SDEFP section (P < .01). Residents at a program with a FTAUS answered 0.95% more questions correctly in the SDEFP than those without a FTAUS (P < .001). For these residents, there was an improvement of approximately 0.66% on the percentage of questions answered correctly on the ISE overall (P < .001). Performance improved significantly as residents progressed from PGY-2-PGY-5. CONCLUSION: There is a small but statistically significant improvement in overall ISE and SDEFP sub-section performance.

Optimizing Nutritional Status in Patients Undergoing Radical Cystectomy: A Systematic Scoping Review.

BACKGROUND: Nutrition is a modifiable risk factor for patients undergoing multimodal oncologic interventions and plays a major supportive role in the setting of bladder cancer. For patients undergoing radical cystectomy (RC), malnutrition is associated with increased postoperative complications and mortality. OBJECTIVES: The purpose of this scoping review is to characterize the role of nutritional interventions for patients undergoing RC for bladder cancer. METHODS: A multi-database systematic scoping review based on the Preferred Reporting Items for Systematic Reviews extension for Scoping Reviews (PRISMA-ScR) guidelines was performed. Search terms were developed a priori to identify clinical trials that focused on nutritional interventions for patients with bladder cancer undergoing RC. Eligible articles were original research articles or abstracts from clinical trials evaluating nutritional interventions in adult patients undergoing RC. Articles were excluded if they did not focus on a nutritional intervention, if patients did not carry a diagnosis of bladder cancer, or if RC was not performed. Articles were reviewed independently by the authors, and inclusion/exclusion were based on consensus agreement. RESULTS: A total of 83 articles were identified, of which 17 were included in the final analysis. A total of 49 articles were excluded during abstract screening. An additional 17 articles were excluded based on the review of full-text articles. Results of the scoping review suggest that data on the use of nutritional screening, assessment, and intervention for patients undergoing RC are scarce. Although parenteral nutrition (PN) appears to be associated with greater complications after RC, early introduction of food postoperatively or feeding enterally offers benefit and immunonutrition supplements with a focus on a high protein diet has the potential to better optimize surgical outcomes. CONCLUSIONS: Although the prevalence and consequences of malnutrition among patients undergoing RC are well-established, there are limited data evaluating the use of nutritional screening, assessment, and interventions for this population. The pursuit of future clinical trials in this space is critical.

Near-Miss Diagnoses of Solitary Bladder Tumors Highlight the Importance of Immunohistochemical Staining.

We report three cases of prostate adenocarcinoma appearing as bladder masses and misdiagnosed as muscle-invasive bladder cancer (MIBC). Patients were referred for consideration for radical cystectomy after initial pathological diagnosis suggested poorly differentiated bladder cancer. Pathological review of tissue samples and subsequent immunohistochemical (IHC) staining confirmed advanced prostatic adenocarcinoma. Systemic therapy for prostate cancer was then initiated. These cases highlight the importance of patient history, physical exam, and IHC staining in consideration of a bladder mass, as these patients may have been subject to undue morbidity and surgical intervention without accurate pathologic diagnosis.

A novel role for acid-sensing ion channels in Pavlovian reward conditioning.

Pavlovian fear conditioning has been shown to depend on acid-sensing ion channel-1A (ASIC1A); however, it is unknown whether conditioning to rewarding stimuli also depends on ASIC1A. Here, we tested the hypothesis that ASIC1A contributes to Pavlovian conditioning to a non-drug reward. We found effects of ASIC1A disruption depended on the relationship between the conditional stimulus (CS) and the unconditional stimulus (US), which was varied between five experiments. In experiment 1, when the CS preceded the US signaling an upcoming reward, Asic1a-/- mice exhibited a deficit in conditioning compared to Asic1a+/+ mice. Alternatively, in experiment 2, when the CS coinitiated with the US and signaled immediate reward availability, the Asic1a-/- mice exhibited an increase in conditioned responses compared to Asic1a+/+ mice, which contrasted with the deficits in the first experiment. Furthermore, in experiments 3 and 4, when the CS partially overlapped in time with the US, or the CS was shortened and coinitiated with the US, the Asic1a-/- mice did not differ from control mice. The contrasting outcomes were likely because of differences in conditioning because in experiment 5 neither the Asic1a-/- nor Asic1a+/+ mice acquired conditioned responses when the CS and US were explicitly unpaired. Taken together, these results suggest that the effects of ASIC1A disruption on reward conditioning depend on the temporal relationship between the CS and US. Furthermore, these results suggest that ASIC1A plays a critical, yet nuanced role in Pavlovian conditioning. More research will be needed to deconstruct the roles of ASIC1A in these fundamental forms of learning and memory.

'The eyes see what the mind knows.' Adult-onset Still's disease, a case series and review in a south Asian population.

AIM: Adult-onset Still's disease (AOSD) is a rare disease. Very few cases have been reported from the South-Asian region so the aim of this study is to assess the clinical and laboratory aspects of 15 patients with AOSD in a tertiary referral hospital in Karachi. METHODS: Retrospective data was collected from all patients diagnosed using Yamaguchi criteria for AOSD between January 2004 and December 2010 at Jinnah Medical College Hospital, Karachi. RESULTS: Data of 15 patients with AOSD were analyzed. Their ages ranged from 17 to 55 years, the male-to-female ratio being 6:1. The most common clinical features were fever and articular symptoms (100%), sore throat (60%), rash (53.3%), weight loss (93.3%), lymphadenopathy (40%) and elevated erythrocyte sedimentation rate (86.7%). All patients had leukocytosis with counts>20,000/mm 3 were seen in 40%. Elevated liver enzymes were present in 80% of the case series and hyperferritinemia in 100% with a mean of 3,962 ng/mL (range 555-13,865). Ambiguity in presentation and lack of serologic markers make diagnosis of AOSD difficult as 40% of patients were receiving empirical anti-tuberculous therapy prior to final diagnosis. CONCLUSION: It is necessary for physicians to have a high index of suspicion for AOSD in patients with high-grade fever, arthralgia and leukocytosis.

Emergency department deaths despite active management: experience from a tertiary care centre in a low-income country.

OBJECTIVE: To determine the frequency and causes of ED deaths despite active management, in a tertiary care centre of a low-income country. METHODS: We conducted a retrospective chart review over a 2 year period (January 2001-December 2002) for all patients who died despite active management in an ED in Karachi, Pakistan. RESULTS: Of the 78,418 patient visits, 601 patients (0.7%) were pronounced dead. Of these, 577 patients had complete records. Seventy per cent of these were dead-on-arrival, 1% had do-not-resuscitate orders and 29% (n = 166; 95% confidence interval [CI] 25-32%) died despite active management. Initial vital signs were found to be abnormal in almost all cases (98%). The leading causes of death were sepsis (23%; 95% CI 19-26%), myocardial infarction (19.7%; 95% CI 16-22%), cerebrovascular accident (10.7%; 95% CI 8-13%) and pneumonia (8.2%; 95% CI 6-10%) among adults and sepsis (36.4%; 95% CI 32-40%), myocarditis (15.9%; 95% CI 13-18%) and pneumonia (9.1%; 95% CI 6-11%) among children. CONCLUSION: Sepsis is the leading cause of death in patients of all age groups in the ED of this hospital.