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.

Short-term oncological and surgical outcomes of robot-assisted radical prostatectomy: A retrospective multicenter cohort study in Japan (the MSUG94 group).

INTRODUCTION: We evaluated oncological outcomes of patients undergoing robot-assisted radical prostatectomy (RARP) for prostate cancer (PCa) and their perioperative complications in Japan. We investigated clinical and pathological covariates to predict biochemical recurrence (BCR) after RARP. METHODS: A retrospective multicenter cohort study was conducted in RARP patients with PCa at 10 institutions in Japan. Pre- and postoperative covariates were collected from enrolled patients. The primary endpoint was defined as biochemical recurrence-free survival (BRFS). Additionally, the association between BCR and clinicopathological covariates was determined. RESULTS: We enrolled 2670 patients in this study. The median follow-up period was 26.0 months. RARP-related perioperative complications were identified in 198 patients (7.4%), including 69 patients (2.6%) with grade 3/4 complications according to the Clavien-Dindo classification. The 2-year BRFS was 88.0%. Using the Kaplan-Meier method, initial prostate-specific antigen (PSA) level of ≤7.6 ng/mL, biopsy and pathological Gleason score (GS) of ≤7, clinical and pathological T1/2, and low/intermediate risks according to the National Comprehensive Cancer Network risk classification, and negative surgical margin status had significant BRFS than their counterparts. In multivariate analysis, initial PSA, biopsy and pathological GS, clinical and pathological T stage, and surgical margin status significantly correlated with BCR after RARP. CONCLUSION: In this study, RARP achieved a lower incidence of perioperative complications than other studies.

A PATIENT WITH RETROPERITONEAL MYXOID LIPOSARCOMA RECURRENCE WHO ACHIEVED REMARKABLE IMPROVEMENTS IN PERFORMANCE STATUS WHEN TREATED WITH COMBINATION CHEMOTHERAPY WITH GEMCITABINE AND DOCETAXEL.

We report a patient with retroperitoneal myxoid liposarcoma recurrence who achieved remarkable improvements in performance status (PS) and maintained stable disease for approximately 5 months when treated with combination chemotherapy with gemcitabine (GEM) and docetaxel combination chemotherapy (GD). A 51-year-old woman was referred to our hospital with the chief complaint of a palpable mass in the left side of the abdomen. A retroperitoneal liposarcoma was diagnosed on the basis of magnetic resonance imaging and computed tomography results, and tumor resection was performed. The histopathological evaluation showed myxoid liposarcoma, which was classified as grade 2 according to the French Federation of Cancer Centers Sarcoma Group (FNCLCC) system.Two months later, the tumor regionally recurred as peritoneal dissemination with rapid growth. Five months after the surgery, the growing tumor caused appetite loss and pleural effusion in the left lung. GD was administered (800 mg/m2 GEM on days 1 and 8, and 60 mg/m2 docetaxel on day 8) and 4 cycles were administered.The resulting decrease in abdominal girth and in the amount of pleural effusion allowed the patient to regain her appetite, and the patient's PS greatly improved from 3 to 1.Initially, GD was shown to be effective for the treatment of leiomyosarcoma and pleomorphic sarcoma, and it is now recommended as one of the first-line regimens in the National Comprehensive Cancer Network guidelines for soft tissue sarcoma treatment. The patient in this case showed remarkable improvement in PS after tumor recurrence and maintained stable disease for some time, without severe adverse effects.

Clinical response to induction chemotherapy predicts improved survival outcome in urothelial carcinoma with clinical lymph nodal metastasis treated by consolidative surgery.

BACKGROUND: To determine the indications for post-chemotherapy consolidative surgery in patients with clinical lymph node (LN) metastatic (cN+) urothelial carcinoma (UC). METHODS: Sixty UC patients with measurable cN+ but without detectable systemic visceral/bone dissemination received induction platinum-based chemotherapy. Consolidative surgery was offered to all patients except for those with progressive disease. We retrospectively analyzed the clinicopathological response to induction chemotherapy and identified prognostic factors for overall survival (OS). RESULTS: The primary cancer site was the urinary bladder in 31 patients (52 %) and upper urinary tract in 29 (48 %). The median number of chemotherapy courses was 4. Forty-five patients (75 %) showed a clinically objective response to the induction chemotherapy. Fifty-one patients (85 %) underwent subsequent consolidative surgery. Histopathological analysis indicated pT0 status in 10 (20 %) and pN0 in 17 (33 %). When all 60 patients were considered, clinical tumor response was found to be significantly correlated with achievement of pathological complete response. At the median follow-up of 22 months, the median progression-free survival and OS periods were excellent: 18.6 and 31.6 months, respectively. In the multivariate analysis, clinical tumor response was found to be an independent pre-surgical prognostic factor for OS, and pathologically negative lymph node, negative resection margin, more LNs removed, and negative lymphovascular invasion were found to be independent post-surgical prognostic parameters for OS. CONCLUSIONS: The median OS in induction chemotherapy followed by consolidative surgery was very encouraging. Our results suggest that achieving a good clinical response to pre-surgical induction chemotherapy is a good indication for subsequent consolidative surgery in UC patients with cN+ to improve OS through a good pathological response.

Clinical efficacy and prognostic factors for overall survival in Japanese patients with metastatic renal cell cancer treated with sunitinib.

UNLABELLED: Study Type--Therapy (case series). Level of Evidence 4. What's known on the subject? and What does the study add? A randomized prospective phase III clinical trial for systemic treatment-naïve metastatic renal cell cancer (RCC) patients demonstrated the superiority of sunitinib over interferon with an acceptable safety profile. However, a commonly asked question is whether patients with RCC in clinical trials are representative of those with this disease being seen in ordinary clinical practice. To our knowledge, this is the first report of sunitinib for the Japanese patients with metastatic RCC in ordinary clinical practice. The estimated median PFS and OS in this study were 9.3 and 32.2 months, respectively. The application of the MSKCC model distinctly separated OS curves (P<0.001), suggesting that MSKCC prognostic factors might be still valid to predict survival in metastatic RCC in the era of molecular targeted therapy. OBJECTIVES: • To report the treatment efficacy and safety profile of sunitinib for patients with metastatic renal cell carcinoma (RCC) in ordinary clinical practice. • In addition, to investigate the prognostic clinicopathological factors in these patients. PATIENTS AND METHODS: • The present study consisted of native Japanese patients with metastatic RCC, comprising 29 pretreated and 34 systemic treatment-naïve patients. • Univariate and multivariate analyses were performed by the log-rank test and the Cox proportional hazards model, respectively. RESULTS: • Estimated median progression-free survival and overall survival (OS) were 9.3 months (95% confidence interval, CI, 5.0-13.7) and 32.2 months (95% CI, 24.4-40.0), respectively. • Among the patients pretreated before sunitinib, two patients were treated with initialized systemic therapy with sorafenib and the remaining 27 were initialized with interferon-α. • The OS from the initial systemic therapy of the patients in pretreated groups was 79.6 months (95% CI, 14.6-144.5). • The application of the Memorial Sloan-Kettering Cancer Center model distinctly separated the OS curves (P < 0.001). • The most common grade 3 adverse events were fatigue (53%), thrombocytopaenia (48%), hand-foot syndrome (16%), anaemia (20%), hypertension (10%) and leucopaenia (9%), although these events were manageable and reversible. CONCLUSIONS: • Sunitinib has a favourable efficacy/safety profile for Japanese metastatic RCC patients in clinical practice. • The estimated median OS was >2 years with acceptable tolerability. • The median OS from the initial systemic therapy of the pretreated patients was >6 years. • Memorial Sloan-Kettering Cancer Center prognostic factors still appear to be valid for predicting survival in metastatic RCC in the era of molecular targeted therapy.

Tumor size is a potential predictor of response to tyrosine kinase inhibitors in renal cell cancer.

OBJECTIVES: To investigate the correlations between the initial tumor size and size reduction rate in patients treated with targeted agents. To select the patients who can benefit the most from treatment with targeted agents, it will be necessary to find a tumor characteristic that predicts their effectiveness. METHODS: The data from 139 metastatic and 16 primary lesions treated with the targeted agents were retrospectively analyzed. They consisted of 86 sunitinib-treated and 69 sorafenib-treated lesions in 54 patients with metastatic renal cell carcinoma who had undergone treatment from April 2008 to July 2010. The relationship between the longest tumor diameter at baseline and the rate of reduction in tumor size was assessed using the Spearmancorrelation test. RESULTS: A linear, moderate to strong association between the initial tumor size and tumor size reduction rate was shown (correlation coefficient -0.441, P < .001). When these tumors were divided into 2 groups at the threshold value (23.95 mm), which was decided by the receiver operating characteristic curve analysis, the smaller tumors demonstrated a significantly greater size reduction than the larger tumors according to the Mann-Whitney U test (P < .001). Both univariate and multivariate linear regression analyses revealed that only the initial tumor size was associated with the rate of reduction in individual tumors (P < .001). CONCLUSIONS: The initial tumor size was a good predictor of the tumor size reduction. This simple observation could be useful for physicians who treat patients with metastatic renal cell carcinoma. In addition, in assessing clinical trials of targeted agents for metastatic renal cell carcinoma using the ResponseEvaluation Criteria in Solid Tumors, perhaps this association should be considered.

Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells.

Genistein is a phytoestrogen that has been reported to suppress the AKT signaling pathway in several malignancies. However, the molecular mechanism of genistein action is not known. We tested the hypothesis that genistein activates expression of several aberrantly silenced tumor suppressor genes (TSGs) that have unmethylated promoters such as PTEN, CYLD, p53 and FOXO3a. We report here that genistein activates TSGs through remodeling of the heterochromatic domains at promoters in prostate cancer cells by modulating histone H3-Lysine 9 (H3-K9) methylation and deacetylation. Genistein activation involved demethylation and acetylation of H3-K9 at the PTEN and the CYLD promoter, while acetylation of H3-K9 at the p53 and the FOXO3a promoter occurred through reduction of endogenous SIRT1 activity. There was a decrease of SIRT1 expression and accumulation of SIRT1 in the cytoplasm from the nucleus. Increased expression of these TSGs was also reciprocally related to attenuation of phosphorylated-AKT and NF-kappaB binding activity in prostate cancer cells. This is the first report describing a novel epigenetic pathway that activates TSGs by modulating either histone H3-Lysine 9 (H3-K9) methylation or deacetylation at gene promoters leading to inhibition of the AKT signaling pathway. These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer.

Decreased survival of prostate cancer cells in vitro by combined treatment of heat and an antioxidant inhibitor diethyldithiocarbamate (DDC).

The aim of this study was to examine a modulation of thermotolerance by treatment with combination of heat and the antioxidant inhibitor diethyldithiocarbamate (DDC) of the PC-3 prostate cancer cells. To determine thermotolerance, cells were heated once or twice. Two 1 h exposures at 43 degrees C, with a recovery period in between, revealed better survival/recovery of cells after the second exposure than after the first (fig. 1A + 1B). Additional experiments were performed, heating cells twice (fig. 1B + 1C). First, cells were heated at 43 degrees C for 1 h and, after various recovery times (intervals) at 37 degree C, subsequently reheated at 44 degrees C for 1 h. To ensure effective cell killing, efficiency of the combined treatments of 1 mM DDC and heating at 43 or 44 degrees C for 1 h was estimated by measuring cell survival, reactive oxygen species (ROS) generation, superoxide dismutase (SOD) activity and heat shock protein 70 (hsp 70) expression. To obtain a more effective method for subsequent heat exposure, cells were heated twice after a 24 h interval in the presence or absence of 1 mM DDC. ROS generation and SOD activity immediately increased correlating with duration of heating, but their levels gently decreased with time after discontinuation of heating. On the other hand, hsp 70 levels slowly increased, also correlating with duration of heating but continued to increase with time after discontinuation of heating for a certain period. DDC administration coupled with heating at 43 or 44 degrees C significantly decreased cell survival compared to heating alone (p < 0.05). Furthermore, significant decreases in numbers of viable cells were observed for cells after the first heat exposure when combined with DDC as compared to heat alone at 43 and 44 degrees C (p < 0.05). These findings suggest that heat combined with DDC could have potential benefits in the treatment of prostate cancer.