市川 智彦

BACKGROUND/AIM: Biochemical failure after radiotherapy for prostate cancer occurs infrequently, but some cases progress to a poor outcome. The aim of this study was to examine prognosis after biochemical failure. PATIENTS AND METHODS: A total of 728 patients were treated with carbon ion radiotherapy, and biochemical failure occurred in 90 (12.4%). Their outcomes were examined according to risk factors, histological findings, and androgen deprivation therapy (ADT). RESULTS: Biochemical failure rates were 12%, 6%, and 15% in low-, intermediate- and high-risk patients. Most patients responded favorably to salvage therapy. Some high-risk patients (25%) progressed to poor outcome; half experienced failure after ADT, while the rest during ADT, indicating that ADT had a slight influence. Patients who died from their disease had approximately two years of biochemical failure-free time and three years of survival after failure. Their tumor showed the presence and the increased proportion of histologically high-grade growth patterns. CONCLUSION: Histological growth patterns and short biochemical failure-free time are prognostic factors for poor outcome regardless of ADT.

BACKGROUND: In 2003, the Japanese Urological Association (JUA) and Japanese Society of Endourology (JSE) established a urological laparoscopic skill qualification system, called the Endoscopic Surgical Skill Qualification System in Urological Laparoscopy of JUA and JSE (ESSQSJJ). The main goal of the system is to decrease the prevalence of complications associated with laparoscopic surgery. To validate the qualification system, perioperative outcome and the prevalence of complications in different types of urological laparoscopic surgery performed by accredited surgeons were evaluated. METHODS: One hundred thirty-six surgeons who obtained the qualification in 2004 were prospectively asked to submit intraoperative and postoperative data of their latest 20 cases at the end of 2009, along with the number of laparoscopic urological surgeries performed in each year for a 5-year period (2004-2009). Intraoperative and postoperative complications were graded according to the Satava classification and modified Clavien classification, respectively. RESULTS: Data of 2,590 urological laparoscopic surgeries of 130 surgeons, including 904 laparoscopic radical nephrectomies, 430 laparoscopic nephroureterectomies, 390 laparoscopic adrenalectomies, 320 laparoscopic radical prostatectomies, and 170 laparoscopic partial nephrectomies, were analyzed. Complications were noted in 97 (3.7%) patients. Major intraoperative complications (grade II or III) occurred in 32 (1.2%) patients, and major postoperative complications (grade III or higher) occurred in 24 (0.9%) patients. The prevalence of conversion to open surgery, allogeneic transfusion, and perioperative mortality was 2.5%, 1.6%, and 0%, respectively. The number of surgeries performed by each qualified surgeon or the role of the surgeon (main operator vs. mentor/instructor) in the surgery did not affect the prevalence of intraoperative complications or postoperative complications. The open conversion rate was significantly higher in surgeons with a low surgical volume. CONCLUSIONS: ESSQSJJ can ensure urological laparoscopic surgeons who can perform various types of urological laparoscopic surgeries with a low prevalence of perioperative complications and reasonable outcomes.

In 1994, carbon-ion radiotherapy was started at the National Institute of Radiological Sciences using the Heavy-Ion Medical Accelerator in Chiba. Between June 1995 and March 2000, two phaseI/II dose escalation studies (protocols 9402 and 9703) of hypofractionated carbon-ion radiotherapy for both early- and advance-stage prostate cancer patients had been carried out to establish radiotherapy technique and to determine the optimal radiation dose. To validate the feasibility and efficacy of hypofractionated carbon-ion radiotherapy, a phaseII study (9904) was initiated in April 2000 using the shrinking field technique and the recommended dose fractionation (66 gray equivalents in 20 fractions over 5weeks) obtained from the phaseI/II studies, and was successfully completed in October 2003. The data from 175 patients in the phaseII study showed the importance of an appropriate use of androgen deprivation therapy according to tumor risk group. Since November 2003, carbon-ion radiotherapy for prostate cancer was approved as "Highly Advanced Medical Technology" from the Ministry of Health, Labor, and Welfare, and since then approximately 1100 patients have received carbon-ion radiotherapy as of July 2011. In this review, we introduce our steps thorough three clinical trials carried out at National Institute of Radiological Sciences, and show the updated data of carbon-ion radiotherapy obtained from approximately 1000 prostate cancer patients. In addition, our recent challenge and future direction will be also described. © 2012 The Japanese Urological Association.

BACKGROUND: Primary aldosteronism caused by aldosterone-producing adenoma is the most common curable cause of secondary hypertension, but despite resection, many patients continue to require antihypertensive medications to control their blood pressure postoperatively. The Aldosteronoma Resolution Score is a preoperative 4-item predictive model for the complete postoperative resolution of hypertension. Our aim was to validate the accuracy of this model in predicting postoperative resolution of hypertension in Japanese patients. METHODS: The records of 91 Japanese patients who underwent unilateral adrenalectomy for aldosterone-producing adenoma were surveyed retrospectively. Patients were distributed into 2 groups according to whether blood pressure was normal without antihypertensive medications at 6 months postoperatively. Clinical and biochemical data were evaluated at baseline and after the 6-month follow-up. RESULTS: At 6 months, blood pressure had normalized in 45% of the patients without antihypertensive medications. Multivariate logistic regression analysis revealed that patients who had complete resolution of hypertension were significantly more likely to have been taking ≤2 antihypertensive medications preoperatively, have a duration of hypertension of <6 years, and be female. The predictive accuracy of the Aldosteronoma Resolution Score was assessed using the area under the curve of receiver operator characteristics analysis. The value of the area under the curve was 0.81. CONCLUSION: Our external validation revealed that the Aldosteronoma Resolution Score developed using Western data can identify accurately Japanese individuals with aldosterone-producing adenoma who are likely to have complete resolution of hypertension after adrenalectomy.

Combined androgen blockade is widely used to treat patients with advanced prostate cancer. Recently, zoledronic acid was proven to be effective in preventing skeletal-related events for prostate cancer patients with bone metastases. Aim of the present study was to assess the effect of adding zoledronic acid to combined androgen blockade in the treatment of hormone-naïve metastatic prostate cancer patients by analyzing the changes of biomarker levels. Patients were treated with either a combination of combined androgen blockade and zoledronic acid (n=23) or combined androgen blockade alone (historical control combined androgen blockade group, n=42). Zoledronic acid was injected intravenously at 4 mg every 4 weeks for 2 years. Prostate-specific antigen and bone turnover markers (alkaline phosphatase and pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen) were examined before treatment and at 3, 6, and 12 months after treatment. Sequential changes of prostate-specific antigen, alkaline phosphatase and pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen for the two groups versus pretreatment levels were compared. Prostate-specific antigen values in both groups significantly declined at 3, 6 and 12 months compared with pretreatment levels. However, the decline of the prostate-specific antigen was lower in the combined androgen blockade group. Alkaline phosphatase significantly declined at 6 and 12 months in the combination of combined androgen blockade and zoledronic acid group, with no significant changes seen in the combined androgen blockade group. The addition of zoledronic acid to combined androgen blockade showed prostate-specific antigen and bone turnover markers response compared with combined androgen blockade therapy only, suggesting a potential antitumor effect of zoledronic acid in the management of metastatic prostate cancer patients.

Fork-head box protein A1 (FOXA1) is a "pioneer factor" that is known to bind to the androgen receptor (AR) and regulate the transcription of AR-specific genes. However, the precise role of FOXA1 in prostate cancer (PC) remains unknown. In this study, we report that FOXA1 plays a critical role in PC cell proliferation. The expression of FOXA1 was higher in PC than in normal prostate tissues (P = 0.0002), and, using immunohistochemical analysis, we found that FOXA1 was localized in the nucleus. FOXA1 expression levels were significantly correlated with both PSA and Gleason scores (P = 0.016 and P = 0.031, respectively). Moreover, FOXA1 up-regulation was a significant factor in PSA failure (P = 0.011). Depletion of FOXA1 in a prostate cancer cell line (LNCaP) using small interfering RNA (siRNA) significantly inhibited AR activity, led to cell-growth suppression, and induced G0/G1 arrest. The anti-proliferative effect of FOXA1 siRNA was mediated through insulin-like growth factor binding protein 3 (IGFBP-3). An increase in IGFBP-3, mediated by depletion of FOXA1, inhibited phosphorylation of MAPK and Akt, and increased expression of the cell cycle regulators p21 and p27. We also found that the anti-proliferative effect of FOXA1 depletion was significantly reversed by simultaneous siRNA depletion of IGFBP-3. These findings provide direct physiological and molecular evidence for a role of FOXA1 in controlling cell proliferation through the regulation of IGFBP-3 expression in PC.

BACKGROUND: Our recent analyses of miRNA expression signatures showed that miR-1 and miR-133a were significantly reduced in several types of cancer. Interestingly, miR-1 and miR-133a are located on the same chromosomal locus in the human genome. We examined the functional significance of miR-1 and miR-133a in prostate cancer (PCa) cells and identified the novel molecular targets regulated by both miR-1 and miR-133a. METHODS and RESULTS: The expression levels of miR-1 and miR-133a were significantly downregulated in PCa compared with non-PCa tissues. Restoration of miR-1 or miR-133a in PC3 and DU145 cells revealed significant inhibition of proliferation, migration, and invasion. Molecular target identification by genome-wide gene expression analysis and luciferase reporter assay showed that purine nucleoside phosphorylase (PNP) was directly regulated by both miRNAs. Silencing of the PNP gene inhibited proliferation, migration, and invasion in both PC3 and DU145 cells. Immunohistochemistry detected positive staining of PNP in PCa specimens. CONCLUSIONS: Downregulation of miR-1 and miR-133a was a frequent event in PCa and both function as tumour suppressors. The PNP is a novel target gene of both miRNAs and potentially functions as an oncogene. Therefore, identification of novel molecular networks regulated by miRNAs may provide new insights into the underlying causes of PCa oncogenesis. British Journal of Cancer (2012) 106, 405-413. doi:10.1038/bjc.2011.462 www.bjcancer.com Published online 8 November 2011 (C) 2012 Cancer Research UK

BACKGROUND: Urinary dysfunction is common in Parkinson's disease (PD); however, little is known about urinary dysfunction in early and untreated PD patients. METHODS: Fifty consecutive untreated PD patients (mean age, 66.7; mean disease duration, 23.6 months; and mean Hoehn & Yahr scale, 1.9) were recruited; those with other conditions that might have influenced urinary function were excluded. Patients were evaluated using a urinary questionnaire and urodynamic studies. RESULTS: Sixty-four per cent complained of urinary symptoms (storage, 64.0%; voiding, 28.0%). Urodynamic studies showed abnormal findings in the storage phase in 84%, with detrusor overactivity (DO) and increased bladder sensation without DO in 58.0% and 12.0% of patients, respectively. In the voiding phase, detrusor underactivity, impaired urethral relaxation such as detrusor sphincter dyssynergia, and bladder outlet obstruction were present in 50.0%, 8.0% and 16% of patients, respectively. In patients with both storage and voiding phase abnormalities, DO+detrusor underactivity was the most common finding. Few patients experienced urge incontinence and/or quality-of-life impairment owing to urinary dysfunction; none had low-compliance bladder or abnormal anal-sphincter motor unit potential. These urinary symptoms and urodynamic findings were not correlated with gender, disease severity or motor symptom type. CONCLUSION: Urinary dysfunction, manifested primarily as storage disorders with subclinical voiding disorders and normal anal-sphincter electromyography, occurs in early and untreated PD patients. In cases with severe voiding disorder and/or abnormal anal-sphincter electromyography, other diagnoses should be considered.

The aim of the present study was to compare the accuracy of three prognostic models in predicting recurrence-free survival among Japanese patients who underwent nephrectomy for non-metastatic renal cell carcinoma (RCC). Patients originated from two centers: Chiba University Hospital (n = 152) and Chiba Cancer Center (n = 65). The following data were collected: age, sex, clinical presentation, Eastern Cooperative Oncology Group performance status, surgical technique, 1997 tumor-node-metastasis stage, clinical and pathological tumor size, histological subtype, disease recurrence, and progression. Three western models, including Yaycioglu's model, Cindolo's model and Kattan's nomogram, were used to predict recurrence-free survival. Predictive accuracy of these models were validated by using Harrell's concordance-index. Concordance-indexes were 0.795 and 0.745 for Kattan's nomogram, 0.700 and 0.634 for Yaycioglu's model, and 0.700 and 0.634 for Cindolo's model, respectively. Furthermore, the constructed calibration plots of Kattan's nomogram overestimated the predicted probability of recurrence-free survival after 5 years compared with the actual probability. Our findings suggest that despite working better than other predictive tools, Kattan's nomogram needs be used with caution when applied to Japanese patients who have undergone nephrectomy for non-metastatic RCC.

The aim of this study was to establish the discriminating accuracy of Kanao's pre-operative nomogram for renal cell carcinoma in predicting cause-specific survival among representative patients who underwent nephrectomy. Patients originated from two centers: Chiba University Hospital (n= 151) and Chiba Cancer Center (n = 91). We validated the predictive accuracy, which was assessed using Harrell's concordance-index. The concordance-index values were 0.692 and 0.834 for Chiba University Hospital and Chiba Cancer Center, respectively, although it was 0.822 for the combined data sets. Results of external validation were different at each cohort. We constructed calibration plots of Kanao's nomogram and confirmed the tendency at each institution. Inconsistency of results among two centers makes it difficult to reach a valid conclusion. Therefore, the predictive accuracy of Kanao's nomogram was not settled. Clinicians need to confirm the predictive accuracy of Kanao's nomogram and construct calibration plots when applying this nomogram to different patient populations.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression, primarily at the post-transcriptional level. Growing evidence suggests that miRNAs function as oncogenes or tumor suppressors in human cancers. The down-regulation of miR-145 has been reported in many types of human cancer, including prostate cancer (PC), suggesting that miR-145 functions as a tumor suppressor. Using the PC cell lines, PC3 and DU145, gain-of-function assays revealed that miR-145 transfection inhibited cell proliferation, migration and invasion. Fascin homolog 1 (FSCN1), an actin-bundling protein, is a candidate target gene of miR-145 based on genome-wide gene expression analysis. A luciferase reporter assay showed a significantly decreased signal at two miR-145 target sites at the 3'UTR of FSCN1, suggesting that miR-145 directly regulates FSCN1. In FSCN1 loss-of-function assays, cell growth, migration and invasion were all inhibited, implying that FSCN1 is associated with the progression of PC. The identification of tumor suppressive miRNAs and their target genes could provide new insights into the potential mechanisms of prostate carcinogenesis.

褐色細胞腫は，腫瘍摘出後に低血圧となり輸液による容量負荷のみでは改善せず，カテコラミン補充を必要とする症例が少なからず存在する．今回，当院において褐色細胞腫に対して副腎摘除術を施行した症例を用いて，術後カテコラミン補充に関する臨床的検討を行った．1997年8月から2010年9月までに手術施行され診療録から術後カテコラミン補充に関する経過が確認できた44例を対象とした．術後カテコラミン補充の有無及びその補充期間に関して，各臨床項目との関係を統計学的に解析した．多重ロジスティック回帰分析の結果，術後カテコラミン補充が必要となる症例を予測する因子として，術前の血中アドレナリン値及び術中の最大Catecholamine Indexで有意差を認めた．術後カテコラミン補充を必要とした期間と有意な相関を認める臨床項目はなかった．