TNFSF9 Is Associated with Favorable Tumor Immune Microenvironment in Patients with Renal Cell Carcinoma Who Are Treated with the Combination Therapy of Nivolumab and Ipilimumab.

Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.

Association Between Acute Kidney Injury and the Trendelenburg Position Angle During Robot-assisted Radical Prostatectomy.

BACKGROUND/AIM: Robot-assisted radical prostatectomy (RARP) has been widely adopted as the standard treatment for localized prostate cancer. RARP is safer and results in better oncological control than conventional open total prostatectomy. However, it has also been reported that acute kidney injury (AKI) can be caused by the use of carbon dioxide pneumoperitoneum and a steep Trendelenburg position. We investigated the incidence of AKI after RARP and its relationship with the Trendelenburg position angle. PATIENTS AND METHODS: Seventy-seven patients underwent RARP at our institution. They were divided into two groups: Those in which a Trendelenburg position with the head down at 20 degrees was employed (group A) and those in which a Trendelenburg position with the head down at 25 degrees was used (group B). To detect AKI, the serum creatinine concentration was measured at the following four points: Prior to surgery, on postoperative day 0 (immediately after RARP), and on postoperative days 1 and 6 after RARP. RESULTS: The incidence of AKI on POD 0 was lower in group B than in group A (p=0.0408). On POD 6, the renal function of all patients had improved to preoperative levels. Hypertension was a predictor of the incidence of AKI immediately after RARP. CONCLUSION: Although there was a significant Trendelenburg position angle-dependent difference in the incidence of AKI immediately after RARP, it was temporary. Hypertension is a predictor of AKI immediately after RARP. It is recommended that a 25-degree Trendelenburg position angle should be employed during RARP.

L-type amino acid transporter 1 inhibitor JPH203 prevents the growth of cabazitaxel-resistant prostate cancer by inhibiting cyclin-dependent kinase activity.

L-type amino acid transporter 1 (LAT1, SLC7A5) is an amino acid transporter expressed in various carcinomas, and it is postulated to play an important role in the proliferation of cancer cells through the uptake of essential amino acids. Cabazitaxel is a widely used anticancer drug for treating castration-resistant prostate cancer (CRPC); however, its effectiveness is lost when cancer cells acquire drug resistance. In this study, we investigated the expression of LAT1 and the effects of a LAT1-specific inhibitor, JPH203, in cabazitaxel-resistant prostate cancer cells. LAT1 was more highly expressed in the cabazitaxel-resistant strains than in the normal strains. Administration of JPH203 inhibited the growth, migration, and invasive ability of cabazitaxel-resistant strains in vitro. Phosphoproteomics using liquid chromatography-mass spectrometry to comprehensively investigate changes in phosphorylation due to JPH203 administration revealed that cell cycle-related pathways were affected by JPH203, and that JPH203 significantly reduced the kinase activity of cyclin-dependent kinases 1 and 2. Moreover, JPH203 inhibited the proliferation of cabazitaxel-resistant cells in vivo. Taken together, the present study results suggest that LAT1 might be a valuable therapeutic target in cabazitaxel-resistant prostate cancer.

Spontaneous Bladder Rupture in a Catatonic Schizophrenia Patient.

Catatonia is a psychiatric emergency in schizophrenia that often leads to excessive activation of the sympathetic nervous system. Urinary retention in catatonia is often underestimated but has potentially detrimental consequences. Herein, we present the case of a woman in her 40s with schizophrenia treated for catatonia during a relapse. When treated as an inpatient, the patient suddenly complained of severe abdominal pain. Computed tomography revealed a spontaneous rupture of the posterior wall of the bladder, requiring emergency repair surgery in the urology department. The patient was readmitted to our hospital following surgery and ultimately discharged 1 month later. Bladder rupture is life-threatening, and delayed diagnosis and treatment can be fatal. This case report serves as a warning that psychiatrists should not overlook urinary retention in patients with catatonia and should consider bladder rupture in the differential diagnosis when these patients have abdominal pain.

A case of ipsilateral three simultaneous renal cell carcinomas with different histologic types.

Introduction: Few reports have presented sporadic multifocal renal cell carcinomas of different histologic types occurring simultaneously in a single kidney. Here, we present a case of three ipsilateral renal cell carcinomas with three histologic types. Case presentation: A 44-year-old man with end-stage renal disease due to nephrosclerosis was referred to our hospital for an incidental renal tumor. Following the introduction of hemodialysis, enhanced computed tomography revealed a renal tumor suggestive of clear-cell renal cell carcinoma with a cystic component. With a preoperative diagnosis of one renal tumor, he underwent laparoscopic radical nephrectomy. However, pathological examination revealed three renal cell carcinomas with three histological diagnoses: clear-cell, papillary, and clear-cell papillary renal cell carcinomas. Conclusion: Preoperative imaging may not detect all synchronous ipsilateral multifocal renal cell carcinomas. Patients with severe renal function impairment may have synchronous multifocal renal cell carcinomas.

Investigation on the Usefulness of Photodynamic Diagnosis-assisted Targeted Bladder Biopsy: Japanese Real-world Study.

BACKGROUND/AIM: Photodynamic diagnosis (PDD)-assisted transurethral resection of a bladder tumor (PDD-TURBT) in a patient receiving 5-aminolevulinic acid improved the detection of micro- and flat lesions of the bladder. This study used real-world data in Japan to examine the diagnostic accuracy of PDD-assisted targeted biopsies and white-light (WL) random biopsies and reevaluated the necessity of random biopsies. PATIENTS AND METHODS: A total of 133 patients diagnosed with bladder cancer who underwent TURBT from April 2020 to March 2022 were included in the study. Biopsy specimens obtained from 407 flat lesions or normal-like lesions, excluding biopsies from elevated lesions and TUR specimens, were used to analyze diagnostic accuracy in PDD and WL findings. RESULTS: The respective sensitivities, specificities, and negative predictive values of PDD vs. WL findings were 81.4% vs. 54.0% (p=0.0039), 70.4% vs. 81.4% (p=0.0012), and 96.4% vs. 90.6% (p=0.0144), indicating that PDD was useful for a diagnosis of exclusion. Combining the PDD and WL findings improved the detection of malignant flat lesions. Ten (PDD-positive and WL-negative) specimens from 9 patients were diagnosed as malignant. The results of PDD-assisted targeted biopsy provided an accurate assessment of the risk classification for recurrence and progression of non-muscle invasive bladder cancer (NMIBC) as defined by the Japanese Urological Association (JUA) guidelines. CONCLUSION: For NMIBC treatment, a more accurate diagnosis is important for postoperative treatment decisions. PDD-assisted targeted biopsy may be necessary and sufficient for diagnosis of flat lesions in patients with bladder cancer for treatment decision making based on JUA risk classification.

A case of metastatic renal cell carcinoma successfully treated with deferred cytoreductive nephrectomy following lenvatinib plus pembrolizumab combination therapy.

Introduction: Combination therapy using immuno-oncology drugs with tyrosine kinase inhibitors is increasingly important in the therapeutic strategy for metastatic renal cell carcinomas. Here, we report a case of metastatic renal cell carcinoma that was successfully treated with deferred cytoreductive nephrectomy following lenvatinib plus pembrolizumab combination therapy. Case presentation: A 49-year-old man was referred to our hospital with a diagnosis of advanced right kidney cancer with multiple lung metastases (cT3aN0M1). The size of the primary tumor was so huge that it exceeded 20 cm in diameter, pushing the liver and intestines to the left. After administration of lenvatinib and pembrolizumab combination as first-line treatment, all the metastatic lung lesions disappeared, and the primary lesion shrank significantly. Robot-assisted radical nephrectomy was successfully performed, resulting in complete surgical remission. Conclusion: Deferred cytoreductive nephrectomy following a lenvatinib plus pembrolizumab combination is a useful therapeutic strategy for achieving complete remission of metastatic renal cell carcinomas.

Relationship between Preoperative Pyuria and Bacille Calmette-Guerin Treatment in Intravesical Recurrence after Transurethral Resection of High-Risk, Non-Muscle Invasive, Bladder Carcinoma: A Retrospective Study of Human Data.

Some researchers have found that preoperative pyuria is a risk factor for recurrence after transurethral resection of high-risk non-muscle invasive bladder cancer. However, to our knowledge, none have clarified the risks associated with pyuria according to bacille Calmette-Guerin (BCG) treatment status. We retrospectively selected patients with high-risk non-muscle invasive bladder cancer according to Japanese Urological Association guidelines. Pyuria was defined as ≥10 white blood cells per high-powered field. We analyzed recurrence-free rates (RFS) in 424 patients who had and had not undergone BCG treatment. The median duration of follow-up was 45.2 months. According to multivariate analysis, postoperative intravesical BCG induction and preoperative pyuria were independent risk factors for intravesical recurrence in the whole study cohort. We found no significant risk factors for recurrence in the BCG-treated group (n = 179). In the non-BCG-treated group (n = 245), patients with pyuria were much more frequently female and more often had T1 disease than patients without pyuria. According to univariate and multivariate analysis, preoperative pyuria is an independent risk factor for intravesical recurrence. There was no significant difference in the severity of pyuria between the BCG and non-BCG-treated groups. Aggressive BCG treatment may need to be considered in patients with high-risk NMIBC and pyuria.

A clinical investigation of recurrence and lost follow-up after renal cell carcinoma surgery: a single-center, long-term, large cohort, retrospective study.

BACKGROUND: Late recurrence of renal cell carcinoma (RCC) is observed in some postoperative patients. In addition, some of these patients are lost to long-term postoperative follow-up. We reviewed the treatment results and prognosis of postoperative patients with RCC at Chiba University Hospital, with the aim of clarifying the proportion and background of patients lost to follow-up. METHODS: This retrospective study included 1176 RCC patients who underwent radical or/and partial nephrectomy. Overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and lost follow-up free survival (LFFS) were evaluated and the risk factors for LFFS identified. RESULTS: The median RFS for stage II and II cases was 188.3 and 104.0 months, respectively. Even in stage I, recurrence was observed in about 20% of patients 20 years after surgery. The Kaplan-Meier curve for LFFS showed a linear descent over time, with 50% of patients lost to follow-up within 25 years. Older age (≥ 62 years), histological type (clear cell RCC), and no recurrence were significant risk factors for lost follow-up. CONCLUSIONS: Long-term follow-up is necessary after RCC surgery because late recurrence cases are not uncommon. We believe that lifelong follow-up with imaging studies is recommended for postoperative RCC patients. Early detection of recurrence in postoperative patients is a very important issue, and it may be worthwhile for improving the prognosis of postoperative patients to focus on patients lost to follow-up who may have been overlooked.

Fully automated and highly specific plasma ß-amyloid immunoassays predict ß-amyloid status defined by amyloid positron emission tomography with high accuracy.

BACKGROUND: Clinicians, researchers, and patients alike would greatly benefit from more accessible and inexpensive biomarkers for neural ß-amyloid (Aß). We aimed to assess the performance of fully automated plasma Aß immunoassays, which correlate significantly with immunoprecipitation mass spectrometry assays, in predicting brain Aß status as determined by visual read assessment of amyloid positron emission tomography (PET). METHODS: The plasma Aß42/Aß40 ratio was measured using a fully automated immunoassay platform (HISCL series) in two clinical studies (discovery and validation studies). The discovery and validation sample sets were retrospectively and randomly selected from participants with early Alzheimer's disease (AD) identified during screening for the elenbecestat Phase 3 program. RESULTS: We included 197 participants in the discovery study (mean [SD] age 71.1 [8.5] years; 112 females) and 200 in the validation study (age 70.8 [7.9] years; 99 females). The plasma Aß42/Aß40 ratio predicted amyloid PET visual read status with areas under the receiver operating characteristic curves of 0.941 (95% confidence interval [CI] 0.910-0.973) and 0.868 (95% CI 0.816-0.920) in the discovery and validation studies, respectively. In the discovery study, a cutoff value of 0.102 was determined based on maximizing the Youden Index, and the sensitivity and specificity were calculated to be 96.0% (95% CI 90.1-98.9%) and 83.5% (95% CI 74.6-90.3%), respectively. Using the same cutoff value, the sensitivity and specificity in the validation study were calculated to be 88.0% (95% CI 80.0-93.6%) and 72.0% (95% CI 62.1-80.5%), respectively. CONCLUSIONS: The plasma Aß42/Aß40 ratio measured using the HISCL series achieved high accuracy in predicting amyloid PET status. Since our blood-based immunoassay system is less invasive and more accessible than amyloid PET and cerebrospinal fluid testing, it may contribute to the diagnosis of AD in routine clinical practice.

Expression of tertiary lymphoid structure in deferred cytoreductive nephrectomy of metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

INTRODUCTION: Tertiary lymphoid structure expression and immune checkpoint inhibitors have been attracting attention, and their relationship with renal cell carcinoma is controversial. CASE PRESENTATION: Two patients with nivolumab plus ipilimumab treatment response for metastatic renal cell carcinoma underwent cytoreductive nephrectomy and regional lymph node dissection. In both cases, the renal tumor site expressed tertiary lymphoid structures. Despite the absence of treatment after a deferred cytoreductive nephrectomy and the short postoperative observation period, the patients still survived. CONCLUSION: Tertiary lymphoid structures were expressed in deferred cytoreductive nephrectomy specimen in cases treated with nivolumab plus ipilimumab.

Successful treatment of metastatic bladder cancer by gemcitabine-cisplatin re-challenge after pembrolizumab.

INTRODUCTION: The advent of pembrolizumab has contributed to improved treatment outcomes for metastatic urothelial carcinoma, but the outcomes of treatments after second-line treatment have not been established. CASE PRESENTATION: A 72-year-old man was referred to our hospital with gross hematuria and diagnosed with suspicion of bladder cancer cT1N0M0. Transurethral resection of the bladder tumor was performed, but local recurrence and multiple lung metastases appeared 5 months after surgery. Although gemcitabine-cisplatin was performed as first-line chemotherapy, the local lesion increased, and pembrolizumab was used as a second-line treatment. Pembrolizumab was also ineffective; however, re-challenge with gemcitabine-cisplatin as third-line treatment produced a good therapeutic effect. CONCLUSION: We report a successful case in which gemcitabine-cisplatin re-challenge after pembrolizumab therapy was effective in metastatic bladder cancer. Re-administration of chemotherapy after immune checkpoint inhibitors may be a broadly effective treatment option.

Adrenalectomy in Japanese patients with subclinical Cushing syndrome: 1-mg dexamethasone suppression test to predict the surgical benefit.

OBJECTIVES: To investigate whether the result of the 1-mg dexamethasone suppression test can predict the improvement of comorbidities after adrenalectomy in patients with subclinical Cushing syndrome. METHODS: This retrospective study included 117 subclinical Cushing syndrome patients who underwent adrenalectomy. The numbers of prescribed drugs for metabolic comorbidities and the clinical variables at diagnosis were compared with those at the follow up. Patients were classified into subgroups according to the result of the 1-mg dexamethasone suppression test. RESULTS: Significant improvements in blood pressure, serum cholesterol and body mass index were observed. Furthermore, a significant improvement in glycated hemoglobin was observed in patients with diabetes mellitus. These improvements led to a discontinuation or reduction of prescribed drugs after surgery. In addition, the greatest reduction of prescribed drugs was observed in patients whose serum cortisol levels were between 1.8 and 3.0 µg/dL after the 1-mg dexamethasone suppression test. CONCLUSIONS: The result of the 1-mg dexamethasone suppression test can be a useful factor predicting the improvement of comorbidities after adrenalectomy. Current data might give us a new insight into the decision-making for the treatment of subclinical Cushing syndrome.

Relationship between post-void residual urine volume, preoperative pyuria and intravesical recurrence after transurethral resection of bladder carcinoma.

OBJECTIVES: To evaluate the relationship between residual urine volume, pyuria and bladder carcinoma recurrence. METHODS: The clinical data of 305 patients who had post-void residual urine volume measured and preoperative pyuria were retrospectively collected. The patients were classified into three risk groups based on the presence of residual urine and pyuria: good (negative residual urine and pyuria), intermediate (positive residual urine or pyuria) and poor (positive residual urine and pyuria). Predictive factors for intravesical recurrence-free survival were statistically analyzed using Cox proportional hazard models and Kaplan-Meier methods. The propensity score matching method was used to adjust the patients' backgrounds. RESULTS: The median follow-up period for all patients was 44 months. The presence of residual urine (P = 0.0164) and pyuria (P = 0.0233) were two independent prognostic factors for recurrence. After patients were classified into risk groups, the poor-risk group showed significantly shorter recurrence-free survival compared with that of the good- (P = 0.0002) and intermediate-risk groups (P = 0.0090). Even after matching, the presence of residual urine was related to short recurrence-free survival in male patients (P = 0.0012). When stratified by European Organization for Research and Treatment of Cancer risk groups, the presence of pyuria was related to short recurrence-free survival, especially for intermediate-risk patients without bacillus Calmette-Guérin treatment. CONCLUSIONS: Post-void residual urine and preoperative pyuria are two risks for recurrence-free survival in non-muscle-invasive bladder cancer.

Replisome genes regulation by antitumor miR-101-5p in clear cell renal cell carcinoma.

Analysis of microRNA (miRNA) regulatory networks is useful for exploring novel biomarkers and therapeutic targets in cancer cells. The Cancer Genome Atlas dataset shows that low expression of both strands of pre-miR-101 (miR-101-5p and miR-101-3p) significantly predicted poor prognosis in clear cell renal cell carcinoma (ccRCC). The functional significance of miR-101-5p in cancer cells is poorly understood. Here, we focused on miR-101-5p to investigate the antitumor function and its regulatory networks in ccRCC cells. Ectopic expression of mature miRNAs or siRNAs was investigated in cancer cell lines to characterize cell function, ie, proliferation, apoptosis, migration, and invasion. Genome-wide gene expression and in silico database analyses were undertaken to predict miRNA regulatory networks. Expression of miR-101-5p caused cell cycle arrest and apoptosis in ccRCC cells. Downstream neighbor of son (DONSON) was directly regulated by miR-101-5p, and its aberrant expression was significantly associated with shorter survival in propensity score-matched analysis (P = .0001). Knockdown of DONSON attenuated ccRCC cell aggressiveness. Several replisome genes controlled by DONSON and their expression were closely associated with ccRCC pathogenesis. The antitumor miR-101-5p/DONSON axis and its modulated replisome genes might be a novel diagnostic and therapeutic target for ccRCC.

Aberrantly expressed PLOD1 promotes cancer aggressiveness in bladder cancer: a potential prognostic marker and therapeutic target.

Bladder cancer (BC) is the ninth most malignant tumor worldwide. Some BC patients will develop muscle-invasive BC (MIBC), which has a 5-year survival rate of approximately 60% due to metastasis. As such, there is an urgent need for novel therapeutic and diagnostic targets for MIBC. Analysis of novel antitumor microRNA (miRNA)-mediated cancer networks is an effective strategy for exploring therapeutic targets and prognostic markers in cancers. Our previous miRNA analysis revealed that miR-140-5p acts as an antitumor miRNA in BC cells. Here, we investigated miR-140-5p regulation of BC molecular pathogenesis. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) was found to be directly regulated by miR-140-5p, and aberrant expression of PLOD1 was observed in BC clinical specimens. High PLOD1 expression was significantly associated with a poor prognosis (disease-free survival: P = 0.0204; overall survival: P = 0.000174). Multivariate analysis showed PLOD1 expression to be an independent prognostic factor in BC patients (hazard ratio = 1.51, P = 0.0099). Furthermore, downregulation of PLOD1 by siRNAs and a specific inhibitor significantly decreased BC cell aggressiveness. Aberrant expression of PLOD1 was closely associated with BC pathogenesis. In summary, the present study showed that PLOD1 may be a potential prognostic marker and therapeutic target for BC.

Role of pre-miR-532 (miR-532-5p and miR-532-3p) in regulation of gene expression and molecular pathogenesis in renal cell carcinoma.

Analyses of our previously determined microRNA (miRNA) expression signature of renal cell carcinoma (RCC) and The Cancer Genome Atlas (TCGA) database revealed that both strands of the pre-miR-532-duplex-miR-532-5p (the guide strand) and miR-532-3p (the passenger strand)- are closely associated with poor prognosis of RCC patients (P = 0.0411 and P = 0.022, respectively). In this study we investigated the functional significance of these miRNAs and identified gene targets involved in RCC pathogenesis. Ectopic expression of these miRNAs significantly attenuated the malignant phenotypes including proliferation, migration and invasion of two RCC cell lines, 786-O and A498. A combination of genome-wide gene expression and in silico database analyses revealed 36 and 34 genes as putative target oncogenes regulated by miR-532-5p and miR-532-3p, respectively, in RCC cells. Among these targets, expression of aquaporin9 (AQP9), a water channel protein, was directly regulated by both miR-532-5p and miR-532-3p, and high expression levels of AQP9 were significantly associated with poor prognosis of RCC patients (P = 2.03e-05). Multivariate analysis indicated that AQP9 expression is an independent prognostic factor for RCC patients. Aberrant AQP9 expression at both the gene and protein level was detected in RCC clinical specimens. siRNA-mediated knockdown of AQP9 by si-AQP9 inhibited the malignant phenotypes of RCC cells. Rescue assays of AQP9 overexpression showed that the miR-532/AQP9 axis was closely involved in RCC oncogenesis. The identification of antitumor miRNAs and their targets will contribute to an increased understanding of the molecular pathogenesis of RCC.