Sequential Intravesical Chemotherapy for Treatment Naïve, High-Risk Non-Muscle Invasive Bladder Cancer: Oncologic Outcomes, Tolerance, and Comparison to Contemporary Controls.

OBJECTIVE: To assess if receiving sequential intravesical chemotherapy (Gemcitabine-Docetaxel, Gem-Doce) therapy was associated with similar oncologic efficacy to bacillus Calmette-Guérin (BCG) in patients with treatment-naïve, high-risk non-muscle invasive bladder cancer (HR-NMIBC). METHODS: Single-center, retrospective cohort study of 80 patients with HR-NMIBC initiating first-line Gem-Doce or BCG between August 2020 and August 2023. Surveillance was conducted with cystoscopy, urine cytology, and cross-sectional imaging. The primary oncologic outcome was high-grade bladder tumor recurrence during surveillance. Kaplan-Meier method was applied to determine 12- and 24-month recurrence-free survival (RFS) after initiation of therapy. Tolerance of each intravesical therapies was assessed. RESULTS: About 53/80 (66%) received Gem-Doce and 27/80 (34%) received BCG with overall 18-month median follow-up. There were 10 recurrences after Gem-Doce and 7 after BCG. The RFS at 12- and 24-months for Gem-Doce (12-months: 87%, 24-months: 75%) was not significantly different than BCG (12-months: 85%, 24-months: 81%). Lastly, Gem-Doce had significantly fewer patients with AEs compared to BCG (40% vs 74%). Limitations include retrospective design, small cohort size, and intermediate oncologic follow-up. CONCLUSION: Our data suggest that sequential intravesical Gem-Doce is an oncologically efficacious and, potentially better tolerated, alternative to BCG for treatment-naïve HR-NMIBC.

Adoption of robot-assisted radical nephroureterectomy permits a minimally invasive option for management of upper tract urothelial carcinoma in geriatric patients: comparison with non-geriatric patients with intermediate-term oncologic follow-up.

To assess the oncologic efficacy and safety of robot-assisted approach to radical nephroureterectomy (RARNU) in geriatric versus younger patients with upper tract urothelial carcinoma (UTUC). A single-center, retrospective cohort study was conducted from 2009 to 2022 of 145 patients (two cohorts: < 75 and ≥ 75 years old) with non-metastatic UTUC who underwent RARNU. Primary endpoint was UTUC-related recurrence of disease during surveillance (bladder-specific and metastatic). Safety was assessed according to 30-day, modified Clavien-Dindo (CD) classifications (Major: C.D. III-V). Survival estimates were performed using Kaplan-Meier method. There were 89 patients < 75 years (median 65 years) and 56 patients ≥ 75 years (median 81 years). Comparing the young versus geriatric cohorts: median follow-up 38 vs 24 months (p = 0.03, respectively) with similar 3-year bladder-specific recurrence survival (60% vs 67%, HR 0.70, 95% CI [0.35, 1.40], p = 0.31) and metastasis-free survival (79% vs 70%, HR 0.71, 95% CI [0.30, 1.70], p = 0.44). Expectedly, the younger cohort had a significant deviation in overall survival compared to the geriatric cohort at 1-year (89% vs 76%) and 3-years (72% vs 41%; HR 3.29, 95% CI [1.88, 5.78], p < 0.01). The 30-day major (1% vs 0) and minor complications (8% vs 14%, p = 0.87). Limitations include retrospective study design of a high-volume, single-surgeon experience. Compared to younger patients with UTUC, geriatric patients undergoing RARNU have similar oncologic outcomes at intermediate-term follow-up with no increased risk of 30-day perioperative complications. Thus, age alone should not be used to disqualify patients from definitive surgical management of UTUC with RARNU.

The role of preoperative immune cell metrics in renal cell carcinoma with a tumor thrombus.

INTRODUCTION: The objective of this study was to stratify preoperative immune cell counts by cancer specific outcomes in patients with renal cell carcinoma (RCC) and a tumor thrombus after radical nephrectomy with tumor thrombectomy. METHODS: Patients with a diagnosis of RCC with tumor thrombus that underwent radical nephrectomy with thrombectomy across an international consortium of seven institutions were included. Patients who were metastatic at diagnosis and those who received preoperative medical treatment were also included. Retrospective chart review was performed to collect demographic information, past medical history, preoperative lab work, surgical pathology, and follow up data. Neutrophil counts, lymphocyte counts, monocyte counts, neutrophil to lymphocyte ratios (NLR), lymphocyte to monocyte ratios (LMR), and neutrophil to monocyte ratios (NMR) were compared against cancer-specific outcomes using independent samples t-test, Pearson's bivariate correlation, and analysis of variance. RESULTS: One hundred forty-four patients were included in the study, including nine patients who were metastatic at the time of surgery. Absolute lymphocyte count preoperatively was greater in patients who died from RCC compared to those who did not (2 vs 1.4; p < 0.001). Patients with tumor pathology showing perirenal fat invasion had a greater neutrophil count compared to those who did not (7.5 vs 5.5; p = 0.010). Patients with metastatic RCC had a lower LMR compared to those without metastases after surgery (2.5 vs 3.2; p = 0.041). Tumor size, both preoperatively and on gross specimen, had an interaction with multiple immune cell metrics (p < 0.05). CONCLUSIONS: Preoperative immune metrics have clinical utility in predicting cancer-specific outcomes for patients with RCC and a tumor thrombus. Additional study is needed to determine the added value of preoperative serum immune cell data to established prognostic risk calculators for this patient population.

Ileal Conduit versus Cutaneous Ureterostomy after Open Radical Cystectomy: Comparison of 90-Day Morbidity and Tube Dependence at Intermediate Term Follow-Up.

Background: This study aims to compare perioperative morbidity and drainage tube dependence following open radical cystectomy (ORC) with ileal conduit (IC) or cutaneous ureterostomy (CU) for bladder cancer. Methods: A single-center, retrospective cohort study of patients undergoing ORC with IC or CU urinary diversion between 2020 and 2023 was carried out. The 90-day perioperative morbidity, as per Clavien-Dindo (C.D.) complication rates (Minor C.D. I-II, Major C.D. III-V), and urinary drainage tube dependence (ureteral stent or nephrostomy tube) after tube-free trial were assessed. Results: The study included 56 patients (IC: 26, CU: 30) with a 14-month median follow-up. At 90 days after IC or CU, the frequencies of any, minor, and major C.D. complications were similar (any-69% vs. 77%; minor-61% vs. 73%; major-46% vs. 30%, respectively, p > 0.2). Tube-free trial was performed in 86% of patients with similar rates of tube replacement (19% IC vs. 32% CU, p = 0.34) and tube-free survival at 12 months was assessed (76% IC vs. 70% CU, p = 0.31). Conclusions: Compared to the ORC+IC, ORC+CU has similar rates of both 90-day perioperative complications and 12-month tube-free dependence. CU should be offered to select patients as an alternative to IC urinary diversion after RC.

Surgeon-administered regional nerve blocks during radical cystectomy: a feasibility study.

OBJECTIVE: To describe the technique for surgeon-administered, ultrasound-guided transversus abdominis plane (SU-TAP) blocks performed during radical cystectomy as a component of multimodal, perioperative pain management. METHODS: Retrospective, case series of patients receiving SU-TAP blocks just prior to incision for RC. TAP blocks were performed by the surgeon with a standard technique using US guidance to instill an anesthetic solution. The primary outcome was opioid consumption at the intervals of 0-12, 12-24, 24-36, and 36-48 h postoperatively. Opioid consumption was reported as oral morphine milligram equivalents (MME). Secondary outcomes included time to perform SU-TAP blocks, and safety of block procedure. RESULTS: 34 patients were included. During the median length of stay of 4 days (interquartile range [IQR] 3-7), only 30/34 (88%) of patients required opioids within the first 12 h post-op, decreasing to 38% by 48 h post-op. The median consumption decreased in the first 48 h from 21 MMEs (IQR 9-38) to 10 MMEs (IQR 8-15) at the 0-12 and 36-48 h intervals, respectively. The median time to perform block procedure was 6 min (IQR 4-8 min) and there were no safety events related to the SU-TAP blocks. Limitations include no comparative arm for opioid consumption. CONCLUSION: Our data suggest that urologists may feasibly perform US-guided TAP blocks as a practical, efficient, and safe method of regional anesthesia. SU-TAP blocks should be considered in ERAS protocols for RC. Future comparative studies on opioid consumption compared to local infiltration and alternative block techniques are warranted.

Single instillation intravesical chemotherapy after radical nephroureterectomy for upper tract urothelial carcinoma: current evidence and future directions.

Upper urinary tract urothelial carcinoma (UTUC) accounts for 5% to 10% of urothelial carcinomas and two-thirds are high-grade at the time of diagnosis. The gold standard management of high-grade UTUC is radical nephroureterectomy (RNU). Despite primary treatment, disease recurrence involves the bladder in 22% to 47% of cases. Single dose, postoperative intravesical chemotherapy (pIVC) is an adjunct to RNU to decrease bladder recurrences that is currently recommended in guidelines from the European Association of Urology, National Cancer Center Network, and American Urological Association. Two clinical trials, using single dose, postoperative intravesical mitomycin C or pirarubicin, have provided level 1 evidence to support the formation of these guidelines. Despite this evidence, pIVC utilization is reportedly low among urologists, ranging from 12% to 55% among three studies, with non-utilizers citing lack of supporting evidence, safety concerns, and clinical infrastructure as leading rationale. In the past 10 years, no additional trials on single dose pIVC have been completed and validated in systematic reviews or meta-analyses. Utilization of pIVC still has room for improvement and further studies on this subject are warranted to overcome the barriers to implementation. Herein, we describe the critical literature that supports guideline recommendations for single dose pIVC after RNU to understand efficacy, safety, practice patterns, and discuss the future directions of this treatment adjunct.

Stent-free rates in cutaneous ureterostomy urinary diversion after radical cystectomy.

PURPOSE: Cutaneous ureterostomy (CU) urinary diversion after radical cystectomy has been relegated to highly comorbid patients due to presumed rates of stenosis and drainage tube dependence. Rates of stricture as high as 70% have been reported. Though a variety of techniques have been developed to obviate the need for prolonged stenting, CU remains uncommonly performed. Herein, we present our experience with CU diversion after radical cystectomy and stent-free rates post-operatively. MATERIALS AND METHODS: We retrospectively reviewed the records of consecutive patients undergoing radical cystectomy with single-stoma cutaneous ureterostomy from June 2020 to December 2022 at our institution. Demographic and clinical data were summarized. We recorded the presence of ureteral stent, nephrostomy, or nephroureteral catheter at the last follow-up. The primary outcome was "stent-free survival" incorporating all modalities of tube-dependent urinary drainage. Kaplan-Meier analysis was performed to determine stent-free survival at 12 months. RESULTS AND CONCLUSIONS: We identified 28 patients meeting inclusion criteria with median age of 73 years (IQR: 66-78) and median body mass index of 25 (IQR: 22-28). Of patients that underwent stent-free trial (N = 23), the stent-free survival at 12 months was 74%. Five of 28 patients had continued tube dependence due to locally advanced disease with hydronephrosis rather than CU stenosis. These results suggest that single-stoma CU should be considered a viable option for patients undergoing radical cystectomy. Longer follow-up is needed to assess durability of stent-free rates.

Urothelial Carcinoma Recurrence With an Ileal Conduit: Multimodal Management With Extirpative Surgery, Chemotherapy, and Immunotherapy.

Ileal conduit (IC) is the most performed urinary diversion after radical cystectomy (RC) for urothelial carcinoma (UC) of the bladder. While UC recurrence after RC is well-described, recurrence of UC within a urinary diversion is much less prevalent, and thus, management of these lesions is not well understood. Here, we report the case of a 59-year-old male with a history of invasive UC with glandular differentiation of the urinary bladder who had carcinoma in situ recurrence after induction, intravesical Bacille Calmette-Guerin therapy. He underwent robot-assisted laparoscopic radical cystoprostatectomy (RALC) with bilateral pelvic lymph node dissection and intracorporal ileal conduit (IC) urinary diversion. Two years later, he presented to the emergency department with hematuria. Computed tomography demonstrated a mass within the IC. He subsequently underwent IC resection and ligation of bilateral ureters and had permanent nephrostomy tubes placed, with the final pathology confirming high-grade UC. Positron emission tomography revealed hypermetabolic soft tissue implants within the greater omentum and retroperitoneum for which he underwent fine-needle aspiration, demonstrating recurrence of poorly differentiated UC. Ultimately, the patient started treatment with systemic gemcitabine and carboplatin and completed 4 cycles before transitioning to maintenance avelumab therapy. No disease progression was noted at 16 months post-treatment. Herein, we present a review of the literature and our management of the present patient.

Outcomes After Laparoscopic Cholecystectomy in Hyperkinetic Biliary Dyskinesia.

BACKGROUND: Biliary dyskinesia (BD) is a poorly understood functional gallbladder disorder. Diagnosis is made with abdominal pain and an intact gallbladder without signs of anatomical obstruction on imaging or pathology. Our aim was to assess whether laparoscopic cholecystectomy (LC) resolves hyperkinetic BD symptoms. METHODS: Records of patients ≥18 years of age, who underwent LC by four surgeons at a tertiary care center between 2012 and 2020, were retrospectively reviewed. Patients were excluded if they had a documented gallbladder ejection fraction (GBEF) <80% or had biliary stones or sludge on pathology or imaging. Demographic information, HIDA results, preoperative testing, operative details, gallbladder pathology, and symptom status at follow-up were collected from electronic medical records. Improvement in BD symptoms was assessed using McNemar's test. Risk differences with standard errors were employed to estimate percent reduction in symptoms. RESULTS: Ninety-eight patients met inclusion criteria. Of those who presented for follow-up (n = 91), 92.3% (n = 84) reported partial or complete resolution of symptoms. Preoperative symptoms, including back pain (16.7%, 95% CI: [7.9%, 25.5%]; P < .0001), epigastric pain (31.1% [21.3%, 41.3%]; P < .0001), nausea (56.7% [45.0%, 65.8%]; P < .0001), RUQ pain (57.8% [46.1%, 66.9%]; P < .0001), and vomiting (27.8% [18.4%, 37.7%]; P < .0001) showed significant improvement after LC. Chronic cholecystitis and/or cholesterolosis were present on pathology in 79.8% of gallbladders. DISCUSSION: Our study currently represents the largest cohort of patients with hyperkinetic BD. Laparoscopic cholecystectomy appears to result in resolution of symptoms for this clinical entity.

TGF-ß-mediated enhancement of TH17 cell generation is inhibited by bone morphogenetic protein receptor 1α signaling.

The cytokines of the transforming growth factor-ß (TGF-ß) family promote the growth and differentiation of multiple tissues, but the role of only the founding member, TGF-ß, in regulating the immune responses has been extensively studied. TGF-ß is critical to prevent the spontaneous activation of self-reactive T cells and sustain immune homeostasis. In contrast, in the presence of proinflammatory cytokines, TGF-ß promotes the differentiation of effector T helper 17 (TH17) cells. Abrogating TGF-ß receptor signaling prevents the development of interleukin-17 (IL-17)-secreting cells and protects mice from TH17 cell-mediated autoimmunity. We found that the receptor of another member of TGF-ß family, bone morphogenetic protein receptor 1α (BMPR1α), regulates T helper cell activation. We found that the differentiation of TH17 cells from naive CD4+ T cells was inhibited in the presence of BMPs. Abrogation of BMPR1α signaling during CD4+ T cell activation induced a developmental program that led to the generation of inflammatory effector cells expressing large amounts of IL-17, IFN-γ, and TNF family cytokines and transcription factors defining the TH17 cell lineage. We found that TGF-ß and BMPs cooperated to establish effector cell functions and the cytokine profile of activated CD4+ T cells. Together, our data provide insight into the immunoregulatory function of BMPs.