Phase I/II study of multipeptide cancer vaccine IMA901 after single-dose cyclophosphamide in Japanese patients with advanced renal cell cancer with long-term follow up.

BACKGROUND: IMA901 is the first therapeutic vaccine for renal cell cancer (RCC). It contains multiple tumor-associated peptides (TUMAPs) that are naturally present in human cancers. METHODS: In a phase I/II study, we treated a total of 10 Japanese patients with advanced RCC who were human leukocyte antigen A (HLA-A)*02 +. Vaccination involved i.d. injection of GM-CSF (75 µg), followed within 15-30 min by i.d. injection of IMA901 (containing 413 µg of each peptide). No treatment with either anticancer agents or immunosuppressants was allowed within 4 weeks before entering the trial. Patients were scheduled to receive 7 vaccinations during the first 5 weeks of treatment (induction period), followed by 10 further vaccinations at 3-week intervals for up to 30 weeks (maintenance period). The primary endpoints were safety and tolerability, while the secondary endpoints were PFS, OS, and immunogenicity. RESULTS: There were no treatment-related serious adverse events or deaths during the study period. When the response was assessed after 4 months, 10% of patients showed a partial response, 80% had stable disease, and 10% had progressive disease. Among patients in whom the T-cell response was analyzed, five patients showed a vaccine-induced T-cell response against at least one HLA class I-restricted TUMAP and two patients had T-cell responses to multiple TUMAPs. PFS was 5.5 months and OS was 18 months. CONCLUSIONS: This study demonstrated the safety and tolerability of IMA901 vaccine in Japanese RCC patients, and also showed that vaccination elicited an immune response.

Intratumoral and s.c. injection of inactivated hemagglutinating virus of Japan envelope (GEN0101) in metastatic castration-resistant prostate cancer.

Inactivated hemagglutinating virus of Japan envelope (HVJ-E) has an antitumor effect and tumor immunity. We undertook an open-label, phase I, dose-escalation study in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and s.c. injection of HVJ-E (GEN0101). Patients with CRPC, who were resistant to or unable to receive standard of care, were included. GEN0101 was injected directly into the prostate and s.c. in two 28-day treatment cycles. The primary end-points were to evaluate the safety and tolerability of GEN0101 and determine its recommended dose. The secondary end-points were to analyze the antitumor effect and tumor immunity. Three patients received 30 000 mNAU GEN0101 and 6 received 60 000 mNAU. There was no dose-limiting toxicity, and the recommended dose of GEN0101 was defined as 60 000 mNAU. Radiographically, 1 patient had stable disease and 2 had progressive disease in the low-dose group, whereas 5 patients had stable disease and 1 had progressive disease in the high-dose group. Three patients in the high-dose group showed reduction in lymph node metastasis. Prostate-specific antigen increase rates in the high-dose group were suppressed more than those in the low-dose group. Natural killer cell activity was enhanced in 2 patients of the low-dose group and in 5 patients in the high-dose group. In conclusion, intratumoral and s.c. injections of GEN0101 were well-tolerated and feasible to use. The study is registered with the UMIN Clinical Trials Registry (no. UMIN000017092).

Epigenetic silencing of core histone genes by HERS in Drosophila.

Cell cycle-dependent expression of canonical histone proteins enables newly synthesized DNA to be integrated into chromatin in replicating cells. However, the molecular basis of cell cycle-dependency in the switching of histone gene regulation remains to be uncovered. Here, we report the identification and biochemical characterization of a molecular switcher, HERS (histone gene-specific epigenetic repressor in late S phase), for nucleosomal core histone gene inactivation in Drosophila. HERS protein is phosphorylated by a cyclin-dependent kinase (Cdk) at the end of S-phase. Phosphorylated HERS binds to histone gene regulatory regions and anchors HP1 and Su(var)3-9 to induce chromatin inactivation through histone H3 lysine 9 methylation. These findings illustrate a salient molecular switch linking epigenetic gene silencing to cell cycle-dependent histone production.

Disruption of circadian clockwork in in vivo reprogramming-induced mouse kidney tumors.

The circadian clock, which regulates cellular physiology, such as energy metabolism, resides in each cell level throughout the body. Recently, it has been elucidated that the cellular circadian clock is closely linked with cellular differentiation. Moreover, the misregulation of cellular differentiation in mouse embryonic stem cells (ESCs) induced abnormally differentiated cells with impaired circadian clock oscillation, concomitant with the post-transcriptional suppression of CLOCK proteins. Here, we show that the circadian molecular oscillation is disrupted in dysdifferentiation-mediated mouse kidney tumors induced by partial in vivo reprogramming, resembling Wilms tumors. The expression of CLOCK protein was dramatically reduced in the tumor cells despite the Clock mRNA expression. We also showed that a similar loss of CLOCK was observed in human Wilms tumors, suggesting that the circadian molecular clockwork may be disrupted in dysdifferentiation-mediated embryonal tumors such as Wilms tumors, similar to the in vivo reprogramming-induced mouse kidney tumors. These results support our previous reports and may provide a novel viewpoint for understanding the pathophysiological nature of cancers through the correlation between cellular differentiation and circadian clock.

Genome-wide association study identified SNP on 15q24 associated with bladder cancer risk in Japanese population.

Through genome-wide association analysis and an independent replication study using a total of 1131 bladder cancer cases and 12 558 non-cancer controls of Japanese populations, we identified a susceptibility locus on chromosome 15q24. SNP rs11543198 was associated with bladder cancer risk with odds ratio (OR) of 1.41 and P-value of 4.03 × 10(-9). Subgroup analysis revealed rs11543198 to have a stronger effect in male smokers with OR of 1.66. SNP rs8041357, which is in complete linkage disequilibrium (r(2) = 1) with rs11543198, was also associated with bladder cancer risk in Europeans (P = 0.045 for an additive and P = 0.025 for a recessive model), despite much lower minor allele frequency in Europeans (3.7%) compared with the Japanese (22.2%). Imputational analysis in this region suggested CYP1A2, which metabolizes tobacco-derived carcinogen, as a causative candidate gene. We also confirmed the association of previously reported loci, namely SLC14A1, APOBEC3A, PSCA and MYC, with bladder cancer. Our finding implies the crucial roles of genetic variations on the chemically associated development of bladder cancer.

Preoperative lipiodol marking and its role on survival and complication rates of CT-guided cryoablation for small renal masses.

BACKGROUND: Partial nephrectomy for small renal masses (SRM) may be useful for preserving renal function, but is technically more difficult than radical nephrectomy. Cryoablation may be performed under local anesthesia. The objective of the present study is to assess the safety and therapeutic efficacy of cryoablation with lipiodol marking for SRM. METHODS: Cryoablation therapy was performed on 42 patients under local anesthesia. Their median age was 74 years (31-91). The median tumor diameter was 21 mm (10-42). Responses to the treatment were evaluated using modified Response Evaluation Criteria in Solid Tumors (mRECIST) by contrast-enhanced CT. In six patients (14.3%) for whom it was not possible to use contrast medium, plain CT findings were assessed according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Twenty-nine (69%) and five (12%) patients achieved complete responses (CR) and partial responses (PR), respectively, while four (10%) and four (10%) patients each had stable disease (SD) and progressive disease (PD) after the first course of therapy. A second course of cryoablation therapy with lipiodol marking was performed on three out of four patients with PD after the first course of therapy, and resulted in a total of 32 patients achieving CR (76%). Four (36.4%) out of 11 patients for whom lipiodol marking was not conducted had PD, whereas none of the 31 patients for whom lipiodol marking was conducted had PD. All grade complications were reported in 11 (24.4%) patients while grade 3 in two (4.4%) patients. 11 (24.4%) A significant difference was observed in postoperative hemorrhagic events in all grades (18% in patients undergoing cryoablation without lipiodol marking vs. 0% in patients undergoing cryoablation without lipiodol marking). CONCLUSIONS: Although further studies involving more patients are needed in order to evaluate long-term results, cryoablation therapy appears to be a useful treatment option for SRM. Preoperative marking with lipiodol was helpful for improving complication and survival rates with cryoablation.

PAX2 promoted prostate cancer cell invasion through transcriptional regulation of HGF in an in vitro model.

Elucidating the mechanism of prostate cancer cell invasion may lead to the identification of novel therapeutic strategies for its treatment. Paired box 2 (PAX2) and hepatocyte growth factor (HGF) proteins are promoters of prostate cancer cell invasion. We found that PAX2 protein activated the HGF gene promoter through histone H3 acetylation and upregulated HGF gene expression. Deletion analysis revealed that the region from -637 to -314 of the HGF gene was indispensable for HGF promoter activation by PAX2. This region contains consensus PAX2 binding sequences and mutations of the sequences attenuated HGF promoter activation. Using an in vitro invasion model, we found that PAX2 and HGF promoted prostate cancer cell invasion in the same pathway. Knockdown of HGF expression attenuated the cells' invasive capacity. Moreover, in tissue samples of human prostate cancers, HGF and PAX2 expression levels were positively correlated. These results suggested that upregulation of HGF gene expression by PAX2 enhanced the invasive properties of prostate cancer cells. The PAX2/HGF pathway in prostate cancer cells may be a novel therapeutic target in prostate cancer patients.

Diversity in treatment modalities of Stage II/III urothelial cancer in Japan: sub-analysis of the multi-institutional national database of the Japanese Urological Association.

OBJECTIVE: We aimed to survey treatment modalities for the patients with Stage II/III urothelial cancer in Japan. METHODS: We used the multi-institutional national database of the Japanese Urological Association from 348 Japanese institutions, in which a total of 3707 patients with muscle-invasive bladder cancer and 1538 with upper urinary tract urothelial carcinoma were registered in 2008 and 2011, respectively. Primary treatment was classified as surgery alone, surgery with chemotherapy, surgery with radiation, radiation alone, chemotherapy alone, combination of radiation and chemotherapy and observation. Overall and cancer-specific survivals were examined using the Kaplan-Meier method, and survival in the subgroups was analyzed using the log-rank test. RESULTS: In Stage II/III bladder cancer patients, 49.7% of those were treated with radical operation and 22.3% received observation only. A total 97.2% of Stage II/III upper urinary tract urothelial carcinoma patients treated with radical surgery. A total 30.4% of Stage II/III bladder cancer patients received chemotherapy. Majority of the patients received cisplatin-based regimen, however, regimens of chemotherapy was rich in variety up to 13 regimens. Chemotherapy regimens for the patients with upper urinary tract urothelial carcinoma were also various up to eight regimens. Overall and cancer-specific survivals were statistically significantly stratified according to the clinical stage. The upper urinary tract urothelial carcinoma patients diagnosed with clinical stage T3 had significantly poor prognosis compared with those diagnosed with clinical stage T2. CONCLUSIONS: This study demonstrated the variety of treatments used for Japanese patients with Stage II/III urothelial cancer. Treatment standardization for these entities may be necessary.

Post-chemotherapy laparoscopic retroperitoneal lymph node dissection is feasible for stage IIA/B non-seminoma germ cell tumors.

OBJECTIVE: To assess the efficacy, outcome and complications of post-chemotherapy laparoscopic retroperitoneal lymph node dissection (L-RPLND) for stage IIA/B testicular germ cell tumor (GCT) patients in comparison with open RPLND (O-RPLND). METHODS: L-RPLND was performed in 14 patients with stage IIA/B non-seminoma GCTs among 154 non-seminoma patients who received RPLND after completion of chemotherapy with tumor marker normalization at our institution between 1998 and 2013. Their outcomes were compared with those of 14 patients with stage IIA/B non-seminoma GCTs treated with O-RPLND during the same period. Clinical parameters were compared between L-RPLND and O-RPLND. RESULTS: There were no significant differences in the background characteristics of the two groups except for follow-up duration (36 months for L-RPLND, 70 months for O-RPLND; p = 0.02). Blood loss during surgery was significantly less for the L-RPLND group than for the O-RPLND group (155 mL for L-RPLND, 700 mL for O-RPLND; p < 0.001). Parameters related to post-operative recovery were significantly better for the L-RPLND group than for the O-RPLND group. Histopathological examination showed no difference between the two groups. Neither group had disease recurrence. CONCLUSION: Post-chemotherapy L-RPLND with a bilateral template and nerve-sparing method was safe, effective, and showed a high preservation rate of antegrade ejaculation with no deterioration of outcomes compared to O-RPLND.

Comparison of diameter-axial-polar nephrometry and RENAL nephrometry score for treatment decision-making in patients with small renal mass.

INTRODUCTION: The aim of this study was to evaluate our institution's experience in performing laparoscopic radical nephrectomy (LRN) and partial nephrectomy (PN) in patients with small renal masses. METHODS: 142 patients with cT1aN0M0 lesions were identified. 68 of these subjects were treated with LRN and 74 were treated with laparoscopic PN (LPN). The clinicopathological characteristics of the two groups of patients, including diameter-axial-polar (DAP) nephrometry and RENAL nephrometry score (RENAL-NS), operative results, and outcomes, were retrospectively analyzed. RESULTS: A multivariate logistic regression analysis for the selection of PN as the treatment showed that tumor size, DAP nephrometry, RENAL-NS and imperative condition were all independent factors. The area under the curve receiver operating characteristics (ROC-AUC) of DAP and RENAL-NS for performing LPN were 0.897 and 0.825, respectively. CONCLUSIONS: Although LRN was performed in patients with a high nephrometry score in this study, open partial nephrectomy (OPN) should be considered for patients with a high nephrometry score in T1a renal cell carcinoma (RCC) because of better functional and similar oncological outcomes. Based on ROC analysis, when DAP is 6 or less, LPN should be considered and when DAP is 7 or more, OPN should be considered.

Differences in adverse event profiles between everolimus and temsirolimus and the risk factors for non-infectious pneumonitis in advanced renal cell carcinoma.

BACKGROUND: There have been few reports of the differences in safety between the mammalian target of rapamycin inhibitors, everolimus and temsirolimus. The purpose of this study is to compare the adverse event profiles of both agents and to estimate the risk factors for non-infectious pneumonitis in patients with advanced renal cell carcinoma on the basis of our real-world clinical experience. METHODS: Data from 218 consecutive patients that received either everolimus or temsirolimus for advanced renal cell carcinoma at five Japanese centers were retrospectively analyzed. Chi-squared test and univariate and multivariate logistic regression analyses were performed to investigate the differences in adverse event profiles and the risk factors associated with non-infectious pneumonitis, respectively. RESULTS: A total of 196 patients were evaluable. In the everolimus group compared with temsirolimus, stomatitis (56 vs 30 %, p < 0.001) and non-infectious pneumonitis (38 vs 22 %, p = 0.018) were more frequently observed, and asthenia (11 vs 23 %, p = 0.027), rash (20 vs 36 %, p = 0.018), and fatigue (33 vs 48 %, p = 0.032) occurred less frequently in all grades. On multivariate analysis, male gender (odds ratio 3.65; 95 % confidence interval 1.44-9.26, p = 0.007) and everolimus treatment (odds ratio 2.00; 95 % confidence interval 1.01-3.96, p = 0.046) were significantly associated with development of non-infectious pneumonitis. CONCLUSION: Our findings suggest that adverse event profiles may differ between everolimus and temsirolimus and that non-infectious pneumonitis may occur more frequently in patients treated with everolimus than temsirolimus. Further investigations are needed to confirm these results.

Initial experience of combined use of photodynamic diagnosis and narrow band imaging for detection of flat urothelial lesion.

BACKGROUND: This preliminary study is the first report to compare photodynamic diagnosis (PDD) with narrow band imaging (NBI) in the same patients with flat urothelial lesions suspicious of carcinoma in situ (CIS) of the bladder. METHODS: Between November 26, 2012 and April 1, 2013, 10 patients underwent transurethral resection of bladder tumor using PDD and NBI simultaneously because of suspicion of CIS. The bladder was mapped first under white light (WL), then under NBI, and subsequently under blue light in odd-numbered patients. The bladder was mapped first under WL, then under blue light, and subsequently under NBI in even-numbered patients. Biopsies were carried out from all suspicious areas, noting whether NBI, PDD or both detected lesions. Random cold cup biopsies from healthy mucosa of bladder were performed from lesions negative on PDD and NBI. RESULTS: The sensitivity and specificity of PDD for detection of CIS and dysplasia were 0.916 and 0.827, respectively. The sensitivity and specificity of NBI for detection of CIS and dysplasia were 0.625 and 0.879. The area under the curve (AUC) for detection of CIS and dysplasia was 0.872 with PDD and 0.752 with NBI. The AUC with combined use of PDD and NBI was 0.918. There was no cancer or dysplasia identified in 43 lesions that were both PDD- and NBI-negative. CONCLUSION: When both PDD and NBI are negative, the possibility of CIS or dysplasia might be very low. The usefulness of the combination of PDD with NBI was suggested in this study.

The efficacy of radio-frequency ablation for metastatic lung or liver tumors of male germ cell tumors as an alternative minimally invasive therapy after salvage chemotherapy.

BACKGROUND: The aim of this study was to assess the efficacy of radio-frequency ablation (RFA) for metastatic lung or liver tumors of germ cell tumors (GCTs) after chemotherapy. METHODS: RFA with computed tomography guidance and monitoring was performed in 24 patients with 48 metastatic lung or liver tumors of GCTs. Group A consisted of 9 patients with tumor marker normalization after salvage chemotherapy and group B consisted of 15 patients without tumor marker normalization in spite ofintensive treatment. RESULTS: Out of 48 tumors, 41 tumors in 21 patients were evaluated for the efficacy of the RFA treatment. Of the 41 tumors, successful ablation was achieved in 34 (82.9 %). The patients in group A had significantly better survival than the patients in group B (p = 0.0003). In group A, all 9 patients are still alive with no evidence of disease (NED). Patients with a solitary tumor had significantly better survival than those with multiple tumors (p = 0.0247). In group B, 2 patients are alive with NED, 1 patient is alive with disease, and the remaining 12 patients have died a tumor-related death. Three cases of pneumothorax requiring intubation were observed. CONCLUSIONS: RFA is less invasive than surgery and is an effective treatment option for curative and palliative therapy as an alternative to invasive salvage surgery for post-chemotherapeutic metastatic lung or liver lesions from GCT.

Comprehensive assessment for novel prostate cancer markers in the prostate-specific antigen era: focusing on Asians and Asian countries.

We reviewed the current evidence for three novel prostate tumor markers (PCA3, TMPRSS2:ERG and proPSA) that have been recently reported predominantly in Western countries. We focus our attention on Asian men in both clinical and basic research studies. There have been no reports on the clinical usefulness of these three markers for Asians living in Western countries. In Asian countries, evidence for the clinical usefulness of PCA3 and proPSA-related indices including Prostate Health Index is being accumulated, mainly in Japan. The process for how a novel marker is approved in the clinical setting is also discussed.

Percutaneous nephrolithotripsy and antegrade ureterolithotripsy in a 10-month-old infant with urinary stones in both kidney and ureter.

The prevalence of urinary tract stones in the pediatric population is lower than that in adults. Although methods of surgery and medical equipment have developed, medical treatments for urinary tract stones are limited for pediatric cases. We report the case of a 10-month-old male infant with urinary stones in the left kidney and ureter who underwent percutaneous nephrolithotripsy and ureterolithotripsy using antegrade insertion of a ureteroscope through the same nephrostomy tract.

Salvage combined chemotherapy with paclitaxel, ifosfamide and nedaplatin for patients with advanced germ cell tumors.

OBJECTIVES: To investigate the efficacy of combined regimen with paclitaxel, ifosfamide and nedaplatin as salvage chemotherapy in patients with cisplatin-refractory or multiple relapsed germ cell tumors. METHODS: A total of 65 patients refractory to cisplatin-based chemotherapy or with relapse after induction or salvage chemotherapy received paclitaxel 210 mg/m(2) on day 1, ifosfamide 1.2 g/m(2) on days 2-6 and nedaplatin 100 mg/m(2) on day 2 of a 3-week cycle. The primary and secondary end-points were the response rate and overall survival, respectively. RESULTS: Paclitaxel, ifosfamide and nedaplatin therapy was carried out as second-line therapy in 17 patients, third-line in 31 and fourth-line or later in 17. Patients were pretreated with a median of six cycles of platinum-based chemotherapy (range 3-15 cycles). The overall response rate was 62.9%, including one patient with complete response and 38 with partial response. Serum tumor marker levels normalized in 35 (56.5%) patients. Overall survival at a median follow up of 34 months was 59.3%, and median time to progression was 12 months. Multivariate analysis showed that serum tumor marker normalization was the only independent predictor of better progression-free survival and overall survival. Grade 3/4 of neutropenia, anemia and thrombocytopenia was observed in 96.9%, in 81.5%, and in 90.8% of patients, respectively. CONCLUSION: Paclitaxel, ifosfamide and nedaplatin chemotherapy appears to be effective when used as first or second salvage treatment in advanced relapsed germ cell tumors. Even after fourth-line therapy, patients with serum tumor marker normalization might have a chance for a cure.

Clinical outcomes and histological findings of patients with advanced metastatic germ cell tumors undergoing post-chemotherapy resection of retroperitoneal lymph nodes and residual extraretroperitoneal masses.

OBJECTIVES: To assess clinical outcomes of patients with advanced germ cell tumor undergoing post-chemotherapy retroperitoneal lymph node dissection with or without extraretroperitoneal mass resection. METHODS: Between 1998 and 2013, 175 retroperitoneal lymph node dissections for advanced metastatic germ cell tumors were carried out at Kyoto Prefectural University of Medicine, Kyoto, Japan. Of patients receiving retroperitoneal lymph node dissections, 156 underwent post-chemotherapy retroperitoneal lymph node dissection with or without extraretroperitoneal mass resection as first surgery after completion of chemotherapy. Of these 156 patients, 47 underwent both post-chemotherapy retroperitoneal lymph node dissection and extraretroperitoneal mass resection. RESULTS: The histological findings were necrosis in 59.6%, teratoma in 31.4% and viable cancer in 9.0% at retroperitoneal lymph node. At extraretroperitoneal mass resection, necrosis was present in 59.6%, teratoma in 31.9% and viable cancer in 8.5%. Overall histological discordance between retroperitoneal lymph node and extraretroperitoneal mass was found in 31.9%. Five-year disease-free survival stratified by retroperitoneal lymph node histology in 156 patients was 91.3% for necrosis, 78.7% for teratoma and 63.5% for viable cancer (log-rank, P = 0.009). Antegrade ejaculation was preserved in 80.9%. In the worst histology of post-chemotherapy retroperitoneal lymph node dissection or extraretroperitoneal mass resection in 156 patients, 5-year disease-free survival was 93.2% for necrosis, 79.0% for teratoma and 63.4% for viable cancer (log-rank, P < 0.001). Independent prognostic factors for disease-free survival were presence of viable cancer in retroperitoneal lymph node histology and salvage chemotherapy. CONCLUSION: The presence of viable cancer at the retroperitoneal lymph node is an independent predictor of disease recurrence. In approximately one-third of cases, there is a histological discordance between retroperitoneal lymph node and extraretroperitoneal mass. Resection of residual retroperitoneal lymph node and extraretroperitoneal masses remains an important procedure in the management of advanced germ cell tumors.

Laparoscopic off-clamp partial nephrectomy using soft coagulation.

OBJECTIVES: To assess the effectiveness of soft coagulation in off-clamp laparoscopic partial nephrectomy. METHODS: A total of 32 patients with renal tumors underwent laparoscopic partial nephrectomy with off-clamp using soft coagulation between May 2012 and September 2013. Tumor resection was carried out using a combination of bipolar forceps and a ball electrode using the soft coagulation system without hilar clamping. The outcomes of these patients were compared with those of 30 patients treated with hilar clamping. RESULTS: This off-clamp procedure was successfully completed in 31 cases. No significant differences were observed in the mean age (60 vs 61 years), sex (male/female; 25/7 vs 20/10), mean RENAL nephrometry score (5.7 vs 5.8), mean body mass index (24.4 vs 23) or tumor size (15 mm vs 16 mm) between the two groups. No significant differences were noted in positive surgical margins (0 vs 0) or blood loss (104 vs 115 cc) as well. In contrast, a significant difference was noted in the total operative time (278 vs 238 min). Serum creatinine percentage changes at 3 months were 6.4 versus 7.3% in the off-clamp and hilum-clamp groups, respectively, which were not significantly different. CONCLUSIONS: Off-clamp laparoscopic partial nephrectomy can be safely carried out by using a soft coagulation technique.

Clinicopathological characteristics and oncological outcomes in patients with renal cell carcinoma registered in 2007: The first large-scale multicenter study from the Cancer Registration Committee of the Japanese Urological Association.

OBJECTIVES: To describe the clinicopathological features and oncological outcomes of renal cell carcinoma diagnosed in Japan in 2007, the results of the large-scale renal cell carcinoma registration study carried out by the Japanese Urological Association are reported. METHODS: The renal cell carcinoma survey was carried out by the Japanese Urological Association in 2012 to register newly diagnosed renal cell carcinoma cases in 2007 from 340 institutions nationwide. The survey included clinicopathological details, such as sex, age, family history, past history, smoking history, body mass index, reason for diagnosis, TNM classification, stage, histopathology, treatment and clinical outcomes. RESULTS: A total of 3663 cases diagnosed in 2007 were registered in this renal cell carcinoma registry program from 340 institutions. A total of 15 patients with a final diagnosis of oncocytoma were excluded, and 3648 cases of renal cell carcinoma were analyzed to evaluate oncological outcomes. The patients' median age was 63.9 years (range 5.9-95.1 years). Clear cell renal cell carcinoma was the most common histological subtype (77.2%), followed by papillary (5.0%) and chromophobe (3.2%) renal cell carcinoma. The most common initial treatment was radical nephrectomy (72.6%), and the most common secondary treatment was cytokine therapy (13.1%). Five-year overall survival rates in stages I, II, III, and IV were 94.8%, 90.2%, 78.8% and 39.6%, respectively. The 5-year overall survival rates for clear cell, papillary and chromophobe renal cell carcinomas, and carcinoma of the collecting ducts of Bellini were 88.6%, 79.8%, 93.0% and 40.0%, respectively. CONCLUSIONS: The present report is the first nationwide large-scale study to describe the clinicopathological characteristics and oncological outcomes of patients with renal cell carcinoma in Japan. Oncological outcomes depend on the clinical stage and histological subtype. Further investigations will be required to show improved oncological outcomes in the molecular targeted therapy era using the results of the present study as a baseline.

Cycloamylose-nanogel drug delivery system-mediated intratumor silencing of the vascular endothelial growth factor regulates neovascularization in tumor microenvironment.

RNAi enables potent and specific gene silencing, potentially offering useful means for treatment of cancers. However, safe and efficient drug delivery systems (DDS) that are appropriate for intra-tumor delivery of siRNA or shRNA have rarely been established, hindering clinical application of RNAi technology to cancer therapy. We have devised hydrogel polymer nanoparticles, or nanogel, and shown its validity as a novel DDS for various molecules. Here we examined the potential of self-assembled nanogel of cholesterol-bearing cycloamylose with spermine group (CH-CA-Spe) to deliver vascular endothelial growth factor (VEGF)-specific short interfering RNA (siVEGF) into tumor cells. The siVEGF/nanogel complex was engulfed by renal cell carcinoma (RCC) cells through the endocytotic pathway, resulting in efficient knockdown of VEGF. Intra-tumor injections of the complex significantly suppressed neovascularization and growth of RCC in mice. The treatment also inhibited induction of myeloid-derived suppressor cells, while it decreased interleukin-17A production. Therefore, the CH-CA-Spe nanogel may be a feasible DDS for intra-tumor delivery of therapeutic siRNA. The results also suggest that local suppression of VEGF may have a positive impact on systemic immune responses against malignancies.