Cross-sectional and longitudinal analyses of urinary extracellular vesicle mRNA markers in urothelial bladder cancer patients.

We designed this multi-center prospective study with the following objectives: (1) the cross-sectional validation of extracellular vesicles (EV) mRNA markers to detect urothelial bladder cancer (UBC) before transurethral resection of bladder cancer (TURBT), and (2) the longitudinal validation of EV mRNA markers to monitor non-muscle invasive bladder cancer (NMIBC) recurrence after TURBT. EV mRNA markers evaluated in this study were KRT17, GPRC5A, and SLC2A1 in addition to two additional markers from literatures, MDK and CXCR2, and measured by quantitative RT-PCR with normalization by a reference gene (ALDOB). Diagnostic performances of EV mRNA markers were compared to conventional markers. Regarding the first objective, we confirmed that EV mRNA biomarkers in urine were higher in UBC patients, particularly those with higher stage/grade tumors, than in those without UBC (n = 278 in total) and the diagnostic performance of EV mRNA MDK and KRT17 outperformed conventional biomarkers with AUC 0.760 and 0.730, respectively. Concerning the second objective, we prospectively analyzed the time courses of EV mRNA markers while NMIBC patients (n = 189) (median follow-up 19 months). The expression of EV mRNA KRT17 was significantly high in patients with recurrence, while it gradually decreased over time in those without recurrence (p < 0.01).

Validation of the Japanese version of the Body Image Scale for bladder cancer patients.

The Body Image Scale (BIS) is a 10-item tool that measures the body images of cancer patients. This study aims to validate the Japanese version of the BIS for bladder cancer patients. A multicenter cross-sectional survey was used to identify the participants, which included Japanese bladder cancer patients. The percentage of missing responses, internal consistency, and known-group validity were evaluated. The correlations between the BIS and two HRQOL instruments (the Bladder Cancer Index and the SF-12) were assessed to determine convergent validity. Among 397 patients, 221 patients were treated by transurethral resection of bladder tumor (TURBT) endoscopically, 49 patients underwent cystectomy with neobladder, and 127 patients underwent cystectomy involving stoma. The percentage of missing responses in the BIS ranged from 8.1 to 15.6%. Cronbach's α coefficient was 0.924. Higher BIS scores indicate negative body image, and the median BIS score for patients with native bladders after TURBT (0.5) was significantly lower than those of the patients with neobladder (4.0) and stoma formation (7.0), which indicated the discriminatory ability of the BIS. Each domain of the Bladder Cancer Index and the role summary score of the SF-12 correlated to the BIS scores, which confirmed the convergent validity. A range of BIS scores were identified among patients who reported similar physical summary scores and mental summary scores of the SF-12. This study confirmed the reliability and validity of the Japanese version of the BIS for bladder cancer patients.

Efficacy of nivolumab plus ipilimumab as first-line therapy for primary tumors in patients with renal cell carcinoma.

OBJECTIVES: With the emergence of several effective combination therapies, information on their effects at the primary site will be crucial for planning future cytoreductive nephrectomy (CN). The present study focused exclusively on changes in primary tumor sizes following treatment with nivolumab plus ipilimumab and investigated the clinical factors associated with a good response in primary tumors. METHODS AND MATERIALS: We retrospectively assessed 27 patients diagnosed with advanced renal cell carcinoma (RCC) who started treatment with nivolumab plus ipilimumab. Changes in tumor sizes at the primary site were described using waterfall and spider plots, respectively. We analyzed the correlation of tumor shrinkage between primary and metastatic site. The parameters analyzed between responders and non-responders according to primary tumor sizes were International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, peripheral blood markers, and CRP. RESULTS: The median age and follow-up period were 66 years and 9.3 months, respectively. The median IMDC risk score was 3 (range: 1-6). Nineteen patients were diagnosed with clear-cell RCC (ccRCC) and 8 patients with non-ccRCC. Among ccRCC patients, 9 (47.4%) achieved a significant response with a maximum reduction of 30% or more in the size of the primary tumor from baseline within 4 months, while 3 (37.5%) out of 8 patients with non-ccRCC achieved a significant response. Shrinkage of the primary tumor correlated with the metastatic tumors in both ccRCC and non-ccRCC cases. Of note, 6 patients underwent CN and no viable tumor cells were detected in the surgical specimens of 3 patients whose primary tumors shrank by approximately 50%-60% with a reduction to 4 cm or less. Among ccRCC patients, the neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio were slightly lower in responders than in non-responders (P = 0.0944 and P = 0.0691). The platelet-to-lymphocyte ratio was significantly lower in responders than in non-responder (P = 0.0391). CONCLUSIONS: Significant responses in primary tumors to nivolumab plus ipilimumab were observed in 50% of ccRCC patients, while responses varied among non-ccRCC patients. Inflammation markers may be predictive factors of treatment responses in primary tumors. Although further studies are needed, the present results suggest the importance of considering CN from radiological and pathological viewpoints.

Health-related quality of life in Japanese patients with bladder cancer measured by a newly developed Japanese version of the Bladder Cancer Index.

INTRODUCTION: We validated a Japanese version of the Bladder Cancer Index (BCI) as a tool for measuring health-related quality of life (HRQOL) in bladder cancer patients treated with various surgical procedures. METHODS: The reliability and validity of the Japanese BCI were examined in 397 Japanese patients with bladder cancer via cross-sectional analysis. The patients simultaneously completed the Short Form (SF)-12, EQ-5D, and the Functional Assessment of Cancer Therapy-General and Bladder (FACT-G and FACT-BL). The differences in BCI subscales among various treatment groups were analyzed. RESULTS: This study involved 397 patients (301 males and 96 females), with a mean age of 70 years and a median disease duration of 29 months (IQR: 12-66 months). Of these patients, 221 underwent transurethral resection of a bladder tumor, and 176 patients underwent radical cystectomy (ileal conduit: 101 patients, ileal neobladder: 49, and ureterostomy: 26). Cronbach's alpha coefficient was ≥ 0.78 for all subscales, except the bowel bother subscale. Despite moderate correlations being detected between the function and bother score in urinary and bowel domains, the sexual function score was inversely correlated with the sexual bother score (r = - 0.19). A missing value percentage of > 15% was associated with old age (p < 0.05). The mean domain scores differed significantly among distinct clinically relevant treatment groups. CONCLUSIONS: Although revisions are needed to make it easier for elderly patients to comprehend, we confirmed the reliability and validity of the Japanese BCI. The Japanese BCI could be used for cross-cultural assessments of HRQOL in bladder cancer patients.

Chemotherapy-Induced IL8 Upregulates MDR1/ABCB1 in Tumor Blood Vessels and Results in Unfavorable Outcome.

Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues (n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo, the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance. SIGNIFICANCE: These findings show that inhibition of ABCB1 in tumor endothelial cells may improve clinical outcome, where ABCB1 expression contributes to drug resistance and metastasis following first-line chemotherapy.

Oncological outcomes of a multicenter cohort treated with axitinib for metastatic renal cell carcinoma.

The present study aimed to evaluate the efficacy of the real-world use of axitinib and to develop a prognostic model for stratifying patients who could derive long-term benefit from axitinib. This was a retrospective, descriptive study evaluating the efficacy of axitinib in patients with metastatic renal cell carcinoma that had been treated with 1 or 2 systemic antiangiogenic therapy regimens at 1 of 36 hospitals belonging to the Japan Urologic Oncology Group between January 2012 and February 2019. The primary outcome was overall survival (OS). Using a split-sample method, candidate variables that exhibited significant relationships with OS were chosen to create a model. The new model was validated using the rest of the cohort. In total, 485 patients were enrolled. The median OS was 34 months in the entire study population, whereas it was not reached, 27 months, and 14 months in the favorable, intermediate, and poor risk groups, respectively, according to the new risk classification model. The following 4 variables were included in the final risk model: the disease stage at diagnosis, number of metastatic sites at the start of axitinib therapy, serum albumin level, and neutrophil : lymphocyte ratio. The adjusted area under the curve values of the new model at 12, 36, and 60 months were 0.77, 0.82, and 0.82, respectively. The efficacy of axitinib in routine practice is comparable or even superior to that reported previously. The patients in the new model's favorable risk group might derive a long-term survival benefit from axitinib treatment.

'Trifecta' outcomes of robot-assisted partial nephrectomy: a large Japanese multicenter study.

OBJECTIVE: The objective of this study was to evaluate the early surgical outcomes of robot-assisted partial nephrectomy (RAPN) for small renal masses in a large Japanese multicenter series. METHODS: A total of 804 consecutive cases of RAPN were examined at 42 institutes between 2011 and 2016. Medical records for clinical, pathological characteristics and perioperative outcomes were retrospectively reviewed. Univariable and multivariable analyses were performed to determine factors predicting Trifecta achievement. RESULTS: The median tumor size was 2.6 cm. The median RENAL score was 7. The median warm ischemia time was 21 min. The median estimated blood loss was 30 mL. Eight patients (1.0%) were converted to radical nephrectomy. The overall and Clavien-Dindo grade ≥ 3 complication rates were 13.0% and 5.8%, respectively. Pathologically, 91.4% of tumors were malignant and the positive surgical margin (PSM) rate was 1.1%. During the median 27.1-month observation period, the recurrence rate was 1.6%. Postoperative preservation rates of eGFR at 1, 6, 12 and 24 months were 90.3, 89.8, 89.4 and 89.2%, respectively. Trifecta was achieved in 62.1%. Multivariable analysis demonstrated that tumor diameter, estimated blood loss and hilar location of the tumor were significant negative factors predicting Trifecta achievement. The rate of Trifecta achievement for T1b tumors and hilar tumors was significantly lower (48.4% and 50.0%, respectively). CONCLUSIONS: RAPN was safely performed with acceptable oncological and functional outcomes, but the rate of Trifecta accomplishment for T1b or hilar tumors was significantly lower than that for T1a or non-hilar tumors, respectively.

Impact of Surgeon and Hospital Volume on the Safety of Robot-Assisted Radical Prostatectomy: A Multi-Institutional Study Based on a National Database.

INTRODUCTION: We aimed to perform a multi-institutional study using a national database led by the Japanese Society of Endourology to investigate the effect of surgeon or hospital volume on the safety of robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: Clinical data of 3,214 patients who underwent RARP for the treatment of clinically localized prostate cancer between April 2012 and March 2013 in Japan were evaluated. Surgical outcomes and all intra- and perioperative complications were collected. RESULTS: The intraoperative complication rate was 0.56%. In a total number of 241 patients, 261 perioperative complications were observed. The following percentages of patients presented the Clavien-graded complications: 7.2%, grades 1-2; 0.84%, grade 3; and 0.093%, grade 4a. No cases of multiple organ dysfunction or death (grades 4b and 5) were found. Multivariable logistic regression analysis showed that the hospital volume (OR 3.6; p = 0.010) for intraoperative complications and surgeon volume (OR 0.19; p < 0.0001) and extended lymph node discectomy (OR 3.9; p < 0.0001) for perioperative complications were significant independent risk factors. CONCLUSIONS: Hospital volume for intraoperative complications and surgeon volume and extended lymph node dissection for perioperative complications were significantly associated with increased risk of each complication in RARP.

Reality of nerve sparing and surgical margins in surgeons' early experience with robot-assisted radical prostatectomy in Japan.

OBJECTIVE: To analyze nerve sparing performance at an early stage of robot-assisted radical prostatectomy, and the correlation between the surgeons' experience and the risk of a positive surgical margin in patients treated with robot-assisted radical prostatectomy. METHODS: Patients' records from January 2009 to March 2013 were retrospectively reviewed, and 3469 patients with localized prostate cancer were identified at 45 institutions. Individual surgeon's experience with nerve sparing was recorded as the number of nerve sparing cases among total robot-assisted radical prostatectomies beginning with the first case during which nerve sparing was carried out. Patients were selected by propensity score matching for nerve sparing, and predictive factors of positive surgical margins were analyzed in patients with and without positive surgical margins. RESULTS: A total of 152 surgeons were studied, and the median number of robot-assisted radical prostatectomy cases for all surgeons was 21 (range 1-511). In all, 54 surgeons (35.5%) undertook nerve sparing during their first robot-assisted radical prostatectomy case. For 2388 patients selected with (1194) and without (1194) nerve sparing, predictive factors for positive surgical margin were high initial prostate-specific antigen level (P < 0.0001), high biopsy Gleason score (P = 0.0379), presence of neoadjuvant hormone therapy (P = 0.0002) and surgeon's experience with >100 cases (P = 0.0058). Thus, nerve sparing was not associated with positive surgical margins. CONCLUSION: The surgeon's experience influences the occurrence of positive surgical margins, although a considerable number of surgeons carried out nerve sparing during their early robot-assisted radical prostatectomy cases. Surgeons should consider their own experience and prostate cancer characteristics before carrying out a nerve sparing robot-assisted radical prostatectomy.

Is Memorial Sloan-Kettering Cancer Center risk classification appropriate for Japanese patients with metastatic renal cell carcinoma in the cytokine era?

OBJECTIVES: We investigated the prognosis of Japanese patients with metastatic renal cell carcinoma (RCC), and analyzed the validity of Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification. MATERIALS AND METHODS: The endpoint of the present study was overall survival. Relationships between overall survival and potential prognostic factors were assessed using the Cox proportional hazard model with a step-wise procedure. Prognostic assessment was also performed according to the MSKCC risk classification. The predictive accuracy of the MSKCC risk classification was measured employing the concordance index. RESULTS: The median survival for all patients was 22 months (95% CI, 19-28 months). The eight factors were identified as independent prognostic factor; time from initial diagnosis to metastasis, low hemoglobin (Hb), lactate dehydrogenase (LDH), corrected serum calcium (cCa), C-reactive protein (CRP), and the presence or absence of liver metastasis, bone metastasis, and lymph node metastasis. When the MSKCC risk classification was applied to patients, the median overall survival was not reached and 26 and 10 months in the patients classified as favorable, intermediate, and poor risk, respectively. The c-index was 0.73. CONCLUSIONS: The prognosis of Japanese metastatic renal cell carcinoma patients may be better than that of previous studies from North America or Europe. Although there are some differences in the rate of patients in the risk groups and survival time by risk group between these patients, the MSKCC risk classification may be applicable for Japanese patients with metastatic renal cell carcinoma.

Lymphoepithelioma-like carcinoma of the renal pelvis.

Lymphoepithelioma-like carcinoma (LELC), best known to occur in the nasopharynx, can arise in a variety of sites, such as the salivary gland, thymus, lung, stomach, skin and uroepithelium. Primary LELC of the uroepithelium is very rare and there is only limited information in the published reports. We managed a case of a 75-year-old woman who presented with nausea and gross painless hematuria. She was treated with laparoscopic nephroureterectomy and was diagnosed with a T1N1M0 LELC of the renal pelvis. Unlike nasopharyngeal lymphoepithelioma, immunohistochemical analysis of this urinary LELC was negative for the Epstein-Barr virus. Herein we report on one more case of primary LELC of the renal pelvis and review of the published reports, particularly those concerning Epstein-Barr virus expressions. Recognition of this tumor and complete resection are essential for saving patients.

Adult paratesticular rhabdomyosarcoma.

BACKGROUND: A 29-year-old male patient presented with a history of painless enlargement of the left hemiscrotum. INVESTIGATIONS: Laboratory tests for beta-human chorionic gonadotrophin, alpha-fetoprotein, and lactate dehydrogenase, physical examination, and CT of the chest, abdomen and pelvis. Histologic examination, nerve-sparing retroperitoneal lymph-node dissection. DIAGNOSIS: Paratesticular rhabdomyosarcoma with lymph node metastasis. MANAGEMENT: Inguinal radical orchiectomy and adjuvant chemotherapy for 48 weeks. Radiotherapy and additional chemotherapy were administered following local recurrence.

[Serous papillary adenocarcinoma of the tunica vaginalis of the testis: a case report].

A 20-year-old man was referred to our hospital for investigation of left scrotal swelling. CT scan showed intrascrotal fluid collection and calcification. Surgical exploration was performed, and histopathological diagnosis was serous papillary adenocarcinoma of the tunica vaginalis. Since it was believed that the carcinoma originated from the tunica vaginalis, left radical orchiectomy and hemiscrotal resection was performed. Patient survives without recurrence for 38 months after the surgery. Müllerian-type tumors such as serous papillary adenocarcinoma occurring in male are quite rare. In the literature, only 2 cases of serous papillary adenocarcinoma of the tunica vaginalis have been reported; ours is the 3rd case.