Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced/Metastatic Genitourinary Tumors.

PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.

The impact of metabolic syndrome on short term radical cystectomy complications.

PURPOSE: Radical cystectomy is a highly morbid procedure with short term perioperative complications rates cited to be as high as 60%. Short term perioperative complications have been demonstrated to be more frequent in underweight and overweight patients. We sought to evaluate the impact of metabolic syndrome on surgical outcomes. MATERIALS AND METHODS: We identified 19,071 eligible patients who underwent radical cystectomy for nonmetastatic bladder cancer using the American College of Surgeons National Surgical Quality Improvement Program database between the years 2014 to 2021. The primary exposure was the presence of metabolic syndrome (body mass index >30, hypertension, diabetes) and included 1,566 patients. Our primary outcome was the development of a post operative surgical complication with secondary outcomes of the impact on length of stay, return to operating room, readmission, and 30 day mortality. RESULTS: Metabolic syndrome was associated with an increased rate of complications following radical cystectomy (P < 0.001). Complications were demonstrated in 68% of patients with metabolic syndrome in comparison to 60% of those without. Following multivariable adjustment for relevant demographic, comorbidity, and treatment factors, compared to patients without metabolic syndrome, patients with metabolic syndrome were significantly more likely to experience a complication in the 30 days following cystectomy. Among the secondary outcomes, on multivariable analysis significant differences were found in the risk of readmission and extended length of stay. Critically, the risk of 30 day morbidity was associated with a 1.8 fold increase in those with metabolic syndrome. CONCLUSIONS: Metabolic syndrome demonstrates significantly worse perioperative outcomes following radical cystectomy for bladder cancer.

Role and Results of Constrained Insert in Computer-Assisted Primary Total Knee Arthroplasty: A Propensity-Matched Study.

Purpose: Mild ligament imbalance is often encountered in the mediolateral plane during complex primary total knee arthroplasty. A constrained (CP) polyethylene insert compatible with the primary femur is useful to manage these cases without the need to fall back on revision implants. The aim of the study was to define the correct indications of the use of a CP insert based on objective data from computer assisted surgery and to compare the early results of a CP insert with a standard posterior stabilized (PS) insert through one-to-one propensity score matching. Methods: This is a retrospective case study from a prospectively collected database. One-to-one matching without replacement was used with a caliper width of 0.2 to match the scores between CP (N = 64) and PS groups (N = 1624), resulting in equal covariate matching of PS (N = 64) and CP (N = 64) cohorts. Patients were assessed radiographically and functionally at a minimum follow-up of 3 years. Result: Average coronal and sagittal plane deformities were similar in both the group CP (varus 13.1 ± 5.2 valgus 13 ± 7.9) and the group PS (varus 13.4 ± 4.6 valgus 10.9 ± 8.6). The average residual medial lateral gap difference was significantly higher in group CP (3.8 ± 1.8) in comparison to group PS (1.3 ± 1) (P < .05). A CP insert was chosen where mild ligament imbalance of 3-5 mm persisted after medial soft tissue releases in a varus knee and in cases with residual medial collateral ligament laxity in valgus knees. Conclusions: Constrained insert used with the primary femoral component is a valuable option to handle mild ligamentous instability in complex primary total knee arthroplasty after mechanical alignment is achieved with computer navigation. Level of Evidence: III.

Cancer Surveillance in Solid Organ Transplant Recipients With a Pretransplant History of Malignancy: Multidisciplinary Collaborative Expert Opinion.

With improved medical treatments, the prognosis for many malignancies has improved, and more patients are presenting for transplant evaluation with a history of treated cancer. Solid organ transplant (SOT) recipients with a prior malignancy are at higher risk of posttransplant recurrence or de novo malignancy, and they may require a cancer surveillance program that is individualized to their specific needs. There is a dearth of literature on optimal surveillance strategies specific to SOT recipients. A working group of transplant physicians and cancer-specific specialists met to provide expert opinion recommendations on optimal cancer surveillance after transplantation for patients with a history of malignancy. Surveillance strategies provided are mainly based on general population recurrence risk data, immunosuppression effects, and limited transplant-specific data and should be considered expert opinion based on current knowledge. Prospective studies of cancer-specific surveillance models in SOT recipients should be supported to inform posttransplant management of this high-risk population.

Utilization and Timing of Cystoscopy for Hematuria Evaluation by Advanced Practice Providers and Urologists.

OBJECTIVE: To characterize differences between urologists and advanced practice providers (APPs) in the utilization of cystoscopy for hematuria. METHODS: We identified patients initially evaluated for hematuria by a urologist or urology APP between 2015 and 2020 in the MarketScan Research Databases. We determined whether they received a cystoscopy within 6 months of their urology visit and the number of days until cystoscopy. We used multivariable regression to analyze the association between these outcomes and whether the urology clinician was an advanced practice registered nurse (APRN), physician assistant (PA), or urologist. RESULTS: We identified 34,470 patients with microscopic hematuria and 17,328 patients with gross hematuria. Patients evaluated by urologists more often received a same-day cystoscopy than those evaluated by APPs (13% vs 5.8%). The odds that patients evaluated for microscopic and gross hematuria received a cystoscopy were 46.2% and 26.2% lower, respectively, if they were evaluated by an APRN vs a urologist. Patients seeing an APRN for microscopic and gross hematuria also waited approximately 7 and 14 days longer for their cystoscopy, respectively. No differences were observed for patients evaluated by PAs vs urologists. CONCLUSION: Patients evaluated for hematuria by an APRN were less likely to receive a cystoscopy and had a longer wait until the procedure compared to those evaluated by a urologist; however, no differences were observed between PAs and urologists. Better understanding APP integration into urology clinics is warranted.

Necrotizing granulomatous epididymo-orchitis post intravesical BCG administration after brachytherapy for prostate cancer.

Urothelial carcinoma of the bladder remains a challenging disease to treat. Intravesical instillation of BCG has demonstrated tremendous efficacy in preventing recurrence. BCG related necrotizing granulomatous epididymo-orchitis is rare and has not been previously linked to brachytherapy for adenocarcinoma of the prostate. We hypothesize that prior brachytherapy has a deleterious effect on the verumontanum that can result in retrograde transmission of BCG particles leading to granulomatous epididymo-orchitis. This is the first case report of necrotizing granulomatous epididymo-orchitis related to BCG in a patient status post brachytherapy for adenocarcinoma of the prostate.

Standardization of the evaluation and surveillance of patients with BCG unresponsive high grade non-muscle invasive bladder cancer clinical trials.

There are multiple ongoing and planned clinical trials that are evaluating novel therapies to treat patients with BCG-unresponsive high grade nonmuscle invasive bladder cancer (NMIBC). Importantly, there is considerable variation in surveillance strategies between these clinical trials, specifically with regards to the use of advanced imaging, enhanced cystoscopy, and mandatory biopsies, which could impact landmark efficacy assessments of investigational agents. To present guideline recommendations for the standardization of cystoscopic evaluation, surveillance, and efficacy assessments for patients with BCG-unresponsive NMIBC participating in clinical trials. On September 29, 2023 at the annual meeting of the International Bladder Cancer Network, a breakout session was convened, during which representatives from various disciplines discussed potential guidance statements with opportunity for discussion and comment. A set of statements regarding use of white light and enhanced cystoscopy were developed to help guide a pragmatic approach to surveillance and efficacy assessments of patients in clinical trials. The use of "for cause" and "mandatory" biopsies was also addressed. A standard approach to evaluation of patients within the context of clinical trials is necessary to accurately assess the efficacy of novel agents, especially within single arm trials that lack an appropriate comparator. Additionally, the utilization and timing of mandatory biopsies is critical, as these biopsies may impact both disease evaluations and the determination of duration of response.

Functional and oncologic outcomes of prostate capsule-sparing radical cystectomy: A systematic review and meta-analysis.

Radical cystectomy (RC) is the gold standard treatment for patients with organ-confined bladder cancer. However, despite the success of this treatment, many men who undergo orthotopic neobladder substitution develop significant erectile dysfunction and urinary symptoms, including daytime and nighttime urinary incontinence. Prostate-capsule-sparing radical cystectomy (PCS-RC) with orthotopic neobladder (ONB) has been described in the literature as a surgical technique to improve functional outcomes in appropriately selected patients. We performed a systematic review and meta-analysis of manuscripts on PCS-RC with ONB published after 2000. We included retrospective and prospective studies with more than 25 patients and compared PCS-RC with nerve-sparing or conventional RC. Studies in which the entire prostate was spared (including the transitional zone) were excluded. Comparative studies were analyzed to assess rates of daytime continence, nighttime continence, and satisfactory erectile function in patients undergoing PCS-RC compared with those undergoing conventional RC. Fourteen reports were included in the final review. Our data identify high rates of daytime (83%-97%) and nighttime continence (60%-80%) in patients undergoing PCS-RC with ONB. In comparative studies, meta-analysis results demonstrate no difference in daytime continence (RR:1.12; 95% CI: 0.72-1.73) in those undergoing PCS-RC compared to those undergoing conventional RC. Similarly, nighttime continence was similar between the 2 groups (RR:1.85; 95% CI: 0.57-6.00. Erectile function was improved in those undergoing PCS-RC (RR 5.35; 95% CI: 1.82-15.74) in the PCS-RC series. Bladder cancer margin positivity and recurrence rates were similar to those reported in the literature with conventional RC with an average weighted follow-up of 52.2 months. While several studies utilized different prostate cancer (CaP) screening techniques, the rates of CaP were low (incidence 0.02; 95% CI:0.01-0.04), and oncologic outcomes were similar to standard RC. PCS-RC is associated with improved nighttime continence and erectile function compared to conventional RC techniques. Further work is needed to standardize CaP screening before surgery, but the data suggest low rates of CaP with similar oncologic outcomes when compared to RC.

Bladder-Preserving Trimodality Therapy With Capecitabine.

INTRODUCTION: Many patients with muscle-invasive bladder cancer are poor candidates for radical cystectomy or trimodality therapy with maximal transurethral resection of bladder tumor (TURBT) and chemoradiotherapy with cisplatin or mitomycin C. Given the benefit of chemotherapy in bladder-preserving therapy, less-intense concurrent chemotherapy regimens are needed. This study reports on efficacy and toxicity for patients treated with trimodality therapy using single-agent concurrent capecitabine. MATERIALS AND METHODS: Patients deemed ineligible for radical cystectomy or standard chemoradiotherapy by a multidisciplinary tumor board and patients who refused cystectomy were included. Following TURBT, patients received twice-daily capecitabine (goal dose 825 mg/m2) concurrent with radiotherapy to the bladder +/- pelvis depending on nodal staging and patient risk factors. Toxicity was evaluated prospectively in weekly on-treatment visits and follow-up visits by the treating physicians. Descriptive statistics are provided. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival were estimated using the Kaplan-Meier method. RESULTS: Twenty-seven consecutive patients met criteria for inclusion from 2013 to 2023. The median age was 79 with 9 patients staged cT3-4a and 7 staged cN1-3. The rate of complete response in the bladder and pelvis was 93%. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival at 2 years were estimated as 81%, 65%, 91%, 75%, and 92%, respectively. There were 2 bladder recurrences, both noninvasive. There were 7 grade 3 acute hematologic or metabolic events but no other grade 3+ toxicities. CONCLUSION: Maximal TURBT followed by radiotherapy with concurrent capecitabine offers a high rate of bladder control and low rates of acute and late toxicity.

Purple urine bag syndrome: An unusual manifestation of urinary tract infection, our experience at a tertiary care center.

Background: Purple urine bag syndrome (PUBS) is an unusual condition in which a purple discoloration of urine and bag occurs in people with urinary catheters. People with purple urine usually do not complain of any symptoms. The purple discoloration of the urine bag is often the only finding, frequently noted by caregivers. Materials and methods: This prospective observational study was conducted at our tertiary care institute from June 2018 to May 2020. A total of 46 patients with PUBS were included in this study. The objective of our study was to record the prevalence of each predisposing factor and to correlate the pathological mechanism through which the PUBS is manifested. Results: The mean age of PUBS patients was 67.4years and 67.4% were males. Most patients of PUBS (60.9%) had a urethral catheter, while there was percutaneous nephrostomy in 26.1% patients and 13% patients had a percutaneous suprapubic cystostomy catheter. Among the patients, 69.65% were bedridden or in an institutionalized situation, 73.9% were suffering from chronic constipation, 21.7% were associated with dementia, and 47.8% were cerebrovascular accidents with hemiparesis patients. In addition, 93.5% of patients presented with alkaline urine and 3 patients with acidic urine. The most common bacteria isolated in urine culture were E coli and Pseudomonas. Conclusions: Urinary catheter associated urinary tract infection and PUBS is most commonly documented in females, but our study showed that it is more common in males. The appearance of a purple bag does not depend on the material and type of the catheter or the catheterization method. In addition, no correlation was found between the microorganisms isolated from the environment and patients' urine.

The "Wind Surf" Deformity-Correcting Fixed Flexion Deformity and Hyperextension in Bilateral CAS TKA.

Severe knee arthritis can result in complex coronal and sagittal angular deformities. Windswept deformity is used to describe a varus deformity and contralateral valgus deformity. We recognized a new sagittal pattern at the time of computer-assisted surgery (CAS) in total knee arthroplasty (TKA) in which one knee has a fixed flexion deformity (FFD), while the contralateral knee has a hyperextension deformity. We propose to define it as "wind surf" deformity mimicking the opposite pull of the wind and a surfer. The incidence of "wind surf" deformity in this series was 0.96% among a cohort of 2,291 bilateral TKAs performed between 2013 and 2018. Twenty-two patients were identified with an FFD of 5° to 20° on one knee and recurvatum of -5° to -20° on the contralateral knee. Additional bone resection and soft-tissue releases were performed for the FFD with a goal to maintain residual 1° to 3° of flexion. Minimal bone resection and soft-tissue disruption were performed on the knee with hyperextension with a goal to maintain 5° to 7° of flexion. These opposite strategies applied with the help of CAS prevented recurrence resulting in satisfactory clinical results at 2-year follow-up. The "wind surf" deformity variant should be identified in patients presenting with severe knee arthritis to guide surgical treatment, prevent recurrence, and obtain favorable clinical patient outcomes.

IL-15 Superagonist NAI in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer.

BACKGROUND: Patients with Bacillus Calmette­Guérin (BCG)­unresponsive non­muscle-invasive bladder cancer (NMIBC) have limited treatment options. The immune cell­activating interleukin-15 (IL-15) superagonist Nogapendekin alfa inbakicept (NAI), also known as N-803, may act synergistically with BCG to elicit durable complete responses (CRs) in this patient population. METHODS: In this open-label, multicenter study, patients with BCG-unresponsive bladder carcinoma in situ (CIS) with or without Ta/T1 papillary disease were treated with intravesical NAI plus BCG (cohort A) or NAI alone (cohort C). Patients with BCG-unresponsive high-grade Ta/T1 papillary NMIBC also received NAI plus BCG (cohort B). The primary end point was the incidence of CR at the 3- or 6-month assessment visit for cohorts A and C, and the disease-free survival (DFS) rate at 12 months for cohort B. Durability, cystectomy avoidance, progression-free survival, disease-specific survival (DSS), and overall survival were secondary end points for cohort A. RESULTS: In cohort A, CR was achieved in 58 (71%) of 82 patients (95% confidence interval [CI]=59.6 to 80.3; median follow-up, 23.9 months), with a median duration of 26.6 months (95% CI=9.9 months to [upper bound not reached]). At 24 months in patients with CR, the Kaplan­Meier estimated probability of avoiding cystectomy and of DSS was 89.2% and 100%, respectively. In cohort B (n=72), the Kaplan­Meier estimated DFS rate was 55.4% (95% CI=42.0% to 66.8%) at 12 months, with median DFS of 19.3 months (95% CI=7.4 months to [upper bound not reached]). Most treatment-emergent adverse events for patients receiving BCG plus NAI were grade 1 to 2 (86%); three grade 3 immune-related treatment-emergent adverse events occurred. CONCLUSIONS: In patients with BCG-unresponsive bladder carcinoma in situ and papillary NMIBC treated with BCG and the novel agent NAI, CRs were achieved with a persistence of effect, cystectomy avoidance, and 100% bladder cancer­specific survival at 24 months. The study is ongoing, with an estimated target enrollment of 200 participants (Funded by ImmunityBio.)

Flat intraurothelial lesions of the urinary bladder-do hyperplasia, dysplasia, and atypia of unknown significance need to exist as diagnostic entities? and how to handle in routine clinical practice.

Classification of the putative flat preneoplastic and neoplastic lesions of the urothelium with features subthreshold for urothelial carcinoma in situ remains a challenging, indeed, vexing problem in diagnostic surgical pathology. This area, subtending lesions including flat urothelial hyperplasia, urothelial dysplasia, and atypia of unknown significance, has struggled under evolving classifications, changing criteria, and limited clinical actionability, all confounded by the recognized lack of diagnostic reproducibility. Herein, we review the state of the literature around these lesions, reviewing contemporary criteria and definitions, assessing the arguments in favor and against of retaining hyperplasia, dysplasia, and atypia of unknown significance as diagnostic entities. We clarify the intent of the original definitions for dysplasia as a lesion felt to be clearly neoplastic but with morphologic features that fall short of the threshold of urothelial carcinoma in situ. While several pathologists, including some experts in the field, conflate the term dysplasia with urothelial atypia of unknown significance, the latter is defined as a descriptive diagnosis term to express diagnostic uncertainty of a lesion of whether it is clearly reactive or neoplastic. Both molecular studies and clinical needs are considered, as we outline our approach on diagnosing each of these lesions in clinical practice. Recommendations are made to guide consistency and interoperability in future scholarship, and the place of these lesions in context of evolving trends in the field is considered.

Incidence of Preoperative Antibiotic Use and Its Association with Postoperative Infectious Complications after Radical Cystectomy.

OBJECTIVE: To determine exposure rates to antibiotics prior to radical cystectomy and determine if there is correlation with post-operative infections. METHODS AND MATERIALS: 2248 patients were identified in the 2016 SEER-Medicare linkage who underwent radical cystectomy between 2008 and 2014 with complete prescription information. An outpatient prescription for an antibiotic within 30 days prior to cystectomy was considered exposure. Antibiotic class and combinations were recorded. Postoperative infectious diagnoses and readmissions were tabulated within 30 days of cystectomy. RESULTS: Fifty one percent of patients (n = 1149) were prescribed an outpatient antibiotic prior to cystectomy. Patients receiving antibiotics were more likely to be female (31% vs 25%, P < .01) and had been diagnosed with an infection (17% vs 11%, P < .01). Antibiotic bowel prophylaxis was prescribed to 42% of patients receiving antibiotics. Postoperatively, the exposure group had higher rates of any infection, (56% vs 51% P < .01) and UTI (36% vs 31% P < .01). All-cause readmission within 30 days was higher in the exposure cohort (26% vs 22%, P = .02) Multivariable logistic regression showed outpatient preoperative antibiotics were an independent risk factor for any infection (HR 1.19, P < .05) and readmission (hazards ratio 1.24, P = .03) in the 30 days after radical cystectomy. CONCLUSION: Outpatient antibiotic use prior to radical cystectomy is common and may be associated with increased risk of postoperative infection and readmission. Antibiotic use prior to radical cystectomy should be examined as a modifiable factor to decrease post-operative morbidity.

Robotic Nerve Sheath Tumor Resection With Intraoperative Neuromonitoring: Case Series and Systematic Review.

BACKGROUND: Retroperitoneal nerve sheath tumors present a surgical challenge. Despite potential advantages, robotic surgery for these tumors has been limited. Identifying and sparing functional nerve fascicles during resection can be difficult, increasing the risk of neurological morbidity. OBJECTIVE: To review the literature regarding robotic resection of retroperitoneal nerve sheath tumors and retrospectively analyze our experience with robotic resection of these tumors using a manual electromyographic probe to identify and preserve functional nerve fascicles. METHODS: We retrospectively analyzed the clinical courses of 3 patients with retroperitoneal tumors treated at the National Institutes of Health by a multidisciplinary team using the da Vinci Xi system. Parent motor nerve fascicles were identified intraoperatively with a bipolar neurostimulation probe inserted through a manual port, permitting tumor resection with motor fascicle preservation. RESULTS: Two patients with neurofibromatosis type 1 underwent surgery for retroperitoneal neurofibromas located within the iliopsoas muscle, and 1 patient underwent surgery for a pelvic sporadic schwannoma. All tumors were successfully resected, with no complications or postoperative neurological deficits. Preoperative symptoms were improved or resolved in all patients. CONCLUSION: Resection of retroperitoneal nerve sheath tumors confers an excellent prognosis, although their deep location and proximity to vital structures present unique challenges. Robotic surgery with intraoperative neurostimulation mapping is safe and effective for marginal resection of histologically benign or atypical retroperitoneal nerve sheath tumors, providing excellent visibility, increased dexterity and precision, and reduced risk of neurological morbidity.

EZR-ROS1 fusion renal cell carcinoma mimicking urothelial carcinoma: report of a previously undescribed gene fusion in renal cell carcinoma.

A subset of renal cell carcinomas harbor gene fusions, and we report the first case of an EZR-ROS1 fusion in renal cell carcinoma. A 47-year-old female presented with hematuria and a mass involving the renal pelvis. Renal biopsy revealed a tumor with solid and tubular architecture that was diffusely positive for PAX8, CK7, and vimentin; retained expression of INI1; focally positive for P504S; and negative for GATA3 and TFE3. Partial nephrectomy was performed, and histologically, the tumor had solid and tubular architecture with mucin-like content within tubules. The nuclei corresponded to WHO/ISUP grade 2 and 3. The morphology was neither specific nor diagnostic, and a final diagnosis of unclassified renal cell carcinoma with solid and tubular architecture was rendered. Molecular sequencing revealed an EZR-ROS1 fusion: a fusion that has never been reported in renal cell carcinoma. Recognition of this fusion is of significance if the tumor becomes metastatic as treatment with crizotinib may be considered.