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Introduction: To evaluate the incidence and risk factors for postoperative inguinal hernia (IH) after robot-assisted radical prostatectomy (RARP) and to assess whether a newly developed prevention technique reduces the incidence of IH after RARP., Methods: We included 161 consecutive patients (322 groins) who underwent RARP between September 2011 and October 2013. The prevention technique was as follows: (1) sufficient incision of peritoneum around the internal inguinal ring; (2) separation of spermatic vessels; (3) dissection of vas deferens., Results: Postoperative IH occurred in 14 cases (19.4%) occurring in the observation group compared to 2 cases (2.2%) in the prevention group. Patent processus vaginalis (PPV) was the only risk factor. Time-to-event analysis demonstrated a significant decrease in IH incidence in the IH prevention group (p = 0.005)., Conclusion: Our data reveal a higher incidence of IH after RARP, with the existence of PPV as the only identified risk factor. Our simple IH-prevention technique, which does not involve the use of artificial materials, appears safe and effective., (© 2016 S. Karger AG, Basel.)

The Japan Aerospace Exploration Agency developed the mouse Habitat Cage Unit (HCU) for installation in the Cell Biology Experiment Facility (CBEF) onboard the Japanese Experimental Module ("Kibo") on the International Space Station. The CBEF provides "space-based controls" by generating artificial gravity in the HCU through a centrifuge, enabling a comparison of the biological consequences of microgravity and artificial gravity of 1 g on mice housed in space. Therefore, prior to the space experiment, a ground-based study to validate the habitability of the HCU is necessary to conduct space experiments using the HCU in the CBEF. Here, we investigated the ground-based effect of a 32-day housing period in the HCU breadboard model on male mice in comparison with the control cage mice. Morphology of skeletal muscle, the thymus, heart, and kidney, and the sperm function showed no critical abnormalities between the control mice and HCU mice. Slight but significant changes caused by the HCU itself were observed, including decreased body weight, increased weights of the thymus and gastrocnemius, reduced thickness of cortical bone of the femur, and several gene expressions from 11 tissues. Results suggest that the HCU provides acceptable conditions for mouse phenotypic analysis using CBEF in space, as long as its characteristic features are considered. Thus, the HCU is a feasible device for future space experiments.

Gravity change affects many immunological systems. We investigated the effects of hypergravity (2G) on murine thymic cells. Exposure of mice to 2G for three days reduced the frequency of CD4+CD8+ thymocytes (DP) and mature medullary thymic epithelial cells (mTECs), accompanied by an increment of keratin-5 and keratin-8 double-positive (K5+K8+) TECs that reportedly contain TEC progenitors. Whereas the reduction of DP was recovered by a 14-day exposure to 2G, the reduction of mature mTECs and the increment of K5+K8+ TEC persisted. Interestingly, a surgical lesion of the inner ear's vestibular apparatus inhibited these hypergravity effects. Quantitative PCR analysis revealed that the gene expression of Aire and RANK that are critical for mTEC function and development were up-regulated by the 3-day exposure and subsequently down-regulated by the 14-day exposure to 2G. Unexpectedly, this dynamic change in mTEC gene expression was independent of the vestibular apparatus. Overall, data suggest that 2G causes a temporary reduction of DP and a persistent reduction of mature mTECs in a vestibular system-dependent manner, and also dysregulates mTEC gene expression without involving the vestibular system. These data might provide insight on the impact of gravity change on thymic functions during spaceflight and living.

Real-time three-dimensional transesophageal echocardiography (RT3D-TEE) can provide unique visualization and better understanding of the relationship among cardiac structures. Here, we report the case of an 85-year-old woman with an obstructed mitral prosthetic valve diagnosed promptly by RT3D-TEE, which clearly showed a leaflet stuck in the closed position. The opening and closing angles of the valve leaflets measured by RT3D-TEE were compatible with those measured by fluoroscopy. Moreover, RT3D-TEE revealed, in the ring of the prosthetic valve, thrombi that were not visible on fluoroscopy. RT3D-TEE might be a valuable diagnostic technique for prosthetic mitral valve thrombosis., (© 2014 Wiley Periodicals, Inc.)

Infective endocarditis (IE) associated with atrial septal defect (ASD) is extremely rare. However, tricuspid regurgitation (TR) secondary to right ventricular overload is a potential cause of IE, and once it occurs, the development of a paradoxical embolism may lead to fatal complications. We herein report the case of a 50-year-old woman who was admitted due to a persistent fever resistant to antibiotics. Echocardiography showed secundum ASD, moderate TR and a mobile vegetation measuring 15×10 mm attached to the tricuspid valve. Given the risk of developing a paradoxical embolism, urgent surgery was successfully performed.

Purpose: The purpose of this study was to obtain a set of correction factors of the radiophotoluminescent glass dosimeter (RGD) output for field size changes and wedge insertions., Methods: Several linear accelerators were used for irradiation of the RGDs. The field sizes were changed from 5 × 5 cm to 25 × 25 cm for 4, 6, 10, and 15 MV x-ray beams. The wedge angles were 15°, 30°, 45°, and 60°. In addition to physical wedge irradiation, nonphysical (dynamic/virtual) wedge irradiations were performed., Results: The obtained data were fitted with a single line for each energy, and correction factors were determined. Compared with ionization chamber outputs, the RGD outputs gradually increased with increasing field size, because of the higher RGD response to scattered low-energy photons. The output increase was about 1% per 10 cm increase in field size, with a slight difference dependent on the beam energy. For both physical and nonphysical wedged beam irradiation, there were no systematic trends in the RGD outputs, such as monotonic increase or decrease depending on the wedge angle change if the authors consider the uncertainty, which is approximately 0.6% for each set of measured points. Therefore, no correction factor was needed for all inserted wedges. Based on this work, postal dose audits using RGDs for the nonreference condition were initiated in 2010. The postal dose audit results between 2010 and 2012 were analyzed. The mean difference between the measured and stated doses was within 0.5% for all fields with field sizes between 5 × 5 cm and 25 × 25 cm and with wedge angles from 15° to 60°. The standard deviations (SDs) of the difference distribution were within the estimated uncertainty (1SD) except for the 25 × 25 cm field size data, which were not reliable because of poor statistics (n = 16)., Conclusions: A set of RGD output correction factors was determined for field size changes and wedge insertions. The results obtained from recent postal dose audits were analyzed, and the mean differences between the measured and stated doses were within 0.5% for every field size and wedge angle. The SDs of the distribution were within the estimated uncertainty, except for one condition that was not reliable because of poor statistics.

To evaluate the feasibility and reproducibility of a simple technique for identifying the initial cutting point of the bladder neck during robot-assisted radical prostatectomy. To precisely identify the prostatovesical junction, we first pulled the anterior bladder wall in an upward direction with the second arm to identify the precise location of the prostatovesical junction where anterior bladder neck dissection is initiated. After one experienced surgeon had established this technique, three surgeons who were less experienced in robot-assisted radical prostatectomy utilized this method for 50 consecutive robot-assisted radical prostatectomy cases. The pathological results and the time required to transect the anterior bladder wall were evaluated. There were no cases of positive resection margin on the site of bladder neck. The mean resection time was not significantly different when comparing less experienced surgeons with the experienced surgeon (P = 0.29). In conclusion, this method is a simple and reproducible way to identify the bladder neck during robot-assisted radical prostatectomy. This technique is also useful (for laparoscopic or open radical prostatectomy) even in difficult scenarios, such as post-transurethral resection of prostate cases., (© 2014 The Japanese Urological Association.)

This work introduces a novel nonparametric density index defined on graphs, the Sum-over-Forests (SoF) density index. It is based on a clear and intuitive idea: high-density regions in a graph are characterized by the fact that they contain a large amount of low-cost trees with high outdegrees while low-density regions contain few ones. Therefore, a Boltzmann probability distribution on the countable set of forests in the graph is defined so that large (high-cost) forests occur with a low probability while short (low-cost) forests occur with a high probability. Then, the SoF density index of a node is defined as the expected outdegree of this node on the set of forests, thus providing a measure of density around that node. Following the matrix-forest theorem and a statistical physics framework, it is shown that the SoF density index can be easily computed in closed form through a simple matrix inversion. Experiments on artificial and real datasets show that the proposed index performs well on finding dense regions, for graphs of various origins.

Respiratory motion management (RMM) systems in external and stereotactic radiotherapies have been developed in the past two decades. Japanese medical service fee regulations introduced reimbursement for RMM from April 2012. Based on thorough discussions among the four academic societies concerned, these Guidelines have been developed to enable staff (radiation oncologists, radiological technologists, medical physicists, radiotherapy quality managers, radiation oncology nurses, and others) to apply RMM to radiation therapy for tumors subject to respiratory motion, safely and appropriately.

Chondroitin sulfate (CS), the carbohydrate chain of chondroitin sulfate proteoglycans, is involved in neuronal circuit formation during development. CS shows great structural diversity with combination of disaccharide units of different structure (A-, C-, D-, or E-unit). However, whether its structural diversity contributes to pathway formation remains unclear. We chemically coupled the reducing end of various types of CS to the amino group of phosphatidylethanolamine (lipid-derivatized CS, CS-PE) and established an in vitro time-lapse assay to observe the behaviors of growth cones of retinal ganglion cells from embryonic day 6 chick retina on exposure to beads coated with lipid-derivatized CS (CS-PE beads). Among CS-PEs with different content of the structural units, the beads coated with E-unit-containing CS-PE [E-unit: GlcAβ1-3GalNAc(4,6-O-disulfate)] (CSE-PE beads) significantly caused the growth cones to retract and to turn away from the beads, but the beads coated with CSA-, CSC- or CSD-PE beads did not. Importantly, not all the growth cones retracted equally from the CSE-PE beads, but they showed continuum of the repulsive behaviors; some behaved moderately and others remarkably. The growth cones distinguished different samples of CS: CSE and the others. Moreover, the continuum of the repulsive behaviors suggests that CS might be involved with the fine regulation of growth cones' behavior through its characteristic structure., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: Although radiotherapy has been important in the therapy for localized prostate cancer, prostate-specific antigen failure may occur. This study evaluated the effects and side effects of (125)I low-dose-rate brachytherapy for patients with postradiation local failure., Patients and Methods: 15 patients who received salvage brachytherapy were analyzed. A prescribed dose of 144 Gy was selected. Median follow-up calculated from the date of salvage brachytherapy was 33.0 months (range 6-51)., Results: 5 patients (33.3%) developed prostate-specific antigen failure. The biochemical relapse-free survival rate was 100% at 1 year, 91.7% at 2 years, and 60.2% at 3 years. All acute genitourinary and gastrointestinal adverse events were in grade 1-2 according to Common Terminology Criteria for Adverse Events version 3. As for late adverse events, 1 patient (6.7%) developed grade 3 hematuria at 17 months postsalvage., Conclusions: Although careful patient selection is needed, salvage (125)I prostate brachytherapy appears to provide good prostate cancer control with an acceptable rate of complications for patients with local recurrence of prostate cancer after initial radiotherapy., (Copyright © 2013 S. Karger AG, Basel.)

We retrospectively evaluated the outcome of oral low-dose dexamethasone (DXM) therapy for androgen-independent prostate cancer (AIPC). Between January 1999 and April 2006, 99 consecutive patients with AIPC were enrolled in this study. The median patient age was 70 years (range 46-86), and the median pretreatment prostate-specific antigen (PSA) level was 243 ng/ml (range 8.2-29600). Median follow-up was 41.9 months (range 11.4-170.4). Upon biochemical failure, patients were treated with oral low-dose DXM. A total of 40 of the 99 cases (40.4%) showed a ≥50% decrease in serum PSA levels (PSA responders). Twenty-five cases (25.2%) showed a <50% decrease in PSA, and the remaining 34 cases (34.3%) had increased PSA levels (PSA non-responders). The median PSA progression-free survival was 3.0 (range 0-27) and 8.0 months (range 2-27) for the entire cohort and PSA responders, respectively. The PSA responders had a significantly increased survival (median 30.1 months) compared to the non-responders (median 8.8 months, P<0.001). Of the 34 patients who were under pain control for bone metastases before the administration of DXM, 23 (67.6%) were able to discontinue the regular use of analgesics. The PSA responders also showed an increase in hemoglobin levels. The change in serum interleukin-6 levels was significantly associated with a response to DXM (P=0.0065). Severe adverse events of DXM were rare. Clinicopathological factors predicting the PSA response to DXM were age, time from initial androgen deprivation therapy to DXM and PSA velocity prior to DXM. In conclusion, oral low-dose DXM led to an acceptable PSA response in patients with AIPC. Thus, this therapy may be an effective and safe alternative for the treatment of AIPC, particularly for patients who are not favourable candidates for chemotherapy.

Background: The component therapy has been recommended for surgical hemorrhage. We investigated whether the component therapy was useful for surgical patients undergoing the scheduled peritonectomy for pseudomyxoma peritonei or peritoneal dissemination., Methods: Twenty patients were divided into two groups (the component therapy for 7 patients and the early transfusion of flesh frozen plasma therapy for 13 patients). We studied the change of prothrombin time (PT), hepaplastin test (HPT) and fibrinogen level during operations., Results: In the component therapy group, PT, HPT and fibrinogen level decreased to 28.5 +/- 11.8%, 25.9 +/- 9.3%, 99.5 +/- 61.3 mg x dl(-1), respectively, during surgical intervention, but no difference was found postoperatively between the two groups. One patient in the component therapy group was reoperated for bleeding., Conclusions: If the hemorrhage of more than the circulation volume is suspected before the operation, early transfusion therapy seems to provide good effect for coagulation in scheduled peritonectomy of pseudomyxoma peritonei or peritoneal dissemination.

Objectives: Although several nomograms for prostate cancer detection have been developed for Western populations, the models constructed on Japanese data would be more useful for the Japanese population because of various differences between Western and Asian populations. We previously developed a model for predicting the probability of a positive initial prostate biopsy using clinical and laboratory data from Japanese males. In the present study, a predictive model for Japanese males with a prostate-specific antigen (PSA) < 10 ng/mL was developed to guide decision-making for prostate biopsies., Methods: The age, total PSA level, free to total PSA ratio, prostate volume, and the digital rectal examination findings of 1037 Japanese males with a PSA < 10 ng/mL undergoing initial prostate biopsy as part of individual screening were analyzed. For study validation, 20% of these data was randomly reserved. Logistic regression analysis estimated relative risk, 95% confidence intervals, and P-values., Results: Age and the independent predictors of a positive biopsy result (elevated PSA, decreased free to total PSA ratio, small prostate volume, and abnormal digital rectal examination findings) were used to develop a predictive nomogram. The area under the receiver operating characteristic curve was significantly higher for the model (73.0%) than for PSA alone (55.0%). If externally validated, the use of this nomogram could reduce unnecessary biopsies by 26% and overall prostate biopsies by 7.8%., Conclusions: This predictive nomogram could provide more precise risk-analysis information for individual Japanese patients with PSA levels less than 10 ng/mL and may help to identify patients who need a prostate biopsy.

Introduction: The characteristics of a glass dosimeter were investigated for its potential use as a tool for postal dose audits. Reproducibility, energy dependence, field size and depth dependence were compared to those of a thermoluminescence dosimeter (TLD), which has been the major tool for postal dose audits worldwide., Materials and Methods: A glass dosimeter, GD-302M (Asahi Techno Glass Co.) and a TLD, TLD-100 chip (Harshaw Co.) were irradiated with gamma-rays from a (60)Co unit and X-rays from a medical linear accelerator (4, 6, 10 and 20 MV)., Results: The dosimetric characteristics of the glass dosimeter were almost equivalent to those of the TLD, in terms of utility for dosimetry under the reference condition, which is a 10 x 10 cm(2) field and 10 cm depth. Because of its reduced fading, compared to the TLD, and easy quality control with the ID number, the glass dosimeter proved to be a suitable tool for postal dose audits. Then, we conducted postal dose surveys of over 100 facilities and got good agreement, with a standard deviation of about 1.3%., Conclusions: Based on this study, postal dose audits throughout Japan will be carried out using a glass dosimeter.

Objective: Most of the metastatic diseases initially respond to maximum androgen blockade, but then relapse and lose response, and finally die. After relapse, the disease progresses in various courses. The present study was aimed to establish the predicting factors influencing the survival period of patients at prostate-specific antigen (PSA) relapse (entering the hormone refractory state)., Materials and Methods: Fifty-six patients with prostate cancer and bone metastasis, who were treated during the entire disease period at the same hospital and died were studied. To calculate PSA-doubling time, assay of PSA was carried out every 3 months or less., Results: The period between PSA relapse and death was related with PSA-doubling time at relapse, nadir PSA and the period between the start of treatment and PSA relapse. The PSA-doubling time of 2 months or less at relapse was suggestive of a poor outcome. Final PSA-doubling time was not correlated with the survival period after PSA relapse., Conclusion: The PSA-doubling time at relapse is one of the relevant factors for predicting the survival period after PSA relapse.

Field survey on output for X-ray therapeutic accelerators took place three times in Saitama Prefecture. The result of the field survey in 1997 showed the different rate from the designated dose at peak depth of 35 beams in 18 institutions. As different rate within +/-5% stood 91.4% in all beams, so different rate within +/-3% stood 85.7% in the same beams. The average different rate from the designated dose at peak depth was 11.06%. The standard deviation of the same condition was 3.72.The result of the field survey in 2005 showed the different rate from the designated dose at correction depth of 36 beams in 18 institutions. As different rate within +/-5% stood 100% in all beams, so different rate within +/-3% stood 91.6% in the same beams. The average different rate from the designated dose at correction depth was +0.80%. The standard deviation of the same condition was 1.46.We understood that the different rate from the designated dose at radiotherapeutic institutions decreased and even the value of the standard deviation was decreasing, by receiving 3 times of field surveys that was held in Saitama Pref. Also we understood that the beam numbers of different rate within +/-5% and the beam numbers of different rate within +/-3% were going up. We recognized that the good result of accurate dose is obtained more, by doing a continual field survey. The field survey was carried out in 2006 in Tochigi Prefecture and was the insufficient result in 10% of institutions.

We evaluated the effects of bisphosphonate (BP) treatment in five patients with hormone-refractory prostate cancer (HRPC), experiencing bone pain from metastases to the bone, and assessed changes in serum prostate specific antigen (PSA) levels, bone pain, and quality of life (QOL). Treatment with incadronate disodium (10 mg) in saline was administered at 2-week intervals for a total of 6 times. Evaluation of the treatment included the incidence of adverse events, QOL, bone pain, pain scale, and blood analyses including tumor markers. BP treatment was generally well tolerated by all five patients. The effects of BP treatment on serum PSA values were evaluated as prominent response (PR), no change (NC) and progressive disease (PD) in one, two and two cases of PD, respectively. During BP treatment, serum type I procollagen values decreased in patients, but there was no large change in serum type I collagen values. Only one patient experienced increased pain; pain was well controlled in the others. The QOL evaluation by Short-Form 36 (SF-36), showed no change in scores during BP treatment except for general health. These results suggested that BP treatment is safe and feasible. It may be effective for the treatment of those HRPC patients with bone pain and may become one of the choices for treatment of HRPC.

Purpose: The prognosis of metastatic prostate cancer significantly differs among individuals. While various clinical and biochemical prognostic factors for survival have been suggested, the progression and response to treatment of those patients may also be defined by host genetic factors. In this study, we evaluated genetic polymorphisms as prognostic predictors of metastatic prostate cancer., Patients and Methods: One hundred eleven prostate cancer patients with bone metastasis at the diagnosis were enrolled in this study. Thirteen genetic polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism or an automated sequencer with a genotyping software., Results: Among the polymorphisms, the long allele (over 18 [CA] repeats) of insulin-like growth factor-I (IGF-I) and the long allele (over seven [TTTA] repeats) of cytochrome P450 (CYP) 19 were significantly associated with a worse cancer-specific survival (P = .016 and .025 by logrank test, respectively). The presence of the long allele of either the IGF-I or CYP19 polymorphisms was an independent risk factor for death (P = .019 or .026, respectively). Furthermore, the presence of the long allele of both the IGF-I and CYP19 polymorphisms was a stronger predictor for survival (P = .001)., Conclusion: The prognosis of metastatic prostate cancer patients is suggested to be influenced by intrinsic genetic factors. The IGF-I (CA) repeat and CYP19 (TTTA) repeat polymorphisms may be novel predictors in prostate cancer patients with bone metastasis at the diagnosis.

Background: Ligand-independent activation of the androgen receptor (AR) by cytokines has been implicated in the progression of androgen-independent prostate cancer (PCa). To determine the potential effects of elevated levels of interleukin-4 (IL-4) in patients with PCa, six different cytokines were examined for their ability to activate the AR., Materials and Methods: LNCaP cells were transiently transfected with prostate-specific antigen (PSA) (-630 / +12)-luciferase and treated with R1881, six kinds of cytokines including IL-4, or vehicle. Transactivation assays were also performed in LNCaP cells co-transfected with the 5xGal4UAS-TATA-luciferase and AR-(1-558)-Gal4DBD prior to incubation with R1881, IL-4, IL-6, or vehicle. Seventy-two patients with pre-treatment PCa, 17 patients with hormone-refractory metastatic PCa receiving androgen ablation therapy, 20 patients with benign prostatic hypertrophy and 10 healthy male volunteers were enrolled in this retrospective study. The concentration of serum IL-4 was measured by chemiluminescence enzyme immunoassay., Results: IL-4 induced androgen-response element-driven reporters and activated the AR N-terminal domain (NTD) in a ligand-independent manner in transiently transfected LNCaP cells. Levels of IL-4 in the serum were significantly elevated in patients with hormone-refractory PCa as compared to the levels in pre-treatment PCa., Conclusion: IL-4 serum levels were demonstrated to be increased in honnone-refractory PCa and IL-4 was shown to enhance PSA reporter gene activity by the activation of AR NTD in human LNCaP cells. These results suggest that the AR can be activated by cytokines, and that this mechanism may play an important role in the transition from androgen-dependent to androgen-independent PCa after patients receive androgen ablation therapy.

To study the effects of the intake of green tea and polyphenols, which are a component of green tea, on insulin resistance and systemic inflammation, a randomized controlled trial was conducted on 66 patients aged 32-73 y (53 males and 13 females) with borderline diabetes or diabetes. Subjects in the intervention group were asked to take a packet of green tea extracts/powder containing 544 mg polyphenols (456 mg catechins) daily, which was a dose that could be taken without difficulty, and were asked to divide the green tea extracts/powder in a packet into 3 or 4 fractions dissolved in hot water everyday and to take a fraction after every meal or snack for 2 mo, in addition to daily food intake. The subjects in the control group were simply followed. To calculate the level of green tea polyphenol intake that the subject usually drank at home, the subject was asked to taste 3 teas of different strengths (1, 2 and 3%) and the tea that was closest to the one that the subject drank at home, was selected by each subject. After 2 mo, the mean daily polyphenol intake in the intervention group was 747 mg, which was significantly higher than that of 469 mg in the control group. In the intervention group, the body weight, BMI, systolic and diastolic blood pressures, blood glucose level, Hb A1c level, insulin level and HOMA index after taking the supplementation for 2 mo, were lower than the respective value before intervention: however, these parameters in the intervention group at 2 mo did not significantly differ from those in the control group. Within the intervention group, changes in insulin level tended to be associated with changes in polyphenol intake. In addition, changes in BMI were associated with changes in blood glucose level and insulin level. In conclusion, the daily supplementary intake of 500 mg green tea polyphenols did not have clear effects on blood glucose level, Hb A1c level, insulin resistance or inflammation markers. The positive correlation between the level of polyphenol intake and insulin level warrants further studies on the effect of green tea on insulin resistance.

Background: Loss of heterozygosity (LOH) on chromosome 2 is thought to occur only occasionally in prostate cancer (PCa), but allelic losses in this region are frequent in other types of human cancer, such as lung, thyroid, head and neck, and cervix. Here, we show a high-resolution deletion map of markers on chromosome 2 in Japanese patients with PCa., Methods: Tissue samples were obtained from 66 patients with PCa. DNA from normal, tumor, or metastatic tissue was used as the template for polymerase chain reaction amplification for LOH using 24 microsatellite markers on human chromosome 2., Results: Nineteen of the 66 cases (29%) showed LOH for at least one locus on chromosome 2. LOH on 2p was observed more frequently in cancer death cases than in organ confined and regional diseases (P < 0.001). Paired DNAs were available from both primary and metastatic tumors in the eight cases of cancer death; among those pairs, we detected LOH on 2p in four primary tumors, and in all metastatic foci (P < 0.05). Detailed deletion mapping in these tumors identified four distinct commonly deleted regions on 2p 16.3, 2p 12-cent, 2q 21.3, and 2q 23.1-2q 32.1., Conclusions: These results suggest that inactivation of putative tumor suppressor genes on chromosome 2 that may play an important role in the progression of Japanese patients with PCa., ((c) 2005 Wiley-Liss, Inc.)

Introduction: The concept of neuroendocrine (NE) differentiation in prostate cancer has become more widely recognized as its diagnostic, prognostic, and therapeutic usefulness., Patients and Methods: We enrolled 38 patients with stage D prostate cancer who underwent endocrine therapy by medical or surgical castration and oral antiandrogen. According to PSA response, serum levels of CGA as a marker of NE differentiation were measured at the multiple points of time; (1) pre-treatment, (2) complete response (CR), (3) a nadir level of PSA, (4) PSA failure or hormone independent progression. We compared these serum values in relation to efficacy of endocrine therapy., Results: There was no correlation between serum PSA and CGA values. Patients consisted of 27 with CR and 11 without CR. Serum CGA increased as intervals of endocrine therapy became longer with positive correlation (p < 0.05). Its velocity was higher in patients with PSA failure than in those without it (6.98 vs. 2.09 ng/ml/month, p = 0.011)., Conclusion: During endocrine therapy in metastatic prostate cancer patients, serum CGA values were not related to serum PSA levels, and increased as treatment periods became longer. It is suggested that CGA velocity has potential to predict androgen independent progression after endocrine therapy.

In Western countries underestimation of energy intake (EI) is considered a serious problem in dietary surveys, but information on the accuracy of EI among Japanese people is sparse. We compared estimated EI with measured total energy expenditure (TEE) in 21 Japanese women aged 20-22 y. Dietary intake was estimated by 7-d weighed dietary records (7dWR) and a self-administered diet history questionnaire (DHQ). TEE was measured for 25+/-3 d (mean+/-standard deviation, range: 16-27 d) by a uniaxial accelerometer. Both EI by 7dWR (1,498+/-305 kcal/d) and EI by DHQ (1,599+/-331 kcal/d) were significantly lower than TEE (1,865+/-179 kcal/d) (p<0.001 and p<0.01, respectively), but neither estimated EI nor the magnitude of EI underestimation (20+/-15% for 7dWR and 13+/-23% for DHQ) was significantly different between two methods (p=0.25 and p=0.22, respectively). The Spearman correlation (r) between TEE and EI was 0.51 (p=0.2) for 7dWR and 0.09 (p=0.71) for DHQ, indicating better ranking of individuals by 7dWR. The accuracy of EI (EI/TEE) was negatively associated with the percentage of EI from protein in 7dWR (r=-0.44, p=0.049) and positively associated with the percentage of EI from fat in both 7dWR (r=0.45, p=0.04) and DHQ (r=0.62, p<0.01), suggesting selective overestimation of protein and selective underestimation of fat. These results indicate not only underestimation of habitual EI but also selective under- and/or overestimation of macronutrients in both 7dWR and DHQ.

Objective: Androgen ablation has been the initial treatment of choice for men with metastatic prostate cancer, but the disease generally relapses to an androgen-independent state thereafter. To understand which groups respond well or poorly to endocrine therapy is thus important. Several studies have shown that pretreatment serum testosterone (T) levels and the length of the CAG repeat at the N-terminal region of the androgen receptor are significant. However, the relevance of a combination of these factors has not been reported. We therefore investigated the clinical significance of CAG repeat length and pretreatment serum T levels among Japanese patients with metastatic prostate cancer (TxNxM1), and analyzed their relevance to survival., Methods: Fifty-two Japanese patients with metastatic prostate cancer were enrolled in this study. We determined the length of the CAG repeat by both PCR sequencing and fragment analysis. Pretreatment serum T levels were measured using a radioimmunoassay. We examined the clinical significance of the CAG repeats and T levels individually and in combination with respect to several clinical factors., Results: The pretreatment T level in the responder group was significantly higher than that in the non-responders (p=0.009) and the mean was 4.33+/-2.12 ng/ml. Kaplan-Meier analyses revealed that cause-specific survival was significantly enhanced in patients with higher levels of T (p=0.0489). The length of the CAG repeat was positively associated with age at diagnosis (p=0.032). The mean CAG repeat length was 22.5+/-3.0 and this value was significantly shorter in patients with poorly differentiated, than with well and moderately differentiated tumors (p=0.019). Kaplan-Meier analyses revealed a significantly better cause-specific survival rate as well as progression-free survival rate in patients with longer CAG repeats. Cause-specific survival curves were better in patients with higher T levels and longer CAG repeats than with lower T levels and shorter CAG repeats (p=0.0066). A multivariate analysis showed that the most significant prognostic factor was histological grade, followed by EOD grade, marker response and the combination of T and CAG., Conclusion: Pretreatment serum T levels together with the length of the N-terminal CAG repeat of the androgen receptor gene can distinguish responders from non-responders to androgen ablation. These parameters appear to be clinically useful, in that therapies appropriate to individual patients could be selected. Further studies are necessary to confirm these results.

Objective: Pretreatment serum level of testosterone (T) is a potential prognostic factor for prostate cancer. The present study was conducted to evaluate the clinical significance of pretreatment serum T level in patients with clinically localized prostate cancer., Materials and Methods: The subjects were 82 clinically localized prostate cancer patients treated with radical prostatectomy, whose pretreatment T levels were recorded. We investigated clinical and pathological factors such as pretreatment serum T level, age, pretreatment PSA or pathological Gleason score concerning the association with pathological stage and biochemical recurrence., Results: The mean pretreatment T level was significantly lower in patients with non-organ-confined prostate cancer (pT3-T4, N1; 3.44+/-1.19 ng/ml) than in patients with organ-confined cancer (pT2; 4.33+/-1.42 ng/ml) (p=0.0078). Multivariate analysis demonstrated that pathological Gleason score, pretreatment serum T level and pretreatment PSA were significant predictors of extraprostatic disease. When the patients were divided into high and low T level groups according to the median value, pretreatment T levels were not significantly associated with PSA recurrence rates (p=0.7973)., Conclusions: A lower pretreatment T level appears to be predictive of extraprostatic disease in patients with localized prostate cancer.

Prostate cancer is one of the most common cancers in Western men. In Japan, the incidence of this malignancy is increasing. Recent advances in molecular biology brought new biomarkers to prostate cancer diagnosis. In this article, we describe new biomarkers including serum and genetic and histochemical markers for screening, staging and drug selection for the management of prostate cancer patients.

Purpose: Degradation of the extracellular matrix by malignant tumor cells has an essential role in the process of tumor invasion and metastasis. The 2 gelatinolytic matrix metalloproteinases (MMPs) MMP-2 and MMP-9 are believed to be key enzymes in this process. We investigated the possible relationship between in situ gelatinolytic activity of MMPs and clinicopathological factors in patients with bladder cancer to clarify whether these proteins would be critical for tumor advancement in this disease., Materials and Methods: We evaluated the intensity of gelatinolytic activity in 25 bladder cancer tissues by film in situ zymography (FIZ). To clarify the MMP(s) responsible for gelatinolytic activity in bladder cancer tissues we examined MMP-2 and MMP-9 expression in bladder tissues by gelatin zymography. MMP expression was also confirmed by reverse transcriptase-polymerase chain reaction and Western blotting. We then investigated the association between MMP expression detected by gelatin zymography and the intensity of gelatinolytic activity determined by FIZ., Results: FIZ demonstrated that all tumor tissues had in situ gelatinolytic activities. There was a statistically significant correlation between the intensity of gelatinolytic activity, and tumor grade, stage, vessel invasion and cause specific survival (p <0.05). Stronger in situ gelatinolytic patterns were documented in cases with higher pro and active MMP-2 expression., Conclusions: FIZ enables the direct assessment of in situ gelatinolytic activity in bladder cancer tissues. The intensity of activity appears to affect the biology of carcinoma tissues. Our results indicate a major role for MMP-2 in in situ gelatinolysis in bladder cancer.

A significant increase in calculation ability was observed in the glucose, fructose and sucrose administration groups during both the first and second half of the Uchida Kraepelin test. There was no significant difference in alpha waves between carbohydrate groups (glucose, fructose and sucrose) and control groups at baseline. After a stress situation, there was a significant increase in alpha waves at 11-20 min (p<0.05) in glucose, 11-20 min (p<0.01) and 21-30 min (p<0.01) in fructose, and 0-10 min (p<0.05) in sucrose compared, with each control group. There was no significant difference in beta waves in any of the paired groups.

The calibration coefficients of a parallel plate ionization chamber are examined by comparing the coefficients obtained through three methods: a calculation from a 60Co calibration coefficient, N(D, omega, 60Co), a cross-calibration of a parallel plate ionization chamber using a cylindrical ionization chamber at the plateau region of a mono-energetic beam and a cross-calibration of the chamber using a cylindrical chamber at the middle of the SOBP of the therapeutic beams. This paper also examines reference conditions for determining absorbed dose to water in the cases of therapeutic carbon and proton beams. In the dose calibration procedure recommended by IAEA, irradiation fields should be larger than 10 cm in diameter and the water phantom should extend by at least 5 cm beyond each side of the field. These recommendations are experimentally verified for proton and carbon beams. For proton beams, the calibration coefficients obtained by these three methods approximately agreed. For carbon beams, the calibration coefficients obtained by the second method were about 1.0% larger than those obtained by the third method, and the calibration coefficients obtained by cross-calibration using 290 MeV/u beams were 0.5% lower than those obtained using 400 MeV/u beams. The calibration coefficient obtained by the first method agreed roughly with the results obtained by SOBP beams.

Purpose: We studied the efficiency of second or third line hormonal therapy for prostate cancer relapse after hormone therapy., Materials and Methods: The study included 70 patients with advanced prostate cancer treated with hormonal therapy, androgen deprivation monotherapy or maximum androgen blockade including surgical or medical castration combined with steroidal antiandrogen, 100 mg chlormadinone acetate daily or nonsteroidal antiandrogens, 375 mg flutamide (FLT) daily or 80 mg bicalutamide (BCL) daily. When the disease relapsed, we discontinued the antiandrogen and evaluated the patient for the antiandrogen withdrawal syndrome (AWS). Thereafter we administrated an alternative antiandrogen and evaluated its effect., Results: The incidence of the AWS after first, second and third line hormonal therapy was 35.8%, 8.0% and 0%, respectively. The efficiency of subsequent hormonal therapy was not related to the occurrence of the AWS. Nonsteroidal antiandrogens as alternative therapies for disease relapse from primary therapy were effective in second line (FLT 38.1%, BCL 44.4%) or in third line (FLT 30.0%, BCL 28.6%) hormonal therapy. Of 5 (80%) patients who responded to second line therapy 4 (80%) had effective third line therapy, while only 1 of 12 (8.3%) second line nonresponders had effective third line therapy (p = 0.003). The survival of second line responders was significantly better than that of nonresponders (5-year survival rate 92.3% vs 23.9%, p <0.001), indicating a potential predictive value for second line responsiveness. No significant clinical factor identified second line responsiveness., Conclusions: Subsequent nonsteroidal antiandrogen therapies were effective against prostate cancer relapse after hormonal therapy. The response to third line therapy was more effective and survival was improved from the time of first line therapy relapse among second line responders than that in nonresponders. Our data support the notion that second line responders are androgen independent but still hormonally sensitive.

To evaluate the clinical usefulness of power Doppler imaging (PDI), we compared this method to gray-scale transrectal ultrasound (TRUS) in the detection of prostate cancer. A total of 101 men with abnormally high serum prostate specific antigen (PSA) levels and/or abnormal digital rectal examination (DRE) findings were assessed using TRUS and PDI. Random systematic sextant and bilateral far lateral prostate biopsies were performed in all cases. In addition, when TRUS revealed a hypoechoic lesion or PDI revealed a hypervascular lesion (HVL), these lesions were directly biopsied. Of the 101 patients, 48 (47.5%), 42 (41.5%) and 42 (41.5%) were suspicious of having prostate cancer by DRE, TRUS and PDI, respectively. Prostate needle biopsy revealed prostate cancer in 39 patients (38.6%) and benign prostatic diseases in 62 patients (61.4%). If prostate needle biopsy was avoided when PDI was negative, then PDI eliminated the need for biopsy in 59 of the 101 patients (rate of biopsy procedures saved: 58.4%) and missed only 8 (13.6%) prostate cancers. Moreover, in 63 patients with intermediate PSA (3-10 ng/ml), the rate of biopsy procedures saved by DRE, TRUS, and PDI was 60.3%, 65.1%, and 68.3%, respectively, and the rate of cancers missed was 26.3%, 19.5%, and 14.0%, respectively. In a total of 826 specimens of TRUS-guided prostate biopsy, 126 (15.3%) specimens had adenocarcinoma. Site by site based analysis of the present series revealed 34.1% of prostate cancer sites were isoechoic and hypervascular. On a site by site basis, PDI had better sensitivity, specificity, positive predictive value and negative predictive value than TRUS. In 48 patients without abnormal DRE findings, on a site by site basis, the sensitivities of TRUS and PDI were 22.9% and 34.4%, respectively. Gleason score was associated with a positive rate of PDI on both a patient basis and site by site basis. From these results, on a patient basis, we conclude that PDI was helpful in the indication for prostate biopsy for all patients or patients with intermediate PSA level. On a site by site basis, PDI may be able to select prostate cancer sites at biopsy, in particular in patients without abnormal DRE findings.

Purpose: beta-D-glucan values in the vitreous were investigated in order to evaluate their usefulness for the diagnosis of fungal endophthalmitis., Methods: The vitreous or vitreous perfusate were collected from twenty-six patients who underwent vitreous surgery at the Department of Ophthalmology, Yokohama City University, School of Medicine and beta-D-glucan values in these samples were examined., Results: Two samples with fungal endophthalmitis showed remarkably high concentration beta-D-glucan values. The other samples, except one, without fungal endophthalmitis showed significantly low beta-D-glucan values of less than 10.0 pg/ml., Conclusion: It is expected that beta-D-glucan values in the vitreous may be more sensitive than culture methods, and may be useful for the diagnosis of fungal endophthalmitis.

From the standpoint of quality assurance in radiotherapy, it is very important to compare the dose distributions realized by an irradiation system with the distribution planned by a treatment planning system. To compare the two dose distributions, it is necessary to convert the dose distributions on CT images to distributions in a water phantom or convert the measured dose distributions to distributions on CT images. Especially in heavy-ion radiotherapy, it is reasonable to show the biologically equivalent dose distribution on the CT images. We developed tools for the visualization and comparison of these distributions in order to check the therapeutic beam for each patient at the National Institute of Radiological Sciences (NIRS). To estimate the distribution in a patient, the dose is derived from the measurement by mapping it on a CT-image. Fitting the depth-dose curve to the calculated SOBP curve also gives biologically equivalent dose distributions in the case of a carbon beam. Once calculated, dose distribution information can be easily handled to make a comparison with the planned distribution and display it on a grey-scale CT-image. Quantitative comparisons of dose distributions can be made with anatomical information, which also gives a verification of the irradiation system in a very straightforward way.

In heavy-ion radiotherapy, an accelerated beam is modified to realize a desired dose distribution in patients. The setup of the beam-modifying devices in the irradiation system is changed according to the patient, and it is important to check the depth dose distributions in the patient. In order to measure dose distributions realized by an irradiation system for heavy-ion radiotherapy, a multi-layer ionization chamber(MLIC) was developed. The MLIC consists of 64 ionization chambers, which are stacked mutually. The interval between each ionization chamber is about 4.1 mm water. There are signal and high voltage plates in the MILC, which are used as electrodes of the ionization chambers and phantom. Depth dose distribution from 5.09 mm to 261.92 mm water can be measured in about 30 seconds using this MLIC. Thus, it is possible to check beam quality in a short amount of time.

The broad-beam three-dimensional irradiation system under development at National Institute of Radiological Sciences (NIRS) requires a small ridge filter to spread the initially monoenergetic heavy-ion beam to a small spread-out Bragg peak (SOBP). A large SOBP covering the target volume is then achieved by a superposition of differently weighted and displaced small SOBPs. Two approaches were studied for the definition of a suitable ridge filter and experimental verifications were performed. Both approaches show a good agreement between the calculated and measured dose and lead to a good homogeneity of the biological dose in the target. However, the ridge filter design that produces a Gaussian-shaped spectrum of the particle ranges was found to be more robust to small errors and uncertainties in the beam application. Furthermore, an optimization procedure for two fields was applied to compensate for the missing dose from the fragmentation tail for the case of a simple-geometry target. The optimized biological dose distributions show that a very good homogeneity is achievable in the target.

The signals that direct the excision of introns from mammalian pre-mRNA are not yet well understood. However, at least three kinds of signals--5'-splice site signals, 3'-splice site signals and branch point signals--play important roles in the excision of introns. In the present paper we treat only the 5'-splice sites. In addition to a consensus sequence for 5'-splice signals, several methods have been proposed, based on a statistical model, and used to analyze relative importance of each nucleotide at each position. In our approach a nucleotide sequence is regarded as a string with symbols of 'A', 'T', 'G' and 'C'; important substrings of 5'-splice site sequences, called pattern sequences, are extracted. A pattern sequence expresses which nucleotide is needed at a limited number of positions around the 5'-splice site. It is observed that a particular pattern sequence matches predominantly 5'-splice site sequences nearest to the 5'-end of a gene and another pattern sequence matches predominantly the second nearest ones. Moreover, it is confirmed that the pattern sequences accurately predict authentic 5'-splice sites for unknown genes and explain some mutation examples.

In order to investigate the immunogenetic factors associated with hepatitis B virus (HBV) carrier state, the HBe seroconversion and the development of chronic liver disease, HLA typing were performed in 278 asymptomatic HBV carriers (ASC) and 110 patients with chronic B type hepatitis (CH). HLA typing was also performed in 178 vaccinees who had received hepatitis B vaccine. The significantly decreased frequencies of DR1 and DRw13 were found in ASC, CH and non-responders to HB vaccine. This suggests that DR1 and DRw13 may be associated with the elimination of HBV. The frequency of DR4.2 was increased in ASC, but decreased in CH. The seroconversion rate of DR4.2 positive CH as well as ASC was high. Therefore DR4.2 may have relevance to the seroconversion from HBeAg to anti-HBe.

The signals which direct the excision of introns from eukaryotic pre-mRNA are not yet well understood. In order to define the signals for 5'-splice sites of mRNA splicing, nucleotide sequences including 5'-splice junctions of mammalian pre-mRNAs are analysed by means of syntactic pattern analysis. Taking this approach, we infer the grammatical rules which specify 5'-splice sites and construct a finite automaton which is the recognizer of the nucleotide sequences at 5'-splice sites. By scanning the automaton along nucleotide sequences, we can identify the positions of 5'-splice junctions with a degree of discrimination of up to 94-97% in the known genes, while the degree of prediction is in the range 50-55% in new genes.

1. Critical studies on the distribution of Ntau-methylhistidine (3-methylhistidine; Me-His) among organs and tissues in adult rats are reported. Adult rats contained 46-5+/-3-6 mg Me-His/kg body-weight. Almost 90% of the Me-His in the body was recovered from skeletal muscle. These results support the hypothesis that fractional catabolic rates of myosin and actin in skeletal muscle can be estimated by measuring urinary excretion of Me-His. 2. Dietary protein level did not affect the total amount of Me-His in the body. However, urinary excretion of Me-His increased as dietary protein intake was increased. 3. From these results it was concluded that fractional catabolic rates of myosin and actin increase as dietary protein intake increases.