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Background/Aim: The duration of pembrolizumab use in actual daily practice might be shorter than that in clinical trials because termination of pembrolizumab therapy is at the discretion of the physician. We retrospectively reviewed the response to pembrolizumab in Japanese patients with metastatic urothelial carcinoma (mUC) in relation to the time to response (TTR). Patients and Methods: The records of 165 patients treated with pembrolizumab for mUC were retrospectively analyzed. Response was evaluated at 2, 4, 6 and 8 months. TTR along with time to best response were analyzed. Phase II-III clinical trials were also reviewed to compare the TTR and time to best overall response. Results: The median patient age was 70 years. The objective response rate in the total cohort was 27.1% (42 out of 155 patients). Median TTR was 2.4 months and the time to best response was 3.1 months. Radiological evaluation at each time point significantly predicted overall survival (OS). Considering the evaluation of response at 2, 4, 6 and 8 months, the response at later time points tended to predict OS better. Multivariate analysis showed that the evaluation of response at 8 months (hazard ratio=1.91, 95% confidence interval=1.16-3.16 months; p

Background/Aim: In clinical practice, platinum-based systemic chemotherapy works to shrink pelvic lymph nodes. Intra-arterial (IA) bolus infusion may result in more favorable results than systemic chemotherapy. In the present study, we investigated the distribution of cisplatin administrated by IA infusion in varying organs, specifically focusing on the node tissue, in comparison with the intra-venous (IV) route. Materials and Methods: Under anesthesia, cisplatin 0.42 mg/body was administrated by IA or IV infusion in rats to mimic a balloon-occluded arterial infusion model used in clinical practice. The kidney, bladder, lymphatic tissue, and peripheral blood were extracted to analyze the amount of cisplatin by inductively coupled plasma-mass spectrometry. Results: Concertation of cisplatin by IA infusion was higher than that by the IV route in the peripheral blood and kidney. IA infusion led to a significantly high concentration of cisplatin in the bladder compared to IV infusion (1.3±0.452 vs. 0.2 ppb/mg ± 0.055, p=0.050). Furthermore, the IA method led to an extremely high concentration of cisplatin in the lymphatic tissue compared to the IV method (0.1±0.036 vs. 13.3±5.36, p=0.048). Conclusion: High cisplatin accumulation in the lymphatic tissue and bladder by IA administration may have a potential role for treating patients with node-positive bladder cancer.

There has been accumulating evidence for the clinical benefit of chemoradiation therapy (CRT), whereas mechanisms in CRT-recurrent clones derived from the primary tumor are still elusive. Herein, we identified an aberrant BUB1B/BUBR1 expression in CRT-recurrent clones in bladder cancer (BC) by comprehensive proteomic analysis. CRT-recurrent BC cells exhibited a cell-cycle-independent upregulation of BUB1B/BUBR1 expression rendering an enhanced DNA repair activity in response to DNA double-strand breaks (DSBs). With DNA repair analyses employing the CRISPR/cas9 system, we revealed that cells with aberrant BUB1B/BUBR1 expression dominantly exploit mutagenic nonhomologous end joining (NHEJ). We further found that phosphorylated ATM interacts with BUB1B/BUBR1 after ionizing radiation (IR) treatment, and the resistance to DSBs by increased BUB1B/BUBR1 depends on the functional ATM. In vivo, tumor growth of CRT-resistant T24R cells was abrogated by ATM inhibition using AZD0156. A dataset analysis identified FOXM1 as a putative BUB1B/BUBR1-targeting transcription factor causing its increased expression. These data collectively suggest a redundant role of BUB1B/BUBR1 underlying mutagenic NHEJ in an ATM-dependent manner, aside from the canonical activity of BUB1B/BUBR1 on the G2/M checkpoint, and offer novel clues to overcome CRT resistance.

Background We assessed the prognostic value of body mass index (BMI) in Asian patients with localized RCC who underwent nephrectomy. Methods A total of 665 patients who underwent nephrectomy for localized RCC were enrolled in the present study and divided into the two BMI groups: i.e., BMI > 25 in 202 (30.4%) patients. Results In total, there were 482 (72.5%) males and 183 (27.5%) females. Five-year cancer-specific survival (CSS) rates were significantly higher in increased BMI than the lower BMI group (97.1 and 92.5%: P = 0.007). When stratified by sex, significantly longer CSS in higher BMI was confirmed in males (5-year CSS of 92.7% in BMI 25, p = 0.005), while there was no difference in CSS between BMI groups for female patients. Multivariable analysis exhibited that higher BMI was an independent predictor for favorable CSS in male (cox model: p = 0.041, Fine & Gray regression model: p = 0.014), but not in the female. Subgroup analysis for CSS revealed that favorable CSS with higher BMI was observed in patient subgroups of age p = 0.019), clear cell histology (p = 0.018), and tumor size > 4 cm, p = 0.020) as well as male (p = 0.020). Conclusion Our findings collected from the multi-institutional Japanese dataset demonstrated longer survival in patients with higher BMI than lower BMI for non-metastatic RCC treated with nephrectomy. Intriguingly, this finding was restricted to males, but not to females.

OBJECTIVES To assess whether a new risk stratification system according to predictors for overall survival (OS) at the diagnosis of metastatic castration-resistant prostate cancer (mCRPC) could determine treatment outcomes and assist in treatment decision-making. PATIENTS AND METHODS Two independent clinical cohorts of patients, treated with androgen signalling inhibitors (ASIs: abiraterone and enzalutamide) or docetaxel as a first-line treatment for mCRPC, were used in this study: a derivation cohort (196 patients with mCRPC) and an external validation cohort (211 patients with mCRPC). RESULTS Three independent predictors for OS, including duration of initial androgen deprivation therapy 350 U/dL and haemoglobin level

Whether adjuvant chemotherapy (AC) for patients with upper tract urothelial carcinoma (UTUC) offers survival benefit is still controversial. To explore the impact of AC on overall survival (OS) of cN0M0 UTUC patients, we conducted a propensity score-matched analysis using the regression model, including pathologic features such as lymphatic and vascular invasion.A multi-institutional cohort of 413 UTUC patient record was used. Propensity score matching was performed to reduce bias by potential confounding factors for survival, including pathologic features from the specimen of radical nephroureterectomy (RNU), RESULTS: Ninety-eight patients were identified as pair-matched groups (49 patients in RNU and 49 patients in RNU + AC). Kaplan-Meier curves demonstrated that a 5-year OS rate of 72.7% for patients treated with RNU + AC was significantly higher than 51.6% for those treated with RNU (p = 0.0156). On multivariate analysis, pathologic vascular invasion (HR 3.41, 95% CI 1.24-10.66, p = 0.0166) and administration of AC (HR 0.45, 95% CI 0.19-0.98, p = 0.0438) still remained as the significant predictors for OS. In patients with pathologic vascular invasion (51 of 98 patients), a significantly longer OS in RNU + AC groups was observed (median OS of 30 and 70 months in RNU and RNU + AC groups, respectively: p = 0.0432), whereas there was no significant difference in the OS between RNU (median OS: not reached) and RNU + AC (median OS: not reached) groups in patients without the invasion (p = 0.4549).The result indicates a significant benefit for OS by the administration of AC, and pathologic vascular invasion in the specimen of RNU could help the patient selection to better predict the effect of AC.

Current targeted cancer therapies are largely guided by mutations of a single gene, which overlooks concurrent genomic alterations. Here, we show that RNASEH2B , RB1 , and BRCA2 , three closely located genes on chromosome 13q, are frequently deleted in prostate cancer individually or jointly. Loss of RNASEH2B confers cancer cells sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to impaired ribonucleotide excision repair and PARP trapping. When co-deleted with RB1 , however, cells lose their sensitivity, in part, through E2F1-induced BRCA2 expression, thereby enhancing homologous recombination repair capacity. Nevertheless, loss of BRCA2 resensitizes RNASEH2B/RB1 co-deleted cells to PARP inhibition. Our results may explain some of the disparate clinical results from PARP inhibition due to interaction between multiple genomic alterations and support a comprehensive genomic test to determine who may benefit from PARP inhibition. Last, we show that ATR inhibition can disrupt E2F1-induced BRCA2 expression and overcome PARP inhibitor resistance caused by RB1 loss.

Current targeted cancer therapies are largely guided by mutations of a single gene, which overlooks concurrent genomic alterations. Here, we show that RNASEH2B, RB1, and BRCA2, three closely located genes on chromosome 13q, are frequently deleted in prostate cancer individually or jointly. Loss of RNASEH2B confers cancer cells sensitivity to poly(ADP–ribose) polymerase (PARP) inhibition due to impaired ribonucleotide excision repair and PARP trapping. When co-deleted with RB1, however, cells lose their sensitivity, in part, through E2F1-induced BRCA2 expression, thereby enhancing homologous recombination repair capacity. Nevertheless, loss of BRCA2 re-sensitizes RNASEH2B/RB1 co-deleted cells to PARP inhibition. Our results may explain some of the disparate clinical results from PARP inhibition due to interaction between multiple genomic alterations and support a comprehensive genomic testing to determine who may benefit from PARP inhibition. Finally, we show that ATR inhibition can disrupt E2F1-induced BRCA2 expression and overcome PARP inhibitor resistance caused by RB1 loss.

Prostate cancer (PCa) is one of the common malignancies in male adults. Recent advances in omics technology, especially in next-generation sequencing, have increased the opportunity to identify genes that correlate with cancer diseases, including PCa. In addition, a genetic screen based on CRISPR/Cas9 technology has elucidated the mechanisms of cancer progression and drug resistance, which in turn has enabled the discovery of new targets as potential genes for new therapeutic targets. In the era of precision medicine, such knowledge is crucial for clinicians in their decision-making regarding patient treatment. In this review, we focus on how CRISPR screen for PCa performed to date has contributed to the identification of biologically critical and clinically relevant target genes.

Serum C-reactive protein (CRP) is known to be a biomarker for systemic inflammatory reactions. In the present study, we sought to measure the predictive value of serum CRP level for metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab and nivolumab using our real-world clinical dataset including non-clear cell RCC (nccRCC). The clinical record of patients who underwent the first-line ipilimumab plus nivolumab treatment for mRCC including ccRCC and nccRCC from 2018 to 2021 was retrospectively analyzed. All patients were diagnosed with either intermediate or poor-risk group defined by IMCD (international metastatic RCC database consortium). In total, 74 patients were involved. The median age was 68 years and 24 (32.4%) patients deceased during the follow-up. Forty-five (61%) and 29 (39%) patients were classified into intermediate and poor-risk groups. The one-year overall survival (OS) rate and objective response rate were 65% and 41% for all 74 mRCC patients, respectively. The receiver operating characteristic curve identified 1.0 mg/dL of serum CRP level as an ideal cut-off for predicting overall survival (OS). Serum CRP > 1.0 mg/dL and nccRCC were the independent predictors for OS in 74 mRCC patients. OS for patients with CRP > 1 mg/dL was significantly shorter than those with CRP < 1 mg/dL in both ccRCC (58 patient: p = 0.009) and nccRCC (16 patients: p = 0.008). The present study indicated that serum CRP level is a prognostic indicator for OS in both ccRCC and nccRCC patients treated with the first-line ipilimumab plus nivolumab treatment.

Pembrolizumab has emerged as the new standard of care in patients with platinum-refractory metastatic urothelial carcinoma (mUC), whereas the optimal risk stratification to predict survival outcomes is still controversial. We examined a risk model for overall survival (OS) in mUC treated with pembrolizumab using our multi-institutional dataset (212 patients). The median age was 72 years old. Median OS from the initiation of pembrolizumab treatment was 11.7 months. The objective response rate (ORR) was 26.4%. On multivariate analysis, multiple metastatic sites and an NLR &gt, 3.50 at the initiation of pembrolizumab treatment were identified as independent predictors for OS. We next developed a risk model using those two predictors. Patients without any factors were assigned to the favorable-risk group (26.5%). Patients with either factor and both factors were assigned to the intermediate-risk group (44.3%), and poor-risk group (29.2%), respectively. Kaplan–Meier curves showed clear discrimination of OS among the risk groups (p &lt, 0.001). The ORR in each group was 35.7% in the favorable-risk group, 27.7% in the intermediate-risk group, and 17.7% in the poor-risk group. Given that the model can be concisely determined at the initiation of pembrolizumab treatment, physicians may be encouraged to consider the risk group for daily practice.

OBJECTIVE: To examine the association between the body mass index (BMI) and the risk of survival, and to evaluate whether tumor characteristics differ by BMI in patients with upper tract urothelial carcinoma (UTUC) managed by surgery. METHODS: A clinical series on 876 patients with localized UTUC following nephroureterectomy with a bladder cuff, with data from Osaka Medical College registry (discovery cohort) and the Nagoya group (validation cohort) was examined. In addition to analyzing the overall survival and cancer-specific survival (CSS), the survival impact adjusted by pathological variables was also assessed by the BMI group. RESULTS: The percentage of high risk features including positive lymphovascular invasion was doubled in the discovery cohort compared to the validation cohort. The group of BMI ≥ 25 kg/m2 was associated with improved CSS in the discovery cohort (p = 0.004), and this tendency was verified in the validation cohort (p = 0.006). Nonproportional hazards existed for the group of BMI ≥ 25 kg/m2 and the BMI 18.5-25 kg/m2 relative to the group of BMI < 18.5 kg/m2, with a change in the CSS hazard. In multivariable Cox models, the BMI group had a superior predictive value compared with other pre-clinical factors both in the discovery cohort (HR = 3.85, p = 0.01; 95%CI: 0.09–0.73) and the validation cohort (HR = 1.56, p = 0.01; 95%CI: 0.45–0.91). When adjusted by lymphovascular invasion, the concordance of the model proposed by the discovery cohort (0.52) challenged in the validation cohort was 0.59. CONCLUSIONS: We found a clinically relevant signature for high risk patients with BMI grouping. Further research is necessary on whether tailoring recommendations for weight and nutrition management to tumor characteristics will improve outcomes.

We developed a novel chemically modified miR-143 (miR-143#12), and with it we investigated the contribution of miR-143 to the pathogenesis of bladder cancer (BC), in which miR-143 is extremely downregulated. Since miR-143 silenced K-RAS and RAS effector-signaling molecules Erk and Akt, we performed the ectopic expression of miR-143 in human BC 253J-BV cells, and we examined the growth inhibition and the mechanism of it in vitro and in orthotopic model mice. As a result, miR-143#12 induced a marked growth inhibition with apoptosis through impairing RAS-signaling networks, including SOS1, which exchanges guanosine diphosphate (GDP)/RAS for active guanosine triphosphate (GTP)/RAS. In the in vivo study, miR-143#12 exhibited a marked anti-tumor activity by either systemic or intravesical administration with polyionic copolymer (PIC) as the carrier, compared with the activity obtained by use of lipofection. These findings raised the possibility that the chemically modified miR-143#12 would be a candidate of microRNA (miRNA) medicine for BC delivered by intravesical infusion. Keywords: miR-143, K-RAS, SOS1, bladder cancer, PI3K/Akt, MEK/Erk signaling, intravesical infusion

To understand the role of RAS-signaling networks in the pathogenesis of renal cell carcisnoma, we clarified the relationship between miR-143 and RAS. The expression of miR-143 was extremely downregulated in tumor tissues from renal cell carcinoma patients compared with that in the adjacent normal tissues and Caki-1 cells. We developed a synthetic miR-143#12, and we found that the ectopic expression of it inhibited cell growth with autophagy in Caki-1 cells. Also, the expression level of c-Myc was markedly decreased, resulting in the perturbation of cancer-specific energy metabolism by negatively modulating the expression of GLUT1 and the PTBP1/PKMs axis. A partial metabolic shift from glycolysis to oxidative phosphorylation induced autophagy through increasing the intracellular level of reactive oxygen species (ROS). In an in vivo study, the potent anti-tumor activity of polyion complex (PIC)-loaded miR-143#12 (miR-143#12/PIC) was shown by systemic administration of it to Caki-1 cell-xenografted mice. Higher levels of miR-143 were found in both blood and tumor tissues after the systemic administration with miR-143#12/PIC compared to those with lipoplexes in the xenografted mice. These findings indicated that this synthetic miR-143#12 induced a marked growth inhibition by impairing K-RAS-signaling networks in vitro and in vivo., Synthetic miR-143 loaded with a PIC nanocarrier can be delivered specifically to tumor tissue. Also, the miR-143 can induce marked growth inhibition, cell-cycle arrest, and autophagy through impairing K-RAS-signaling networks.

It has been well established that microRNA (miR)‐143 is downregulated in human bladder cancer (BC). Recent precision medicine has shown that mutations in BC are frequently observed in FGFR3, RAS and PIK3CA genes, all of which correlate with RAS signaling networks. We have previously shown that miR‐143 suppresses cell growth by inhibiting RAS signaling networks in several cancers including BC. In the present study, we showed that synthetic miR‐143 negatively regulated the RNA‐binding protein Musashi‐2 (MSI2) in BC cell lines. MSI2 is an RNA‐binding protein that regulates the stability of certain mRNAs and their translation by binding to the target sequences of the mRNAs. Of note, the present study clarified that MSI2 positively regulated KRAS expression through directly binding to the target sequence of KRAS mRNA and promoting its translation, thus contributing to the maintenance of KRAS expression. Thus, miR‐143 silenced KRAS and MSI2, which further downregulated KRAS expression through perturbation of the MSI2/KRAS cascade.

Most patients with metastatic urothelial carcinoma experience no objective response to pembrolizumab and have poor overall survival (OS). Here, we investigated the prognostic value of fluctuation in the neutrophil-lymphocyte ratio (NLR) at 6 weeks of pembrolizumab treatment, focusing on its association with the achievement of objective response.The clinical records of 177 metastatic urothelial carcinoma patients treated with pembrolizumab were retrospectively analyzed.The median age was 72 years, and the median OS was 14 months. The objective response rate in the total cohort was 26.5% (47 of 177 patients). Multivariable analysis showed that objective response achievement (hazard ratio 0.3 [95% confidence interval 0.15-0.59], P0.001) and decline in NLR from that at baseline at 6 weeks of treatment (0.54 [0.34-0.88], P = 0.013) were independent prognostic factors for improved OS. For 47 (26.5%) patients who achieved an objective response, OS was similar regardless of NLR fluctuation at 6 weeks of treatment (P = 0.723). Intriguingly, of the 130 (73.5%) patients with no objective response, those who showed a decreased NLR at 6 weeks of pembrolizumab treatment (57 patients) from that at baseline had significantly longer OS than those with elevated NLR (73 patients) (14 vs. 6 months, P = 0.007).The fluctuation in NLR from that at baseline at 6 weeks of pembrolizumab treatment may be useful for patients without an objective response. This could potentially aid decision-making for post pembrolizumab therapies.

The identification of early or primary resistance to androgen signaling inhibitors (ASIs) is of great value for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the predictive value of prostate-specific antigen (PSA) response at dour weeks of first-line ASIs treatment for mCRPC patients. A total of 254 patients treated with ASIs (abiraterone acetate: AA and enzalutamide: Enz) at the first-line treatment are retrospectively analyzed. Patients are stratified according to the achievement of &gt, 30% PSA decline at 4 and 12 weeks from the treatment initiation. At four weeks of the treatment, 157 patients (61.8%) achieved &gt, 30% PSA decline from the baseline. Thereafter, 177 patients (69.7%) achieved &gt, 30% PSA decline at 12 weeks of the treatment. A multivariate analysis exhibits &gt, 30% PSA decline at four weeks as an independent predictor for overall survival (OS). We note that 30 of 97 (30.9%) patients who did not achieve &gt, 30% PSA decline at four weeks consequently achieved &gt, 30% PSA decline at 12 weeks, and had a comparable favorable three years OS rate as the 147 patients achieving &gt, 30% PSA decline at both 4 and 12 weeks. To identify the variables that discriminate the patient survival in 97 patients without achieving &gt, 30% PSA decline at four weeks, a multivariate analysis is performed. The duration of androgen deprivation therapy before CRPC &le, 12 months and Eastern Cooperative Oncology Group Performance Status &ge, 1 are identified as independent predictors for shorter OS for those patients. These data offer a concept of early treatment switch after four weeks of first-line ASIs when not observing &gt, 30% PSA decline at four weeks&mdash, particularly in patients with a modest effect of ADT and poor performance status.

PurposeWe assessed the prognostic value of body mass index (BMI) in Asian patients with localized RCC who underwent nephrectomy.Material and MethodsA total of 665 patients who underwent nephrectomy for localized RCC were enrolled in the present study and divided into the two BMI groups: i.e., BMI >25 in 202 (30.4%) patients.ResultsThere were 482 (72.5%) and 183 (27.5%) patients in male and female, respectively. No significant difference in the distribution of sex was seen between BMI groups (p=0.498). Five-year cancer-specific survival (CSS) and recurrence-free survival (RFS) rate were significantly higher in higher BMI (97.1 and 91.1%) compared to lower BMI group (92.5 and 82.7%) (P = 0.007 for CSS, and p=0.019 for RFS). When stratified by sex, significantly longer CSS in higher BMI was confirmed in male (5-year CSS of 92.7% in BMI 25, p=0.005), while there was no difference in CSS between BMI groups for female patients (5-year CSS of 91.9% in BMI 25, p=0.738). Multivariate analysis revealed that BMI was an independent predictor for CSS in male (HR: 0.4, 95%CI: 0.14 - 0.95, p=0.036), but not in female (HR: 0.73, 95%CI: 0.20 – 2.10, p=0.576).ConclusionOur findings collected from the multi-institutional Japanese dataset demonstrated the longer survival in patients with higher BMI compared to lower BMI for non-metastatic RCC treated with nephrectomy. Intriguingly, this finding was restricted to males, but not to females.

BackgroundChemoradiation therapy (CRT) has been increasingly reported as a possible alternative to total cystectomy (TC) for localized bladder cancer (BC). Pembrolizumab is the standard of care for platinum-refractory metastatic urothelial carcinoma, although it is unknown whether the efficacy of pembrolizumab in patients previously treated with curative CRT varies from the results of benchmark trials.MethodsWe retrospectively assessed whether the survival benefit of pembrolizumab differs between patients previously treated with TC or CRT as radical treatment. A total of 212 patient records were collected for a logistic regression propensity score model. An independent dataset with next-generation sequencing (n=289) and PD-L1 Combined Positive Score (CPS: n=266) was analyzed to assess whether CRT-recurrent tumor harbors distinct CD274/PD-L1 profiles.ResultsPropensity score matching was performed using putative clinical factors, from which 30 patients in each arm were identified as pair-matched groups. There was no significant difference in overall survival from the initiation of pembrolizumab (p=0.80) and objective response rate (p=0.59) between CRT and TC treatment groups. In the independent 289 BC cohort, 22 samples (7.6%) were collected as CRT-recurrent tumors. There was no significant difference in CD274 mRNA expression level between CRT-naïve and CRT-recurrent tumors. The compositions of CD274 isoforms were comparable among all isoforms detected from RNAseq between CRT-naïve (n=267) and CRT-recurrent (n=22) tumors. No actionable exonic mutation in CD274 was detected in CRT-recurrent tumors. PD-L1 CPS was positively correlated with CD274 mRNA expression level, and PD-L1 CPS was comparable between CRT-naïve and CRT-recurrent tumors.ConclusionsThe efficacy of pembrolizumab for patients previously treated with CRT was similar to those treated with TC. The enhanced tumor regression by combining programmed cell death protein 1/PD-L1 inhibitor and CRT might be expected only in the concurrent administration.

Despite considerable research on K-Ras inhibitors, none had been established until now. We synthesized nuclease-resistant synthetic miR-143 (miR-143#12), which strongly silenced K-Ras, its effector signal molecules AKT and ERK, and the K-Ras activator Sos1. We examined the anti-proliferative effect of miR-143#12 and the mechanism in human colon cancer DLD-1 cell (G13D) and other cell types harboring K-Ras mutations. Cell growth was markedly suppressed in a concentration-dependent manner by miR-143#12 (IC50 : 1.32 nmol L-1 ) with a decrease in the K-Ras mRNA level. Interestingly, this mRNA level was also downregulated by either a PI3K/AKT or MEK inhibitor, which indicates a positive circuit of K-Ras mRNA expression. MiR-143#12 silenced cytoplasmic K-Ras mRNA expression and impaired the positive circuit by directly targeting AKT and ERK mRNA. Combination treatment with miR-143#12 and a low-dose EGFR inhibitor induced a synergistic inhibition of growth with a marked inactivation of both PI3K/AKT and MAPK/ERK signaling pathways. However, silencing K-Ras by siR-KRas instead of miR-143#12 did not induce this synergism through the combined treatment with the EGFR inhibitor. Thus, miR-143#12 perturbed the K-Ras expression system and K-Ras activation by silencing Sos1 and, resultantly, restored the efficacy of the EGFR inhibitors. The in vivo results also supported those of the in vitro experiments. The extremely potent miR-143#12 enabled us to understand K-Ras signaling networks and shut them down by combination treatment with this miRNA and EGFR inhibitor in K-Ras-driven colon cancer cell lines.

// Teruo Inamoto 1 , Hideyasu Matsuyama 2 , Shigeru Sakano 2 , Naokazu Ibuki 1 , Kiyoshi Takahara 1 , Kazumasa Komura 1 , Tomoaki Takai 1 , Takuya Tsujino 1 , Yuki Yoshikawa 1 , Koichiro Minami 1 , Kazuhiro Nagao 2 , Ryo Inoue 2 and Haruhito Azuma 1 1 Department of Urology, Osaka Medical College, Osaka, Japan 2 Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Japan Correspondence to: Teruo Inamoto, email: tinamoto@osaka-med.ac.jp Keywords: Glasgow Prognostic Score; upper tract urothelial carcinoma; prognosis Received: June 27, 2017 Accepted: October 30, 2017 Published: November 23, 2017 ABSTRACT Introduction and Objective: The combination of C-reactive protein and albumin, the Glasgow Prognostic Score (GPS), had independent prognostic value in patients with varying cancers, except for upper tract urothelial carcinoma (UTUC). The aim of this study was to describe the relationship between GPS and survival in patients with UTUC after adjustment for other prognostic factors. Materials and Methods: We queried 2 UTUC databases. Retrospective clinical series on patients with localized UTUC managed by nephroureterectomy with bladder cuff, for whom data from the Yamaguchi Uro-Oncology Group and Osaka Medical College registry, including age, presence of bladder cancer, pT stage, lymphovascular invasion, C-reactive protein (CRP) and albumin, were analyzed. The GPS was constructed by combining CRP and albumin. Cancer specific survival (CSS) and overall survival (OS) and relative excess risk of death were estimated by GPS categories after adjusting for gender, age, ECOG performance status (PS), grade, and lymphovascular invasion (LVI). Results: Seven hundred and twenty four UTUC patients were identified. Our final cohort included 574 patients; of these, 29.2% died during a maximum follow up of 16.7 years. The estimated mean 10-year CSS of patients with GPS of scre-0, -1, and -2 was 99.5, 95.1, and 75.9 months, respectively. Patients with GPS of score-2 had poorest 10-year estimated mean OS of 67.6 months (57.2–77.9). Raised GPS also had a significant association with excess risk of cancer death at 10 years (GPS 2: Relative Excess Risk = 1.74, 95% CI 1.20–2.54) after adjusting for gender, patients’ age, ECOG PS, and tumor focality. C-index of GPS both for CSS and OS were superior to patients’ age and tumor focality, and comparable to grade. Conclusions: The GPS is an independent prognostic factor for CSS and OS after surgery with curative intent for localized UTUC. It significantly increases the accuracy of established prognostic factors. The GPS may provide a meaningful adjunct for patient counseling and clinical trial design.

The modified Glasgow Prognostic Score (mGPS) by measurement of serum C-reactive protein and albumin levels has been shown to provide prognostic value in various cancer types. The purpose of this study was to evaluate whether preoperative assessment of the mGPS predicts patient survival outcome in renal cell carcinoma (RCC). Clinicopathological and follow-up data in 219 RCC patients, all of whom underwent curative or non-curative nephrectomy, were collected. Overall survival (OS) and cancer-specific survival (CSS) after nephrectomy were evaluated, and univariate and multivariate analyses were conducted to assess the predictive value of the variables, including the mGPS. During the median follow-up of 57 months, 53 patients (24.2%) were deceased within 22 months of the median OS. The 5-year OS rate from nephrectomy was 85.9 and 18.8% in non-metastatic (n = 195) and metastatic (n = 24) patients, respectively. Increasing mGPS was associated with shorter OS in non-metastatic patients (2-year OS rate of 98.2% in mGPS0, 73.3% in mGPS1, and 44.4% in mGPS2; hazard ratio [HR] 9.96, 95% confidence interval [CI] 4.88–20.13, p

A 19-year-old Japanese male recipient, who received a living related kidney transplantation from his father at 5 years old, was hospitalized for second renal transplantation from a cadaveric donor. The recipient had had an antibody-mediated rejection (AMR) to the first transplanted kidney. HLA typing of A, B, and DRB showed 2 of 6 mismatches. Lymphocyte cytotoxicity test (LCT) and flow cytometry crossmatches (FCXM) were negative on T cells. Tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab induction were used as the standard immunosuppressive therapy. After second renal transplantation, his serum creatinine level favorably decreased until postoperative day (POD) 7, but his serum creatinine level raised from POD 8. We performed steroid pulse and intravenous immunoglobulin (IVIG). The episode biopsy showed AMR although FCXM and LCT were still negative on T cell. To determine the cause of AMR, we examined LABScreen single antigen test (One Lambda, Canoga Park, Calif., United States), and there was a donor-specific antibody (DSA) that is DQB8 in pre- and post-second renal transplantation. The DSA was suspected de novo DSA for the first transplanted kidney. AMR was successfully treated with plasma exchange, IVIG, and rituximab.

This study aimed to assess the clinical value of C-reactive protein-albumin ratio (CAR) at the initiation of first-line treatment for castration-resistant prostate cancer (CRPC). We identified 221 CRPC patients treated with either androgen-signaling inhibitors (ASIs: abiraterone and enzalutamide) or docetaxel as the first-line treatment. The value of CAR was evaluated at the initiation of first-line treatment. The optimal cutoff value of CAR for the prediction of lethality was defined by the receiver operating characteristic curve and the Youden Index. The primary endpoints of the study included overall survival (OS) and cancer-specific survival (CSS). The median age was 74 years. The optimal cutoff value of CAR in newly diagnosed CRPC patients was 0.5 (CAR 0.5: n = 77 and CAR ≤ 0.5: n = 144). The 3-year OS and CSS rate in patients with CAR 0.5 were significantly lower than those with CAR ≤ 0.5 (OS: 30.9% vs 55.5%, p 0.001) (CSS: 42.5% vs 65.4%, p 0.001). A multivariate analysis consistently demonstrated that CAR was an independent predictor for both OS and CSS. When stratified by the first-line treatments, patients with CAR 0.5 has significantly shorter CSS than those with CAR ≤ 0.5 in abiraterone (median of 23 vs 49 months, p 0.001) and enzalutamide (median of 23 vs 41 months, p = 0.0016), whereas no difference was observed in patients treated with docetaxel as the first-line treatment (median of 34 and 37 months, p = 0.7708). Despite the limited cohort size and retrospective design, increased CAR seemed to serve as an independent predictor of OS and CSS for patients newly diagnosed with CRPC.

Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of PI3K/AKT and MAPK/ERK signaling pathways has been reported, and inhibition of these pathways is an important therapeutic strategy. MiR-143 is known to act as a tumor suppressor in several cancers, such as bladder cancer, breast cancer, colorectal cancer, and gastric cancer. In the current study, we developed a novel chemically-modified miR-143 and explored the functions of this synthetic miR-143 (syn-miR-143) in HER2-positive gastric cancer. The expression level of miR-143 was down-regulated in GC cell lines, including HER2-positive GC cell lines, MKN7, and KATO-III. The ectopic expression of miR-143 in those cell lines suppressed cell growth through systemic silencing of KRAS and its effector signaling molecules, AKT and ERK. Furthermore, syn-miR-143 indirectly down-regulated the expression of HER2, an upstream molecule of KRAS, through silencing DEAD/H-box RNA helicase 6 (DDX6), RNA helicase, which enhanced HER2 protein expression at the translational step in HER2-positive GC cells. These findings suggested that syn-miR-143 acted as a tumor suppressor through the impairment of KRAS networks including the DDX6.

A myriad of studies have demonstrated the clinical association of systemic inflammatory and nutrition status (SINS) including C-reactive protein/albumin ratio (CAR), the neutrophil/lymphocyte ratio (NLR), and the platelet/hemoglobin ratio (PHR). This study aimed to investigate the predictive value of the score integrating these variables (CANLPH) in patients with renal cell carcinoma (RCC). Using cohort data from a multi-institutional study, 757 of 1109 patients were retrospectively analyzed. The optimal cutoff value for outcome prediction of continuous variables in CAR, NLR, and PHR was determined and the CANLPH score was then calculated as the sum score of 0 or 1 by the cutoff value in each ratio. The median follow-up time was 76 months for the patients who survived (n = 585) and 31 months for those who died (n = 172). The Youden Index offered an optimal cutoff of 1.5 for CAR and 2.8 for NLR, and a higher value from the cutoff was assigned as a score of 1. The cutoff value of the PHR was defined as 2.1 for males and 2.3 for females. The patients were assigned a CANLPH score of 0 (47.2%), 1 (31.3%), 2 (13.1%), or 3 (8.5%). In the multivariate analysis, the CANLPH score served as an independent predictor of cancer-specific mortality in both localized and metastatic RCC. The score was well-correlated with clinical outcome for the RCC patients. Because this score can be concisely measured at the point of diagnosis, physicians may be encouraged to incorporate this model into the treatment for RCC.

Background: We vigorously reviewed patients' operation record who had adhesion of the Denonvilliers' fascia and found out most of these patients had prostatic bleeding after prostatic gland biopsies. We examined the magnitude of prostatic bleeding and frequency after biopsies and the relationship with oncological outcomes. Materials and Methods: A total of 285 patients were selected for the final analyses. Inclusion criteria were as follows: receiving MRI three weeks after biopsiesand laparoscopic radical prostatectomy within 300 days after biopsy. We divided the patients into two groups with (group A) or without (group B) prostatic bleeding. We examined the magnitude of prostatic bleeding after biopsies and the relationship with operation time (OT), positive surgical margin (PSM), biochemical recurrence (BCR) and other factors. Furthermore, we created a logistic-regression model to derive a propensity score for prostatic bleeding after biopsies, which included all patient and hospital characteristics as well as selected interaction terms, and we examined the relationship with PSM and BCR. Results: In all patients, the OT in the group B was shorter than the group A (p < 0.001). Prostatic bleeding was associated with PSM (p=0.000) and BCR (p=0.036). In this propensity-matched cohort, 11 of 116 patients in the group B had PSM as compared with 36 of 116 patients from group A (match-adjusted odds ratio, 4.30; 95%CI confidence interval, 2.06 to 8.96; P=0.000). In addition, eight of 116 patients in group B encountered BCR, as compared with 18 of 116 patients in group A (match-adjusted odds ratio, 2.48; 95%CI, 1.03 to 5.96; P=0.042). Kaplan-Meier analysis in the propensity matching cohort showed a significant biochemical recurrence-free survival advantage for being free of prostate bleeding after biopsies. Conclusions: Our findings in the present cohort should help equip surgeons to pay attention to careful excision especially for those who experienced deferred prostatic bleeding.

INTRODUCTION AND OBJECTIVE:The FDA has approved the first targeted therapy for bladder cancer with its accelerated approval of erdafitinib for the treatment of adult patients with locally advanced ...

The C-reactive protein to albumin ratio (CAR) has been shown to provide prognostic information in several cancers. The objective in the study is to examine the prognostic value of CAR in patients with RCC who underwent nephrectomy.The record data from multi-institutional study of 1,028 patients was analyzed in the study. The cut-off value of the CAR was defined by receive operating characteristic (ROC) analysis. Overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were evaluated, and univariate and multivariate analyses were conducted to assess the predictive value of the variables including CAR.The optimal cut-off value of 0.073 in CAR was defined according to the ROC analysis. The AUC in CAR for CSS was greater than that of NLR and PLR, and that for RFS was also greater than GPS and mGPS. Multivariate analysis demonstrated that the CAR was an independent prognostic factor for OS (P0.001), CSS (P0.001) in total cohort and RFS (P = 0.029) in nonmetastatic cohort.The findings of the present study suggested that the preoperative CAR is an independent prognostic indicator of OS, CSS and RFS for patients with RCC. Since CAR can be assessed prior to surgery, clinicians should this take into account for the treatment decision making.

Serine and arginine rich splicing factor 3 (SRSF3), an SR-rich family protein, has an oncogenic function in various kinds of cancer. However, the detailed mechanism of the function had not been previously clarified. Here, we showed that the SRSF3 splicer regulated the expression profile of the pyruvate kinase, which is one of the rate-limiting enzymes in glycolysis. Most cancer cells express pyruvate kinase muscle 2 (PKM2) dominantly to maintain a glycolysis-dominant energy metabolism. Overexpression of SRSF3, as well as that of another splicer, polypyrimidine tract binding protein 1 (PTBP1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), in clinical cancer samples supported the notion that these proteins decreased the Pyruvate kinase muscle 1 (PKM1)/PKM2 ratio, which positively contributed to a glycolysis-dominant metabolism. The silencing of SRSF3 in human colon cancer cells induced a marked growth inhibition in both in vitro and in vivo experiments and caused an increase in the PKM1/PKM2 ratio, thus resulting in a metabolic shift from glycolysis to oxidative phosphorylation. At the same time, the silenced cells were induced to undergo autophagy. SRSF3 contributed to PKM mRNA splicing by co-operating with PTBP1 and hnRNPA1, which was validated by the results of RNP immunoprecipitation (RIP) and immunoprecipitation (IP) experiments. These findings altogether indicated that SRSF3 as a PKM splicer played a positive role in cancer-specific energy metabolism.

Much controversy exists over the performance of elderly living donor kidney transplantation. We report the safety of 2 cases of elderly living kidney donations in our hospital. CASE 1: An 82-year-old man was a living kidney donor for his 56-year-old son. The donor suffered from hypertension, but has successfully managed his blood pressure with only one medication. His serum creatinine was 0.7 mg/dL and inulin clearance was 122.5 mL/min, which met the usual criteria for living kidney donors. This was his son's secondary kidney transplantation, and no other donors existed. CASE 2: An 80-year-old woman was a living kidney donor for her 45-year-old son. Her serum creatinine was 0.61 mg/dL and inulin clearance was 71.7 mL/min, which met the marginal kidney donor criteria. In both cases, we determined that the donor kidney function was acceptable. Though we explained the risks of the transplantation thoroughly, the patients' strong will to offer a kidney to their family member did not change. We decided to carry out the transplantation. At the time of publication, nearly 2 years have passed since the transplantation, but both donors and recipients are doing well. In the future, it seems more likely that the number of elderly living donor kidney transplantation will rise. On one hand, there is no absolute contraindication for elderly donors, while on the other hand, the criteria for a living kidney donor must be strictly examined. Furthermore, careful observation of both donors and recipients after transplantation is required.

Background Okinoerabu Island and Tokunoshima Island lie in the sea to the south of the Japanese mainland, about 100 km north of Okinawa and about 500 km south of Kyushu. There are no facilities that specialize in kidney transplants, so the patients need to leave the island to undergo the procedure. Up to a few years ago, there were less than five kidney transplant patients on the island. We report the status of transplant medicine on these remote islands, including concrete methods for periodic examinations and how emergencies are handled. Case presentation Recipient age was 60.0 ± 8.9 years (mean ± SD); 15 were males and 10 were females. Donor age was 57.9 ± 8.48 years (mean ± SD); 14 were males and 11 were females. Recipient diseases leading to ESRD were diabetes (36.0%), chronic glomerulonephritis (28.0%), and ADPKD (12.0%). The duration of dialysis prior to transplantation was 382.6 ± 233.2 days (mean ± SD). We physicians specializing in kidney transplants formed an alliance with local facilities a few years back to create specialized outpatient facilities, and the number of transplant patients has gradually increased. Delayed graft function was observed in only one patient, biopsy-proven acute rejection in four patients, and chronic allograft nephropathy in two patients. In these cases, the local doctor performed the treatment in their facilities under our direction. Most of the treatments were performed safely and successfully. The mean follow-up period was 1208 ± 1809 days. None of the patients has had graft loss, with mean SCr (serum Cr level) of 1.35 ± 0.85 mg/dl. Conclusions To coordinate medical care recipients with their primary care physicians, physicians specializing in kidney transplants no longer need to travel long distances to receive follow-up outpatients. Recently, likelihood of kidney transplantation has been much higher among these islands. The number of transplant patients has gradually increased.

Background No standard chemotherapy regimen for advanced urothelial cancer has been established, except for cisplatin-based regimens. We report the case of a patient with double primary cancer, urothelial carcinoma of the upper urinary tract and colorectal cancer, who underwent oxaliplatin-based chemotherapies. Case presentation A 56-year-old Japanese man presented to our hospital with the diagnosis of a left renal pelvic tumor and rectal cancer. Several examinations including ureteroscopic biopsy and computed tomography-guided biopsy were performed; however, the diagnosis of renal pelvic cancer could not be made. Because the rectal cancer had been growing during the course of examination, he underwent five cycles of neoadjuvant chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan. The volumes of both the rectal cancer and renal pelvic tumor drastically decreased. He then underwent pelvic evisceration with colostomy and ureterocutaneostomy. The histological diagnosis of the renal pelvic tumor was urothelial carcinoma. He is free of disease at 12 months after the treatment. Conclusions To the best of our knowledge, this is the first report describing a remarkable response to fluorouracil, leucovorin, oxaliplatin, and irinotecan therapy for renal pelvic cancer. We suggest fluorouracil, leucovorin, oxaliplatin, and irinotecan is an effective therapy for patients with advanced urothelial cancer.

Bladder cancer is one of the most difficult malignancies to control. We explored the use of a novel RNA-interference method for a driver oncogene regulating cancer specific energy metabolism by the combination treatment with a small interfering RNA (siRNA) and a microRNA. After transfection of T24 and 253JB-V cells with miR-145 and/or siR-PTBP1, we examined the effects of cell growth and gene expression by performing the trypan blue dye exclusion test, Western blot, Hoechst 33342 staining, reverse transcription polymerase chain reaction (RT-PCR), and electron microscopy. The anti-cancer effects of xenograft model mice with miR-145 and/or siR-PTBP1 were then assessed. The combination treatment induced the deeper and longer growth inhibition and reduced the levels of both mRNA and protein expression of c-Myc and polypyrimidine tract-binding protein 1 (PTBP1) more than each single treatment. Notably, the combination treatment not only impaired the cancer specific energy metabolism by inhibiting c-Myc/PTBP1/PKMs axis but also inactivated MAPK/ERK and PI3K/AKT pathways examined in vitro and in vivo. Furthermore, the combination treatment induced apoptosis or autophagy; but, in some cells, apoptotic cell death was accompanied by autophagy, because the condensation of chromatin and many autophagosomes were coexistent. This combination treatment could be a novel RNA-interference strategy through the systemic silencing of the Warburg effect-promoting driver oncogene PTBP1 in bladder cancer cells.