Comparative Analyses Define Differences Between Bhd-Associated Renal Tumour and Sporadic Chromophobe Renal Cell Carcinoma

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. METHODS: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. FINDINGS: RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. INTERPRETATION: These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. FUNDING: This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research

Preparation for pyeloplasty for ureteropelvic junction obstruction using a patient-specific laparoscopic simulator: a case report

Abstract Introduction Training systems for laparoscopic surgery are useful for basic training but are not suitable for specific training corresponding to the condition of a given patient. We, therefore, have developed an unusual training system: a patient-specific simulator for laparoscopic surgery. When specific data of each individual patient are entered, this system helps surgeons perform a “rehearsal” operation. We applied this technique in laparoscopic surgery by using volume data obtained by multislice computed tomography imaging. Case presentation A 39-year-old Japanese woman consulted a doctor because of back pain and underwent pyeloplasty after an examination revealed a ureteropelvic junction obstruction. Computed tomography data showed that the network of arteries and veins was very complicated. Therefore, we decided to use our simulator before performing surgery. Simulation was helpful because we could obtain information about the complicated vessel network and “rehearse” the procedure. Conclusions Our simulator allows surgeons to perform a sham operation with different perspectives and tactile sensations and has received favorable reviews from users.</p

GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer

The precise molecular mechanisms responsible for resistance to cisplatin-based chemotherapy in patients with bladder cancer remain elusive, while we have indicated that androgen receptor (AR) activity in urothelial cancer is associated with its sensitivity. Our DNA microarray analysis in control vs. AR-knockdown bladder cancer sublines suggested that the expression of a GABA B receptor GABBR2 and AR was correlated. The present study aimed to determine the functional role of GABBR2 in modulating cisplatin sensitivity in bladder cancer. AR knockdown and dihydrotestosterone treatment considerably reduced and induced, respectively, GABBR2 expression, and the effect of dihydrotestosterone was at least partially restored by an antiandrogen hydroxyflutamide. A chromatin immunoprecipitation assay further revealed the binding of AR to the promoter region of GABBR2 in bladder cancer cells. Meanwhile, GABBR2 expression was significantly elevated in a cisplatin-resistant bladder cancer subline, compared with control cells. In AR-positive bladder cancer cells, knockdown of GABBR2 or treatment with a selective GABA B receptor antagonist, CGP46381, considerably enhanced the cytotoxic activity of cisplatin. However, no additional effect of CGP46381 on cisplatin-induced growth suppression was seen in GABBR2-knockdown cells. Moreover, in the absence of cisplatin, CGP46381 treatment and GABBR2 knockdown showed no significant changes in cell proliferation or migration. These findings suggest that GABBR2 represents a key downstream effector of AR signaling in inducing resistance to cisplatin treatment. Accordingly, inhibition of GABBR2 has the potential of being a means of chemosensitization, especially in patients with AR/GABBR2-positive bladder cancer

Urachal Carcinoma with Peritoneal Dissemination Treated with Chemotherapy and Surgical Resection Leading to Prolonged Survival with No Recurrence

A 56-year-old man was admitted to our hospital for urachal carcinoma with peritoneal dissemination. He received first-line chemotherapy with gemcitabine and cisplatin. After the fifth cycle, a computed tomography (CT) scan revealed abdominal fluid, and his serum tumor marker levels were increased. The patient was started on second-line therapy with FOLFIRI. After 11 cycles, his tumor decreased in size and no new metastatic lesions were detected. The patient underwent complete tumor resection with partial cystectomy and pelvic lymph node dissection. The tumor was removed, along with adhering surrounding organs, including the omentum, peritoneum, abdominal rectus muscle, and vermiform appendix. Although pathological examination confirmed peritoneal dissemination, his tumor markers normalized soon after surgery. The patient has survived 62 months after surgery without any adjuvant therapy and with no evidence of recurrence. To our knowledge, this is the longest duration of survival without recurrence of a patient with urachal carcinoma with peritoneal dissemination who received multimodal therapy

The Impact of Gleason Grade 3 as a Predictive Factor for Biochemical Recurrence after Robot-Assisted Radical Prostatectomy: A Retrospective Multicenter Cohort Study in Japan (The MSUG94 Group)

Background and Objectives: This study’s objective was to examine patients treated with robot-assisted radical prostatectomy (RARP) for intermediate-risk prostate cancer (IR-PCa), and to identify preoperative risk factors for biochemical recurrence (BCR) in these patients in Japan. Materials and Methods: We conducted a retrospective multicenter cohort study of patients with PCa who underwent RARP at 10 institutions in Japan. A total of 3195 patients were enrolled in this study. We focused on patients with IR-PCa who underwent RARP. We obtained data on pre- and postoperative covariates from the enrolled patients. Biochemical recurrence-free survival was the primary endpoint of this study. We also identified useful preoperative predictive factors for BCR in patients with IR-PCa after RARP. Results: A total of 1144 patients with IR-PCa were enrolled in this study. The median follow-up period was 23.7 months. At the end of the follow-up period, 94 (8.2%) patients developed BCR. The 2 and 3 year biochemical recurrence-free survival (BRFS) rates were 92.2% and 90.2%, respectively. Using the Kaplan–Meier method, Gleason grade (GG) 3 was significantly associated with poor BRFS compared with ≤GG 2. In multivariate analysis, GG 3 was a significant predictive factor for BCR in patients with IR-PCa. Conclusions: The results of the study indicated a significant relationship between GG 3 and post-RARP BCR in patients with IR-PCa

Pelvic Lymphadenectomy May Not Improve Biochemical Recurrence-Free Survival in Patients with Prostate Cancer Treated with Robot-Assisted Radical Prostatectomy in Japan (The MSUG94 Group)

In this multicenter retrospective cohort study, we aimed to evaluate whether pelvic lymph node dissection (PLND) improved biochemical recurrence (BCR) in patients with prostate cancer (PCa) who underwent robot-assisted radical prostatectomy (RARP) in Japan. A multicenter retrospective cohort study of 3195 PCa patients undergoing RARP at nine institutions in Japan was conducted. Enrolled patients were divided into two groups: those who underwent RARP without PLND (non-PLND group) and those who underwent PLND (PLND group). The primary endpoint was biochemical recurrence-free survival (BRFS) in PCa patients who underwent PLND. We developed a propensity score analysis to reduce the effects of selection bias and potential confounding factors. Propensity score matching resulted in 1210 patients being enrolled in the study. The 2-year BRFS rate was 95.0% for all patients, 95.8% for the non-PLND group, and 94.3% for the PLND group (p = 0.855). For the all-risk group according to the National Comprehensive Cancer Network risk stratification, there were no significant differences between patients who did and did not undergo PLND. Based on the results of the log-rank study, PLND may be unnecessary for patients with PCa undergoing RARP

A Nomogram for Predicting Prostate Cancer with Lymph Node Involvement in Robot-Assisted Radical Prostatectomy Era: A Retrospective Multicenter Cohort Study in Japan (The MSUG94 Group)

Background: To create a nomogram for predicting prostate cancer (PCa) with lymph node involvement (LNI) in the robot-assisted radical prostatectomy (RARP) era. Methods: A retrospective multicenter cohort study was conducted on 3195 patients with PCa who underwent RARP at nine institutions in Japan between September 2012 and August 2021. A multivariable logistic regression model was used to identify factors strongly associated with LNI. The Bootstrap-area under the curve (AUC) was calculated to assess the internal validity of the prediction model. Results: A total of 1855 patients were enrolled in this study. Overall, 93 patients (5.0%) had LNI. On multivariable analyses, initial prostate-specific antigen, number of cancer-positive and-negative biopsy cores, biopsy Gleason grade, and clinical T stage were independent predictors of PCa with LNI. The nomogram predicting PCa with LNI has been demonstrated (AUC 84%). Using a nomogram cut-off of 6%, 492 of 1855 patients (26.5%) would avoid unnecessary pelvic lymph node dissection, and PCa with LNI would be missed in two patients (0.1%). The sensitivity, specificity, and negative predictive values associated with a cutoff of 6% were 74%, 80%, and 99.6%, respectively. Conclusions: We developed a clinically applicable nomogram for predicting the probability of patients with PCa with LNI