Photodynamic diagnosis-assisted transurethral resection of bladder tumor for high-risk non-muscle invasive bladder cancer improves intravesical recurrence-free survival (BRIGHT study).

OBJECTIVES: In a primary analysis of data from the BRIGHT study (UMIN000035712), photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) using oral 5-aminolevulinic acid hydrochloride reduced residual tumors in high-risk non-muscle invasive bladder cancer (NMIBC). We aimed to evaluate the effectiveness of PDD-TURBT for intravesical recurrence after a second transurethral resection for high-risk NMIBC. METHODS: High-risk NMIBC patients initially treated with PDD-TURBT (PDD group) were prospectively registered between 2018 and 2020. High-risk patients with NMIBC who were initially treated with white-light TURBT (WL group) were retrospectively registered. Intravesical recurrence-free survival after the second transurethral resection was compared between the PDD and WL groups using propensity score matching analysis. RESULTS: In total, 177 patients were enrolled in the PDD group, and 306 patients were registered in the WL group. After propensity score matching (146 cases in each group), intravesical recurrence within 1 year was significantly less frequent in the PDD group than in the WL group (p = 0.004; hazard ratio [HR] 0.44, 95% confidence interval [CI]: 0.25-0.77). In subgroup analysis, PDD-TURBT showed a particularly high efficacy in reducing intravesical recurrence within 1 year, especially in cases of tumors measuring less than 3 cm (p = 0.003; HR 0.31, 95% CI: 0.14-0.67), absence of residual tumor at second transurethral resection (p = 0.020; HR 0.37, 95% CI: 0.16-0.86), and no postoperative intravesical Bacillus Calmette-Guérin therapy (p < 0.001; HR 0.27, 95% CI: 0.13-0.58). CONCLUSIONS: PDD-TURBT may reduce short-term intravesical recurrence in patients with high-risk NMIBC.

Upper extremity contact pressure measurement in robot-assisted pelvic surgery.

Upper extremity complications are often a problem in robot-assisted pelvic surgery (RAPS) with the lithotomy-Trendelenburg position (LT-position). This study focused on upper extremity contact pressure (UEP) and examined the relationship between UEP and upper extremity complications. From May 2020 to April 2022 at the University of Tokyo Hospital, UEP was measured in 155 patients undergoing RARP and 20 patients undergoing RARC. A total of 350 sets of UEP were investigated in this study. UEP was measured using a portable interface pressure sensor (Palm Q, Cape CO., Kanagawa, Japan) in the preoperative lithotripsy position (L-position), preoperative LT-position, and postoperative L-position. UEP was increased in the preoperative LT-position than in the preoperative L-position (right side 5.2 mmHg vs. 17.1 mmHg, left side 5.3 mmHg vs. 17.1 mmHg, P < 0.001, respectively), and was decreased in the postoperative L-position than in preoperative LT-position (right side 17.1 mmHg vs. 10.8 mmHg, left side 17.1 mmHg vs. 10.6 mmHg, P < 0.001, respectively). Eleven upper extremities developed shoulder pain. UEP of the preoperative LT-position tended to be higher in the upper extremity exhibiting shoulder pain (25.6 mmHg (15.4-30.3) vs. 17.1 mmHg (12.0-24.4) P = 0.0901). UEP measurements may help prevent postoperative shoulder pain.

In Curative Stereotactic Body Radiation Therapy for Prostate Cancer, There Is a High Possibility That 45 Gy in Five Fractions Will Not Be Tolerated without a Hydrogel Spacer.

The purpose of this study was to determine the maximum tolerated dose (MTD) for stereotactic body radiation therapy (SBRT) in the treatment of non-metastatic prostate cancer. This study was a phase 1 dose escalation trial conducted in Japan. Patients with histologically proven prostate cancer without lymph nodes or distant metastases were enrolled. The prescribed doses were 42.5, 45, or 47.5 Gy in five fractions. Dose-limiting toxicity (DLT) was defined as grade (G) 3+ gastrointestinal or genitourinary toxicity within 180 days after SBRT completion, and a 6 plus 6 design was used as the method of dose escalation. A total of 16 patients were enrolled, with 6 in the 42.5 Gy group and 10 in the 45 Gy group. No DLT was observed in the 42.5 Gy group. In the 45 Gy group, one patient experienced G3 rectal hemorrhage, and another had G4 rectal perforation, leading to the determination of 42.5 Gy as the MTD. None of the patients experienced biochemical recurrence or death during the follow-up period. We concluded that SBRT for non-metastatic prostate cancer at 42.5 Gy in five fractions could be safely performed, but a total dose of 45 Gy increased severe toxicity.

Development of risk-score model in patients with negative surgical margin after robot-assisted radical prostatectomy.

A total of 739 patients underwent RARP as initial treatment for PCa from November 2011 to October 2018. Data on BCR status, clinical and pathological parameters were collected from the clinical records. After excluding cases with neoadjuvant and/or adjuvant therapies, presence of lymph node or distant metastasis, and positive SM, a total of 537 cases were eligible for the final analysis. The median follow-up of experimental cohort was 28.0 (interquartile: 18.0-43.0) months. We identified the presence of International Society of Urological Pathology grade group (ISUP-GG) ≥ 4 (Hazard ratio (HR) 3.20, 95% Confidence Interval (95% CI) 1.70-6.03, P < 0.001), lymphovascular invasion (HR 2.03, 95% CI 1.00-4.12, P = 0.049), perineural invasion (HR 10.7, 95% CI 1.45-79.9, P = 0.020), and maximum tumor diameter (MTD) > 20 mm (HR 1.9, 95% CI 1.01-3.70, P = 0.047) as significant factors of BCR in the multivariate analysis. We further developed a risk model according to these factors. Based on this model, 1-year, 3-year, and 5-year BCR-free survival were 100%, 98.9%, 98.9% in the low-risk group; 99.1%, 94.1%, 86.5% in the intermediate-risk group; 93.9%, 84.6%, 58.1% in the high-risk group. Internal validation using the bootstrap method showed a c-index of 0.742 and an optimism-corrected c-index level of 0.731. External validation was also carried out using an integrated database derived from 3 other independent institutions including a total of 387 patients for the final analysis. External validation showed a c-index of 0.655. In conclusion, we identified risk factors of biochemical failure in patients showing negative surgical margin after RARP and further developed a risk model using these risk factors.

Bilateral fumarate hydratase deficient renal cell carcinoma in a patient with hereditary leiomyomatosis and renal cell cancer syndrome.

Introduction: Patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome have high risks of uterine and cutaneous leiomyomas and renal cell carcinoma (RCC), which are caused by germline mutation of the fumarate hydratase (FH) gene. RCC lesions are mostly high-grade tumors with a poor prognosis. Case presentation: A 37-year-old man who had previously undergone treatment for a left RCC was referred to our hospital with a diagnosis of right RCC. Robot-assisted partial nephrectomy was performed, and the pathological diagnosis revealed fumarate hydratase (FH)-deficient RCC. The left RCC, which was originally diagnosed as mucinous tubular and spindle cell carcinoma, was reviewed and diagnosed as FH-deficient RCC. The patient's father and uncle both died of RCC, and the father's tumor was also immunohistochemically proven to be FH-deficient RCC. Conclusion: HLRCC-related RCC should be considered in a differential diagnosis of young patients with a family history of RCC.

Associations of concomitant medications with immune-related adverse events and survival in advanced cancers treated with immune checkpoint inhibitors: a comprehensive pan-cancer analysis.

BACKGROUND: While concomitant medications can affect the efficacy of immune checkpoint inhibitors (ICIs), few studies have assessed associations of concomitant medications with the occurrence and profile of immune-related adverse events (irAEs). METHODS: This study assessed associations of concomitant medication (antibiotics/proton pump inhibitors (PPIs)/corticosteroids)-based risk model termed the "drug score" with survival and the occurrence and profile of irAEs in 851 patients with advanced cancer treated with ICIs (with or without other agents). The study also assessed the survival impact of the occurrence of irAEs, using a landmark analysis to minimize immortal time bias. Multivariable Cox proportional hazard analyses were conducted for progression-free survival (PFS) and overall survival (OS). RESULTS: The drug score classified patients into three risk groups, with significantly different PFS and OS. Notably, the score's predictive capability was better in patients treated with ICIs only than in those treated with ICIs plus other agents. The landmark analysis showed that patients who developed irAEs had significantly longer PFS and OS than those without irAEs. Generally, concomitant medications were negatively associated with the occurrence of irAEs, especially endocrine irAEs, whereas PPI use was positively associated with gastrointestinal irAEs, as an exception. CONCLUSIONS: Using a large pan-cancer cohort, the prognostic ability of the drug score was validated, as well as that of the occurrence of irAEs. The negative association between concomitant medications and irAE occurrence could be an indirect measure of the detrimental effect on the immune system induced by one or more concomitant drugs.

A Novel Hypobaric Perfusion Method to Remove Microthrombi in Kidney Grafts with Prolonged Circulatory Arrest: A Pilot Study on a Porcine Model.

Background: Intragraft microthrombi prevent complete organ perfusion, thereby compromising the viability maintained by preservation solutions or machine perfusion. Herein, we developed and evaluated a hypobaric perfusion method for flushing microthrombi from kidney grafts with prolonged circulatory arrest in a porcine model. Methods: Porcine renal grafts with 1-h warm ischemia were flushed with heparin-containing perfusate in a normobaric environment (control group) or a hypobaric environment of -20 to -30 mm Hg (hypobaric perfusion group) for 10 min using a gravity drip from a 1-m height. Perfusion parameters, histological findings in ex vivo blood perfusion experiments (2 control and 4 hypobaric perfusion kidneys), and safety in allogeneic porcine transplantation experiments (1 donor to 2 recipients) were evaluated. Results: The -20 mm Hg hypobaric perfusion group exhibited greater maximal flow than the control group (20.4 versus 6.9 mL/min; P = 0.028). Histological evaluation following 3 h of static cold storage and 10 min ex vivo porcine whole-blood perfusion revealed statistically significant reductions in congestion and edema (1.5 versus 3, and 0.5 versus 4 on a 5-point scale, from 0 to 4; P = 0.014 and 0.006, respectively) in the medulla along with improved ischemia-reperfusion injury scores (4.0 versus 4.7 on a 6-point scale, from 0 to 5; P = 0.004) in the -20 mm Hg hypobaric perfusion group. Kidney grafts perfused under -30 mm Hg hypobaric environment followed by 3 h of static cold storage could be used for porcine allogeneic transplantation without any macroscopic damage to the graft, effect on intraoperative handling, or perioperative adverse events. Thus, the hypobaric perfusion method was considered safe. Conclusions: Perfusion in a hypobaric environment may prevent graft congestion, edema, and further reperfusion injury by flushing out erythrocytes occluding the medullary capillaries, improving marginal renal graft quality, and reducing the number of discarded grafts.

Maturation and development of fetal pig intestinal tissue in immunodeficient mice.

PURPOSE: This study aimed to compare the degree of maturation and development of fetal pig segmental intestinal tissue with that of spheroids created by in-vitro reaggregation of dissociated fetal intestinal cells after transplantation into immunodeficient mice. METHODS: Fetal pig small intestines were transplanted as segmental grafts into the omentum and subrenal capsules of immunodeficient mice or enzymatically treated to generate single cells. Spheroids made by in-vitro reaggregation of these cells were transplanted into the subrenal capsules of immunodeficient mice. The segmental grafts and spheroids were harvested four and eight weeks after transplantation, and the structural maturity and in-vivo development of these specimens were histologically evaluated. RESULTS: The spheroids were engrafted and supplied blood vessels from the host mice, but an intestinal layered structure was not clearly observed, and there was almost no change in size. On the other hand, the segmental grafts formed deep crypts in the mucus membrane, the inner circular layer, and outer longitudinal muscles. The crypts of the transplanted grafts harvested at eight weeks were much deeper, and the smooth muscle layer and the enteric nervous system were more mature than those of grafts harvested at the fourth week, although the intestinal peristaltic wave was not observed. CONCLUSIONS: Spheroids created from fetal small intestinal cells could not form layered structures or mature sufficiently. Conversely, segmental tissues structurally matured and developed after in-vivo transplantation and are therefore potential grafts for transplantation.

Lower bleeding volume contributes to decreasing surgical site infection in radical cystectomy: A propensity score-matched comparison of open versus robot-assisted radical cystectomy.

OBJECTIVES: To compare the incidence of surgical site infections (SSI) between robot-assisted and open radical cystectomies and investigate the risk factors for SSI after radical cystectomies. METHODS: Consecutive patients who underwent radical cystectomy between July 2008 and December 2022 were retrospectively reviewed. The prevalence and characteristics of SSI after open and robot-assisted radical cystectomies were compared, and the risk factors for SSI were investigated using propensity score matching. RESULTS: This study enrolled 231 patients (open: 145, robot-assisted: 86). In the robot-assisted group, urinary diversion was performed using an intracorporeal approach. SSI occurred in 34 (open: 28, robot-assisted: 6) patients, and the incidence was significantly lower in the robot-assisted group (19.3% vs. 7.0%, p = 0.007). After propensity score matching cohort (open: 34, robot-assisted: 34), increased bleeding volume, blood transfusion, and delayed postoperative oral feeding were significantly associated with SSI. Only increased bleeding volume remained a significant risk factor in the multivariate regression analysis (odds ratio, 1.13 [per 100 mL increase]; 95% confidence interval: 1.02-1.25; p = 0.001). The cutoff bleeding volume for predicting SSI was 1630 mL with an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.773, 0.73, and 0.75, respectively. CONCLUSIONS: The incidence of SSI after robot-assisted radical cystectomy was significantly lower than that after the open procedure. However, decreased bleeding volume, which was significantly associated with robot-assisted procedures, was an independent and more significant factor for reducing SSI after radical cystectomy than the differences of the surgical procedure even after propensity score matching.

A case of condyloma acuminatum of the bladder concurrently diagnosed with urothelial carcinoma.

Introduction: Condyloma acuminatum usually occurs in the external genitalia and rarely in the bladder mucosa. Here, we report a case of condyloma acuminatum of the bladder that was detected concurrently with urothelial carcinoma. Case presentation: A 42-year-old man was referred to our urology department with positive urine cytology for urothelial carcinoma. Cystoscopy revealed a broad-base nonpapillary bladder tumor. The patient underwent a transurethral resection of the bladder tumor. Pathological examination revealed urothelial carcinoma, high-grade pT1, and concurrent resection of condyloma acuminatum. DNA was extracted from the paraffin-embedded transurethral resection of the bladder tumor tissue specimens. HPV11 was detected in condylomas by PCR and in situ hybridization, whereas HPV was not detected in urothelial carcinomas. Conclusion: We report a rare case of condyloma acuminatum of the bladder that was concurrently diagnosed with urothelial carcinoma from the same site.

Six-year outcomes of robot-assisted radical prostatectomy versus volumetric modulated arc therapy for localized prostate cancer: A propensity score-matched analysis.

BACKGROUND: Although robot-assisted radical prostatectomy (RARP) and intensity-modulated radiotherapy are the leading respective techniques of prostatectomy and radiotherapy for localized prostate cancer, almost no study has directly compared their outcomes; none have compared mortality outcomes. METHODS: We compared 6­year outcomes of RARP (n = 500) and volumetric modulated arc therapy (VMAT, a rotational intensity-modulated radiotherapy, n = 360) in patients with cT1-4N0M0 prostate cancer. We assessed oncological outcomes, namely overall survival (OS), cancer-specific survival (CSS), radiological recurrence-free survival (rRFS), and biochemical recurrence-free survival (bRFS), using propensity score matching (PSM). We also assessed treatment-related complication outcomes of prostatectomy and radiotherapy. RESULTS: The median follow-up duration was 79 months (> 6 years). PSM generated a matched cohort of 260 patients (130 per treatment group). In the matched cohort, RARP and VMAT showed equivalent results for OS, CSS, and rRFS: both achieved excellent 6­year outcomes for OS (> 96%), CSS (> 98%), and rRFS (> 91%). VMAT had significantly longer bRFS than RARP, albeit based on different definitions of biochemical recurrence. Regarding complication outcomes, patients who underwent RARP had minimal (2.6%) severe perioperative complications and achieved excellent continence recovery (91.6 and 68.8% of the patients achieved ≤ 1 pad/day and pad-free, respectively). Patients who underwent VMAT had an acceptable rate (20.0%) of grade ≥ 2 genitourinary complications and a very low rate (4.4%) of grade ≥ 2 gastrointestinal complications. CONCLUSION: On the basis of PSM after a 6-year follow-up, RARP and VMAT showed equivalent and excellent oncological outcomes, as well as acceptable complication profiles.

The importance of ethnic-specific cut-offs of low muscle mass for survival prediction in oncology.

BACKGROUND & AIMS: While skeletal muscle index (SMI) is the most widely used indicator of low muscle mass (or sarcopenia) in oncology, optimal cut-offs (or definitions) to better predict survival are not standardized. METHODS: We compared five major definitions of SMI-based low muscle mass using an Asian patient cohort with gastrointestinal or genitourinary cancers. We analyzed 2015 patients with surgically-treated gastrointestinal (n = 1382) or genitourinary (n = 633) cancer with pre-surgical computed tomography images. We assessed the associations of clinical parameters, including low muscle mass by each definition, with cancer-specific survival (CSS) and overall survival (OS). RESULTS: During a median follow-up period of 61 months, 303 (15%) died of cancer, and 147 died of other causes. An Asian-based definition diagnosed 17.8% of patients as having low muscle mass, while the other Caucasian-based ones classified most (>70%) patients as such. All definitions significantly discriminated both CSS and OS between patients with low or normal muscle mass. Low muscle mass using any definition but one predicted a lower CSS on multivariate Cox regression analyses. All definitions were independent predictors of lower OS. The original multivariate model without incorporating low muscle mass had c-indices of 0.63 for CSS and 0.66 for OS, which increased to 0.64-0.67 for CSS and 0.67-0.70 for OS when low muscle mass was considered. The model with an Asian-based definition had the highest c-indices (0.67 for CSS and 0.70 for OS). CONCLUSIONS: The Asian-specific definition had the best predictive ability for mortality in this Asian patient cohort.

Efficacy and safety of intravesical dimethyl sulfoxide treatment for patients with refractory Hunner-type interstitial cystitis: Real-world data postofficial approval in Japan.

OBJECTIVES: To examine real-world data regarding intravesical dimethyl sulfoxide (DMSO) therapy after official approval as a treatment for Hunner-type interstitial cystitis (HIC) in Japan. METHODS: This single institution, retrospective observational study was conducted between 2021 and 2022 to evaluate the outcomes of 30 patients with refractory HIC who received intravesical DMSO therapy according to the approved standardized regimen: administration of DMSO every 2 weeks for a total of 12 weeks. Treatment outcomes were evaluated using a 7-graded global response assessment scale, O'Leary and Sant's symptom and problem indices (OSSI/OSPI), the overactive bladder symptom score (OABSS), an 11-point pain intensity numerical rating scale, quality of life (QOL) score, and frequency volume chart variables. Related complications were also documented. RESULTS: The response rates at 2, 4, 6, 8, 10, and 12 weeks were 36.7%, 43.3%, 53.3%, 60.0%, 70.0%, and 70.0%, respectively. Compared with baseline, OSSI/OSPI, pain intensity, urinary frequency, and the QOL score improved significantly from 4 weeks of treatment. The OABSS score and functional bladder capacity also showed a tendency toward moderate improvement, but the difference was not significant. The mean duration of symptom relapse after termination of treatment was 6.4 ± 3.9 months. No patients discontinued treatment due to adverse events, although acute bladder irritation during infusion was noted in 21 patients (70%), which disappeared within 3 days. CONCLUSIONS: This study verifies the safety, moderately durable efficacy, and tolerability of the standard intravesical treatment with DMSO for HIC in Japan.

Latest evidence on clinical outcomes and prognostic factors of advanced urothelial carcinoma in the era of immune checkpoint inhibitors: a narrative review.

The management of advanced (locally advanced or metastatic) urothelial carcinoma has been revolutionized since pembrolizumab was introduced in 2017. Several prognostic factors for advanced urothelial carcinoma treated with pembrolizumab have been reported, including conventional parameters such as performance status and visceral (especially liver) metastasis, laboratory markers such as the neutrophil-to-lymphocyte ratio, sarcopenia, histological/genomic markers such as programmed cell death ligand 1 immunohistochemistry and tumor mutational burden, variant histology, immune-related adverse events, concomitant medications in relation to the gut microbiome, primary tumor site (bladder cancer versus upper tract urothelial carcinoma) and history/combination of radiotherapy. The survival time of advanced urothelial carcinoma has been significantly prolonged (or 'doubled' from 1 to 2 years) after the advent of pembrolizumab, which will be further improved with novel agents such as avelumab and enfortumab vedotin. This review summarizes the latest evidence on clinical outcomes and prognostic factors of advanced urothelial carcinoma in the contemporary era of immune checkpoint inhibitors.

Summary of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma 2023 by the Japanese Urological Association.

This article is an English translation of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma (2nd edition) published in June 2023. The Japanese Urological Association's (JUA) Guidelines Committee on Upper Tract Urothelial Carcinoma (UTUC) created a 2023 update guideline to support clinicians' current evidence-based management of UTUC and to incorporate its recommendations into clinical practice. The new guideline adhered as closely as possible to the Minds Manual for Guideline Development 2020 ver. 3.0. Findings related to epidemiological, pathological, diagnosis, treatment, and follow-up were reviewed. In addition, seven clinical questions (CQs) were set to determine the grade of recommendation and level of evidence. Preconceptions and biases were removed from the preparation process, the overall evidence was evaluated appropriately, and recommendations were made after fully considering the balance between benefits and harms. Although the evidence is still insufficient to be taken up as a CQ, the latest important information is described in seven columns, and clinical issues that should be resolved in the future related to the CQ are described as recommendations for tomorrow. We hope that these guidelines will help medical professionals, patients, and their families involved in the treatment of UTUC in their decision-making, and hope that a critical review of these guidelines will lead to further refinements in the next edition.

Maturation and development of fetal pig intestinal tissue in immunodeficient mice

Purpose: This study aimed to compare the degree of maturation and development of fetal pig segmental intestinal tissue with that of spheroids created by in-vitro reaggregation of dissociated fetal intestinal cells after transplantation into immunodeficient mice. Methods: Fetal pig small intestines were transplanted as segmental grafts into the omentum and subrenal capsules of immunodeficient mice or enzymatically treated to generate single cells. Spheroids made by in-vitro reaggregation of these cells were transplanted into the subrenal capsules of immunodeficient mice. The segmental grafts and spheroids were harvested four and eight weeks after transplantation, and the structural maturity and in-vivo development of these specimens were histologically evaluated. Results: The spheroids were engrafted and supplied blood vessels from the host mice, but an intestinal layered structure was not clearly observed, and there was almost no change in size. On the other hand, the segmental grafts formed deep crypts in the mucus membrane, the inner circular layer, and outer longitudinal muscles. The crypts of the transplanted grafts harvested at eight weeks were much deeper, and the smooth muscle layer and the enteric nervous system were more mature than those of grafts harvested at the fourth week, although the intestinal peristaltic wave was not observed. Conclusions: Spheroids created from fetal small intestinal cells could not form layered structures or mature sufficiently. Conversely, segmental tissues structurally matured and developed after in-vivo transplantation and are therefore potential grafts for transplantation.

Th1/17 polarization and potential treatment by an anti-interferon-γ DNA aptamer in Hunner-type interstitial cystitis.

Hunner-type interstitial cystitis (HIC) is a rare, enigmatic inflammatory disease of the urinary bladder with no curative treatments. In this study, we aimed to characterize the unique cellular and immunological factors specifically involved in HIC by comparing with cystitis induced by Mycobacterium bovis bacillus Calmette-Guérin, which presents similar clinicopathological features to HIC. Here, we show that T helper 1/17 +polarized immune responses accompanied by prominent overexpression of interferon (IFN)-γ, enhanced cGAS-STING cytosolic DNA sensing pathway, and increased plasma cell infiltration are the characteristic inflammatory features in HIC bladder. Further, we developed a mouse anti-IFN-γ DNA aptamer and observed that the intravesical instillation of the aptamer significantly ameliorated bladder inflammation, pelvic pain and voiding dysfunction in a recently developed murine HIC model with little migration into the blood. Our study provides the plausible basis for the clinical translation of the anti-IFN-γ DNA aptamer in the treatment of human HIC.