Focal low-dose-rate prostate brachytherapy for low- and intermediate-risk prostate cancer.

PURPOSE: To prospectively investigate the efficacy and feasibility of focal low-dose-rate (LDR) prostate brachytherapy for low- and intermediate-risk prostate cancer. MATERIAL AND METHODS: Between October 2014 and May 2019, nineteen low- and intermediate-risk prostate cancer patients who presented with abnormality on both diffusion-weighted and T2-weighted magnetic resonance imaging (MRI) underwent focal LDR brachytherapy at our institution. Focal gross tumor volume (F-GTV) was delineated on transrectal ultrasound, based on abnormality seen on fused T2-weighted MRI. F-GTV was expanded by 5 mm, as a safety margin, to create focal clinical target volume (F-CTV). Prescribed dose to F-CTV was 145 Gy. Biochemical recurrence (BCR) was determined using Phoenix criterion (prostate specific antigen nadir + 2 ng/ml). Pre- and post-implant dosimetry data were compared using non-parametric Wilcoxon's rank sum test. Treatment-related toxicities were evaluated using common terminology criteria for adverse events. RESULTS: Mean F-CTV D90% was significantly lower in the post-implant evaluation than in intraoperative planning (p = 0.004). On post-implant dosimetry, the mean D90% for F-GTV and mean V100% for the entire prostate were 222 Gy and 35%, respectively. Median follow-up time for all patients was 31 months. BCR occurred in one patient after 23 months. Kaplan-Meier 2-year BCR-free rate was 92.9% (95% confidence interval [CI]: 79.4-100%). No patients had grade 1 or greater gastrointestinal toxicity. Three patients who were taking α-blockers to treat benign prostatic hyperplasia (present before brachytherapy), experienced no treatment-related genitourinary toxicities. Two patients suffered from temporary grade 2 urinary frequency. None of the remaining patients experienced grade 2 or higher genitourinary toxicity. CONCLUSIONS: Focal LDR prostate brachytherapy appears acceptable for MRI-based index tumors, with a low cumulative incidence of BCR. Such brachytherapy might offer a feasible minimally invasive therapeutic option for localized prostate cancer.

Port site hernia at the robotic arm port after robotic-assisted laparoscopic radical prostatectomy.

INTRODUCTION: Complications unique to laparoscopic surgery have been reported, including port site hernia. We experienced a case of port site hernia in the robotic right-hand port site measuring 8 mm in diameter after robotic-assisted laparoscopic radical prostatectomy. CASE PRESENTATION: A 56-year-old man was indicated a high prostate-specific antigen level of 37.8 ng/ml. Subsequent prostate biopsy revealed adenocarcinoma with a Gleason score of 4 + 4. The patient underwent robotic-assisted laparoscopic radical prostatectomy in Juntendo Hospital. Although his postoperative recovery was generally good, the patient complained of sudden nausea and acute abdominal pain. A contrast computed tomography scan showed an ileus due to a hernia occurring at the robotic right-hand port, the da Vinci Arm I port. We released incarceration under laparoscopic procedure. CONCLUSION: Since the port diameter is relatively small in robot-assisted surgery, port site hernias are expected to be rare. However, careful attention should be paid to the positional deviation of the remote center.

Factors contributing to the ceiling effect of the EQ-5D-5L: an analysis of patients with prostate cancer judged "no-problems".

PURPOSE: The goal of the present study was to determine factors related to a ceiling effect (CE) on the EQ-5D-5L among Japanese patients with prostate cancer (PC). METHODS: An existent cross-sectional observational study dataset was used. Patients were ≥ 20 years of age and diagnosed with PC. For CE determinants on the EQ-5D-5L, we excluded possible "full-health" patients flagged by the EQ-VAS (score = 100) and/or FACT-P (score = 156) instruments. We then divided them into binary variables: A CE group (EQ-5D-5L score = 1) and others (< 1). The associations between CE, sociodemographic and medical characteristics, and FACT-P subscale scores were examined using a multivariate LASSO selection followed by a binomial logistic regression analysis performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 362 patients were analyzed. The LASSO selection variables, including all obtained variables, were as follows: age, palliative treatment, FACT-P physical well-being, and PC subscale score. Statistically significant variables predicting CE were palliative treatment (OR 0.23; 95% CI 0.09-0.60), physical well-being (OR 1.54; 95% CI 1.34-1.76), and PC subscale (OR 1.08; 95% CI 1.03-1.14). CONCLUSIONS: This study revealed that palliative treatment and two FACT-P physical well-being and PC subscale scores were positively related to CE on the EQ-5D-5L. To our knowledge, this is the first study to examine predictors of CE on the EQ-5D-5L. The present results may be helpful for facilitating the consideration of "bolt-on" studies from the standpoint of PC patients.

Movement of target organs and anatomical landmarks caused by body position change during urological laparoscopic surgery.

INTRODUCTION: The aim of our study was to elucidate the impact of patients' physical characteristics on the movement of target organs and anatomical landmarks by comparing supine and lateral CT images. METHODS: This study consisted of 55 patients who underwent laparoscopic surgery in the lateral position. CT images of the area between the abdomen and pelvis were taken preoperatively with patients in both supine and lateral positions. We measured the moving distance of target organs and anatomical landmarks on the body surface used for access port settings. We investigated which covariates from patients' body composition most affected moving distance in correlation analysis. Then, using multiple linear regression analysis, we examined whether we could predict the movement of target organs and anatomical landmarks solely based on information obtained from supine CT images. RESULTS: The moving distance of both the hilum of the kidney and the outer edge of the rectus abdominis muscle were significantly associated with some physical characteristics. Multiple regression analysis showed that a larger visceral fat area could be a useful index for predicting the movement of the kidney toward the counter side. Lower CT density of back muscles and higher BMI could be useful indexes for predicting the movement of the rectus abdominis muscle. CONCLUSION: Our results suggested that body composition characteristics obtained from preoperative CT images can help predict the movement of target organs and anatomical landmarks used to determine proper port-site placement for laparoscopic surgery performed with the patient in the lateral position.

Nivolumab plus ipilimumab versus sunitinib in previously untreated advanced renal-cell carcinoma: analysis of Japanese patients in CheckMate 214 with extended follow-up.

BACKGROUND: Nivolumab plus ipilimumab (NIVO+IPI) demonstrated superior efficacy over sunitinib (SUN) for previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 214, with a manageable safety profile. We report efficacy and safety with extended follow-up amongst Japanese patients. METHODS: CheckMate 214 patients received NIVO (3 mg/kg) plus IPI (1 mg/kg) every 3 weeks for four doses, then NIVO (3 mg/kg) every 2 weeks; or SUN (50 mg) once daily for 4 weeks (6-week cycle). This subgroup analysis assessed overall survival (OS), objective response rate (ORR) and progression-free survival (PFS) per investigator in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate/poor-risk and intent-to-treat (ITT) patients and safety (ITT patients). RESULTS: Of 550 and 546 patients randomized to NIVO+IPI and SUN, 38 and 34, respectively, were Japanese. Of these, 31 (NIVO+IPI) and 29 (SUN) patients were IMDC intermediate/poor-risk. In IMDC intermediate/poor-risk patients with 30 months' minimum follow-up, there was a delayed trend in OS benefit with NIVO+IPI (hazard ratio [HR] 0.56; 95% confidence interval [CI]: 0.19-1.59; P = 0.2670), and 24-month OS probability favoured NIVO+IPI (84%) versus SUN (76%). The ORR was 39% with NIVO+IPI and 31% with SUN (P = 0.6968). PFS was similar in both treatment arms (HR 1.17; 95% CI: 0.62-2.20; P = 0.6220). Efficacy in ITT patients was similar to IMDC intermediate/poor-risk patients. Grade 3-4 treatment-related adverse event incidence was lower with NIVO+IPI versus SUN (58 versus 91%). CONCLUSIONS: Japanese patients with untreated aRCC in the NIVO+IPI arm had a numerically higher ORR and improved safety profile versus patients in the SUN arm. A delayed OS benefit appears to be emerging with NIVO+IPI. Longer follow-up is needed. https://clinicaltrials.gov/ct2/show/NCT02231749?term=NCT02231749&rank=1 identifier: NCT02231749.

Significant association between urethral length measured by magnetic resonance imaging and urinary continence recovery after robot-assisted radical prostatectomy.

INTRODUCTION: To determine the clinical predictive factors affecting the recovery from postoperative urinary incontinence after robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: We consecutively analyzed 320 patients who underwent RARP between January 2012 and March 2015. The restoration of urinary continence was defined as follows: the use of no pads/no leakage of urine or the use of a safety pad. Preoperative covariates were statistically assessed by multivariate logistic regression analysis to investigate their predict factor to recovery of urinary incontinence. Therefore, in this study, we sought to identify predictors of early urinary continence status in a single-center retrospective study of consecutive patients who underwent RARP. RESULTS: Continence rates at 1, 3, 6, and 12 months after the catheter was removed were 44%, 71%, 83%, and 93%, respectively. Age, body mass index, and prostate volume had no significant association with urinary continence recovery. In contrast to this, longer preoperative membranous urethral length (MUL) was significantly associated with earlier postoperative continence recovery. Multivariate analysis demonstrated that longer preoperative MUL is significantly associated with continence recovery at 1 month (P = 0.0235). CONCLUSION: Approximately 70% of patients achieved urinary continence within 3 months after RARP. Multivariate analysis showed that age, body mass index, and prostate volume had no significant association with urinary continence recovery. Preoperative MUL assessed by magnetic resonance imaging was an independent predictor of early recovery from urinary incontinence after RARP.

Three-year follow-up of a phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer and bone metastases.

BACKGROUND: Radium-223 is a first-in-class targeted alpha therapy to prolong overall survival (OS) in castration-resistant prostate cancer with bone metastases (mCRPC). The aim of the present analysis was to assess the long-term safety with radium-223 in Japanese patients with mCRPC. METHODS: Patients with symptomatic mCRPC, ≥ 2 bone metastases and no known visceral metastases received up to 6 injections of radium-223 (55 kBq/kg), one every 4 weeks. Adverse events (AEs) considered to be related to radium-223 were reported until 3 years after the first injection. Pre-specified conditions, such as acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer, or other primary malignancies, were reported regardless of causality. RESULTS: Of the 49 patients enrolled in the study, 44 (89.8%) entered the survival follow-up period and 33 (67.3%) died. Throughout the entire study, there were no reports of second primary malignancy or other pre-specified conditions. Eight patients (16.3%) experienced post-treatment drug-related AEs, which were all hematological (anemia and decreased lymphocyte, platelet, and white blood cell counts). No serious post-treatment drug-related AEs were reported. Updated median OS was 19.3 months (95% CI: 14.2, 28.5). CONCLUSIONS: In Japanese patients with symptomatic mCRPC and bone metastases, radium-223 had a favorable long-term safety profile with no second primary malignancies reported. Taken together with median OS, which was comparable to that in the pivotal phase III ALSYMPCA study, these results support continued benefit from radium-223 in Japanese patients with mCRPC.

Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer.

BACKGROUND: Radium-223 dichloride (radium-223) is the first targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with bone metastases. This study investigated the efficacy and safety of radium-223 in Japanese patients with symptomatic CRPC and bone metastases. METHODS: In this open-label, multicenter, phase II study, patients with progressive, symptomatic CRPC and bone metastases were treated with radium-223 (55 kBq/kg, intravenously) in a 4-week cycle for six cycles. The primary endpoint was the percent change in total alkaline phosphatase (ALP) from baseline at 12 weeks. Secondary endpoints included the percent ALP change from baseline to end of treatment (EOT), ALP response rates, percent change in prostate-specific antigen (PSA) from baseline to 12 weeks and EOT, PSA response rates, overall survival (OS), and time to symptomatic skeletal events (SSEs). Adverse events were monitored throughout the study period. RESULTS: Of the 49 Japanese patients (median age 74 years), 28 completed all infusions. Mean percent change in total ALP and PSA from baseline to 12 weeks was -19.3 and +97.4%, respectively. One-year OS and SSE-free rate at the end of active follow-up were 78 and 89%, respectively. The ALP response rate was 31%, while the PSA response rate was 6%. Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients included decreased lymphocyte count (14%), anemia (14%), anorexia (10%), and bone pain (10%). CONCLUSIONS: Radium-223 is effective and well tolerated in Japanese patients with CRPC and bone metastases. Results were comparable with the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01929655.

Automated renal cortical volume measurement for assessment of renal function in patients undergoing radical nephrectomy.

BACKGROUND: Renal volume change greatly affects renal function after nephrectomy. Although various measuring techniques were reported, no standard measuring method is available. In this study, we examined the computational automated volumetric method, and evaluated the volumetric change to assess the functional outcome in patients undergoing radical nephrectomy. We developed the predictive equation for postoperative renal function from volume alternation and validated the performance. METHODS: Thirty-two patients undergoing radical nephrectomy participated in this study. Renal volume was calculated using three different methods [ellipsoid method, conventional manual voxel count method for renal parenchyma (manual RPV), and automated voxel count method for renal cortex (automated RCV)] through newly developed imaging software. Statistical analysis was performed to evaluate the correlation between renal functional alternation 7 days after the nephrectomy and renal volumetric change. A simple predictive equation for the postoperative renal function by renal volume loss was developed and externally validated through another 12 cases. RESULTS: The automated RCV method had the strongest correlation between renal function alternation and RCV change (R = 0.82), than manual RPV (R = 0.69) and ellipsoid method (R = 0.50). Subsequently, a simple equation for postoperative renal function by renal volume alternation was developed: predicted postoperative estimated glomerular filtration rate (eGFR) from renal volume change = preoperative eGFR × (postoperative renal volume / preoperative renal volume). In the external validation cohort, automated RCV demonstrated the predictive performance of the constructed equations for renal function (R = 0.77). CONCLUSIONS: The computational automated RCV measurements is a simple estimation of renal functional outcome for patients undergoing radical nephrectomy.

Development and Validation of a Novel Recurrence Risk Stratification for Initial Non-muscle Invasive Bladder Cancer in Asia.

BACKGROUND: Some risk classifications to determine prognosis of patients with non-muscle invasive bladder cancer (NMIBC) have disadvantages in the clinical setting. We investigated whether the EORTC (European Organization for Research and Treatment of Cancer) risk stratification is useful to predict recurrence and progression in Japanese patients with NMIBC. In addition, we developed and validated a novel, and simple risk classification of recurrence. METHODS: The analysis was based on 1085 patients with NMIBC at six hospitals. Excluding recurrent cases, we included 856 patients with initial NMIBC for the analysis. The Kaplan-Meier method with the log-rank test were used to calculate recurrence-free survival (RFS) rate and progression-free survival (PFS) rate according to the EORTC risk classifications. We developed a novel risk classification system for recurrence in NMIBC patients using the independent recurrence prognostic factors based on Cox proportional hazards regression analysis. External validation was done on an external data set of 641 patients from Kyorin University Hospital. FINDINGS: There were no significant differences in RFS and PFS rates between the groups according to EORTC risk classification. We constructed a novel risk model predicting recurrence that classified patients into three groups using four independent prognostic factors to predict tumour recurrence based on Cox proportional hazards regression analysis. According to the novel recurrence risk classification, there was a significant difference in 5-year RFS rate between the low (68.4%), intermediate (45.8%) and high (33.7%) risk groups (P<0.001). INTERPRETATION: As the EORTC risk group stratification may not be applicable to Asian patients with NMIBC, our novel classification model can be a simple and useful prognostic tool to stratify recurrence risk in patients with NMIBC. FUNDING: None.

Focal partial salvage low-dose-rate brachytherapy for local recurrent prostate cancer after permanent prostate brachytherapy with a review of the literature.

PURPOSE: To investigate the treatment results for focal partial salvage re-implantation against local recurrence after permanent prostate brachytherapy. MATERIAL AND METHODS: Between January 2010 and September 2015, 12 patients were treated with focal partial salvage re-implantation for local recurrence after low-dose-rate brachytherapy using (125)I seeds. The focal clinical target volume (F-CTV) was delineated on positive biopsy areas in a mapping biopsy, combining the cold spots on the post-implant dosimetry for initial brachytherapy. The F-CTV was expanded by 3 mm to create the planning target volume (PTV) as a margin to compensate for uncertainties in image registration and treatment delivery. The prescribed dose to the PTV was 145 Gy. The characteristics and biochemical disease-free survival (BdFS) rates were analyzed. Genitourinary (GU) and gastrointestinal (GI) toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4. RESULTS: The median prostate-specific antigen (PSA) level at re-implantation was 4.09 ng/ml (range: 2.91-8.24 ng/ml). The median follow-up time was 56 months (range: 6-74 months). The median RD2cc and UD10 were 63 Gy and 159 Gy, respectively. The 4-year BdFS rate was 78%, which included non-responders. Biochemical recurrence occurred in two patients after 7 and 31 months, respectively. The former was treated with hormonal therapy after biochemical failure, and the latter underwent watchful waiting (PSA at the last follow-up of 53 months: 7.3 ng/ml) at the patient's request. No patients had grade 3 GU/GI toxicities or died after salvage re-implantation. CONCLUSIONS: The partial salvage low-dose-rate brachytherapy used to treat local recurrence after permanent prostate brachytherapy is well-tolerated, with high biochemical response rates. This treatment can be not only a method to delay chemical castration but also a curative treatment option in cases of local recurrence of prostate carcinoma after seed implantation.

Effect of a urinary catheter on seed position and rectal and bladder doses in CT-based post-implant dosimetry for prostate cancer brachytherapy.

PURPOSE: To assess the variability in rectal and bladder dosimetric parameters determined according to post-implant computed tomography (CT) images in patients with or without a urethral catheter. MATERIAL AND METHODS: Patients with prostate cancer who were scheduled to undergo CT after brachytherapy between October 2012 and January 2014 were included. We obtained CT series with and without a urinary catheter in each patient. We compared the rectal and bladder doses in 18 patients on each CT series. RESULTS: The shifts in the seed positions between with and without a catheter in place were 1.3 ± 0.3 mm (mean ± standard deviation). The radiation doses to the rectum, as determined on the CT series, with a urethral catheter were higher than those on CT without a catheter (p < 0.001). Radiation doses to the bladder with a catheter were significantly lower than those without a catheter (p = 0.027). CONCLUSIONS: Post-implant dosimetry (PID) with no catheter showed significantly lower rectal doses and higher bladder doses than those of PID with a catheter. We recommend the PID procedure for CT images in patients without a catheter. Use of CT with a catheter is limited to identifying urethral position.

A new two-step accurate CT-MRI fusion technique for post-implant prostate cancer.

PURPOSE: To develop an accurate method of fusing computed tomography (CT) with magnetic resonance imaging (MRI) for post-implant dosimetry after prostate seed implant brachytherapy. MATERIAL AND METHODS: Prostate cancer patients were scheduled to undergo CT and MRI after brachytherapy. We obtained the three MRI sequences on fat-suppressed T1-weighted imaging (FST1-WI), T2-weighted imaging (T2-WI), and T2*-weighted imaging (T2*-WI) in each patient. We compared the lengths and widths of 450 seed source images in the 10 study patients on CT, FST1-WI, T2-WI, and T2*-WI. After CT-MRI fusion using source positions by the least-squares method, we decided the center of each seed source and measured the distance of these centers between CT and MRI to estimate the fusion accuracy. RESULTS: The measured length and width of the seeds were 6.1 ± 0.5 mm (mean ± standard deviation) and 3.2 ± 0.2 mm on CT, 5.9 ± 0.4 mm, and 2.4 ± 0.2 mm on FST1-WI, 5.5 ± 0.5 mm and 1.8 ± 0.2 mm on T2-WI, and 7.8 ± 1.0 mm and 4.1 ± 0.7 mm on T2*-WI, respectively. The measured source location shifts on CT/FST1-WI and CT/T2-WI after image fusion in the 10 study patients were 0.9 ± 0.4 mm and 1.4 ± 0.2 mm, respectively. The shift on CT/FST1-WI was less than on CT/T2-WI (p = 0.005). CONCLUSIONS: For post-implant dosimetry after prostate seed implant brachytherapy, more accurate fusion of CT and T2-WI is achieved if CT and FST1-WI are fused first using the least-squares method and the center position of each source, followed by fusion of the FST1-WI and T2-WI images. This method is more accurate than direct image fusion.

The Advantage of a Ureteroscopic Navigation System with Magnetic Tracking in Comparison with Simulated Fluoroscopy in a Phantom Study.

PURPOSE: To assess whether our ureteroscopic real-time navigation system has the possibility to reduce radiation exposure and improve performance of ureteroscopic maneuvers in surgeons of various ages and experience levels. MATERIALS AND METHODS: Our novel ureteroscopic navigation system used a magnetic tracking device to detect the position of the ureteroscope and display it on a three-dimensional image. We recruited 31 urologists from five institutions to perform two tasks. Task 1 consisted of finding three internal markings on the phantom calices. Task 2 consisted of identifying all calices by ureteroscopy. In both tasks, participants performed with simulated fluoroscopy first, followed by our navigation system. Accuracy rates (AR) for identification, required time (T) for completing the task, migration length (ML), and time exposed to simulated fluoroscopy were recorded. RESULTS: The AR, T, and ML for both tasks were significantly better with the navigation system than without it (Task 1 with simulated fluoroscopy vs with navigation: AR 87.1 % vs 98.9%, P=0.003; T 355 s vs 191 s, P<0.0001; ML 4627 mm vs 2701 mm, P<0.0001. Task 2: AR 88.2% vs 96.7%, P=0.011; T 394 s vs 333 s, P=0.027; ML 5966 mm vs 5299 mm, P=0.0006). In both tasks, the participants used the simulated fluoroscopy about 20% of the total task time. CONCLUSIONS: Our navigation system, while still under development, could help surgeons of all levels to achieve better performances for ureteroscopic maneuvers compared with using fluoroscopic guidance. It also has the potential to reduce radiation exposure during fluoroscopy.

Testosterone replacement alters the cell size in visceral fat but not in subcutaneous fat in hypogonadal aged male rats as a late-onset hypogonadism animal model.

BACKGROUND: Patients with late-onset hypogonadism (LOH) benefit from testosterone replacement by improvement in the parameters of the metabolic syndrome, but fat cell morphology in these patients is still unclear. This study aims to determine the effect of testosterone replacement on the morphology of fat cells in subcutaneous and visceral adipose tissue and on erectile function in hypogonadal aged male rats as a model of LOH. METHODS: Ten male Sprague-Dawley rats aged 20-22 months were randomly allocated to two groups, ie, aged male controls (control group, n=5) and aged males treated with testosterone replacement therapy (TRT group, n=5). Testosterone enanthate 25 mg was injected subcutaneously every 2 weeks for 6 weeks. At 6 weeks, the intracavernous pressure (ICP) and mean arterial blood pressure (MAP) ratio was assessed. Visceral and subcutaneous adipose tissue specimens were collected and analyzed using Image-J software. RESULTS: Body weight at 2, 4, and 6 weeks after TRT was 800.0±35.4 g, 767.5±46.3 g, and 780±40.4 g, respectively (not statistically significant). The ICP/MAP ratio was 0.341±0.015 in the TRT group and 0.274±0.049 in the control group (not statistically significant). The median subcutaneous fat cell size was 4.85×10(3) (range 0.85-12.53×10(3)) µm(2) in the control group and 4.93×10(3) (range 6.42-19.7×10(3)) µm(2) in the TRT group (not statistically significant). In contrast, median visceral fat cell size was significantly smaller in the TRT group (4.93×10(3) µm(2) [range 0.51-14.88×10(3)]) than in the control group (6.08×10(3) µm(2) [0.77-19.97×10(3)]; P<0.001, Mann-Whitney U test). CONCLUSION: This is the first study clearly indicating that TRT can decrease visceral fat cell size, which is a key modulator in the metabolic syndrome. However, a short course of TRT could not improve the ICP response in hypogonadal aged male rats. Further investigation is necessary to clarify the exact rationale of TRT on the visceral fat cell.

Clinical efficacy and prognostic factors of tumor progression in Japanese patients with advanced renal cell carcinoma treated with sorafenib.

OBJECTIVE: Result of clinical trial for registration purpose is often difficult to generalize because of its limited population in number and inclusion criteria. METHODS: To understand the efficacy of sorafenib under daily medical practice, we retrospectively investigated therapeutic outcomes of 175 Japanese patients with advanced renal cell carcinoma treated with sorafenib at 15 centers. RESULTS: The objective response rate and disease control rate were 15.4 and 77.1%, respectively, being similar to those in the Phase II study in Japanese patients (19.4 and 73.6 months). Any tumor shrinkage was observed with 53% of patients, while tumor control without growth was in 61%. Lung lesions were more sensitive to sorafenib than other lesions, in terms of any tumor shrinkage (54%) and the extent of maximal shrinkage, while tumor control was better in lymph node metastases (77%) than in lung (69%). Liver was worse in any tumor shrinkage (35%), tumor control (55%) and the extent of tumor growth. Slightly, shorter median overall survival of 21.1 months compared with Phase II clinical trial (25.3 months) is likely to be attributable to different patient population, because median overall survival was improved to 26.4 months when the population was matched to that in Phase II trial. Univariate and multivariate analyses identified prognostic factors for worse overall survival, including intermediate and poor Memorial Sloan-Kettering Cancer Center risk, Eastern Cooperative Oncology Group performance status ≥1, the presence of non-clear cell component and the presence of liver metastasis. CONCLUSIONS: In conclusion, the present study confirmed the efficacy of sorafenib in the real-world setting on advanced renal cell carcinoma.

Circulating tumor cell count during zoledronic acid treatment in men with metastatic prostate cancer: a pilot study.

PURPOSE: Recent clinical trials have demonstrated that zoledronic acid (ZOL) significantly prolongs survival in prostate cancer patients undergoing androgen deprivation therapy. This pilot study investigated the influence of ZOL on circulating tumor cell (CTC) counts in prostate cancer patients in association with prostate-specific antigen (PSA) used as a serum biomarker. METHODS: Patients with metastatic castration-resistant prostate cancer (CRPC) who were CTC-positive (n=4) were enrolled in treatment with ZOL between April 2012 and December 2013. CTCs were detected using the Cell Search System. The study evaluated CTC fluctuations at 1, 2, and 3 months versus baseline, as well as patient outcomes and adverse events. RESULTS: Two patients showed evidence of temporally decreased CTCs after ZOL treatment. Instead of decreasing the number of CTCs, the PSA level did not go down during the ZOL treatment. One patient could not undergo ZOL treatment due to rapid disease progression. CONCLUSIONS: Although CTC count arguably provides useful information about patients undergoing ZOL treatment, the positive influence of ZOL may be limited to temporary effects for CRPC.

Hypoxia-inducible protein 2 (HIG2), a novel diagnostic marker for renal cell carcinoma and potential target for molecular therapy.

To identify molecules to serve as diagnostic markers for renal cell carcinoma (RCC) and as targets for novel therapeutic drugs, we investigated genome-wide expression profiles of RCCs using a cDNA microarray. We subsequently confirmed that hypoxia-inducible protein-2 (HIG2) was expressed exclusively in RCCs and fetal kidney. Induction of HIG2 cDNA into COS7 cells led to secretion of the gene product into culture medium and resulted in enhancement of cell growth. Small interfering RNA effectively inhibited expression of HIG2 in human RCC cells that endogenously expressed high levels of the protein and significantly suppressed cell growth. Moreover, addition of polyclonal anti-HIG2 antibody into culture medium induced apoptosis in RCC-derived cell lines. By binding to an extracellular domain of frizzled homologue 10 (FZD10), HIG2 protein enhanced oncogenic Wnt signaling and its own transcription, suggesting that this product is likely to function as an autocrine growth factor. ELISA analysis of clinical samples identified secretion of HIG2 protein into the plasma of RCC patients even at an early stage of tumor development, whereas it was detected at significantly lower levels in healthy volunteers or patients with chronic glomerulonephritis. The combined evidence suggests that this molecule represents a promising candidate for development of molecular-targeting therapy and could serve as a prominent diagnostic tumor marker for patients with renal carcinomas.

[Primary signet ring cell carcinoma of the bladder: a case report].

A 71-year-old man complained of dyspnea and general fatigue. His blood tests showed severe renal dysfunction. Computed tomographic scan, bone scintigram, and cystoscopy revealed primary signet ring cell carcinoma of the urinary bladder with multiple bone metastases (cT2N0M1). As the general condition of the patient was poor, nephrostomy was performed. He died one month after the diagnosis due to cancer progression. The prognosis of signet ring cell carcinoma of the bladder is poor because many cases presented at an advanced stage. Fifty cases of signet ring cell carcinoma in the urinary bladder reported in Japan are reviewed.