ERAS for Ambulatory TURBT: Enhancing Bladder Cancer Care (EMBRACE) randomised controlled trial protocol.

INTRODUCTION: Transurethral resection of bladder tumour (TURBT) is one of the more common procedures performed by urologists. It is often described as an 'incision-free' and 'well-tolerated' operation. However, many patients experience distress and discomfort with the procedure. Substantial opportunity exists to improve the TURBT experience. An enhanced recovery after surgery (ERAS) protocol designed by patients with bladder cancer and their providers has been developed. METHODS AND ANALYSIS: This is a single-centre, randomised controlled trial to investigate the effectiveness of an ERAS protocol compared with usual care in patients with bladder cancer undergoing ambulatory TURBT. The ERAS protocol is composed of preoperative, intraoperative and postoperative components designed to optimise each phase of perioperative care. 100 patients with suspected or known bladder cancer aged ≥18 years undergoing initial or repeat ambulatory TURBT will be enrolled. The change in Quality of Recovery 15 score, a measure of the quality of recovery, between the day of surgery and postoperative day 1 will be compared between the ERAS and control groups. ETHICS AND DISSEMINATION: The trial has been approved by the Johns Hopkins Institutional Review Board #00392063. Participants will provide informed consent to participate before taking part in the study. Results will be reported in a separate publication. TRIAL REGISTRATION NUMBER: NCT05905276.

Hand, foot, and mouth disease presenting with a testicular mass in an adult.

The majority of solid testicular tumors are treated with orchiectomy given the high risk of malignancy. We present a case of a testicular mass in an adult patient in the setting of recent hand, foot, and mouth disease that was managed conservatively with serial ultrasounds. Even though cases of viral-associated testicular masses are rare, this differential diagnosis should be considered in patients with a new testicular mass in the setting of recent viral infection and negative tumor markers. For these patients, observation may be an option instead of immediate orchiectomy.

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.

Clinicopathologic and Survival After Cystectomy Outcomes in Squamous Cell Carcinoma of the Bladder.

BACKGROUND: Squamous cell carcinoma of the bladder (SqCC) is a rare disease with limited management data. Thus, we sought to characterize the clinicopathologic and survival outcomes amongst patients with SqCC and explore the association of squamous differentiation within urothelial carcinoma (UC w/Squam), as compared to muscle invasive pure UC. METHODS: We conducted a single-center retrospective cohort study of patients, stratified by histology, who underwent cystectomy for MIBC. Baseline clinicopathologic characteristics were compared, and overall survival was assessed using Kaplan-Meier method. RESULTS: We identified 1,034 patients; 37 (3.58%) with SqCC histology, 908 (87.81%) with UC histology, and 89 (8.61%) with UC w/ Squam histology. Among SqCC patients, a higher proportion were Black and similarly a higher proportion were women; amongst patients with UC w/ Squam a higher proportion had lower BMI; and amongst patients with UC a higher proportion had lower clinical (c) T, cN, pathological (p) T, and pN stages. Patients presenting with UC were more likely to receive intravesical therapy; patients presenting with SqCC were less likely to receive neoadjuvant chemotherapy (NAC). Adjuvant chemotherapy rates were similar. With post-hoc Bonferroni analysis, overall survival, cancer-specific survival, and recurrence-free survival were significantly worse for the UC w/ Squam cohort. CONCLUSIONS: UC w/ Squam histology was associated with worse survival outcomes after cystectomy for muscle invasive bladder cancer compared to UC. Our results suggest that UC w/ Squam is associated with more advanced disease compared to UC, warranting further prospective work on consideration of combination therapies for patients with this disease state.

Appendiceal adenocarcinoma presenting as a bladder tumor.

We present a case of an appendiceal adenocarcinoma that invaded the urinary bladder, which was preoperatively mistaken for urachal adenocarcinoma. The patient underwent open removal of the umbilicus, urachus, partial cystectomy and bilateral pelvic lymph node dissection. Intraoperatively the tumor was noted to involve the appendix, and so an appendectomy was also performed. The pathology showed an appendiceal adenocarcinoma invading the bladder wall. Urologists must have a high degree of suspicion for spread from a gastrointestinal primary when adenocarcinoma is found within the urinary bladder.

Metastasis to the Bladder: A Rare Site of Recurrence of Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is considered to be the deadliest urologic cancer with high rates of metastasis and recurrence after nephrectomy. RCC can metastasize to nearly any organ but most commonly metastasizes to the liver, lung, brain, and bone. To date, there are only about 40 reported cases of RCC with solitary bladder metastasis. The following report contributes to this limited data set of patients with RCC who develop solitary metastasis to the bladder. A 69-year-old male presented with occasional gross hematuria and was found to have a left renal mass infiltrating the collecting system. Ureteroscopic biopsy revealed clear cell RCC, and the patient subsequently underwent radical left nephrectomy. Eight months after nephrectomy, the patient presented to the clinic with gross hematuria. In-office cystoscopy demonstrated a nodular lesion in the bladder arising from the left ureteral orifice. The patient underwent transurethral resection of the bladder mass and pathology demonstrated clear cell RCC. Subsequent imaging showed no evidence of metastatic disease. Five months after transurethral resection, the patient was found to have a left distal ureteral mass and underwent left ureterectomy with partial cystectomy. Pathology again demonstrated clear cell RCC. RCC with solitary metastasis to the bladder is rare, and there are no targeted guideline recommendations for management. Per standard of care, patients with painless hematuria and risk factors for malignancy should undergo cystoscopy. In patients with a history of RCC, metastasis to the bladder should be considered in the differential diagnosis. Patients with metastatic RCC to the bladder should undergo a thorough work-up for additional sites of metastasis. In patients with RCC who develop solitary bladder metastasis amenable to resection following nephrectomy, there is a lack of evidence to guide therapy and a multidisciplinary discussion is warranted. However, if the tumor is amenable to resection, metastasectomy is a reasonable therapeutic approach and offers the patient an improved quality of life and an opportunity for remission.

Primary mesonephric adenocarcinoma of the bladder: A case report.

Primary mesonephric adenocarcinoma of the bladder is a very rare lesion. Only 9 cases have been reported since 1968, when it was first described. Due to its morphological diversity and variable immunohistochemical profile, mesonephric adenocarcinoma presents a diagnostic challenge, especially when seen in male patients, due to the rarity this entity in men. Here we present a rare case of a 63-year-old man who was found to have a bladder tumor and diagnosed with mesonephric adenocarcinoma of the bladder.

Safety and Efficacy of Reproductive Organ-Sparing Radical Cystectomy in Women With Variant Histology and Advanced Stage.

PURPOSE: Muscle invasive bladder cancer surgical management has been historically a radical cystoprostatectomy in males and an anterior exenteration in females. Uterine, ovarian, and vaginal preservation are utilized, but raise concerns regarding risk to oncologic control, especially in variant histopathology or advanced stage. MATERIALS AND METHODS: A retrospective single institutional analysis identified radical cystectomies performed in women, including those with variant histology, which were defined as reproductive organ sparing (uterine, vaginal, and ovary sparing) or nonorgan sparing. The Kaplan-Meier method was used for recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) in patients with advanced disease. RESULTS: From 2000 to 2020, 289 women were identified, 188 underwent reproductive organ-sparing cystectomy. No statistical differences were noted for clinical parameters or presence of variant histology for organ-sparing (ROS) and nonorgan-sparing (non-ROS). Positive margin rates did not differ for ROS and non-ROS; 4.3% vs. 7.9%, P = .19, respectively. Median RFS was not statistically significantly different for ROS vs. non-ROS (26.1 vs. 15.3 months) P = .937 hazard ratio (HR) 1.024. CSS was not statistically different for ROS vs. non-ROS (36.3 vs. 28.6 months), P = .755 HR 0.9. OS was not statistically different for ROS vs. non-ROS (25.8 vs. 23.8 months), P = .5 HR = 1.178. Variant histology did not change survival (HR 1.1, P = .643). CONCLUSION: In this analysis, ROS in women with advanced disease did not increase positive margin rates or decrease RFS, CSS, or OS compared to non-ROS. Variant histology did not decrease survival odds. Based on preoperative assessment and intraoperative findings, ROS in patients with variant histology and advanced disease should be considered.

Understanding Psychosocial and Sexual Health Concerns Among Women With Bladder Cancer Undergoing Radical Cystectomy.

OBJECTIVE: To better understand the physical and psychosocial components of female sexual dysfunction (FSD) among women undergoing radical cystectomy (RC) for bladder cancer (BCa). METHODS: We conducted semistructured individual interviews and a focus group with pre- and post-RC female patients and their partners regarding the impact of RC on sexual health and psychosocial wellbeing. Themes were inductively identified by 2 independent coders and subsequently organized into themes and subthemes using qualitative description and constant comparison. RESULTS: In the preoperative cohort, 6 women and 1 partner participated (50% contact rate, 75% participation rate). In the postoperative cohort, 16 women and 2 partners participated (61% contact rate, 64% participation rate). Major themes that emerged in interviews with both cohorts included concerns about changes to body image, the psychological impact of BCa diagnosis and treatment, concerns about the impact of RC on sexual function, and inadequacies in provider-led sexual health counseling. Participants varied in the importance they placed on sexual function, with factors such as age, relationship status, and oncologic concerns impacting prioritization, although both younger and older patients expressed a desire to retain the option of sexual function. CONCLUSION: Female patients with BCa undergoing RC experience changes in body image, psychological distress, physical disruptions in sexual function, and inadequacies in sexual health counseling and education. Future efforts should be directed towards improving sexual health counseling and psychosocial support resources for women with BCa.

CD117⁺ cells in the circulation are predictive of advanced prostate cancer.

Circulating tumor cells (CTCs) are associated with cancer progression, aggressiveness and metastasis. However, the frequency and predictive value of CTCs in patients remains unknown. If circulating cells are involved in tumor aggressiveness and metastasis, then cell levels should decline upon tumor removal in localized cancer patients, but remain high in metastatic patients. Accordingly, proposed biomarkers CD117/c-kit, CD133, CXCR4/CD184, and CD34-positive cell percentages in the blood of patients undergoing radical prostatectomy for localized cancer were assessed by flow cytometry prior to intervention and 1-3 months postoperatively. Only circulating CD117⁺ cell percentages decreased after radical prostatectomy, increased with cancer progression and correlated with high PSA values. Notably, postoperative CD117⁺ levels did not decrease in patients experiencing biochemical recurrence. In a xenograft model, CD117-enriched tumors were more vascularized and aggressive. Thus, CD117 expression on CTCs promotes tumor progression and could be a biomarker for prostate cancer diagnosis, prognosis, and/or response to therapy.

Combined inhibition of Wee1 and Hsp90 activates intrinsic apoptosis in cancer cells.

Heat shock protein 90 (Hsp90) is an essential, evolutionarily conserved molecular chaperone. Cancer cells rely on Hsp90 to chaperone mutated and/or activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is frequently cytostatic in nature, and efforts to enhance the antitumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In agreement with previous data obtained using Wee1 siRNA, we show that dual pharmacologic inhibition of Wee1 tyrosine kinase and Hsp90 causes cancer cells to undergo apoptosis in vitro and in vivo. Gene expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional downregulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins, as well as activated Akt, was completely abrogated. These data support the hypothesis that Wee1 inhibition sensitizes cancer cells to Hsp90 inhibitors; they establish combined Wee1/Hsp90 inhibition as a novel therapeutic strategy; and they provide a mechanistic rationale for enhancing the pro-apoptotic activity of Hsp90 inhibitors.

Inadequacy of biopsy for diagnosis of upper tract urothelial carcinoma: implications for conservative management.

OBJECTIVE: To report changes in grade and stage between initial diagnostic and repeat biopsies or resection for urothelial carcinoma (UTUC) and investigate the consequences for endoscopic management. Ureteroscopic management of upper tract UTUC is an alternative to nephroureterectomy, which is less invasive and preserves renal function. However, concerns about potential understaging, inaccurate grading, incomplete resection, lack of effective tertiary chemoprevention, and need for ureteroscopic surveillance limits it appeal. METHODS: Clinicopathological records of patients with UTUC treated at our institution were reviewed. Fifty-six patients with a histologic diagnosis of UTUC and 2 or more consecutive biopsies or biopsy followed by surgical resection were included, resulting in 65 biopsy specimens. RESULTS: The median interval between diagnostic biopsy and subsequent biopsy or resection was 6 weeks (range, 1 week to 60 months). Change in grade from the diagnostic biopsy occurred in 24 of 65 biopsies (37%), including 9 in which diagnosis changed from low to high grade. Change in the stage from the diagnostic biopsy occurred in 25 of 65 biopsies (38%). Overall, 24 (43%) patients were reclassified from low-grade, noninvasive disease to high-grade and/or invasive disease. CONCLUSION: A change in grade and/or stage from the diagnostic biopsy occurred in more than one third of patients with UTUC managed conservatively. Because of the short median time interval between biopsies, this finding likely represents variability in tumor sampling on biopsy. Because of the concerns of undergrading and understaging, appropriate patient selection and vigilant endoscopic surveillance are mandatory for UTUC managed endoscopically.

Chronic kidney disease after nephroureterectomy for upper tract urothelial carcinoma and implications for the administration of perioperative chemotherapy.

BACKGROUND: The prevalence of chronic kidney disease (CKD) in patients with upper tract urothelial carcinoma (UTUC) is poorly defined, both before and after nephrouretectomy. Although multimodal treatment paradigms for UTUC are under-developed, this has important implications on patients' ability to receive cisplatin-based combination chemotherapy (CBCC). METHODS: Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula in 336 patients with UTUC, who were treated at the Cleveland Clinic by nephroureterectomy since 1992. An eGFR cutoff of 60 mL/min/1.73 m(2) was used to determine the presence of CKD and eligibility for CBCC. RESULTS: Median age was 72 years and median preoperative eGFR was 59 mL/min/1.73m(2). Before nephroureterectomy, only 48% of patients were eligible to receive CBCC and this decreased to 22% postoperatively (P < .001). In the 144 patients with pT2-pT4 and/or pN1-pN3 disease who are suitable to receive CBCC, these proportions were 40% and 24%, respectively (P = .009). Although 50 patients overall received some form of perioperative chemotherapy, only 3 and 11 patients received neoadjuvant and adjuvant CBCC, respectively. CONCLUSIONS: CKD is prevalent in the UTUC population and a minority of patients has an optimal eGFR to receive neoadjuvant CBCC. Nephrouretectomy may eliminate CBCC as a therapeutic option in 49% of high-risk patients if it is deferred to the adjuvant setting. Multimodal treatment strategies for UTUC should focus on neoadjuvant chemotherapy, as few patients are eligible for adjuvant CBCC because of the substantial decline in eGFR caused by nephroureterectomy.

Comparison of tumor and microenvironment secretomes in plasma and in platelets during prostate cancer growth in a xenograft model.

To survive and metastasize, tumors interact with surrounding tissues by secreting growth factors and cytokines. In return, surrounding host tissues respond by changing their secretome. Numerous factors theoretically function as therapeutic targets or biomarkers of cancer growth and metastatic risk. However, it is unclear if these factors are tumor-derived or actually represent the host defense. To analyze the concentrations of tumor- and microenvironment-derived factors associated with neoplastic growth, we used ELISA-based arrays specific for murine or human proteins to establish a profile of tumor- or host-derived factors circulating in the plasma or within the platelets upon human tumor implantation into mice. Many factors characterized as tumor-derived were actually secreted by host tissues. This study uncovered the origin of various cytokines and revealed their circulation methods. We found that tumor-produced cytokines are predominantly sequestered in platelets. Sequestered proteins are protected from degradation and, thus, may be functional at metastatic sites. These findings identify tumor-specific targets for the detection and prevention of tumor growth and metastasis. As predicted by our model, monocyte chemotactic protein 1 and tumor necrosis factor alpha may be biomarkers for human cancers. Thus, our study identified several potential biomarkers that might be predictive of prostate cancer.

Optimizing orthotopic bladder tumor implantation in a syngeneic mouse model.

PURPOSE: We established a reliable technique for orthotopically implanting bladder tumor cells in a syngeneic mouse model. MATERIALS AND METHODS: MBT-2 murine bladder cancer cells were transurethrally implanted in the bladder of syngeneic C3H/He mice (Jackson Laboratory, Bar Harbor, Maine). Different chemical pretreatments were used before tumor implantation, including phosphate buffered saline (control), HCl, trypsin and poly-L-lysine. MBT-2 cells (1 x 10(6) or 2 x 10(6)) were instilled into the intravesical space after chemical pretreatment. Tumor take and bladder tumor volume were determined by micro ultrasound. Bladders were harvested at the end of the study to measure bladder weight and for histopathological examination. RESULTS: Bladder pretreatment with HCl in 5 preparations was discontinued due to significant adverse reactions, resulting in death in 1 mouse, and severe bladder inflammation and hematuria 3 days after pretreatment in 2. Pretreatment with phosphate buffered saline, trypsin and poly-L-lysine in 6 animals each was tolerated well without significant adverse reactions or mortality. The tumor take rate in the control, trypsin and poly-L-lysine pretreatment groups was 33%, 83% and 83%, respectively. The take rate was higher in mice instilled with 2 x 10(6) cells than in those with 1 x 10(6) cells (93% vs 73%, p <0.05). CONCLUSIONS: We report a reliable, feasible method of orthotopically implanting bladder tumor cells into a syngeneic mouse model. Poly-L-lysine and trypsin are useful adjunctive pretreatment agents to improve bladder tumor uptake. This model may be suitable to evaluate treatment paradigms for bladder cancer.

Epidermoid cyst of the testicle.

We report on a case of testicular mass with classic radiographic appearance for epidermoid cyst.

Role of cystitis cystica et glandularis and intestinal metaplasia in development of bladder carcinoma.

OBJECTIVES: Cystitis cystica et glandularis (CCEG) and intestinal metaplasia (IM) have been suggested to represent precursors of bladder adenocarcinoma. The relationship between these entities and the subsequent development of bladder carcinoma remains unclear. METHODS: We retrospectively evaluated the association among florid CCEG, IM, and bladder carcinoma. The records and imaging findings of patients with a pathologic diagnosis of florid CCEG and/or IM were reviewed for a concurrent or future diagnosis of bladder carcinoma or pelvic lipomatosis. RESULTS: We identified 136 patients from 1982 to 2006 with florid CCEG (n = 117) or IM (n = 19). Of the 117 patients with CCEG, a subset was identified with concurrent mucinous adenocarcinoma (n = 1; <1%), squamous cell carcinoma (n = 4; 3%), or urothelial carcinoma (n = 34; 29%) at diagnosis. Pure IM was identified concurrently with adenocarcinoma in 2 (10%), urothelial carcinoma in 4 (21%), and urothelial carcinoma with glandular differentiation in 1 (5%) of 19 patients. Follow-up for 103 patients (75%) ranged from 7 days to 23.7 years (median 2.6 years, mean 4.4). Only 1 new case of urothelial carcinoma was identified after 3 months in 1 patient with CCEG. None of the patients in our series had associated pelvic lipomatosis. CONCLUSIONS: Both florid CCEG and IM can be identified in benign bladder specimens or in conjunction with bladder carcinoma. Although IM can be associated with a concurrent diagnosis of carcinoma, we found no evidence that it increases the future risk of malignancy and our findings do not support a recommendation for surveillance cystoscopy in such patients. No association was identified between either CCEG or IM and pelvic lipomatosis.