Hiroaki Nishimatsu

Nomogram for predicting survival of postcystectomy recurrent urothelial carcinoma of the bladder

PURPOSE We aimed to identify prognostic clinicopathological factors and to create a nomogram able to predict overall survival (OS) in recurrent urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC). MATERIALS AND METHODS Among 1,087 patients with UCB who had undergone RC at our 11 institutions between 1990 and 2010, 306 patients who subsequently developed distant metastasis or local recurrence or both were identified. Clinical data were collected with medical record review. Univariate and multivariate Cox regression models addressed OS after recurrence. A nomogram predicting postrecurrence OS was constructed based on Cox proportional hazards model, without using postrecurrence factors (systemic chemotherapy and resection of metastasis). The performance of the nomogram was internally validated by assessing concordance index and calibration plots. RESULTS Of the 306 patients, 268 died during follow-up with a median survival of 7 months (95% CI: 5.8-8.5). Postrecurrence chemotherapy was administered in 119 patients (38.9%). Multivariable analysis identified 9 independent predictors for OS; period of time from RC to recurrence (time-to-recurrence), symptomatic recurrence, liver metastasis, hemoglobin level, serum alkaline phosphatase level, serum lactate dehydrogenase level, serum C-reactive protein level, postrecurrence chemotherapy, and resection of metastasis. A nomogram was formed with the following 5 variables to predict OS: time-to-recurrence, symptomatic recurrence, liver metastasis, albumin level, and alkaline phosphatase level. Concordance index rate was 0.75 (95% CI: 0.72-0.78) by internal validation using Bootstraps with 1,000 resamples. Calibration plots showed that the nomogram fitted well. CONCLUSIONS We identified 9 clinicopathological factors as independent OS predictors in postcystectomy recurrence of UCB. We also created a validated nomogram with 5 variables that efficiently stratified those patients regardless of eligibility for chemotherapy. The nomogram would be useful for acquiring relevant prognostic information and for stratifying patients for clinical trials.

Multiple primary malignant neoplasms of the glottis, renal pelvis, urinary bladder, oral floor, prostate, and esophagus in a Japanese male patient: a case report.

Owing to recent advances in diagnostic and surgical techniques for cancer, a patient diagnosed with two or more neoplasms is not rare. We report on the case of a 58-year-old male with multiple primary malignant neoplasms, who suffered from three histological types of malignant neoplasm in six organs, namely the glottis, renal pelvis, urinary bladder, oral floor, prostate, and esophagus in chronological order. The first neoplasm was a squamous cell carcinoma of the glottis diagnosed in 2006. The second and third neoplasms were urothelial carcinomas of the right renal pelvis and urinary bladder, respectively, diagnosed in 2008. The remaining three neoplasms were diagnosed in 2010, namely a squamous cell carcinoma of the oral floor, an adenocarcinoma of the prostate, and a squamous cell carcinoma of the esophagus. The glottic cancer and esophageal cancer were treated by external radiation therapy. The malignant neoplasms of the oral floor and those which originated in the urinary tract were surgically resected. All neoplasms except the malignant neoplasm of the oral floor were well controlled. The patient died of cervical lymph node metastasis from the squamous cell carcinoma of the oral floor in January 2011. As far as we know, the present report is the first one on this combination of primary malignant neoplasms.

Chronological changes in the epidemiological characteristics of upper urinary tract urolithiasis in Japan

To assess epidemiological and chronological trends of upper urinary tract stones in Japan in 2015.

Abstract 94: Genomic landscape and clonal expansions of upper urinary tract urothelial carcinoma

Backgrounds Upper urinary tract urothelial carcinoma (UUTUC) is a relatively rare and poor prognostic cancer which accounts for 5-10% of all urothelial malignancies. Despite the histological similarity, there are epidemiological and clinical differences between UUTUC and bladder urothelial carcinoma (BUC). Compared to BUC, the molecular pathogenesis of UUTUC is poorly understood. Urothelial carcinoma is also characterized by frequent multifocal lesions, suggesting field effects from mutagenic agents in urine and/or a dissemination from the primary tumor. To reveal the origin of the multifocality as well as the molecular pathogenesis of UUTUC, we performed comprehensive molecular analysis of UUTUC with regional multiple sampling. Materials & methods Surgical specimens of UUTUC and matched normal samples were obtained from 57 patients with various stages who underwent nephroureterectomy. Morphologically normal urothelial epithelia were also obtained in 5 cases, all of which were confirmed to be pathologically intact by an expert pathologist. Genomic DNA was extracted from each specimen and was subjected to whole exome sequencing using Hiseq 2500 for the detection of both somatic mutations and copy number lesions. Results In copy number analysis, recurrent deletions in 8p, 9p and 9q were identified, where homo deletions of 9p21.3 (CDKN2A) were most frequent (40.7%) Focal amplifications in 11q13.3 (CCND1) and 12q15 (MDM2) were also found. On average, 230 somatic nonsynonymous mutations per sample were detected. The mutation signature was biased to age-related and APOBEC patterns. Mutations were most frequently observed in KMT2D (42% of cases), followed by TP53 (32%), FGFR3 (24%), KDM6A (24%), EP300 (21%) and CREBBP (13%), which were also reported to be significantly mutated in BUC. However, the frequencies of these genetic lesions were substantially different between UUTUC and BUC. For example, abnormalities in RB1, CDKN1A and PIK3CA were not detected or rare in UUTUC but have been reported to be common targets of genetic lesions in BUC. In the analysis of normal epithelia, an average of 12.7 somatic mutations per sample were found but with low variant allele frequencies between 0.05−0.1. Somatic mutations in adjacent epithelia and preoperative urine were frequently shared by primary tumor, supporting a possibility of tumor disseminations from the original sites through urinary flow. In contrast, in other cases, distant epithelia harbored driver gene mutations that were not shared by the primary tumors, suggesting the presence of a mutagenic field effect on urothelial carcinogenesis. Conclusions Despite the similarity in their mutation spectrum, UUTUC and BUC seemed to have distinct pathogenesis in terms of the difference in mutation frequencies. Our data suggested that both dissemination and field effect might contribute to multifocal occurrence of UUTUC. These findings will provide a new insight into the pathophysiology of UUTUC. Citation Format: Yoichi Fujii, Yusuke Sato, Shigekatsu Maekawa, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Tohru Nakagawa, Haruki Kume, Hiroaki Nishimatsu, Yoshikazu Hirano, Masashi Sanada, Hideki Makishima, Satoru Miyano, Yukio Homma, Seishi Ogawa. Genomic landscape and clonal expansions of upper urinary tract urothelial carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 94.