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.

C-Reactive Protein-Albumin Ratio Predicts Objective Response to Enfortumab Vedotin in Metastatic Urothelial Carcinoma.

BACKGROUND: Enfortumab vedotin (EV), an antibody-drug conjugate that targets Nectin-4, is used for patients with metastatic urothelial carcinoma who have experienced progression on platinum-based chemotherapy and checkpoint inhibitors. Despite the widespread use of the drug, evidence remains scarce regarding clinical indicators that can predict the response to EV treatment. OBJECTIVE: We aimed to explore the predictive value of clinical indicators derived from peripheral blood tests for treatment responses to EV. METHODS: We utilized records of 109 patients with metastatic urothelial carcinoma treated by EV from our multi-institutional dataset. Receiver operating characteristic curve analyses for predicting objective responses including several indicators from blood examinations, such as C-reactive protein-albumin ratio (CAR), hemoglobin, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and lactate dehydrogenase, were performed. The optimal cutoff points were determined by the Youden index. Logistic regression analyses for achieving objective responses to EV treatment were performed among these indicators. RESULTS: The median age of the cohort was 74 years, and the median follow-up duration was 10 months for the entire group. Median overall survival and progression-free survival from the initiation of EV were 12 and 6 months, respectively. The objective response rate and disease control rate were 48% and 70%, respectively. The receiver operating characteristic curve analysis aimed at predicting the achievement of an objective response to EV showed that the concordant index for the CAR was 0.774, significantly surpassing other indicators such as hemoglobin level, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and serum lactate dehydrogenase. The Youden index identified an optimal cutoff value of 1 for CAR (mg/L for C-reactive protein and g/dL for serum albumin level) in predicting the objective response to EV treatment. Using the cutoff value for the CAR, the cohort was divided into 32 patients (29%) with lower CAR and 77 patients (71%) with higher CAR. The objective response rate was observed to be 84% in the lower CAR group and 32% in the higher CAR group (p < 0.0001). A logistic regression analysis revealed that an Eastern Cooperative Oncology Group Performance Status ≥1 (p = 0.04) and a CAR ≥1 (p < 0.001) were identified as independent predictors for the objective response to EV. CONCLUSIONS: The evaluation of the CAR from a concise blood examination at the initiation of EV could effectively predict the treatment response to EV in patients with metastatic urothelial carcinoma after the progression of platinum-based chemotherapy and checkpoint inhibitors.

Enfortumab vedotin, an antibody-drug conjugate that targets Nectin-4, is currently used for patients with metastatic urothelial carcinoma who no longer respond to checkpoint inhibitors. In the present report, we investigated which clinical indicators can predict achieving an objective response to enfortumab vedotin at the initiation of treatment. Among the blood-based putative indicators, the C-reactive protein-albumin ratio showed the highest value for predicting the treatment response to enfortumab vedotin. As the C-reactive protein-albumin ratio can be easily assessed from blood tests, physicians can consider evaluating it at the start of the EV treatment.

Durable Response to Enfortumab Vedotin Compared to Re-challenging Chemotherapy in Metastatic Urothelial Carcinoma After Checkpoint Inhibitors.

BACKGROUND: Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has been used for patients with metastatic urothelial carcinoma (mUC) after progressing on checkpoint inhibitors (CPIs). Re-challenging chemotherapy with platinum agents and continuing CPIs beyond progressive disease (PD) have often been chosen following PD on CPIs, and several studies indicate favorable treatment effects of re-challenging chemotherapy. There is little evidence for comparing EV and re-challenging chemotherapy in real-world clinical practice. OBJECTIVE: The aim was to reveal the real-world treatment outcomes of EV, re-challenging chemotherapy, and continuing CPIs beyond PD in mUC patients. PATIENTS AND METHODS: A multi-institutional dataset of 350 mUC patients treated with CPIs was utilized. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) were evaluated to compare the treatment arms. RESULTS: One hundred and nine mUC patients were treated with EV with a median follow-up of 6.4 months. The ORR and disease control rate (DCR) were 48% and 70%, respectively. The OS from PD on pembrolizumab exhibited significant differences among the three groups, with a median OS of 8, 14, and 29 months in continuing pembrolizumab beyond PD, re-challenging chemotherapy, and EV, respectively. When comparing the survival outcomes from the initiation of the treatment, there is neither a difference in OS (p = 0.124), PFS (p = 0.936), nor ORR (p = 0.816) between EV and re-challenging chemotherapy. Notably, the DOR in patients who achieved an objective response was significantly longer in the EV group than the re-challenging chemotherapy group (a median of 11 and 5 months, p = 0.049). For OS, the difference was not statistically significant (27 and 11 months in EV and re-challenging chemotherapy, respectively: p = 0.05). CONCLUSIONS: A superior effect of EV on patient survival compared to re-challenging chemotherapy and continuing pembrolizumab beyond PD was observed in our real-world analysis, which is attributed to the durable DOR in EV treatment despite the similar ORR to re-challenging chemotherapy.

Enfortumab vedotin (EV) is an antibody­drug conjugate targeting Nectin-4 and is now utilized for patients with metastatic urothelial carcinoma following treatment with checkpoint inhibitors (CPIs). Until recently, repeating chemotherapy using platinum drugs or continuing CPIs were often the treatments used for these patients. In the present study, we reported real-world treatment outcomes, mainly focusing on EV and repeating chemotherapy. Although the objective responses to the treatments were comparable, the duration of response for patients responding to the treatment was significantly longer in patients treated with EV than in those repeating chemotherapy, resulting in extended survival time with EV treatment.

Importance of Management of Lifestyle-Related Diseases After Kidney Donation to Living Donors.

BACKGROUND: Living kidney transplant donors are classified as stage 3 chronic kidney disease after kidney donation. For this reason, we provide daily lifestyle guidance, such as blood pressure and weight management before surgery, and dietary counseling focused on salt restriction. We emphasize providing lifestyle guidance after kidney donation. METHOD: At Osaka Medical and Pharmaceutical University Hospital, living kidney donors are scheduled for their first postoperative visit 1 month after kidney donation, followed by regular checkups every 6 months after that, starting 3 months after the initial visit. When living kidney donors come to the Renal Replacement Therapy Selection Outpatient Clinic before kidney transplantation, we provide sufficient explanations of the potential risks that may arise after kidney donation and ensure that they understand the importance of regular postoperative checkups. Apart from cases where patients reside far away, and we ask another hospital to provide postoperative follow-up, we can achieve regular checkups for almost all cases. RESULTS: Eighty-four living kidney transplant donors are being followed up at Osaka Medical and Pharmaceutical University Hospital. The average age is 59.8 ± 11.8 years, showing a trend of aging. Among the donors under follow-up, 7 developed hyperlipidemia, 2 developed hypertension, and 1 developed diabetes as new-onset lifestyle diseases after kidney donation. CONCLUSION: The ability to empathize with and support the anxieties associated with kidney donation and build a strong relationship of trust with the donors has become a significant factor in achieving a high rate of regular checkups after kidney donation. As a result, it has led to early detection and intervention for donor diseases, contributing to the maintenance of their health. Managing lifestyle-related diseases after kidney donation is essential for living kidney donors.

The medical cost and outcome of desensitization protocol in kidney transplantation recipients with high immunological risks.

BACKGROUND: Kidney transplantation is a well-established alternative in renal replacement therapy. Compared with hemodialysis, low-immunological-risk kidney transplantation can reduce the medical treatment costs associated with end-stage renal disease. However, there are few reports on whether high-immunological-risk kidney transplantation reduces the financial burden on governments. We investigated the medical costs of high-immunological-risk kidney transplantation in comparison with the cost of hemodialysis in Japan. METHODS: We compared the medical costs of high-immunological-risk kidney transplantation with those of hemodialysis. 15 patients who underwent crossmatch-positive and/or donor-specific antibody-positive kidney transplantations between 2020 and 2021 were enrolled in this study. The patients received intravenous immunoglobulin, plasmapheresis, and rituximab as desensitizing therapy. RESULTS: Acute antibody-mediated rejection was detected in nine (60%) recipients, while there were no indications of graft function deterioration during the follow-up. For each patient, the transplant hospitalization cost was 38 428 ± 8789 USD. However, the cumulative costs were 59 758 ± 10 006 USD and 79 781 ± 16 366 USD, at 12 and 24 months, respectively. Compared with hemodialysis (34 286 USD per year), high-immunological-risk kidney transplantation tends to be expensive in the first year, but the cost is likely to be lower than that of hemodialysis after 3 years. CONCLUSIONS: Although kidney transplantation is initially expensive compared with hemodialysis, the medical cost becomes advantageous after 3 years even in kidney transplant recipients with high immunological risk.

Bronchogenic cysts in rare sites (retroperitoneum, skin, spinal cord and pericardial cavity): A case series and characterization of epithelial phenotypes.

Bronchogenic cysts are congenital malformations of the bronchial tree, detected as a cystic and/or mass lesion in the thoracic cavity. Although it occurs in distant locations, such as skin and retroperitoneum, to the best of our knowledge, little is known about the components and phenotypes of the epithelium that line a bronchogenic cyst in rare sites. The present study reviewed 34 bronchogenic cysts that were surgically resected at Osaka Medical and Pharmaceutical University Hospital (Osaka, Japan) from January 1998 to December 2020. Bronchogenic cysts in rare sites were detected and diagnosis was confirmed based on the presence of pseudostratified, ciliated and/or columnar epithelium together with at least one of the following: Cartilage, smooth muscle or seromucous glands. The phenotypes of epithelium lining the cyst were characterized using immunohistochemical analysis. A total of six bronchogenic cysts in rare sites (two cases each in the retroperitoneum and skin and one case each in the cervical spinal cord and pericardial cavity) met the criteria for confirmation of the diagnoses. The epithelium lining the cyst stained positive for cytokeratin CK7 and thyroid transcription factor 1 (a marker expressed in thyroid follicles and bronchial epithelium) and negative for CK20, indicating that the phenotypes were similar to those of the respiratory epithelium. The present study demonstrated that a bronchogenic cyst can occur in rare sites, such as the retroperitoneum, skin, spinal cord and pericardial cavity, suggesting that it should be considered as a differential diagnosis before surgical approach to implement relevant management modalities such as follow-up, simple or radical resection.

TAS0313 plus Pembrolizumab for Post-Chemotherapy Immune Checkpoint Inhibitor-Naïve Locally Advanced or Metastatic Urothelial Carcinoma.

We evaluated the efficacy and safety of TAS0313, a multi-epitope long peptide vaccine, plus pembrolizumab in post-chemotherapy immune checkpoint inhibitor-naïve patients with locally advanced/metastatic urothelial carcinoma (la/mUC). TAS0313 9 mg was administered subcutaneously followed by pembrolizumab 200 mg on Day 1, and as monotherapy on Day 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Biomarkers of response were assessed. In 36 patients enrolled, the ORR was 33.3% (complete response: 7 patients; partial response: 5 patients). Median PFS was 5.0 months; 6- and 12-month progression-free rates were 46.4% and 36.5%, respectively. Median OS was not reached; 6-, 12-, and 24-month OS rates were 83.3%, 72.2%, and 55.1%, respectively. In post hoc analysis, patients with a tumor infiltrating CD8+ lymphocyte (CD8+ TIL) count ≥99 and/or programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥50 and lymphocyte count >1,380 cells/µL had higher ORRs and prolonged PFS versus patients with a CD8+ TIL count <99, PD-L1 CPS <50, and lymphocyte count ≤1,380 cells/µL. Thirty-four (94.4%) patients receiving combination therapy experienced treatment-related adverse events (AE), with pyrexia (n = 15, 41.7%), injection-site reactions (n = 15, 41.7%), injection-site induration (n = 6, 16.7%), and malaise (n = 6, 16.7%) the most common. No grade ≥3 treatment-related AEs occurred in ≥10% of patients. TAS0313 plus pembrolizumab combination therapy showed promising efficacy and manageable safety in la/mUC. Clinical Trial Registration: JapicCTI-183824.

Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study.

BACKGROUND: Immune checkpoint inhibitors can cause various immune-related adverse events (irAEs). This study aimed to evaluate the association between the incidence of irAEs and oncological outcomes of metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab as first-line therapy. PATIENTS AND METHODS: We retrospectively analyzed data from 69 patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy between September 2018 and September 2021 at 4 institutions. Cox regression analyses were performed to investigate the important factors affecting overall survival (OS) in patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy. RESULTS: During observation with a median follow-up of 9.1 months, the median OS was not reached, while the median progression-free survival was 6.0 months. Patients with irAEs had significantly prolonged OS and progression-free survival than those without irAEs (p = .012 and .002, respectively). Multivariate analysis showed that 3 independent factors, including C-reactive protein (CRP), irAEs, and performance status (PS), were significantly associated with OS (p = .04, .02, and .01, respectively). The patients were subsequently divided into 3 groups as follows: group 1, 20 patients with all 3 independent OS predictors; group 2, 18 patients with irAE predictors alone or 2 positive independent OS predictors (irAEs + CRP or irAEs + PS); group 3, 31 patients with 3 negative independent S predictors. OS varied significantly among the 3 groups (p = .004). CONCLUSION: The appearance of irAEs could predict OS in patients with mRCC treated with nivolumab plus ipilimumab as the first-line therapy.

Transplanting old organs promotes senescence in young recipients.

In clinical organ transplantation, donor and recipient ages may differ substantially. Old donor organs accumulate senescent cells that have the capacity to induce senescence in naïve cells. We hypothesized that the engraftment of old organs may induce senescence in younger recipients, promoting age-related pathologies. When performing isogeneic cardiac transplants between age-mismatched C57BL/6 old donor (18 months) mice and young and middle-aged C57BL/6 (3- or 12- month-old) recipients , we observed augmented frequencies of senescent cells in draining lymph nodes, adipose tissue, livers, and hindlimb muscles 30 days after transplantation. These observations went along with compromised physical performance and impaired spatial learning and memory abilities. Systemic levels of the senescence-associated secretory phenotype factors, including mitochondrial DNA (mt-DNA), were elevated in recipients. Of mechanistic relevance, injections of mt-DNA phenocopied effects of age-mismatched organ transplantation on accelerating aging. Single treatment of old donor animals with senolytics prior to transplantation attenuated mt-DNA release and improved physical capacities in young recipients. Collectively, we show that transplanting older organs induces senescence in transplant recipients, resulting in compromised physical and cognitive capacities. Depleting senescent cells with senolytics, in turn, represents a promising approach to improve outcomes of older organs.

Real world evidence of enfortumab vedotin in patients with advanced urothelial cancer: A multicenter observational study.

OBJECTIVES: To explore the characteristics of patients and assess the effectiveness of enfortumab vedotin (EV) in those with treatment-resistant advanced urothelial cancer in a real-world setting. PATIENTS AND METHODS: A multicenter observational study was conducted on 103 evaluable patients with advanced urothelial cancer who received EV. Outcomes were assessed by radiographic response, progression-free survival (PFS), and overall survival (OS), with treatment-related adverse events (trAEs). Radiographic response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1, while trAEs were studied in line with Common Terminology Criteria for Adverse Events version 5.0. RESULTS: The median follow-up was 8.9 months (range, 0.1-16.4). The observed objective response rate was 50.5%. The median PFS was 6.0 months (95% CI: 4.7-9.8), and the median OS was 14.5 months (95% CI: 12.4-not reached). Out of the 103 patients, 19 (18.4%) had an Eastern Cooperative Oncology Group performance status of 2 or more, 14 (14.7%) had an non-urothelial carcinoma histology, and 40 (38.3%) had at least one pre-existing comorbidity. There were 26 (25.2%) patients who reported 49 trAEs, with 9 (18.3%) being grade 3 or higher. The most common trAEs included rash, occurring in 18.4%. CONCLUSIONS: This study describes the characteristics and outcomes of patients with previously treated advanced urothelial cancer receiving EV. The findings demonstrate that EV showed robust anti-tumor activity and had manageable safety profiles outside the clinical trial setting.

Real-world outcomes of avelumab plus axitinib as first-line therapy in patients with advanced renal cell carcinoma in Japan: A multicenter, retrospective, observational study (J-DART).

OBJECTIVES: In the phase 3 JAVELIN Renal 101 trial in patients with advanced renal cell carcinoma (aRCC), objective response rate (ORR) and progression-free survival (PFS) were significantly improved in patients treated with first-line avelumab plus axitinib vs sunitinib. Here we evaluate real-world outcomes with first-line avelumab plus axitinib in Japanese patients with aRCC. METHODS: In this multicenter, noninterventional, retrospective study, clinical data from patients with aRCC treated with first-line avelumab plus axitinib between December 2019 and December 2020 in Japan were reviewed. Endpoints included ORR and PFS per investigator assessment, and time to treatment discontinuation (TTD). RESULTS: Data from 48 patients (median age, 69 years) from 12 sites were analyzed. Median follow-up was 10.4 months (range, 2.6-16.5), and median duration of treatment was 7.4 months (range, 0.5-16.5). International Metastatic RCC Database Consortium risk category was favorable, intermediate, or poor in 16.7%, 54.2%, and 29.2% of patients, respectively. The ORR was 48.8% (95% CI, 33.3%-64.5%), including complete response in 3/43 patients (7.0%). Thirteen patients (27.1%) had disease progression or died, and median PFS was 15.3 months (95% CI, 9.7 months - not estimable). At data cutoff, 24 patients (50.0%) were still receiving avelumab plus axitinib, and median TTD was 15.2 months (95% CI, 7.4 months - not estimable). Three patients (6.3%) received high-dose corticosteroid treatment for immune-related adverse events, and 8 (16.7%) received treatment for infusion-related reactions. CONCLUSIONS: We report the first real-world evidence of the effectiveness and tolerability of first-line avelumab plus axitinib in Japanese patients with aRCC. Results were comparable with the JAVELIN Renal 101 trial.

Pattern of expression of microRNA in patients with radiation induced bladder injury.

INTRODUCTION: Bladder cancer (BC) is sensitive to radiation treatment and a subset of patient experiences radiation induced injuries including shrinkage of bladder due to bladder fibrosis. METHODS: Using a micro-RNA (miRNA) array comparing patient's samples with, or without radiation induced injuries, we have checked the clustering of miRNA expression. RESULTS: Hsa-miR-130a, hsa-miR-200c, hsa-miR-141, and hsa-miR-96 were found to be highly expressed (>50 times) in patients with fibrotic bladder shrinkage (FBS) compared to those with intact bladder (IB) function. In patients with FBS, hsa-miR-6835, hsa-miR-4675, hsa-miR-371a, and hsa-miR-6885 were detected to have lesser than half expression to IB patients. We have analyzed the significance of these genes in relation to overall survival of 409 BC patients retrieved from TCGA data set. We have run combined survival analysis of mean expression of these four miRNAs highly expressed in FBS patients. 175 patients with high expression had longer median survival of 98.47 months than 23.73 months in 233 patients with low expression (HR: 0.53; 0.39 - 0.72, logrank P value: 7.3e-0.5). Combination analysis of all 8 genes including hsa-miR-6835, hsa-miR-4675, hsa-miR-371a, and hsa-miR-6885 showed the same HR for OS. Target scanning for these miRNAs matched specific cytokines known as an early biomarker to develop radiation induced fibrosis. CONCLUSIONS: BC patients with fibrotic radiation injury have specific miRNA expression profile targeting pro-fibrotic cytokines and these miRNAs possibly renders to favorable survival.

Expression of Preferentially Expressed Antigen in Melanoma, a Cancer/Testis Antigen, in Carcinoma In Situ of the Urinary Tract.

Carcinoma in situ (CIS) of the urinary tract comprises 1-3% of all urothelial malignancies and is often a precursor to muscle-invasive urothelial carcinoma (UC). This study aimed to examine the expression profiles of preferentially expressed antigen in melanoma (PRAME), a cancer/testis antigen, and assess its diagnostic and therapeutic applications in CIS, given that its expression in UC has been minimally studied and has not yet been analyzed in CIS. We selected consecutive patients with CIS who underwent biopsy and/or transurethral tumor resection at the Osaka Medical and Pharmaceutical University Hospital. Immunohistochemical staining for PRAME and p53 was performed. Overall, 53 patients with CIS (6 females and 47 males) were included. Notably, PRAME expression was observed in 23 of the 53 patients (43.4%), whereas it was absent in the non-neoplastic urothelial epithelium. Furthermore, no correlation was found between PRAME expression and aberrant p53 expression. Therefore, PRAME expression may serve as a useful marker for CIS of the urinary tract. Furthermore, PRAME may be a candidate for the novel therapeutic target for standard treatment-refractory CIS patients.

A successful plasma exchange in bridging to rituximab for severe neuropsychiatric lupus and lupus nephritis with viral infections and aspiration pneumonia.

Systematic lupus erythematosus (SLE) is a chronic autoimmune disease involving several organs such as the kidneys, skin, vessels, and central nervous system. Neuropsychiatric SLE (NPSLE) is a life-threatening condition that needs treatment with the combination of glucocorticoids and Immunosuppressants (IS). This includes cyclophosphamide and rituximab (RTX) which can lead to several infections. Therapeutic apheresis is an optional treatment for inflammatory diseases and has less risks of infections than IS. Plasma exchange (PE) is one of the most common apheresis, and is recommended for the management of NPSLE. We report a refractory NPSLE case with bacterial pneumonia and cytomegalovirus antigenemia. PE was performed prior to RTX. After the initiation of RTX which was incompatible due to infection such as aspiration pneumonia and cytomegalic virus, PE was scheduled considering the pharmacokinetics of RTX. Her SLE activity was well managed after PE and RTX without flare. PE treatment plan bridging to IS and RTX may effectively work in refractory SLE patients with infections.

The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer.

BACKGROUND: Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA). METHODS: A multi-omics analysis on 389 BLCA and 35 adjacent normal tissues from a cohort of OMPU-NCC Consortium Japan was retrospectively performed by integrating the whole-exome and RNA-sequence dataset and clinicopathological record. A median follow-up duration of all BLCA cohort was 31 months. RESULTS: FGFR3 alterations (aFGFR3), including recurrent mutations and fusions, accounted for 44% of non-muscle invasive bladder cancer (NMIBC) and 15% of muscle-invasive bladder cancer (MIBC). Within MIBC, the consensus subtypes LumP was significantly more prevalent in aFGFR3, whereas the Ba/Sq subtype exhibited similarity between intact FGFR3 (iFGFR3) and aFGFR3 cases. We revealed that basal markers were significantly increased in MIBC/aFGFR3 compared to MIBC/iFGFR3. Transcriptome analysis highlighted TIM3 as the most upregulated immune-related gene in iFGFR3, with differential immune cell compositions observed between iFGFR3 and aFGFR3. Using EcoTyper, TME heterogeneity was discerned even within aFGFR cases, suggesting potential variations in the response to checkpoint inhibitors (CPIs). Among 72 patients treated with CPIs, the objective response rate (ORR) was comparable between iFGFR3 and aFGFR3 (20% vs 31%; p = 0.467). Strikingly, a significantly higher ORR was noted in LumP/aFGFR3 compared to LumP/iFGFR3 (50% vs 5%; p = 0.022). This trend was validated using data from the IMvigor210 trial. Additionally, several immune-related genes, including IDO1, CCL24, IL1RL1, LGALS4, and NCAM (CD56) were upregulated in LumP/iFGFR3 compared to LumP/aFGFR3 cases. CONCLUSIONS: Differential pathways influenced by aFGFR3 were observed between NMIBC and MIBC, highlighting the upregulation of both luminal and basal markers in MIBC/aFGFR3. Heterogeneous TME was identified within MIBC/aFGFR3, leading to differential outcomes for CPIs. Specifically, a favorable ORR in LumP/aFGFR3 and a poor ORR in LumP/iFGFR3 were observed. We propose TIM3 as a potential target for iFGFR3 (ORR: 20%) and several immune checkpoint genes, including IDO1 and CCL24, for LumP/iFGFR3 (ORR: 5%), indicating promising avenues for precision immunotherapy for BLCA.

Nephron-sparing ureteroscopic surgery vs. radical nephroureterectomy: comparable survival-outcomes in upper tract urothelial carcinoma.

PURPOSE: This study investigates the utility of ureteroscopic surgery (URS) as an alternative to radical nephroureterectomy (RNU) in managing upper tract urothelial carcinoma (UTUC), with a focus on survival outcomes and re-evaluation of current the European Association of Urology guidelines criteria. METHODS: We conducted a retrospective, multi-institutional review of 143 UTUC patients treated with URS (n = 35) or RNU (n = 108). Clinicopathological factors were analyzed, and survival outcomes were assessed using Kaplan-Meier analysis and Cox proportional-hazards models. RESULTS: The median follow-up period was 27 months. Overall survival (OS) and radiographic progression-free survival (rPFS) were comparable between the URS and RNU groups (OS: HR 2.42, 95% CI 0.63-9.28, P = 0.0579; rPFS: HR 1.82, 95% CI 0.60-5.47, P = 0.1641). URS conferred superior renal function preservation. In patients characterized by factors such as radiographically invisible lesions, negative cytology, pTa stage, low-grade tumors, and multiple lesions, the OS outcomes with URS were comparable to those with RNU as follows: radiographically invisible lesions (P = 0.5768), negative cytology (P = 0.7626), pTa stage (P = 0.6694), low-grade tumors (P = 0.9870), and multiple lesions (P = 0.8586). CONCLUSION: URS offers survival outcomes similar to RNU, along with better renal function preservation, especially in low-risk UTUC patients. These findings underscore the urgency of re-evaluating the current EAU guidelines and encourage further research into determining the ideal patient selection for URS in UTUC treatment.

Predicting Objective Response of Pembrolizumab in Platinum-Refractory Urothelial Carcinoma Based on NLR Fluctuation and Liver Metastases.

BACKGROUND AND PURPOSE: It is well known that patients with objective response to pembrolizumab have a durable duration of response leading to favorable survival outcomes. We investigated the possibility of predicting the objective response with concise indicators obtained from daily clinical practice. Methods In our multi-institutional cohort, 220 platinum-refractory metastatic urothelial carcinomas (mUC) treated with pembrolizumab for at least six weeks with complete information of objective response were investigated. Results The median follow-up was 7.3 months, and 119 patients deceased during the follow-up. A multivariate logistic regression analysis exhibited two independent variables predicting the objective response, including the neutrophil-lymphocyte ratio (NLR) change at six weeks of treatment and liver metastasis. We proposed a risk group using these two indicators. Patients with no predictive indicators / one of those were assigned to favorable (42%) / intermittent (47%) risk groups. Patients with both indicators were assigned to poor risk (11%). Notably, the objective response rate was well delineated in 41%, 25%, and 0% for favorable, intermediate, and poor risk groups, respectively (p<0.001). Distinct overall survival (OS) between the risk groups was also confirmed with the median OS of 14.1, 11.7, and 4.2 months in favorable, intermediate, and poor risk groups, respectively. CONCLUSIONS: At the six weeks of the pembrolizumab treatment, our risk model predicts the objective response rate precisely. Notably, those classified as 'poor risk'-marked by liver metastasis and a heightened NLR-should be considered for alternative therapy with a different mode of action, highlighting a critical decision point in treatment optimization.

Real-world survival outcome comparing abiraterone acetate plus prednisone and enzalutamide for nonmetastatic castration-resistant prostate cancer.

BACKGROUND: There is little evidence of abiraterone acetate (AA) plus prednisone for patients with non-metastatic castration-resistant prostate cancer (nmCRPC). In this study, we conducted a comparative analysis of real-world survival outcomes between AA plus prednisone and enzalutamide (Enz) in patients with nmCRPC, utilizing our consortium dataset. MATERIALS AND METHODS: The clinical records of 133 nmCRPC patients treated with first-line Enz or AA plus prednisone were analyzed. The primary endpoints of the study were overall survival (OS) and cancer-specific survival (CSS). Cumulative incidence function (CIF) using Fine and Gray models was also utilized to assess non-cancer-caused death considering the competing risk of cancer-caused death. RESULTS: During a median follow-up of 36 months, 34 patients (25.6%) had deceased, with a median OS of 99 months in the entire cohort. There were no significant differences in comorbidities between the Enz and AA groups. Time to PSA progression (TTPP: HR 0.81, 95% CI 0.51-1.30, P = 0.375) and CSS (HR 1.32, 95% CI 0.55-3.44, P = 0.5141) were comparable between the two groups. However, intriguingly, there was a trend towards shorter OS in patients treated with AA plus prednisone compared to Enz (HR 0.57, 95% CI 0.29-1.12, P = 0.0978, median of 99 and 69 months in Enz and AA groups, respectively). CIF analysis revealed that nmCRPC patients treated with AA plus prednisone were more likely to result in non-cancer-caused death than those treated with Enz (HR 5.22, 95% CI 1.88-14.50, P = 0.0014). CONCLUSIONS: Our real-world survival analysis suggests that while AA plus prednisone may demonstrate comparable treatment efficacy to Enz in the context of nmCRPC, there may be an increased risk of non-cancer-caused death. Physicians should take into consideration this information when making treatment decisions for patients with nmCRPC.

Tertiary lymphoid structure and neutrophil-lymphocyte ratio coordinately predict outcome of pembrolizumab.

Emerging evidence suggests that the presence of tertiary lymphoid structures (TLS) and neutrophil-lymphocyte ratio (NLR) in peripheral blood is associated with the treatment response to checkpoint inhibitors (CPIs), whereas there is limited knowledge regarding whether these factors reciprocally impact the treatment outcomes of CPIs in metastatic urothelial carcinoma (mUC). Herein, we investigated treatment outcomes of platinum-refractory mUC patients (50 cases with whole-exome and transcriptome sequencing) treated with pembrolizumab. The pathological review identified 24% of cases of TLS in the specimens. There was no significant difference in the NLR between the TLS- and TLS+ groups (p = 0.153). In the lower NLR group, both overall survival and progression-free survival were significantly longer in patients with TLS than in those without TLS, whereas the favorable outcomes associated with TLS were not observed in patients in the higher NLR group. We explored transcriptomic differences in UC with TLS. The TLS was comparably observed between luminal (20%) and basal (25%) tumor subtypes (p = 0.736). Exploring putative immune-checkpoint genes revealed that ICOSLG (B7-H2) was significantly increased in tumors with lower NLR. KRT expression levels exhibited higher basal cell markers (KRT5 and KRT17) in the higher NLR group and lower differentiated cell markers (KRT8 and KRT18) in patients with TLS. In conclusion, the improved outcomes of pembrolizumab treatment in mUC are restricted to patients with lower NLR. Our findings begin to elucidate a distinct molecular pattern for the presence of TLS according to the NLR in peripheral blood.

Detection of the Vesical Arteries Using Three-dimensional Digital Subtraction Angiography Relevant to Intra-arterial Infusion Chemotherapy for Bladder Cancer Using Double-balloon Catheters.

Purpose: This study aims to assess and measure the origin of the superior vesical artery and its distance from the anterior trunk of the internal iliac artery, to which the anticancer drug is infused via double-balloon-occluded arterial infusion bladder-preserving therapy for locally invasive bladder cancer. Material and Methods: The 160 pelvic sides of 80 patients were analyzed. Double-balloon catheters were bilaterally introduced into the contralateral superior gluteal artery via the internal iliac arteries using a bilateral transfemoral approach. The proximal balloon is placed at the internal iliac artery, proximally from superior gluteal artery bifurcation, whereas the distal balloon at the origin of the superior gluteal artery to isolate the anterior trunk of the internal iliac artery discharging to the targeted vesical arteries between the balloons. The side hole between the distal and proximal balloons was adjusted at the origin of the anterior trunk of the internal iliac artery to allow clear visualization of the angiographic flow into the bladder. After the distal and proximal balloons were inflated, three-dimensional rotational digital subtraction angiography was performed by simultaneous contrast injection from one extension tube connected to bilateral catheters. The distance (X) between the origins of anterior trunk of the internal iliac artery and superior vesical artery was measured on three-dimensional digital subtraction angiography images, and the origin of the inferior vesical artery was investigated. Results: All superior vesical artery originated from anterior trunk of the internal iliac artery. The mean x was 7.2 mm (range 1.0-22.0 mm). All inferior vesical arterys branched from anterior trunk of the internal iliac artery or its branches. Conclusions: Superior vesical artery commonly originates from the proximal portion of anterior trunk of the internal iliac artery close to superior gluteal artery bifurcation.