Case in which percutaneous fibrin glue injection was useful for refractory urinary fistula following robot-assisted partial nephrectomy.

Introduction: Urinary fistula is a rare complication following robot-assisted partial nephrectomy. For cases refractory to conservative treatment, only ureteral stent placement and percutaneous drainage are the established treatment alternatives. Case presentation: A 44-year-old man presented with urinary fistula 3 weeks after robot-assisted partial nephrectomy for right renal cell carcinoma. Follow-up observations were conducted for 2 weeks; however, no improvements were observed. Additionally, the patient did not improve following percutaneous drainage and ureteral stent insertion. Subsequently, the patient received percutaneous injections of fibrin glue, with the urinary fistula showing significant improvements on the following day. Conclusion: Our findings indicated that percutaneous fibrin glue injection can effectively treat refractory urinary fistula following partial nephrectomy.

Risk of stricture after endoscopic submucosal dissection in the cervical esophagus and efficacy of local steroid injection for stricture prevention.

BACKGROUND AND AIMS: There is a high incidence of stricture after endoscopic submucosal dissection (ESD) for cervical esophageal cancer. We aimed to elucidate the risk factors for stricture and evaluate the efficacy of steroid injection for stricture prevention in the cervical esophagus. METHODS: We retrospectively analyzed 100 patients who underwent ESD for cervical esophageal cancer to: (1) identify the factors associated with stricture among patients who did not receive steroid injection; (2) compare the incidence of stricture between patients with and without steroid injection. RESULTS: Among 48 patients who did not receive steroid injection, there were significant differences in tumor size (P = .026), resection time (P = .028), and circumferential extent of the mucosal defect (P = .005) between patients with stricture (n = 5) and without stricture (n = 43). Compared with patients without steroid injection, patients with steroid injection had a significantly lower incidence of stricture when the post-ESD mucosal defect was < 3/4 and ≥ 1/2 (40% versus 8%, P = .039). As for the patients with a post-ESD mucosal defect of ≥ 3/4 (n = 13), local steroid injection was performed for all the patients, and 6 patients (46%) developed stricture. CONCLUSIONS: Patients who underwent ≥ 1/2 circumferential resection were at high risk of cervical esophageal stricture. Steroid injection had a stricture-prevention effect in patients with < 3/4 and ≥ 1/2 circumferential resection, but seemed to be insufficient in preventing stricture in patients with ≥ 3/4 circumferential resection.

[A Case of Metastatic Prostate Cancer with Neuroendocrine Differentiation with Long-Term Survival after Multidisciplinary Therapy].

A 74-year-old man visited the urology clinic with the chief complaint of urinary retention in December 2014. Serum level of initial prostate specific antigen (PSA) was 50 ng/ml and he was diagnosed with Gleason Score 4＋4 prostate adenocarcinoma with regional lymphadenopathy (cT3aN1M0). PSA level had declined after the treatment with combined androgen blockade. In November 2018, he was diagnosed with castration resistant prostate cancer (CRPC) as local progression was detected by computed tomography (CT) while PSA level did not increase. Since local symptoms worsened, resulting in repeated hematuria after the treatment with enzalutamide, palliative radiation therapy to the prostate (45 Gy) was performed. Five months later, follow-up CT showed multiple metastasis in bilateral lung and left testicle. Serum level of neuron-specific enolase (NSE) was 24.4 ng/ml without an elevated in serum PSA level. He received rebiopsy of the prostate, but no malignant findings were observed. Consequently, bilateral orchiectomy was performed for diagnosis of left testicular tumor. Pathological examination revealed metastasis of neuroendocrine prostate cancer (NEPC). Chemotherapy using cisplatin and irinotecan was administered after orchiectomy. Complete response of lung lesions was achieved and serum level of NSE decreased within normal range. No recurrence has been confirmed for 4 years after the completion of chemotherapy.

Oncological outcomes of prophylactic urethrectomy at the time of radical cystectomy for bladder cancer: A nationwide multi-institutional study.

OBJECTIVES: To determine the effects of prophylactic urethrectomy (PU) on oncological and perioperative outcomes in patients with bladder cancer (BC) undergoing radical cystectomy (RC). METHODS: This retrospective study analyzed data on 1976 evaluable patients with BC who underwent RC. Patients were drawn from 36 institutions within the Japanese Urological Oncology Group. Oncological outcomes were compared using restricted mean survival times (RMSTs) based on inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves for non-urinary tract recurrence-free survival (NUTRFS), cancer-specific survival (CSS), and overall survival (OS). Interaction terms within IPTW-adjusted Cox regression models were examined to assess the heterogeneity of treatment effect based on the risk of urethral recurrence (UR). The association between PU, estimated blood loss (EBL), and the incidence of severe postoperative surgical complications (SPSCs) (Clavien-Dindo grade 3 or higher) was analyzed. RESULTS: Of 1976 patients, 1448 (73.3%) received PU. IPTW adjustment was used to balance baseline characteristics between the treatment groups. Within the 107-month window of patient monitoring, PU showed no survival benefits (NUTRFS difference: 0.2 months [95% confidence interval: -6.8 to 7.3]; CSS, 1.2 [-4.9 to 7.3]; OS, 0 [-6.5 to 6.5]). No significant interactions were observed with factors associated with UR, and PU was associated with unfavorable perioperative outcomes (EBL, 1179 mL vs. 983 mL; SPSC, 14.6% vs. 7.0%). CONCLUSIONS: This study showed that (1) PU was not associated with survival in patients with BC undergoing RC, regardless of UR-associated factors, and (2) PU was associated with unfavorable perioperative outcomes.

A novel artificial intelligence-based endoscopic ultrasonography diagnostic system for diagnosing the invasion depth of early gastric cancer.

BACKGROUND: We developed an artificial intelligence (AI)-based endoscopic ultrasonography (EUS) system for diagnosing the invasion depth of early gastric cancer (EGC), and we evaluated the performance of this system. METHODS: A total of 8280 EUS images from 559 EGC cases were collected from 11 institutions. Within this dataset, 3451 images (285 cases) from one institution were used as a development dataset. The AI model consisted of segmentation and classification steps, followed by the CycleGAN method to bridge differences in EUS images captured by different equipment. AI model performance was evaluated using an internal validation dataset collected from the same institution as the development dataset (1726 images, 135 cases). External validation was conducted using images collected from the other 10 institutions (3103 images, 139 cases). RESULTS: The area under the curve (AUC) of the AI model in the internal validation dataset was 0.870 (95% CI: 0.796-0.944). Regarding diagnostic performance, the accuracy/sensitivity/specificity values of the AI model, experts (n = 6), and nonexperts (n = 8) were 82.2/63.4/90.4%, 81.9/66.3/88.7%, and 68.3/60.9/71.5%, respectively. The AUC of the AI model in the external validation dataset was 0.815 (95% CI: 0.743-0.886). The accuracy/sensitivity/specificity values of the AI model (74.1/73.1/75.0%) and the real-time diagnoses of experts (75.5/79.1/72.2%) in the external validation dataset were comparable. CONCLUSIONS: Our AI model demonstrated a diagnostic performance equivalent to that of experts.

A machine learning model for predicting the lymph node metastasis of early gastric cancer not meeting the endoscopic curability criteria.

BACKGROUND: We developed a machine learning (ML) model to predict the risk of lymph node metastasis (LNM) in patients with early gastric cancer (EGC) who did not meet the existing Japanese endoscopic curability criteria and compared its performance with that of the most common clinical risk scoring system, the eCura system. METHODS: We used data from 4,042 consecutive patients with EGC from 21 institutions who underwent endoscopic submucosal dissection (ESD) and/or surgery between 2010 and 2021. All resected EGCs were histologically confirmed not to satisfy the current Japanese endoscopic curability criteria. Of all patients, 3,506 constituted the training cohort to develop the neural network-based ML model, and 536 constituted the validation cohort. The performance of our ML model, as measured by the area under the receiver operating characteristic curve (AUC), was compared with that of the eCura system in the validation cohort. RESULTS: LNM rates were 14% (503/3,506) and 7% (39/536) in the training and validation cohorts, respectively. The ML model identified patients with LNM with an AUC of 0.83 (95% confidence interval, 0.76-0.89) in the validation cohort, while the eCura system identified patients with LNM with an AUC of 0.77 (95% confidence interval, 0.70-0.85) (P = 0.006, DeLong's test). CONCLUSIONS: Our ML model performed better than the eCura system for predicting LNM risk in patients with EGC who did not meet the existing Japanese endoscopic curability criteria. We developed a neural network-based machine learning model that predicts the risk of lymph node metastasis in patients with early gastric cancer who did not meet the endoscopic curability criteria.

Comparison of Oncological Outcomes between Transperitoneal and Retroperitoneal Approaches in Laparoscopic Nephroureterectomies for Upper Tract Urothelial Carcinoma.

Background and Objectives: Our aim was to clarify the oncological outcomes of the two different approaches to laparoscopic nephroureterectomies (LNUs) in Japan, and to examine whether there were any significant differences between the transperitoneal approach and the retroperitoneal approach. Materials and Methods: We retrospectively evaluated patients who underwent an LNU for upper tract urothelial carcinoma (UTUC) from January 2013 to December 2022. We identified 52 patients who underwent a transperitoneal LNU (tLNU) and 93 who underwent a retroperitoneal LNU (rLNU). We adopted age, smoking, and pT-stage matching, and 43 patients were classified in each group. We investigated the time from surgery to recurrence (RFS: recurrence-free survival), the time to death (OS: overall survival), and the time to non-urothelial-tract recurrence-free survival (NUTRFS). A Cox regression analysis was performed to evaluate the risk factors that influenced recurrence. Results: There were no significant differences in the RFS, OS, and NUTRFS between the two matched groups. In the multivariate Cox regression analysis, the pT stage (pT3≥ vs. pT2≤) had an HR = 2.09 and a p = 0.01, and was an independent prognostic risk factor regarding cancer recurrence. Conclusions: There were no significant differences in the oncological outcomes between the tLNU and rLNU groups. It is suggested that the transperitoneal approach should be selected for LNUs.

Real-world sequential treatment patterns and clinical outcomes among patients with advanced urothelial carcinoma in Japan.

OBJECTIVES: Immune checkpoint inhibitors and enfortumab vedotin have opened new avenues for sequential treatment strategies for locally advanced/metastatic urothelial carcinoma (la/mUC). In the pre-enfortumab vedotin era, many patients could not receive third-line treatment owing to rapid disease progression and poor general status. This study aimed to analyze real-world sequential treatment practices for la/mUC in Japan, with a focus on patients who do not receive third-line treatment. METHODS: We analyzed data for 1023 la/mUC patients diagnosed between January 2020 and December 2021 at 54 institutions from a Japanese nationwide cohort. RESULTS: At the median follow-up of 28.5 months, the median overall survival from first-line initiation for 905 patients who received systemic anticancer treatment was 19.1 months. Among them, 81% and 32% received second- and third-line treatment. Notably, 52% had their treatment terminated before the opportunity for third-line treatment. Multivariate logistic regression analysis revealed that low performance status (≥1), elevated neutrophil-to-lymphocyte ratio (≥3), and low body mass index (<21 kg/m2) at the start of first-line treatment were independent risk factors for not proceeding to third-line treatment (p = 0.0024, 0.0069, and 0.0058, respectively). In this cohort, 33% had one of these factors, 36% had two, and 15% had all three. CONCLUSIONS: This study highlights the high frequency of factors associated with poor tolerance to anticancer treatment in la/mUC patients. The findings suggest the need to establish optimal sequential treatment strategies, maximizing efficacy within time and tolerance constraints, while concurrently providing strong supportive care, considering immunological and nutritional aspects.

Efficacy of prophylactic clip closure in reducing the risk of delayed bleeding after colorectal endoscopic submucosal dissection in patients on anticoagulant therapy: Multicenter prospective study.

OBJECTIVES: The high rate of delayed bleeding after colorectal endoscopic submucosal dissection (ESD) in patients undergoing anticoagulant therapy remains a problem. Whether prophylactic clip closure reduces the rate of delayed bleeding in these patients is unclear. This study aimed to evaluate the efficacy of prophylactic clip closure in patients receiving anticoagulants. METHODS: This multicenter prospective interventional trial was conducted at nine referral centers in Japan. Patients regularly taking anticoagulants, including warfarin potassium or direct oral anticoagulants, and undergoing ESD for colorectal neoplasms were enrolled. The discontinuation of anticoagulants was minimized according to recent guidelines. After the ESD, post-ESD ulcers were prophylactically closed using endoclips. The primary end-point was the incidence of delayed bleeding. The sample size was 45 lesions, and prophylactic clip closure was considered effective when the upper limit of the 90% confidence interval (CI) for delayed bleeding did not exceed 20%. RESULTS: Forty-five lesions were used, and three were excluded. Complete closure was achieved in 41/42 lesions (97.6%). The overall delayed bleeding rate was low, at 4.9% (2/41; 90% [CI] 0.8-14.5), which was significantly lower than that at the prespecified threshold of 20% (P = 0.007). The median closure procedure time was 17 min, and the median number of clips was nine. No massive delayed bleeding requiring transfusion, interventional radiology, or surgery was observed, and no thromboembolic events were observed. CONCLUSION: Prophylactic clip closure may reduce the risk of delayed bleeding following colorectal ESD in patients receiving anticoagulants. TRIAL REGISTRATION: UMIN Clinical Trial Registry (UMIN000036734).

Prognostic impact of histological discordance between transurethral resection and radical cystectomy.

OBJECTIVE: To analyse the impact of histological discordance of subtypes (subtypes or divergent differentiation [DD]) in specimens from transurethral resection (TUR) and radical cystectomy (RC) on the outcome of the patients with bladder cancer receiving RC. PATIENTS AND METHODS: We analysed data for 2570 patients from a Japanese nationwide cohort with bladder cancer treated with RC between January 2013 and December 2019 at 36 institutions. The non-urinary tract recurrence-free survival (NUTR-FS) and overall survival (OS) stratified by TUR or RC specimen histology were determined. We also elucidated the predictive factors for OS in patients with subtype/DD bladder cancer. RESULTS: At median follow-up of 36.9 months, 835 (32.4%) patients had NUTR, and 691 (26.9%) died. No statistically significant disparities in OS or NUTR-FS were observed when TUR specimens were classified as pure-urothelial carcinoma (UC), subtypes, DD, or non-UC. Among 2449 patients diagnosed with pure-UC or subtype/DD in their TUR specimens, there was discordance between the pathological diagnosis in TUR and RC specimens. Histological subtypes in RC specimens had a significant prognostic impact. When we focused on 345 patients with subtype/DD in TUR specimens, a multivariate Cox regression analysis identified pre-RC neutrophil-lymphocyte ratio and pathological stage as independent prognostic factors for OS (P = 0.016 and P = 0.001, respectively). The presence of sarcomatoid subtype in TUR specimens and lymphovascular invasion in RC specimens had a marginal effect (P = 0.069 and P = 0.056, respectively). CONCLUSION: This study demonstrated that the presence of subtype/DD in RC specimens but not in TUR specimens indicated a poor prognosis. In patients with subtype/DD in TUR specimens, pre-RC neutrophil-lymphocyte ratio and pathological stage were independent prognostic factors for OS.

Non-Pure Intestinal Phenotype as an Indicator of Progression in Sporadic Nonampullary Duodenal Adenomas: A Multicenter Retrospective Cohort Study.

INTRODUCTION: We aimed to evaluate the natural course of sporadic nonampullary duodenal adenomas (SNDAs) and determine the risk factors of progression. METHODS: We retrospectively analyzed the follow-up outcomes of patients with biopsy-diagnosed SNDA between April 2010 and March 2016 at 13 institutions. All initial biopsy specimens were centrally evaluated. Only those diagnosed with adenomas were included. Mucinous phenotypes were classified into pure intestinal and non-pure intestinal phenotypes. Cumulative incidence rates of carcinoma and tumor enlargement were evaluated. Tumor enlargement was defined as a ≥25% or 5-mm increase in tumor size. RESULTS: Overall, 121 lesions were analyzed. Within a median observation period of 32.7 months, 5 lesions were diagnosed as carcinomas; the cumulative 5-year incidence of carcinoma was 9.5%. Male sex ( P = 0.046), initial lesion size ≥10 mm ( P = 0.044), and non-pure intestinal phenotype ( P = 0.019) were significantly associated with progression to carcinoma. Tumor enlargement was observed in 22 lesions, with a cumulative 5-year incidence of 33.9%. Initial lesion size ≥10 mm ( P < 0.001), erythematous lesion ( P = 0.002), high-grade adenoma ( P = 0.002), Ki67 negative ( P = 0.007), and non-pure intestinal phenotype ( P = 0.001) were risk factors of tumor enlargement. In a multivariate analysis, an initial lesion size ≥10 mm ( P = 0.010) and non-pure intestinal phenotype ( P = 0.046) were independent and significant risk factors of tumor enlargement. DISCUSSION: Lesion size ≥10 mm and non-pure intestinal phenotype on initial biopsy are risk factors of cancer progression and tumor enlargement in cases with SNDA. Thus, management effectiveness may be improved by focusing on lesion size and the mucinous phenotype.

Investigation of eligibility for adjuvant therapy from real-world data of patients with urothelial carcinoma undergoing radical cystectomy and radical nephroureterectomy.

OBJECTIVE: Adjuvant nivolumab prolonged disease-free survival compared with placebo in patients at high risk of recurrence following radical cystectomy or radical nephroureterectomy in the CheckMate 274 trial. However, the ideal eligibility criteria for adjuvant therapy in real-world clinical practice remain controversial. METHODS: We retrospectively analyzed clinical data of 409 patients who underwent radical cystectomy (n = 252) or radical nephroureterectomy (n = 157) and validated the risk of recurrence based on the classification used in the CheckMate 274 trial. We also investigated the impact of perioperative chemotherapy, lymph node dissection and pathological factors on prognosis. RESULTS: The median follow-up time was 37.5 and 32.1 months in bladder cancer and upper tract urothelial carcinoma, respectively. Among the high-risk patients based on CheckMate 274 trial, disease-free survival was considerably shorter for bladder cancer and upper tract urothelial carcinoma patients than for low-risk patients (hazard ratios: 4.132 and 7.101, respectively). The prevalence of adjuvant chemotherapy in high-risk patients was low (24 and 38% for bladder cancer and upper tract urothelial carcinoma, respectively). The extent of lymph node dissection in bladder cancer and presence of lymph node dissection in upper tract urothelial carcinoma did not affect prognosis. Cox proportional multivariate analysis revealed CheckMate 274-high-risk as a poor prognostic factor in bladder cancer and upper tract urothelial carcinoma. CONCLUSIONS: This study validated the risk classification for recurrence following radical cystectomy and radical nephroureterectomy using the CheckMate 274 criteria in real-world practice. Further research would help assess the degree of benefit obtained from adjuvant nivolumab.

Trend in overall survival from the start of first-line chemotherapy in patients with metastatic urothelial carcinoma.

New approaches involving immune checkpoint inhibitors and antibody-drug conjugates prolong overall survival in patients with metastatic urothelial carcinoma. However, the access to such systemic therapy in clinical practice is suboptimal, and whether these agents improve overall survival in patients with metastatic urothelial carcinoma over time remains unclear. Hence, we investigated the overall survival trend from the initiation of first-line therapy with these agents to identify changes due to the medication and time of treatment initiation. We retrospectively evaluated 195 patients from a single center. They were treated with chemotherapy, pembrolizumab, or avelumab or enfortumab vedotin. The treatment was categorized into chemotherapy, pembrolizumab or avelumab/enfortumab vedotin period. The new agents prolonged overall survival from the start of first-line therapy. Furthermore, sequential treatment with these agents in real-world clinical practice has been reported to prolong overall survival. These study results will have major implications when a new first-line therapy is approved in the future.

[Unmet Needs from the Cancer Patient Perspective].

An unmet needs survey was conducted among cancer patients, their families, and others affected by cancer during the 10-year period from 2011 to 2022 to clarify the actual situation regarding access to information, treatment choices, daily quality of life, and psychosocial support from the perspective of cancer patients, and to explore characteristics, problems, and issues in the categories of common cancers, rare cancers, and pediatric cancers. The desire for successful treatment itself is the same regardless of the type of cancer. However, economic and psychological burdens are closely related to age and life stage, and second opinions and necessary information differ by cancer type. Aspects of daily living difficulties, hospital visits, and financial burdens are also apparent. In addition, a comparison with a survey of clinical trials taken exclusively with rare cancer patients in 2018 was discussed. We believe that focusing on these differences will lead to measures to address unmet needs so that no one is left behind.

DNA Methylation Aberrations in Dimethylarsinic Acid-Induced Bladder Carcinogenesis.

Arsenic is a known human urinary bladder carcinogen. While arsenic is known to cause aberrant DNA methylation, the mechanism of arsenic-triggered bladder carcinogenesis is not fully understood. The goal of this study was to identify aberrant DNA methylation in rat bladder urothelial carcinoma (UC) induced by dimethylarsinic acid (DMAV), a major organic metabolite of arsenic. We performed genome-wide DNA methylation and microarray gene expression analyses of DMAV-induced rat UCs and the urothelium of rats treated for 4 weeks with DMAV. We identified 40 genes that were both hypermethylated and downregulated in DMAV-induced rat UCs. Notably, four genes (CPXM1, OPCML, TBX20, and KCND3) also showed reduced expression in the bladder urothelium after 4 weeks of exposure to DMAV. We also found that CPXM1 is aberrantly methylated and downregulated in human bladder cancers and human bladder cancer cells. Genes with aberrant DNA methylation and downregulated expression in DMAV-exposed bladder urothelium and in DMAV-induced UCs in rats, suggest that these alterations occurred in the early stages of arsenic-induced bladder carcinogenesis. Further study to evaluate the functions of these genes will advance our understanding of the role of aberrant DNA methylation in arsenic bladder carcinogenesis, and will also facilitate the identification of new therapeutic targets for arsenic-related bladder cancers.

The apelin­apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells.

Cancer­associated fibroblasts (CAFs) are pivotal in tumor progression. TP53­deficiency in cancer cells is associated with robust stromal activation. The apelin­apelin receptor (APJ) system has been implicated in suppressing fibroblast­to­myofibroblast transition in non­neoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelin­APJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53­wild colon cancer, HCT116, and Caco­2; TP53­mutant colon cancer, SW480, and DLD­1; and colon fibroblasts, CCD­18Co), resected human tissue samples of colorectal cancers, and immune­deficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts co­cultured with p53­suppressed colon cancer cells (HCT116sh p53 cells) was significantly lower than in control colon cancer cells (HCT116sh control cells). APJ­suppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblast­like properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma­ and Mad­related protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJ­suppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116sh p53 cells inhibited APJ expression, and inhibition of miR­5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cell­derived exosomes induced CAF­like properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.

Second-line Pembrolizumab for Metastatic Urothelial Carcinoma: Differences in Treatment Outcomes According to the Primary Site.

BACKGROUND/AIM: To evaluate the difference in the clinical efficacy and safety of pembrolizumab between patients with metastatic upper tract urothelial carcinoma (UTUC), which includes renal pelvic urothelial carcinoma (UC) and ureteral UC, and those with metastatic lower tract urothelial carcinoma (LTUC). PATIENTS AND METHODS: A total of 752 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. We compared progression-free survival (PFS), overall survival (OS) and adverse events (AEs) in patients with renal pelvic UC, ureteral UC, and LTUC. RESULTS: The median follow-up period was 42.5 [interquartile range (IQR)=35.1-47.4] months. The primary tumor site was in the upper tract in 362 (48.1%) patients [renal pelvis, n=219 (60.5%); ureter, n=143 (39.5%)] and in the lower tract in 390 (51.9%) patients. The estimated glomerular filtration rate before pembrolizumab treatment in the UTUC group was significantly lower than that in the LTUC group (p<0.001). The median PFS in the UTUC and LTUC groups was 3.4 months, respectively (p=0.271). The median OS in the UTUC and LTUC groups was 10.1 months and 11.7 months, respectively (p=0.195). In an analysis of UTUC divided into renal pelvic UC, ureteral UC, and LTUC, patients with renal pelvic UC had a significantly poorer prognosis in comparison to the other two groups (p=0.041). The incidence of any-grade AEs (51.7% vs. 47.9%, p=0.343) and grade ≥3 AEs (12.2% vs. 12.8%, p=0.826) in the two groups was not statistically significantly different. CONCLUSION: No significant differences were found between the UTUC and LTUC groups with regard to the oncological outcomes and safety of pembrolizumab. Patients with renal pelvic UC had a significantly poorer prognosis than those with other ureteral UCs and LTUCs.

A novel role for Helicobacter pylori cytotoxin-associated gene A in negative regulation of autophagy in human gastric cells.

BACKGROUND: Autophagy plays an important role in carcinogenesis and tumor progression in many cancers, including gastric cancer. Cytotoxin-associated gene A (CagA) is a well-known virulent factor in Helicobacter pylori (H. pylori) infection that plays a critical role in gastric inflammation and gastric cancer development. However, its role in autophagy during these processes remains unclear. Therefore, we aimed to clarify the role of CagA in autophagy in CagA-related inflammation. METHODS: We evaluated the autophagic index of AGS cells infected with wild-type cagA-positive H. pylori (Hp-WT) and cagA-knockout H. pylori (Hp-ΔcagA) and rat gastric mucosal (RGM1) cells transfected with CagA genes. To identify the mechanisms underlying the down regulation of autophagy in AGS cells infected with H. pylori, we evaluated protein and mRNA expression levels of autophagy core proteins using western blotting and quantitative reverse transcription-polymerase chain reaction (RT-PCR). To determine whether autophagy induced the expression of the pro-inflammatory mediator, cyclooxygenase-2 (COX-2), we evaluated COX-2 expression in AGS cells treated with an autophagy inducer and inhibitor and infected with H. pylori. In addition, we evaluated whether COX-2 protein expression in AGS cells influenced beclin-1 (BECN1) expression with si-RNA transfection when infected with H. pylori. RESULTS: Autophagic flux assay using chloroquine showed that autophagy in AGS cells was significantly suppressed after H. pylori infection. The autophagic index of AGS cells infected with Hp-WT was decreased significantly when compared with that in AGS cells infected with Hp-ΔcagA. The autophagic index of RGM1 cells transfected with CagA was lower, suggesting that CagA inhibits autophagy. In addition, BECN1 expression levels in AGS cells infected with Hp-WT were reduced compared to those in AGS cells infected with Hp-ΔcagA. Furthermore, COX-2 expression in AGS cells infected with H. pylori was controlled in an autophagy-dependent manner. When AGS cells were transfected with small interfering RNA specific for BECN1 and infected with Hp-WT and Hp-ΔcagA, COX-2 was upregulated significantly in cells infected with Hp-ΔcagA. CONCLUSIONS: In conclusion, the H. pylori CagA protein negatively regulated autophagy by downregulating BECN1. CagA-induced autophagy inhibition may be a causative factor in promoting pro-inflammatory mediator production in human gastric epithelial cells.

Recent advances in immune checkpoint inhibitors in the treatment of urothelial carcinoma: A review.

Treatment options for urothelial carcinoma were limited until the emergence of immune checkpoint inhibitors, and even now, the prognosis of metastatic disease is poor compared with the other two major genitourinary cancers, renal cell carcinoma and prostate cancer. Despite the increasing use of immune checkpoint inhibitors in the sequential treatment of urothelial carcinoma, conflicting results from similar randomized clinical trials call into question the efficacy of this treatment. In addition, physicians must be aware of the clinical characteristics of immune checkpoint inhibitors, including immune-related adverse events, pseudo- and hyperprogression. This review summarizes the conflicting results of recent clinical trials and provides insights into the role of immune checkpoint inhibitors in the treatment of urothelial carcinoma.