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.

Differences in oncological benefits from second transurethral resection between white-light initial surgery and photodynamic diagnosis-guided initial surgery for primary high-risk non-muscle invasive bladder cancer.

OBJECTIVES: The aim of this study was to compare clinical outcomes between patients receiving second TUR after initial white-light transurethral resection of bladder tumor (WL-TURBT) and initial photodynamic diagnosis (PDD)-assisted TURBT. METHODS: A total of 1007 patients were divided into four groups based on the treatment pattern: WL-TURBT with second TUR (161 patients, WL-second group) or without second TUR (540 patients, WL-alone group) and PDD-TURBT with second TUR (112 patients, PDD-second group) or without second TUR (194 patients, PDD-alone group). Oncologic outcomes (bladder cancer recurrence, progression, urothelial cancer-specific mortality) and rates of residual tumor and risk stratification of non-muscle-invasive bladder cancer (NMIBC) after second TUR were evaluated. RESULTS: After propensity score-matching 121 patients were included each in the WL-alone and WL-second groups, and 63 patients each in the PDD-alone and PDD-second groups. In the WL group, the second TUR was significantly associated with improved progression-free (p = 0.012) and urothelial cancer-specific free survival (p = 0.011), but not with recurrence-free survival (p = 0.93). Patients initially treated with PDD-TURBT, and with a tumor diameter <30 mm and multifocality had a relatively high benefit from second TUR. The rates of residual tumor and risk stratification of NMIBC did not significantly differ between WL-TURBT and PDD-TURBT groups. CONCLUSIONS: Our findings suggested that a second TUR could be omitted after an initial PDD-TURBT in selected patients with high-risk NMIBC.

Methotrexate-associated lymphoproliferative disorder: A rare pancreatic tumor diagnosed via endoscopic ultrasound-guided fine-needle biopsy.

A 73-year-old woman with a history of rheumatoid arthritis treated with methotrexate (MTX) for the last 10 years was referred to our hospital for a pancreatic tumor examination. Contrast-enhanced abdominal computed tomography revealed a 20-mm-diameter hypovascular tumor in the pancreatic tail. A hypoechoic mass with heterogeneous internal echo was found on an endoscopic ultrasound (EUS). An EUS-guided fine-needle biopsy (EUS-FNB) was performed with a 22-gauge Franseen-tip needle. Histologic examination of EUS-FNB specimens from the pancreatic tumor revealed the proliferation of atypical spindle cells. Immunohistochemical staining for CD20 and Ki-67 was positive in the atypical cells. Immunohistochemical staining for CD3 was partially positive in the atypical cells. Epstein-Barr virus-encoded RNA in situ hybridization showed positive staining. MTX-related lymphoproliferative disorder (MTX-LPD) with Epstein-Barr virus infection was diagnosed. MTX treatment was immediately discontinued, and treatment was initiated by a hematologist. However, her condition rapidly deteriorated, and she died of multiple organ failure 4 weeks after diagnosis. MTX-LPD can complicate gastrointestinal lesions. However, most lesions are localized in the stomach and rarely complicate pancreatic lesions. MTX-LPD is classified as an "iatrogenic" LPD. Therefore, immediate action, such as MTX discontinuation, is necessary. In conclusion, endoscopists should be aware that MTX-LPD lesions can occur in the pancreas and gastrointestinal tract. Moreover, EUS-FNB can be useful in the diagnosis of this rare pancreatic tumor.

Improvement of liver histology in hepatic sarcoidosis due to treatment with corticosteroids and ursodeoxycholic acid: a case report.

We report the case of a 48-year-old male with a history of pulmonary and ocular sarcoidosis. Non-caseating granulomas, identified histologically, are the most characteristic manifestation of sarcoidosis. Hepatic sarcoidosis is difficult to diagnose using radiological imaging. In the patient reported in this study, ultrasound and contrast-enhanced computed tomography scans identified multiple intra-abdominal lymphadenopathies, with evidence of liver and splenic infiltrations. The first liver biopsy revealed non-caseating granulomatous hepatitis consistent with hepatic sarcoidosis. The patient was treated with ursodeoxycholic acid (UDCA), but his laboratory parameters did not improve. Prednisone was initiated at a dose of 30 mg daily and slowly tapered. At a dose of 12.5 mg daily, marked improvements in the fibrotic and sarcoid-like lesions were noted at the second biopsy. A third biopsy was performed, with the patient on a prednisone taper of 5 mg/day showed mild fibrous expansion in the portal tracts and mild parenchymal necro-inflammatory lesions. However, overall, fibrosis marker levels remained stable over the course of treatment. A fourth biopsy was performed after a 5-year course of 5 mg/day prednisone. This revealed minimal lobular inflammation without fibrosis. Thus, treatment of this patient with corticosteroids and UDCA resulted in marked improvements in his biochemical and histological parameters.

New risk stratification for adjuvant nivolumab for high-risk muscle-invasive urothelial carcinoma.

Objectives: We aim to evaluate the risk of recurrence after neoadjuvant chemotherapy followed by radical cystectomy, particularly in ypT2 disease in patients with urothelial carcinoma, because it is not clear if all eligible patients with high-risk muscle-invasive urothelial carcinoma should be treated with adjuvant nivolumab. Materials and Methods: We analysed the radiological and clinicopathological features, including cT and ypT stages, of 197 patients who had undergone two to four cycles of cisplatin-based neoadjuvant chemotherapy and radical cystectomy without adjuvant chemotherapy. We stratified the risk of postoperative recurrence by these factors. Results: The median observation period was 29.6 (interquartile range, 11.4-71.7) months, and disease recurrence was observed in 58 patients. Multivariate analysis revealed that ypT stage (P = 0.019) and lymphovascular invasion (P = 0.015) were independent risk factors for postoperative recurrence. The ypT2 group (n = 38) had significantly better recurrence-free survival than the ypT3 group (n = 41) (median recurrence-free survival: not reached vs. 13.4 months, respectively, P = 0.005). In ypT2 disease, the cT2 and ypT2 group (n = 15), which was diagnosed as cT2 preoperatively and then diagnosed as ypT2 postoperatively, had significantly better recurrence-free survival than the cT3/4 and ypT2 group (n = 23) (median recurrence-free survival: not reached vs. 63.1 months, respectively, P = 0.034). There was no significant difference in recurrence-free survival between the ypT ≤ 1 (n = 106) and the cT2 and ypT2 groups (median recurrence-free survival: not reached in both, P = 0.962). Conclusion: Patients with cT2 and ypT2 stage have a relatively low risk of recurrence and thus have a lower need for adjuvant nivolumab, particularly those with ypT2.

Comparative assessment of disease recurrence after transurethral resection of non-muscle-invasive bladder cancer with and without a photodynamic diagnosis using 5-aminolevulinic acid: a propensity score-matching analysis.

BACKGROUND: Among patients with non-muscle-invasive bladder cancer (NMIBC), systematic reviews showed lower recurrence rate in patients treated with photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) than with white-light (WL) TURBT. However, the result is not consistent between clinical trials and the significance of preoperatively available factors in disease recurrence after PDD-TURBT remains unclear. METHODS: The present study retrospectively analyzed 1174 NMIBC patients who underwent TURBT and were followed up for ≥ 6 months. Among 1174 patients, 385 and 789 underwent PDD-TURBT with oral 5-aminolevulinic acid (the PDD group) and WL-TURBT (the WL group), respectively. Recurrence-free survival (RFS) was compared between the PDD and WL groups before and after propensity score matching, and the impact of several baseline parameters on RFS between the 2 groups was investigated after matching. RESULTS: Before propensity score matching, RFS was significantly longer in the PDD group than in the WL group (P = 0.006). After matching, 383 patients were included in both groups, and RFS was significantly longer in the PDD group than in the WL group (P < 0.001). In the cohort after matching, RFS between the two groups was compared in each subgroup classified according to baseline parameters, including age, sex, history of previous or concomitant upper urinary tract urothelial carcinoma, preoperative urinary cytology, tumor multiplicity, and tumor size, and significantly longer RFS was observed in the PDD group in all subgroups, except for the patients with tumors ≥ 30 mm (P = 0.21). CONCLUSION: These results suggest that PDD-TURBT prolongs RFS in NMIBC patients, except for those with tumors ≥ 30 mm.

Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis.

BACKGROUND: Immune-related adverse events (irAEs) in patients treated with immune check inhibitors are associated with favourable response rate and survivals in multiple cancers, including renal cell carcinoma (RCC). The aim of this study was to investigate how irAEs were associated with improved survivals in advanced RCC patients treated with nivolumab plus ipilimumab. MATERIALS AND METHODS: This retrospective study included patients who received nivolumab plus ipilimumab at six centres, institutions, or hospitals between September 2018 and February 2022. We assessed associations of the development and the number of irAEs with overall survival (OS) and progression-free survival (PFS). To eliminate immortal time bias, landmark analysis and a Cox model with time-dependent variables were used. RESULTS: This study included 129 patients with a median follow-up of 12.3 months. The 2-year OS and PFS rates were 55% and 42%, respectively. Ninety six patients experienced irAEs. The development of irAEs was positively associated with OS and PFS rates (hazard ratio [HR] 0.328, 95% confidence interval [CI] 0.165-0.648, p = 0.001; HR 0.334, 95% CI 0.151-0.737, p = 0.007). Patients who experienced multiple irAEs had longer OS (HR 0.507, 95% CI 0.235-1.097, p = 0.085 or HR 0.245, 95% CI 0.110-0.544, p < 0.001) and PFS (HR 0.572, 95% CI 0.316-1.036, p = 0.085 or HR 0.267, 95% CI 0.113-0.628, p = 0.002) compared with those who experienced single or zero irAE. CONCLUSIONS: Developing irAEs, particularly multiple irAEs, is associated with favourable survivals in advanced RCC patients treated with nivolumab plus ipilimumab.

Impact on Japanese healthcare economics of photodynamic diagnosis-assisted transurethral resection of bladder tumor for non-muscle invasive bladder cancer: A multicenter retrospective cohort study.

OBJECTIVES: Bladder cancer, especially non-muscle invasive bladder cancer (NMIBC), is one of the most costly cancers owing to its long-term management. Photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) reduces the risk of intravesical recurrence. However, its impact on healthcare economics in Japan remains unclear. We evaluated the comprehensive medical costs of Japanese healthcare economics regarding PDD-TURBT. METHODS: This large-scale, multicenter, retrospective study included a dataset of 1531 patients who were diagnosed with primary NMIBC who underwent initial TURBT between April 2006 and June 2021. A one-to-one propensity-score matching analysis was used for an unbiased comparison based on postTURBT follow-up periods. The total medical costs, including hospitalization, surgical procedures for TURBT and salvage radical cystectomy, adjuvant intravesical therapies, and follow-up examinations, were compared between white light (WL)-TURBT and PDD-TURBT groups. RESULTS: After propensity-score matching, 468 patients each of WL- and PDD-TURBT groups were matched. Total costs were 510 337 128 and 514 659 328 ¥ in WL- and PDD-TURBT groups, respectively. The costs of adjuvant intravesical therapies, follow-up examinations, and salvage radical cystectomy in PDD-TURBT group were equivalent to or lower than those in WL-TURBT group. Furthermore, total costs of high- and highest-risk NMIBC in PDD-TURBT group were either equivalent or lower compared to those in WL-TURBT group. CONCLUSIONS: The total costs associated with PDD-TURBT were higher compared to WL-TURBT, while there is the potential of PDD-TURBT to reduce the burden on healthcare economics in limited cases.

Additional oncological benefit of photodynamic diagnosis with blue light cystoscopy in transurethral resection for primary non-muscle-invasive bladder cancer: A comparative study from experienced institutes.

Objectives: The objective of this work is to evaluate the additional oncological benefit of photodynamic diagnosis (PDD) using blue-light cystoscopy in transurethral resection (TURBT) for primary non-muscle-invasive bladder cancer (NMIBC) based on the International Bladder Cancer Group (IBCG)-defined progression and the subsequent pathological pathways. Patients and Methods: We reviewed 1578 consecutive primary NMIBC patients undergoing white-light TURBT (WL-TURBT) or PDD-TURBT during 2006-2020. One-to-one propensity score-matching was performed using multivariable logistic regression to obtain balanced groups. IBCG-defined progression of NMIBC included stage-up and grade-up as well as conventional definitions such as the development of muscle-invasive BC or metastatic disease. Nine oncological endpoints were evaluated. Sankey diagrams were generated to visualize follow-up pathological pathways after the initial TURBT. Results: Comparison of event-free survival between the matched groups revealed that PDD use decreased the bladder cancer recurrence risk and IBCG-defined progression risk, whereas no significant difference was noted in conventionally defined progression. This was attributable to a reduced risk of stage-up, from Ta to T1, and grade-up. Sankey diagrams of the matched groups showed that patients with primary Ta low-grade tumour and first-recurrence Ta low-grade tumour did not have bladder recurrence or progression, while some of those in the WL-TURBT group developed recurrence after treatment. Conclusions: The multiple survival analysis demonstrated that the risk of IBCG-defined progression was significantly decreased by PDD use in NMIBC patients. Sankey diagrams revealed possible differences in pathological pathways after the initial TURBT between the two groups, demonstrating that repeated recurrence could be prevented by PDD use.

Clinical outcomes of nivolumab plus ipilimumab in patients with metastatic non-clear cell renal cell carcinoma: Real-world data from a Japanese multicenter retrospective study.

OBJECTIVES: Although nivolumab plus ipilimumab has become a standard treatment regimen for metastatic clear cell renal cell carcinoma (ccRCC), its efficacy in non-clear cell carcinoma (nccRCC) has not been fully examined. In the current study, we evaluated the clinical outcomes of nivolumab plus ipilimumab in nccRCC compared with ccRCC. METHODS: We retrospectively analyzed 22 patients with metastatic and/or locally advanced unresectable nccRCC who received nivolumab plus ipilimumab as a first-line therapy and compared them with 107 patients with ccRCC. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicity were compared between the nccRCC and ccRCC groups. RESULTS: The histology of nccRCC included eight papillary, six unclassified, three chromophobe, two collecting duct carcinoma, and three other subtypes. Best objective response in nccRCC patients included three complete responses and five partial responses, resulting in an ORR of 36%, while that in ccRCC patients was 50% (p = 0.22). With a median follow-up of 11.9 months, OS was significantly shorter in patients with nccRCC than in those with ccRCC (median 20.8 months vs. not reached, p = 0.04), while there was no significant difference in PFS (median 6.3 vs. 10.8 months, p = 0.21). Treatment-related adverse events occurred in 14 (64%) nccRCC patients and 81 (76%) ccRCC patients. CONCLUSIONS: Combination treatment with nivolumab and ipilimumab demonstrated modest clinical efficacy in patients with nccRCC compared with patients with ccRCC, suggesting it could be a therapeutic option for metastatic nccRCC patients.

Progressive metastatic pheochromocytoma induced by multiple endocrine neoplasia type 2A with a lethal outcome.

Introduction: Patients with multiple endocrine neoplasia type 2A (MEN2A) harboring a pathological variant in the RET gene are characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. Although pheochromocytoma is currently defined as a malignant tumor, MEN2A-associated pheochromocytoma is known to have a small risk of metastasis. Case presentation: The case was a 62-year-old Japanese male with bilateral pheochromocytoma, multiple metastases in the liver and bones, and a cardiac thrombus. Genetic testing revealed a pathological variant at codon 634 of the RET gene, thereby leading a diagnosis of MTC. We considered that the multiple metastases were due to MTC; however, a liver biopsy revealed metastasis of pheochromocytoma. Conclusion: When pheochromocytoma precedes MTC, the diagnosis of MEN2A may be difficult.

Efficacy of abiraterone acetate for high-risk hormone-naïve metastatic prostate cancer: A comparison with combined androgen blockade therapy with bicalutamide and androgen deprivation therapy alone.

BACKGROUND: The treatment landscape for men with metastatic hormone-naïve prostate cancer (mHNPC) has dramatically changed with the approval of next-generation anti-androgen drugs. We compared the treatment efficacy of abiraterone with that of combined androgen blockade (CAB) therapy and androgen deprivation therapy (ADT) alone in men with high-risk mHNPC. METHODS: In total, 146 Japanese men with high-risk mHNPC were retrospectively analyzed. As initial hormonal therapy, 30, 83, and 33 men were treated with ADT plus abiraterone (ABI group), ADT plus bicalutamide (CAB group), and ADT alone (ADT group), respectively. Treatment efficacy was compared using time to castration resistance (TTCR) and prostate-specific antigen (PSA) response among the groups. Propensity score matching analysis was also performed to adjust for baseline differences. RESULTS: The median (95% confidence interval [CI]) TTCR in the ABI, CAB, and ADT groups were not reached, 10.7 (7.6-13.8) months and 11.0 (7.9-12.4) months, respectively, and it was significantly longer in the ABI group than in the other groups (p = 0.0012, p = 0.0008). In propensity score matching analysis, the median TTCR was also significantly longer in the ABI group than in the other groups (hazard ratio [HR], 0.47; 95% CI, 0.22-0.98; p = 0.010; HR, 0.32; 95% CI, 0.12-0.85; p = 0.004). The number of men who achieved PSA levels ≤0.2 ng/mL after propensity score matching were significantly higher in the ABI group than in the other groups. CONCLUSIONS: Our results provide important evidence regarding the superiority of abiraterone over CAB therapy and ADT alone for initial treatment for men with newly diagnosed mHNPC.

Predictive factors for the effectiveness of novel androgen receptor axis-targeted agents in patients with metastatic prostate cancer.

OBJECTIVE: Novel androgen receptor axis-targeted agents (ARATAs) have been developed for mCRPC and improved overall survival (OS). Here, we aimed to find predictors who will receive the greatest benefits from ARATAs. METHODS: We previously performed a multicenter study to identify prognostic factors for metastatic hormone-sensitive prostate cancer (mHSPC, n = 148) and mCRPC (n = 99), and showed that the bone scan index (BSI) was one of the significant prognostic factors for 3-year OS (PROSTAT-BSI study). mHSPC progressed to mCRPC (n = 101), for which 69 patients were treated with (n = 39) or without ARATAs (n = 30, prior to the approval of ARATAs). The 69 patients were divided into two groups according to patient factors, and these cohorts were further divided into two subgroups by usage of ARATAs. OS was compared between subgroups in each group. RESULTS: The predictors were age (<71.4 years), serum levels of C-reactive protein (≥0.16 ng/ml) and alkaline phosphatase (≥548 U/L), time to PSA progression after ADT (<8.9 months), the lowest PSA level (≥1 ng/ml) after ADT, and the rate of PSA decline 3 months after ADT (<0.987), whereas hemoglobin levels, PSA before ADT, Gleason scores, existence of visceral metastases, and BSI were not. CONCLUSIONS: The present study identified predictors for the effectiveness of ARATAs. The number of bone metastases (≒BSI), existence of visceral metastases, and Gleason scores, which were identified as high-risk factors in the LATITUDE study and disease volume in CHAARTED criteria, did not appear to be useful for predicting effectiveness from ARATAs.

Case Study: A Japanese patient with metastatic renal cell carcinoma who achieved long-term treatment-free survival with pembrolizumab and axitinib in the KEYNOTE-426 phase III trial of pembrolizumab and axitinib versus sunitinib.

Introduction: Our patient treated with pembrolizumab and axitinib is one of the longest survivors in Japan on KEYNOTE 426, despite adverse events, including delayed-onset hepatitis. We herein present a detailed clinical course and short discussion on the case. Case presentation: This was a 49-year-old male with clear cell renal cell carcinoma and lung metastases. After cytoreductive nephrectomy, treatment with pembrolizumab plus axitinib was initiated and the patient demonstrated a radiographic partial response as best response. The main adverse event was pembrolizumab-induced delayed-onset hepatitis, which was successfully treated with prednisolone. Pembrolizumab was re-initiated and completed. Conclusion: The survival benefit in the present case may be due to the initial potent anti-cancer effects of axitinib and durable immune effects of pembrolizumab, leading to long-term treatment-free survival.

Impact of Cytoreductive Nephrectomy Following Nivolumab Plus Ipilimumab Therapy for Patients With Advanced Renal Cell Carcinoma.

BACKGROUND/AIM: CheckMate 214 study revealed that nivolumab plus ipilimumab combination therapy showed a strong and durable effect compared to sunitinib for patients with advanced renal cell carcinoma (aRCC). Most of the patients underwent previous nephrectomy before systemic treatment. We retrospectively investigated the clinical outcomes of Japanese patients treated with cytoreductive nephrectomy following nivolumab plus ipilimumab for aRCC. PATIENTS AND METHODS: Seventy-nine patients were treated with systemic therapy for aRCC between October 2018 and August 2021 at the Saitama Medical University International Medical Center. Ten of 61 patients treated with nivolumab plus ipilimumab underwent cytoreductive nephrectomy after the combined immunotherapy. RESULTS: The median overall survival and progression-free survival were 24.3 and 15.9 months, respectively. The objective response rate was 50.8%; 9.8% of patients had a complete response, and the median time to objective response was 3.2 (range=1.3-19.7) months. The estimated percentage of patients who sustained an objective response at 30 months was 73.0%. Twenty-three patients (74%) in the complete or partial response (CR/PR) group, 11 patients (52%) in the stable disease (SD) group, and two patients (22%) in the progressive disease (PD) group had immune-related adverse events of grade 3 or higher, respectively. For all 10 patients, cytoreductive nephrectomy following nivolumab plus ipilimumab treatment were completed safely. Three patients achieved a pathological complete response without viable cancer cells. Only two patients had residual lesions on images after deferred cytoreductive nephrectomy; the remaining patients achieved radiological CR. CONCLUSION: Cytoreductive nephrectomy after nivolumab plus ipilimumab treatment could be useful in a limited number of cases, possibly resulting in curative nephrectomy due to the durable therapeutic effect of immunotherapy.

Bladder cancer prospective cohort study on high-risk non-muscle invasive bladder cancer after photodynamic diagnosis-assisted transurethral resection of the bladder tumor (BRIGHT study).

OBJECTIVES: Transurethral resection of bladder tumor with photodynamic diagnosis has been reported to result in lower residual tumor and intravesical recurrence rates in non-muscle invasive bladder cancer. We aimed to evaluate the usefulness of photodynamic diagnosis-transurethral resection of bladder tumor combined with oral 5-aminolevulinic acid hydrochloride for high-risk non-muscle invasive bladder cancer. METHODS: High-risk non-muscle invasive bladder cancer patients with an initial photodynamic diagnosis-transurethral resection of bladder tumor (photodynamic diagnosis group) were prospectively registered between 2018 to 2020. High-risk non-muscle invasive bladder cancer cases with a history of initial white-light transurethral resection of bladder tumor (white-light group) were retrospectively registered. Propensity score-matching analysis was used to compare residual tumor rates, and factors that could predict residual tumors at the first transurethral resection of bladder tumor were evaluated. RESULTS: Analyses were conducted with 177 and 306 cases in the photodynamic diagnosis and white-light groups, respectively. The residual tumor rates in the photodynamic diagnosis and white-light groups were 25.7% and 47.3%, respectively. Factor analysis for predicting residual tumors in the photodynamic diagnosis group showed that the residual tumor rate was significantly higher in cases with a current/past smoking history, multiple tumors, and pT1/pTis. When each factor was set as a risk level of 1, cases with a total risk score ≤1 showed a significantly lower residual tumor rate than cases with a total risk score ≥2 (8.3% vs 33.3%, odds ratio 5.46 [1.81-22.28]). CONCLUSIONS: In high-risk non-muscle invasive bladder cancer cases, the odds of a residual tumor after initial photodynamic diagnosis-transurethral resection of bladder tumor were 0.39-fold that of the odds of those after initial white-light transurethral resection of bladder tumor. A risk stratification model could be used to omit the second transurethral resection of bladder tumor in 27% of the cases.

Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells.

Effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T-cell transfer and immune checkpoint blockade. Although SULT2B1b is known to sulfate oxysterols and inactivate their tumor-promoting activity, the expression levels of cholesterol hydroxylases, which mediate oxysterol production, are low in SULT2B1b-expressing cancers. Therefore, SULT2B1b inhibition could be a therapeutic strategy to disrupt tumor immune evasion in oxysterol-non-producing cancers. Thus, our findings define a previously unknown mechanism for tumor immune evasion and provide a novel insight into the development of effective immunotherapies.

Pembrolizumab plus axitinib versus sunitinib in metastatic renal cell carcinoma: outcomes of Japanese patients enrolled in the randomized, phase III, open-label KEYNOTE-426 study.

BACKGROUND: In the phase III open-label KEYNOTE-426 (NCT02853331) study, first-line pembrolizumab and axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC). KEYNOTE-426 evaluated patients enrolled from 25 sites in Japan. METHODS: Patients enrolled in Japan were included in this post hoc subgroup analysis. Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks plus oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off). Dual primary endpoints were OS and PFS as assessed by blinded independent central review. Objective response rate (ORR) and safety were secondary endpoints. RESULTS: The Japanese subgroup comprised 94 patients (pembrolizumab-axitinib, n = 44; sunitinib, n = 50; 11% of the intent-to-treat population). Median time from randomization to data cutoff (January 6, 2020) was 29.5 months (range 24.6-37.3). Consistent with the intent-to-treat population, the OS, PFS, and ORR suggested improvement with pembrolizumab-axitinib versus sunitinib in the Japanese subgroup. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving pembrolizumab-axitinib versus 78% receiving sunitinib; 11 (25%) patients receiving pembrolizumab-axitinib and 13 (27%) patients receiving sunitinib discontinued the study medication due to AEs. TRAEs led to the discontinuation of pembrolizumab, axitinib, pembrolizumab-axitinib, or sunitinib in 32%, 34%, 14%, and 20%, respectively. No deaths from TRAEs occurred. CONCLUSIONS: Efficacy outcomes for the Japanese subgroup were consistent with those of the global population. Safety in Japanese patients was consistent with the results from the global population.

Identification of risk factors associated with oral 5-aminolevulinic acid-induced hypotension in photodynamic diagnosis for non-muscle invasive bladder cancer: a multicenter retrospective study.

BACKGROUND: To investigate risk factors for orally administered 5-aminolevulinic acid (ALA)-induced hypotension for bladder cancer patients receiving photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT). METHODS: Patients were categorized into two groups intraoperatively: a hypotensive group (minimum systolic blood pressure (SBP) ≤80 mmHg) and a non-hypotensive group (minimum SBP > 80 mmHg). We examined differences between the hypotensive group and non-hypotensive groups to identify clinical risk of ALA-induced hypotension using multivariate logistic regression analysis and decision tree analysis. RESULTS: Among 282 cases with ALA-PDD-assisted TURBT from three institutions who were screened, 245 patients were included in the final analysis. In total, 156 patients (63.7%) showed any grade of hypotension during ALA-PDD-assisted TURBT. General anesthesia and spinal anesthesia were induced intraoperatively in 113 patients (46.1%) and 132 patients (53.9%), respectively. Median SBP at baseline (before taking ALA) and at the beginning of anesthesia was 127 mmHg (range, 69-186 mmHg) and 124 mmHg (range, 69-186 mmHg), respectively. Median minimum SBP during ALA-PDD-assisted TURBT was 75 mmHg (range, 43-140 mmHg). Multivariate logistic regression analysis revealed that history of hypertension (odds ratio (OR) 7.568, p < 0.05) and general anesthesia (OR 14.435, p < 0.05) as significantly associated with an increased risk of hypotension incidence. Use of calcium antagonist showed significant negative associations with hypotension (OR 0.183, p < 0.05). Decision tree analysis showed presence of general anesthesia, age ≥ 74 years and American Society of Anesthesiologists physical status (ASA-PS) ≥2 as the most important discriminators. CONCLUSIONS: General anesthesia and hypertension were independent risk factors related to ALA-induced hypotension. In contrast, use of calcium antagonists was identified as a factor associated with reduced risk of ALA-induced hypotension.

Effects of transurethral resection under general anesthesia on tumor recurrence in non-muscle invasive bladder cancer.

BACKGROUND: The effects of the type of anesthesia (spinal (SA) vs. general (GA)) used for transurethral resection of bladder tumor (TURBT) on non-muscle invasive bladder cancer (NMIBC) recurrence and progression are controversial and our aim is to investigate their associations. METHODS: We identified 300 NMIBC patients who underwent initial TURBT with SA or GA. Cox's regression analysis was performed to examine the effects of anesthesia on tumor recurrence. RESULTS: Among 300 patients, 153 (51.0%) received GA and 147 (49.0%) SA. The 5-year recurrence-free survival (RFS) rate was 59.9% in the GA group, which was significantly lower than that in the SA group (74.4%, p = 0.029). GA (HR 1.57, p = 0.048), male sex (HR 2.72, p = 0.012), and tumor multiplicity (HR 1.96, p = 0.006) were independently associated with tumor recurrence. In a subgroup of 137 patients with high-risk NMIBC, the 5-year RFS rate was 50.3% in the GA group, which was significantly lower than that in the SA group (77.6%, p = 0.020), and GA remained an independent indicator of tumor recurrence (HR 2.35, p = 0.016). However, no significant differences were observed in the RFS rates of low- to intermediate-risk NMIBC patients between the GA and SA groups. CONCLUSIONS: The RFS rate was lower in NMIBC patients who received GA during TURBT than in those who received SA. Volatile anesthesia may increase tumor recurrence, particularly in high-risk NMIBC patients, which may be due to the inhibition of the immune response system during surgery.