How asymptomatic are early cancer patients of five organs based on registry data in Japan.

BACKGROUND: One reason for the low cancer screening rate in Japan is that people are not concerned about cancer if they do not have symptoms. METHODS: The authors retrospectively analyzed 18,405 cancer patients using hospital-based cancer registry data collected between 2007 and 2013 at the 13 hospitals of Shimane Prefecture, Japan. The symptomatic rates of five cancers (stomach, colorectal, lung, breast, and cervix) at each stage and the time of early diagnosis were investigated. The early detection rates of symptomatic and asymptomatic individuals were investigated. RESULTS: The percentages of symptomatic cases tended to increase with progressive stages. The odds ratio (OR) of stage IV compared with that of stage I was 12.23 for stomach, 7.21 for colorectal, 16.91 for lung, 10.30 for breast, and 51.62 for cervical cancer. The proportions of early symptomatic cases at the time of diagnosis were low. Compared with the percentage of early symptomatic cases of stomach cancer of 25.5%, the percentage of lung cancer was the lowest, at 8.2% (OR 0.26), and the percentage of breast cancer was the highest, at 30.2% (OR 1.26). The percentages of early symptomatic cases of colorectal and cervical cancer were 18.9% (OR 0.68) and 19.9% (OR 0.73), respectively. The early detection rates of the asymptomatic and symptomatic groups were 77.6 and 36.1%, respectively. CONCLUSION: Cancer registry data indicate that early cancers are asymptomatic, and once symptoms appear, treatment may not be effective. Policy makers should inform people of the necessity of cancer screening before they have symptoms.

Prediction of survival benefit using an automated bone scan index in patients with castration-resistant prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? A bone scan index (BSI) can quantify the extent of bone involvement and response to treatment, but it has not been widely accepted, because of its time-consuming nature. The study is the first to demonstrate that automated BSI calculated with a computer-assisted diagnosis system is effective in judging the chemotherapeutic response of bone metastatic lesions in patients with castration-resistant prostate cancer. OBJECTIVE: • To evaluate the value of an automated bone scan index (aBSI), calculated using a computer-assisted diagnosis system, to indicate chemotherapy response and to predict prognosis in patients with castration-resistant prostate cancer (CRPC) with bone metastasis. PATIENTS AND METHODS: • Forty-two consecutive CRPC patients underwent taxane-based chemotherapy between November 2004 and March 2011 at our institution. • The aBSIs were retrospectively calculated at the diagnosis of CRPC and 16 weeks after starting chemotherapy. • Cox proportional hazards regression models were applied to multivariate analyses with and without aBSI response in addition to the basic model. • Based on the difference in the concordance index (c-index) between each model, the prognostic relevance of adding the aBSI response was determined. RESULTS: • A decrease in aBSI was found in 28 patients (66.7%), whereas a response was shown by bone scan in only 23.8% of patients. • Patients with a reduction in aBSI had longer overall survival (OS) in comparison with the other patients (P= 0.0157). • Multivariate analysis without aBSI response showed that performance status (P= 0.0182) and PSA response (P= 0.0375) were significant prognosticators. • By adding the aBSI response to this basic model, the prognostic relevance of the model was improved with an increase in the c-index from 0.621 to 0.660. CONCLUSIONS: • The aBSI reflected the chemotherapy response in bone metastasis. • The index detected small changes of bone metastasis response as quantified values and was a strong prognostic indicator for patients with CRPC.

Simultaneous implantation of bilateral ureters into bladder acellular matrix graft after partial cystectomy in a porcine model.

UNLABELLED: What's known on the subject? and What does the study add? The process of bladder regeneration with a bladder acellular matrix graft (BAMG) is thought to be accelerated by administration of vascular endothelial growth factor into the host bladder. In the present study, we showed that simultaneous implantation of bilateral ureters into a BAMG after a partial cystectomy is reasonable and provides an increased opportunity to the bio-scaffold for communication with host tissues from which a blood supply and stem cells will be generated. OBJECTIVE: • To evaluate if the implantation of bilateral ureters into a bladder acellular matrix graft (BAMG) at the time of its implantation would enhance bladder regeneration in a partial substitution BAMG. MATERIALS AND METHODS: • Partial cystectomies were performed under general anaesthesia in 12 pigs, followed by augmentation with a BAMG. • Six (ureteric implantation group) also received simultaneous implantation of bilateral ureters into the BAMG, while the remaining six (control group) did not have ureteric implantation. • In both groups, bladder regeneration was evaluated using endoscopic and histopathological methods at 1, 2, 4, and 8 weeks after implantation. RESULTS: • At 1 week after BAMG implantation, there were significant inflammatory changes on the host bladder in both groups, while no significant endoscopic changes were seen on the BAMG luminal surfaces. • At 2 weeks, inflammatory changes were diminished and epithelialisation on the BMAG was identified, especially near the host bladder in both groups. • Similarly, epithelialisation on the BAMG near the implanted ureters was seen in the ureteric implantation group. • At 4 and 8 weeks, epithelialisation remained in progress in both groups, although it was more active and expansive in the ureteric implantation group. CONCLUSIONS: • In our porcine model, endoscopic and histopathological examinations showed that simultaneous implantation of bilateral ureters into a BAMG enhanced epithelialisation of the AMG. • This new approach using host ureters and bladder as a potential source of bladder regeneration may provide for rapid and complete regeneration of a bladder substitute.

Paget's disease of the vulva with bladder invasion: a case report.

Tumor excision and dermal-flap skin graft operations were performed on a 72-year-old woman diagnosed with extramammary Paget's disease at our hospital in August 2001. Paget cells were identified in the external urethral meatus even though nine local excisions of recurrent tumors had been performed. She was suffered from severe vesical pain from May 2007. Urine cytology was class V and physical examination revealed redness in external urethral meatus. Pelvic MRI did not show apparent lymph node swelling and the endoscopic multiple biopsies performed at multiple bladder mucosa and distal urethra. Pathological diagnosis of the endoscopic biopsy showed multiple Paget cells from urethra, posterior and bilateral lateral wall, and bladder neck. Because Paget's disease may infiltrate bladder mucosa and cause severe vesical pain due to bladder invasion, total cystorethrectomy, ileal conduit, and external skin excision were performed. Pathological findings were continuous infiltration of Paget cells from external urethral meatus to bladder mucosa.

A case of primary retroperitoneal serous adenocarcinoma.

Primary retroperitoneal serous adenocarcinoma (PRSA) is an extremely rare malignancy, of which only six cases have been reported in the literature. Here, we describe a PRSA in a 75-year-old woman treated with surgical excision and adjuvant chemotherapy. The pathological features of PRSA resemble those of ovarian serous carcinoma, which suggests that a combination of surgical excision with adjuvant chemotherapy may be the best option.

Patient Safety Activity Under the Social Insurance Medical Fee Schedule in Japan: An Overview of the 2010 Nationwide Survey.

OBJECTIVES: Little is known about patient safety performance under the social insurance medical fee schedule in Japan. The Health Ministry in Japan introduced the preferential patient safety countermeasure fee (PPSCF) to promote patient safety in 2006 and revised the PPSCF system in 2010. This study aims to address the patient safety performance status at hospitals implementing the PPSCF. METHODS: A nationwide questionnaire survey targeting 2674 hospitals with the PPSCF was performed in 2010 to 2011. The 627 participant hospitals were divided into the following three groups: 178 hospitals implementing PPSCF 1 with 400 beds or more (group A), 286 hospitals implementing PPSCF 1 with 399 beds or fewer (group B), and 163 hospitals implementing PPSCF 2 (group C). RESULTS: The mean numbers (standard errors) of patient safety managers were 1.45 (0.07) in group A, 1.12 (0.04) in group B, and 0.37 (0.12) in group C (P < 0.001). The participation number and rates of all staff for the patient safety seminar were 1721 (167) and 1.64 (0.10) in group A, 580 (26) and 1.94 (0.09) in group B, and 349 (31) and 1.98 (0.17) in group C (P < 0.001, P = 0.105).These results can be explained because hospitals with PPSCF 1 (groups A and B) must assign at least one full-time patient safety manager, whereas hospitals with PPSCF 2 (group C) are not required to do so. Patient safety performance at hospitals with PPSCF 1 was more active than that at hospitals with PPSCF 2. However, when the values were converted to per capita or per 100 beds, there were no differences across the three groups. CONCLUSIONS: The PPSCF encourages hospitals to perform actions for patient safety by providing incentives under the social insurance medical fee schedule in Japan.

Impact of a novel, extended approach of perineal radical prostatectomy on surgical margins in localized prostate cancer.

STUDY TYPE: Therapy (case series) Level of Evidence 4. OBJECTIVE: To validate the rationale of extended perineal radical prostatectomy (ePRP) for treating localized prostate cancer. PATIENTS AND METHODS: Between December 2000 and May 2007, 196 patients with localized prostate cancer underwent PRP, among which 91 and 105 patients were treated with conventional PRP (cPRP) and ePRP, respectively. The apex, middle, base, and anterior regions of the prostate were separately analysed, and the focus of analysis was on the distribution, size, Gleason score, and positive surgical margins (PSMs) of prostate cancer foci. RESULTS: The operation time was significantly shorter in ePRP compared with cPRP (161 min vs 188 min; P= 0.001), while there was no significant difference in estimated blood loss between cPRP and ePRP (550 mL vs 500 mL). At the apex and base, there was no significant difference in the PSM rate between cPRP and ePRP. In the middle, there was a lower incidence of PSMs in ePRP (2.4%) than in cPRP (10.9%; P= 0.009). On the anterior side, PSMs were more frequent in cPRP (21.6%) than in ePRP (7.1%; P= 0.029). Logistic regression analysis adjusted by PSA level showed that PSM rate was the most significantly affected by the surgical approach. CONCLUSION: We think that ePRP provides an effective treatment strategy for localized prostate cancer in light of excellent cancer control and minimum potential of surgical invasiveness.

Bcl2 -938C/A polymorphism carries increased risk of biochemical recurrence after radical prostatectomy.

PURPOSE: Approximately 10% to 26% of patients show biochemical failure after radical prostatectomy or radiation therapy. The importance of cell cycle and apoptosis pathways in prostate cancer has been reported. However, to our knowledge there is currently no information on the role of apoptosis and cell cycle related gene polymorphisms in prostate cancer cases. We investigated several polymorphisms related to the cell cycle and apoptosis, and their role in biochemical failure after radical prostatectomy. MATERIALS AND METHODS: We genotyped 6 single nucleotide polymorphisms in 6 genes, including p53 (rs1042522), p21 (rs1801270), MDM2 (rs2279744), PTEN (rs701848), GNAS1 (rs7121) and bcl2 (rs2279115), using polymerase chain reaction-restriction fragment length polymorphism and direct DNA sequencing in 140 patients with prostate cancer and 167 age matched controls. The association of polymorphic variants with prostate specific antigen failure in patients with prostate cancer was analyzed by Kaplan-Meier curves. RESULTS: A significant increase in the frequency of the C/C genotype of GNAS1 rs7121 was observed in patients compared with controls. Interestingly we found a significant difference in biochemical recurrence-free time between the bcl2 C/C and C/A+A/A genotypes. It was also noted that the bcl2 C/C genotype was an independent risk factor for biochemical recurrence after radical prostatectomy on multivariate analysis. There was no statistical difference in the genotype distributions of the other genes between patients and controls. CONCLUSIONS: To our knowledge this is the first report documenting that bcl2 promoter region -938 C/C genotype carriers more frequently show biochemical recurrence than -938C/A+A/A carriers.

Retrospective analysis of the distance between the neurovascular bundle and prostate cancer foci in radical prostatectomy specimens: its clinical implication in nerve-sparing surgery.

OBJECTIVE: To analyse the distance between the ipsilateral neurovascular bundles (NVBs) and foci of prostate cancer (N-T distance) in specimens removed by radical prostatectomy (RP) and identify the predictor for N-T distance for preserving the ipsilateral NVB, as an accurate understanding of the anatomical relationship between prostate cancer foci and the NVB is necessary for establishing the indications for the appropriate use of nerve-sparing (NS) modifications of RP. PATIENTS AND METHODS: The study included 245 patients with prostate cancer who had RP through the perineal or retropubic approach between June 2000 and November 2006. The analysis focused on 302 foci of prostate cancer (192 cases), which involved at least the posterolateral region of the prostate. The N-T distance was separately measured in the apex, middle and base of the prostate, and was correlated with the maximum diameter and Gleason score of the foci, and the preoperative prostate-specific antigen (PSA) level. RESULTS: The mean N-T distance was 2.98, 2.95 and 3.03 mm in the apex (216 foci), middle (195 foci) and base (80 foci), respectively. In the apex, the N-T distance was related to both tumour size and preoperative PSA value (P < 0.001 and P < 0.05, respectively). In the base, tumour size was related to the N-T distance (P < 0.01), but the preoperative PSA level was not related to the N-T distance. In the middle, the association of tumour size with N-T distance was of borderline significance (P = 0.07). Irrespective of tumour location, the Gleason score did not contribute to the N-T distance. CONCLUSIONS: These findings show the basic information necessary when making a decision to perform NS-RP in patients with localized prostate cancer. The application of N-T distance could provide a better strategy for determining indications that warrant the use of NS RP than with the conventional tactile feedback approach.

Five-year longitudinal effect of radical perineal prostatectomy on health-related quality of life in Japanese men, using general and disease-specific measures.

OBJECTIVE: To investigate the longitudinal alteration of health-related quality of life (HRQL) up to 5 years after radical perineal prostatectomy (RPP) among Japanese patients with localized prostate cancer. PATIENTS AND METHODS: In all, 194 patients who had RPP were included in this longitudinal survey. The validated RAND 36-Item Health Survey (SF-36) and the University of California, Los Angeles Prostate Cancer Index (UCLA-PCI) were used to evaluate the HRQL. RESULTS: Among the UCLA-PCI urinary domains, urinary function scores decreased at 3 months after RPP, but they increased 6 months after RPP. Likewise, urinary bother showed a transient decrease at 3 months, but had returned to the baseline level 6 months after RPP. Sexual function (SF) was drastically decreased at 3 months after RPP, but had slightly increased 1 year after RPP. Patients who had a nerve-sparing (NS) RPP showed better SF-related HRQL than those who did not at 6 months after RPP. This favourable alteration involving SF-related HRQL was closely associated with the NS procedure, but not with the patient age. Multivariate analysis showed that later recovery of SF was essentially related to the use of NS RPP, while early recovery of sexual bother was closely related to the patient age. CONCLUSIONS: Our results confirmed the positive effect of RPP on the long-term HRQL in Japanese patients. Although NS surgery conferred the benefit of the recovery of SF, older Japanese patients were not greatly concerned about their decreased SF-related HRQL. The current results provide primary evidence for predicting the alteration of HRQL and understanding the effect of patient age and NS surgery on HRQL after RPP.

Nerve growth factor combined with vascular endothelial growth factor enhances regeneration of bladder acellular matrix graft in spinal cord injury-induced neurogenic rat bladder.

OBJECTIVE: To determine the combined effects of nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) on regeneration of the bladder acellular matrix graft (BAMG) in spinal cord injury (SCI)-mediated neurogenic bladder in rats. MATERIALS AND METHODS: In all, 40 female Sprague-Dawley rats were used. At 8 weeks after spinalization surgery (neurogenic bladder), they were divided into five groups consisting of untreated controls and those whose bladders were injected with either no growth factor, NGF (2 microg/rat), VEGF (2 microg/rat) or both at partial BAMG replacement surgery. After 8 weeks, bladder function was assessed by urodynamic studies and the bladders were harvested for histological examination. Smooth muscle induction, collagen and nerve fibre regeneration were assessed immunohistochemically using antibodies to smooth muscle actin (alpha-actin), Masson's trichrome and protein gene product 9.5, respectively. RESULTS: Bladder capacity and compliance were significantly increased in all BAMG groups 8 weeks after surgery compared with that before bladder replacement surgery. Bladder capacity and compliance were much higher in the VEGF and NGF combined group than in the control, or NGF and VEGF alone groups. There was no significant difference in the residual volume ratio among all groups. CONCLUSIONS: This is the first report showing that NGF has a significant synergistic effect on the development, differentiation and functional restoration of the BAMG when administered with VEGF in neurogenic bladder. Our results indicate that NGF may be a useful cytokine for enhancing the regeneration of a functional bladder following acellular matrix grafting in a neurogenic rat model.

Cluster outbreak of Pneumocystis pneumonia among kidney transplant patients within a single center.

Pneumocystis pneumonia (PCP), a life-threatening opportunistic infection occurring in immunocompromised hosts, developed in 10 patients in the past 35 years at our hospital. Among the 7 outpatients and 3 inpatients, 9 cases clustered within 7 months. The mean time was 32.1 +/- 27.5 months between transplantation and PCP diagnosis. The mortality rate was 33.3%. The patients developing PCP were older at transplantation (46.9 +/- 11.8 vs 34.0 +/- 11.1 years; P = .003) and had a longer pretransplantation dialysis period (146.3 +/- 120.0 vs 51.3 +/- 66.6 months; P < .0001). Multivariate analysis showed that age at transplantation and the use of mycophenolate mofetil (MMF) were risk factors for development of PCP. Despite prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) during the first 3 to 6 months after transplantation, the time period that showed the highest incidence rate of PCP, the disease may occur at later intervals.

Current use of the artificial urinary sphincter and its long-term durability: a nationwide survey in Japan.

OBJECTIVES: Although the artificial urinary sphincter (AUS) is one of the most effective surgical treatments for severe urinary incontinence, little is known about its use in Japan. A nationwide survey was done to determine contemporary trends in AUS use and its long-term durability. METHODS: Data on AUS units sold in Japan were provided directly by Takai Hospital Supply Co., Ltd., Tokyo, Japan, and a survey form was sent to all 44 institutes where AUS implantation had been carried out. The survey included various demographic and preoperative variables, surgical variables, and postoperative outcomes. RESULTS: Between 1994 and 2007, a total of 100 AUS devices had been provided in Japan. Of the 44 institutes, 24 responded to the survey, and a total of 64 patients were enrolled in the study. Post-urological surgery incontinence accounted for 81.3% of the indications. During the mean follow-up of 50 months, mechanical failure occurred in four (6.2%), and the device was removed in 13 (20.3%) due to infection (14.0%), erosion (4.7%), or urination difficulty (1.5%). Of the 58 patients evaluated, 91.4% reported social continence. Five- and 10-year failure-free rates were 74.8% and 70.1%, respectively. On multivariate analysis, operative time was an independent predictor of treatment failure (P = 0.0334). CONCLUSIONS: Considering recent trends in prostate surgery, the AUS may be significantly underused in Japan. Although excellent long-term durability has been achieved, a learning effect appears to be evident. The Japanese urological community needs to provide appropriate patients with this treatment option.

Burden of male stress urinary incontinence: a survey among urologists in Japan.

OBJECTIVE: To determine the burden of male stress urinary incontinence (SUI) in Japan and to identify candidates for artificial urinary sphincter (AUS) implantation. METHODS: In 2008, a survey form was sent to all 1202 training hospitals certified by the Japanese Urological Association. The survey included questions about the number of patients with moderate to severe SUI who could be candidates for AUS implantation, the etiology, and incidence of SUI in 2007. RESULTS: Overall, 682 (56.7%) responded to the survey. The total number of patients was 1276. The most common reported etiology for SUI was post-radical prostatectomy (59.1%), followed by neurogenic bladder (23.0%), surgery for benign prostatic hyperplasia (10.3%), neobladder reconstruction (2.8%), urethral injury (2.4%), and others (2.4%). There were 203 new cases in 2007. Adjusted by the response rate, the prevalence and annual incidence were estimated to be 2235 and 358 cases, respectively. CONCLUSIONS: This survey confirms that a significant number of men suffer from moderate to severe SUI, with the majority of cases being post-prostatectomy incontinence. The Japanese urological community needs to provide appropriate treatment for these patients.

Primary care doctor fostering and clinical research training in Sweden: Implications for Japan.

In 2018, a new training program for primary care physicians was launched in Japan. As physicians responsible for the training of new primary care physicians, we have faced many problems, particularly in rural areas. The influence of this new program on primary care physicians in rural areas of Japan has not been sufficiently investigated. The aim of this research was to improve training for primary care physicians in Japan by examining training programs in Sweden, where the population challenges are similar to those seen in Japan. In this paper, we will express our opinions and describe the differences in the primary care fostering systems and clinical research training for generalist in Japan and Sweden.

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.

Rationale and clinical implication of combined chemotherapy with cisplatin and oestrogen in prostate cancer: primary evidence based on methylation analysis of oestrogen receptor-alpha.

OBJECTIVE: To determine whether oestrogen enhances platinum sensitivity, and if promoter CpG methylation of the oestrogen receptor-alpha (ER-alpha) gene determines the potential of cisplatin-induced apoptosis in prostate cancer, as the high-mobility group 1 (HMG1) preferentially binds to cisplatin-modified DNA and is up-regulated after oestrogen treatment in breast cancer cell line MCF-7. MATERIALS AND METHODS: The study comprised prostate cancer cell lines (LNCaP and PC-3), 156 pathologically confirmed 156 radical prostatectomy samples and eight hormone-refractory prostate cancer (HRPC) samples (from needle biopsy). Expression of HMG1 in cell lines was analysed by Western blotting or differential reverse-transcription-polymerase chain reaction (PCR). The methylation status of ER-alpha was analysed by methylation-specific PCR using bisulphite DNA as a template or bisulphite DNA sequencing. RESULTS: In LNCaP cells, treatment with oestrogen increased HMG1 expression and co-treatment with cisplatin and oestrogen reduced cell viability by accelerating apoptosis, compared with cisplatin alone. However, in PC-3, oestrogen did not up-regulate HMG1 or accelerate the cisplatin-induced apoptosis. Although ER-beta was expressed in both LNCaP and PC-3, ER-alpha was expressed only in LNCaP. Bisulphite DNA sequencing of the ER-alpha promoter showed partial methylation in LNCaP but complete methylation in PC-3. ER-alpha AS transfection diminished the cisplatin-induced apoptosis in oestrogen-treated LNCaP cells. In clinical samples there was ER-alpha hypermethylation in 40% of prostate cancers this correlated with Gleason score (GS, 31% for GS < 7, 50% for GS = 7 and 56% for GS > 7). In addition, five of eight HRPC samples showed ER-alpha hypermethylation. CONCLUSION: These findings suggest that HMG1 induction as an enhancer of platinum sensitivity is mediated through interaction between oestrogen and ER-alpha. As CpG hypermethylation of the ER-alpha promoter is a frequent event in aggressive prostate cancer, negative conversion of ER-alpha methylation is essential to achieve the most beneficial effect when combined chemotherapy of cisplatin with oestrogen is used in patients with prostate cancer.

Long-term control or possible cure? Treatment of stage D2 prostate cancer under chemotherapy using cisplatin and estramustine phosphate followed by maximal androgen blockade.

Metastatic prostate cancer (PC) is incurable by androgen deprivation therapy alone, due to the presence of androgen-independent/supersensitive cells in hormone-naive PC. A 67-year-old man was diagnosed with PC (Gleason score, 5 + 4) with multiple bone metastases. He was treated by chemohormonal therapy with cisplatin and estramustine phosphate (EMP) followed by maximal androgen blockade, and showed a complete response. As of the time of writing, no clinical or prostate-specific antigen recurrence has been observed for over 15 years, despite cessation of the treatment. This is the first report to indicate a possible cure of metastatic PC by chemohormonal therapy combined with appropriate anti-tumor drugs targeted to both androgen-independent and -dependent clones before the hormone-refractory state.

Epigenetic inactivation of the dioxin-responsive cytochrome P4501A1 gene in human prostate cancer.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is a toxic environmental contaminant that works through dioxin response elements (DRE) to activate gene expression. We tested the hypothesis that cancer-related epigenetic changes suppress dioxin activation of the cytochrome P4501A1 (CYP1A1) gene. 5-Aza-2'-deoxycytidine (5-aza-CdR), an inhibitor of DNA methylation, increases TCDD-inducible CYP1A1 mRNA expression in cancerous LNCaP cells but not in noncancerous PWR-1E and RWPE-1 cells (all human prostate cell lines). Bisulfite DNA sequencing shows that the TCDD-responsive CYP1A1 enhancer is highly methylated in LNCaP cells but not in RWPE-1 cells. In vivo footprinting experiments reveal that unmethylated DRE sites do not bind protein in response to TCDD in LNCaP cells, whereas inducible DRE occupancy occurs in RWPE-1 cells. Pretreatment of LNCaP cells with 5-aza-CdR partially restores TCDD-inducible DRE occupancy, showing that DNA methylation indirectly suppresses DRE occupancy. Chromatin immunoprecipitation experiments reveal that LNCaP cells lack trimethyl histone H3 lysine 4, a mark of active genes, on the CYP1A1 regulatory region, whereas this histone modification is prevalent in PWR-1E and RWPE-1 cells. We also analyzed CYP1A1 enhancer methylation in human prostate tissue DNA. We do not detect CYP1A1 enhancer methylation in 30 DNA samples isolated from noncancerous prostate tissue. In contrast, 11 of 30 prostate tumor DNA samples have detectable CYP1A1 enhancer methylation, indicating that it is hypermethylated in prostate tumors. This is the first report that shows that CYP1A1 is aberrantly hypermethylated in human prostate cancer and has an altered, inaccessible chromatin structure that suppresses its dioxin responsiveness.

Additional Medical Costs Due to Hospital-Acquired Falls.

OBJECTIVES: To explore the additional medical costs (AMCs) due to hospital-acquired falls (falls), as well as their impact on clinical services within hospitals under the nationally uniform universal health insurance system in Japan. METHODS: With the use of administrative profiling data based on accounting systems linked with the Japanese social insurance medical fee schedule, we analyzed data from 2 teaching hospitals: Shimane University Hospital (SUH) and St. Mary's Hospital (SMH). We extracted 588 fall cases from 4669 incident reports in SUH and 1168 fall cases from 7717 incident reports in SMH that potentially incurred AMCs. RESULTS: Additional medical costs were 364 ± 2129 USD for minor injuries and 4336 ± 3645 USD for major injuries at SUH (P < 0.001) and 114 ± 124 USD for minor injuries and 2267 ± 2811 USD for major injuries at SMH (P < 0.001). Among the clinical services provided, imaging services were the most frequently used, with 89.9% (n = 205) of 228 minor injuries at SUH and 86.7% (n = 339) of 391 minor injuries at SMH; imaging services were used in all major injury cases at both hospitals. Although the number of cases using additional procedure/surgery services was lower than those using imaging services at both hospitals, AMCs for procedure/surgery services accounted for the highest proportions of total AMCs in both hospitals. CONCLUSIONS: Although falls with minor injuries outnumbered falls with major injuries, fall-related AMCs for the latter were higher at both teaching hospitals because procedure/surgery services were required for cases with major injuries such as femoral neck and trochanteric fractures. The findings suggest that hospital administrators and policy makers have to take appropriate measures to prevent major injuries inpatients due to hospital-acquired falls.