Published papers

Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of CAG triplets in the androgen receptor. Because the length of CAG repeat is inversely related with androgen receptor function, patients with a longer CAG repeat are expected to have a lower incidence of prostate cancer. Here, we report an extremely rare case of highstage prostate cancer in a patient with spinal and bulbar muscular atrophy, which responded to maximal androgen blockade therapy.

To understand mechanisms underlying acquisition of pluripotency, it is critical to identify cells that can be converted to pluripotent stem cells. For this purpose, we focused on unipotent primordial germ cells (PGCs), which can be reprogrammed into pluripotent embryonic germ (EG) cells under defined conditions. Treatment of PGCs with combinations of signaling inhibitors, including inhibitors of MAP2K (MEK), GSK3B (GSK-3beta), and TGFB (TGFbeta) type 1 receptors, induced cells to enter a pluripotent state at a high frequency (12.1%) by Day 10 of culture. When we employed fluorescence-activated cell sorting to monitor conversion of candidate cells to a pluripotent state, we observed a cell cycle shift to S phase, indicating enrichment of pluripotent cells, during the early phase of EG formation. Transcriptome analysis revealed that PGCs retained expression of some pluripotent stem cell-associated genes, such as Pou5f1 and Sox2, during EG cell formation. On the other hand, PGCs lost their germ lineage characteristics and acquired expression of pluripotent stem cell markers, such as Klf4 and Eras. The overall gene expression profiles revealed by this system provide novel insight into how pluripotency is acquired in germcommitted cells.

A 22-year-old woman complained of abdominal discomfort. Ultrasonography, computed tomography, and an endocrinologic work-up revealed a 7-cm nonfunctional tumor at the left adrenal lesion. A transumbilical laparo-endoscopic single-site adrenalectomy was successfully completed in 166 min. The postoperative period was uneventful. The pathologic examination confirmed the solid pseudopapillary tumor occurred in the retroperito-neum. There are only five previous reports of extrapan-creatic solid pseudopapillary tumors. In this case, the tumor was separated from the pancreas and no ectopic pancreas was histologically observed. To the best of our knowledge, this case is the first report of a solid pseudopapillary tumor of the retroperitoneum.

Objective: To assess the efficacy and safety of transurethral resection in saline vaporization for symptomatic bladder outlet obstruction and the change in prostate volume. Methods: A total of 106 patients with symptomatic bladder outlet obstruction underwent transurethral resection in saline vaporization. The effectiveness of the treatment was evaluated using the International Prostate Symptom Score (IPSS), quality of life score, urinary peak flow, and prostate volume preoperatively and at 1, 3, 6, and 12 months postoperatively. To assess the treatment effect, the patients were divided into 3 groups according to the preoperative prostate volume: group 1 (≥45 cm 3, n = 40), group 2 (<45 but ≥65 cm 3, n = 34), and group 3 (<65 cm 3, n = 32). Results: The mean perioperative hemoglobin loss was 1.2 g/dL. The mean IPSS, quality of life score, and prostate volume decreased significantly from 24.3, 5.2, and 52.8 cm 3 to 11.1, 2.7, and 29.9 cm 3, respectively (P <.01) and the mean urinary peak flow had increased significantly from 7.3 to 15.1 (P <.01) at 1 month. Moreover, the IPSS, quality of life score, and prostate volume had significantly decreased to 8.8, 2.3, and 26.1 cm 3 at 3 months (P <.05). The investigation of groups classified by prostate size demonstrated that the IPSS in group 3 continued at a significantly lower level than that in groups 1 and 2. The prostate volume decreased gradually and resulted in 52.8% volume reduction for ≤12 months. No significant complications were seen; however, irritative symptoms occurred frequently (11.3%). Conclusion: Transurethral resection in saline vaporization was a safe and effective treatment option and was more efficacious for patients with a larger prostate. The bother scores and prostate volume gradually decreased for ≤12 months.

Monocyte chemoattractant protein-1 (MCP-1/CCL2) is reported to contribute to tumor progression and is regulated by the renin-angiotensin system in hypertensive disease. In this study, we investigated the clinical outcome of MCP-1 expression in patients with prostate cancer (CaP) and the regulation of MCP-1 through angiotensin II (AngII) type 1 receptor (AT1R) in CaP. Specimens were obtained from 138 CaP patients and analyzed by immunostaining for both MCP-1 and macrophages. We investigated the regulation of MCP-1 expression through AT1R both in vivo and in vitro using three human prostate cancer cell lines: LNCaP, C4-2, and C4-2AT6. Specimens with a high Gleason score (<7) and a high pathological classification (≤pT3), and those with castration-resistant prostate cancer showed significantly higher MCP-1 expression and higher macrophage infiltration than low malignant potential CaP. High MCP-1 expression in CaP correlated significantly with high prostate-specific antigen (PSA) recurrence rates. AngII induced significantly higher MCP-1 levels in C4-2AT6 than in LNCaP, whereas AT1R blockade (ARB) inhibited MCP-1 production via the inhibition of the PI3K/Akt pathway in C4-2AT6. ARB also significantly suppressed MCP-1 expression in C4-2AT6 tumors. Our study is the first to demonstrate that both high MCP-1 expression and high macrophage infiltration in CaP specimens correlate with a high PSA recurrence rate and that ARB inhibits MCP-1 expression through the PI3K/Akt pathway and blocks macrophage infiltration in castration-resistant prostate cancer.

Background: The potential role of the renin-angiotensin system (RAS) in the promotion of tumour growth has been investigated, and the administration of RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), may improve disease control in malignancy. We investigated the prognostic impact of RAS inhibitors by analysing data from patients with upper-tract urothelial carcinoma (UTUC). Methods: A total of 279 patients who underwent nephroureterectomy for localised UTUC (pTa-3N0M0) were identified at our three institutions. We retrospectively investigated the prognostic outcomes following nephroureterectomy in patients administered or not administered ACEIs or ARBs. Results: The median follow-up period was 3.4 years. RAS inhibitors were administered to 48 patients (17.2%). Multivariate analysis showed that the appearance of pathological T3, positive lymphovascular invasion, and no RAS inhibitor administration (P=0.027 HR=3.14) were independent risk factors for a decrease in subsequent metastasis-free survival. The 5-year metastasis-free survival rate was 93.0% in patients who administered RAS inhibitors, and 72.8% in their counterparts who did not (P=0.008). Conclusion: The absence of RAS inhibitor administration was an independent risk factor for subsequent tumour metastasis in patients with localised UTUC. We propose RAS inhibitors may be a potent choice as an effective treatment following nephroureterectomy.

Background: We have started using laparo-endoscopic single-site surgery (LESS) in urologic surgery, although its use has not gained momentum due to its level of difficulty. We here report our initial experience with transumbilical LESS for adrenal cortical adenoma by using a single port with a multichannel cannula (SILS port) and bent laparoscopic instrumentation. Findings. A multichannel port (SILS port), bent laparoscopic instrument (Roticulator Endo Mini-Shears) and Opti4 laparoscopic electrodes were used in all cases. The intraperitoneal space was approached through the umbilicus. The SILS port was placed through a 2 cm incision at the inner edge of the umbilicus. A 5 mm flexible laparoscope was introduced to keep the laparoscope outside, and surgical specimens were extracted using an Endocatch bag. In addition, as a case control study, we compared perioperative data of LESS adrenalectomy (LESS-A) with that of conventional laparoscopic adrenalectomy (LA). We performed transumbilical LESS-A for adrenal cortical adenoma in 12 cases, beginning in December, 2009. All procedures were successfully completed, with only one incision through the umbilicus, and without conversion to a standard laparoscopic approach. Mean operative time for LESS-A was 121.2± 7.8 min, which was slightly longer than LA (110.2± 7.3 min). For right adrenal tumors, we used a miniport (2 mm port) in addition to a SILS port, and were able to successfully perform adrenalectomy "with no visible scaring". Tumor laterality and patient BMI did not affect surgical morbidity in these procedures. Moreover, there was no significant difference between LESS-A and LA in blood loss, analgesic requirement, hospital stay, and scar satisfaction. Conclusions: The transumbilical approach in LESS for adrenalectomy is safe and feasible and also improves cosmetic outcome compared with standard laparoscopic procedures. Improvements in surgical devices may aid the further development of this approach.

The Snail family transcription factors have been proposed as important mediators of epithelial-mesenchymal transition because of their role in down-regulation of E-cadherin and up-regulation of matrix metalloproteinases (MMPs). The present study was undertaken to investigate the expression of Snail, Slug and their associations with cancer invasion and prognosis in renal cell carcinomas (RCCs). Ninety-seven primary RCCs were analyzed for the protein expression of Snail, Slug, MMP2 and MMP9 by immunohistochemistry. Snail protein expression level was positively correlated with pathological tumor stage, histological grade and the presence of sarcomatoid carcinoma. On the contrary, Slug protein expression level was negatively correlated with pathological tumor stage, suggesting that Slug was down-regulated in advanced RCCs. Because Snail was positively associated with malignant potential of RCCs, involvement of Snail in the invasiveness of an RCC cell line 786-O was examined in the Matrigel invasion assay by down-regulating the gene expression with small interfering RNA (siRNA). Targeting the Snail, not Slug, expression in 786-O cells with siRNA caused down-regulation of the gene expression of Snail, vimentin, MMP2 and MMP9, but up-regulated the E-cadherin. Invasion of the cells through Matrigel in vitro was inhibited under this condition. Furthermore, expression levels of MMP2 and MMP9 were positively correlated with pathological tumor stage and the presence of sarcomatoid carcinoma. Statistical analysis indicated that elevated Snail, MMP2 and MMP9 protein expression are significantly worse predictors of disease-free and disease-specific survival of the patients with RCC. In conclusion, these data suggest that Snail has an important role in invasion and metastasis, and that silencing the gene may be a potential therapeutic target in RCCs.

Background: We investigated the changes in reactive oxygen species (ROS) and angiogenesis through angiotensin II (Ang II) type 1 receptor (AT1R) after the development of acquired platinum resistance in bladder cancer. Methods: Four invasive human bladder cancer cell lines, T24, 5637, T24PR, and 5637PR, were used in vitro, whereas in vivo, T24 and T24PR cells were used. T24PR and 5637PR cells were newly established at our institution as acquired platinum-resistant sublines by culturing in cisplatin (CDDP)-containing conditioned medium for 6 months. Results: Ang II induced significantly higher vascular endothelial growth factor (VEGF) production in T24PR and 5637PR cells than in their corresponding parent cells in vitro, whereas Ang II induced a further increase in VEGF production. These platinum-resistant cells also showed significantly higher AT1R expression than their corresponding parent cells. ROS was also significantly upregulated in T24PR and 5637PR cells, whereas increased AT1R expression was significantly downregulated by scavenging free radicals. We also demonstrated the efficacy of AT1R blockade at suppressing the growth of platinum-resistant xenograft model. Conclusion: Our findings indicate a new molecular mechanism for upregulated AT1R signalling through increased ROS when tumours progressed after the CDDP-based regimens, and shed light on the importance of AT1R blockade for platinum-resistant bladder cancers.

BACKGROUND Accumulating evidences has suggested that the renin-angiotensin system (RAS) participates in the regulation of tumor angiogenesis. We previously demonstrated that castration-resistant prostate cancer (CRPC) showed significantly higher angiotensin II (Ang II) type-1 receptor (AT1R) expression, and that AT1R blockade (ARB) exerted protective effects by inhibiting angiogenesis. However, the detailed molecular mechanisms for the increase of AT1R expression in CRPC has not been fully elucidated yet. METHODS In this study we used C4-2 and C4-2AT6 cells, which were PTEN-null, androgen receptor (AR) positive, PSA-producing CRPC cell lines. We investigated the association between phosphorylated Akt (pAkt) and AT1R expression, and used LY294002 as a PI3K/Akt inhibitor. RESULTS Western blot analysis revealed C4-2AT6 cells showed significantly higher pAkt expression than C4-2 cells, although there were no significant differences in total Akt (tAkt) expression. Immunohistochemical (IHC) analysis also revealed significant higher pAkt expression in C4-2AT6 tumors obtained from castrated male nude mice. These results indicated that C4-2AT6 cells acquired elevated pAkt status under androgen-ablated treatment in vitro. Treatment with LY294002 at the same dose reduced the viability of C4-2AT6 more effectively than that of C4-2, reflecting the dependency of cancer cells on PI3K/Akt pathway. The up-regulated AT1R expression in C4-2AT6 cells was reduced by LY294002 in a dose-dependent manner. On the other hand, in C4-2 cells, serum starvation induced pAkt up-regulation, which led to an increase of AT1R expression. CONCLUSIONS These findings indicated that up-regulation of pAkt contributed to elevated AT1R expression in CRPC.