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We compared the computed tomography (CT) numbers from monochromatic images obtained using the first-generation (Discovery CT750 HD: GE Healthcare, Milwaukee, WI) and second-generation (Revolution CT: GE HealthCare) dual-energy CT (first and second DECT) scanners in phantom and clinical studies. In a polypropylene phantom, eight polypropylene tubes containing iodine at various concentrations (0.5, 1, 2, 5, 10, 12, 20, 30 mg I per ml) were arranged in an outer circle. The iodine densities and CT numbers obtained after imaging with different-generation DECT scanners were analyzed. The CT numbers from images obtained from 61 consecutive patients with aortic disease who underwent CT with different-generation DECT scanners were compared during the arterial and delayed phases. The iodine concentration obtained from second DECT was more accurate than that from the first DECT in the phantom study. A significantly higher contrast enhancement was observed with the second DECT compared with the first DECT during the arterial phase in the clinical study. Contrast enhancement was higher with the second DECT than with the first DECT, and the second DECT was effective in minimizing the use of contrast materials., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Direct DNA double-strand breaks result in phosphorylation of H2AX, a variant of the histone H2 protein. Phosphorylated H2AX (γH2AX) may be a potential indicator in the evaluation of genotoxicity and hepatocarcinogenicity. In this study, γH2AX and Ki-67 were detected in the short-term responses (24 h after chemical administration) to classify genotoxic hepatocarcinogens (GHs) from non-GH chemicals. One hundred and thirty-five 6-week-old Crl: CD(SD) (SPF) male rats were treated with 22 chemicals including 11 GH and 11 non-GH, sacrificed 24 h later, and immunostained with γH2AX and Ki-67. Positivity rates of these markers were measured in the 3 liver ZONEs 1-3; portal, lobular, and central venous regions. These values were input into 3 machine learning models-Naïve Bayes, Random Forest, and k-Nearest Neighbor to classify GH and non-GH using a 10-fold cross-validation method. All 11 and 10 out of 11 GH caused significant increase in γH2AX and Ki-67 levels, respectively (P < .05). Of the 3 machine learning models, Random Forest performed the best. GH were identified with 95.0% sensitivity (76/80 GH-treated rats), 90.9% specificity (50/55 non-GH-treated rats), and 90.0% overall correct response rate using γH2AX staining, and 96.2% sensitivity (77/80), 81.8% specificity (45/55), and 90.4% overall correct response rate using Ki-67 labeling. Random Forest model using γH2AX and Ki-67 could independently predict GH in the early stage with high accuracy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The ubiquitin-mediated degradation of oocyte translational regulatory proteins is a conserved feature of the oocyte-to-embryo transition. In the nematode Caenorhabditis elegans, multiple translational regulatory proteins, including the TRIM-NHL RNA-binding protein LIN-41/Trim71 and the Pumilio-family RNA-binding proteins PUF-3 and PUF-11, are degraded during the oocyte-to-embryo transition. Degradation of each protein requires activation of the M-phase cyclin-dependent kinase CDK-1, is largely complete by the end of the first meiotic division and does not require the anaphase-promoting complex. However, only LIN-41 degradation requires the F-box protein SEL-10/FBW7/Cdc4p, the substrate recognition subunit of an SCF-type E3 ubiquitin ligase. This finding suggests that PUF-3 and PUF-11, which localize to LIN-41-containing ribonucleoprotein particles, are independently degraded through the action of other factors and that the oocyte ribonucleoprotein particles are disassembled in a concerted fashion during the oocyte-to-embryo transition. We develop and test the hypothesis that PUF-3 and PUF-11 are targeted for degradation by the proteasome-associated HECT-type ubiquitin ligase ETC-1/UBE3C/Hul5, which is broadly expressed in C. elegans. We find that several GFP-tagged fusion proteins that are degraded during the oocyte-to-embryo transition, including fusions with PUF-3, PUF-11, LIN-41, IFY-1/Securin, and CYB-1/Cyclin B, are incompletely degraded when ETC-1 function is compromised. However, it is the fused GFP moiety that appears to be the critical determinant of this proteolysis defect. These findings are consistent with a conserved role for ETC-1 in promoting proteasome processivity and suggest that proteasomal processivity is an important element of the oocyte-to-embryo transition during which many key oocyte regulatory proteins are rapidly targeted for degradation., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Japanese Society for Cancer of the Colon and Rectum guidelines recommend regular, more intensive surveillance of patients who have undergone curative resection of pathological stages I-III colorectal cancer compared with guidelines in Western countries. We conducted a questionnaire survey to clarify the status of surveillance for patients with stage I or II colorectal cancer in high-volume centers in Japan on behalf of the Colorectal Cancer Study Group of the Japan Clinical Oncology Group. Questionnaires were distributed in September 2019. The response rate was 98.3% (59/60 institutions). The survey results indicated that about half of colorectal cancer specialists in Japan perform surveillance for stages I and II colorectal cancer according to the Japanese Society for Cancer of the Colon and Rectum guidelines. For stages I and II disease, 45% and 55% of surgeons, respectively, perform surveillance less intensively than recommended. Our findings suggest the possibility of less intensive surveillance for patients with stage I or II colorectal cancer in Japan., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The study objective was to identify sociodemographic and coronavirus disease 2019 (COVID-19) factors that are associated with COVID-19 vaccine hesitancy among adolescent and young adult (AYA) cancer survivors. Eligible participants were 18 years or older and were diagnosed with cancer as an AYA (ages 15-39 years) and received services through an AYA cancer program. A total of 342 participants completed a cross-sectional survey. Our primary outcome-COVID-19 vaccine hesitancy-was surveyed as a 5-point Likert scale and operationalized as a binary outcome (agree vs hesitant). A large proportion of participants reported COVID-19 vaccine hesitancy (37.1%). In the multivariable regression, female survivors (odds ratio = 1.81, 95% confidence interval = 1.10 to 2.98) and survivors with a high school education or less (odds ratio = 3.15, 95% confidence interval = 1.41 to 7.04) reported higher odds of vaccine hesitancy compared with their male or college graduate or higher counterparts. COVID-19 vaccine hesitancy persists among AYA survivors despite their recommended priority vaccination status and higher chances of severe COVID-19 outcomes., (© The Author(s) 2021. Published by Oxford University Press.)

Background: Although neoadjuvant chemotherapy provides survival benefits in muscle-invasive bladder cancer, the impact of neoadjuvant chemotherapy on health-related quality of life has not been investigated by a randomized trial. The purpose of this study is to compare health-related quality of life in patients with muscle-invasive bladder cancer who received neoadjuvant chemotherapy followed by radical cystectomy or radical cystectomy alone based on patient-reported outcome data., Methods: Patients were randomized to receive two cycles of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin followed by radical cystectomy or radical cystectomy alone. Health-related quality of life was measured using the Functional Assessment of Cancer Therapy-Bladder (version 4) questionnaire before the protocol treatments, after neoadjuvant chemotherapy, after radical cystectomy and 1 year after registration., Results: A total of 99 patients were analysed. No statistically significant differences in postoperative health-related quality of life were found between the arms. In the neoadjuvant chemotherapy arm, the scores after neoadjuvant chemotherapy were significantly lower than the baseline scores in physical well-being, functional well-being, Functional Assessment of Cancer Therapy-General total, weight loss, diarrhoea, appetite, body appearance, embarrassment by ostomy appliance and total Functional Assessment of Cancer Therapy-Bladder. However, there was no difference in scores for these domains, except for embarrassment by ostomy appliance, between the two arms after radical cystectomy and 1 year after registration., Conclusions: Although health-related quality of life declined during neoadjuvant chemotherapy, no negative effect of neoadjuvant chemotherapy on health-related quality of life was apparent after radical cystectomy. These data support the view that neoadjuvant chemotherapy can be considered as a standard of care for patients with muscle-invasive bladder cancer regarding health-related quality of life., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mutations affecting spliceosomal proteins are frequently found in hematological malignancies, including myelodysplastic syndromes and acute myeloid leukemia (AML). DDX41/Abstrakt is a metazoan-specific spliceosomal DEAD-box RNA helicase that is recurrently mutated in inherited myelodysplastic syndromes and in relapsing cases of AML. The genetic properties and genomic impacts of disease-causing missense mutations in DDX41 and other spliceosomal proteins have been uncertain. Here, we conduct a comprehensive analysis of the Caenorhabditis elegans DDX41 ortholog, SACY-1 Biochemical analyses defined SACY-1 as a component of the C. elegans spliceosome, and genetic analyses revealed synthetic lethal interactions with spliceosomal components. We used the auxin-inducible degradation system to analyze the consequence of SACY-1 depletion on the transcriptome using RNA sequencing. SACY-1 depletion impacts the transcriptome through splicing-dependent and splicing-independent mechanisms. Altered 3' splice site usage represents the predominant splicing defect observed upon SACY-1 depletion, consistent with a role for SACY-1 in the second step of splicing. Missplicing events appear more prevalent in the soma than the germline, suggesting that surveillance mechanisms protect the germline from aberrant splicing. The transcriptome changes observed after SACY-1 depletion suggest that disruption of the spliceosome induces a stress response, which could contribute to the cellular phenotypes conferred by sacy-1 mutant alleles. Multiple sacy-1 /ddx41 missense mutations, including the R525H human oncogenic variant, confer antimorphic activity, suggesting that their incorporation into the spliceosome is detrimental. Antagonistic variants that perturb the function of the spliceosome may be relevant to the disease-causing mutations, including DDX41, affecting highly conserved components of the spliceosome in humans., (Copyright © 2020 by the Genetics Society of America.)

Aims: The efficacy and safety of cardiac rehabilitation for patients with persistent atrial fibrillation who restored sinus rhythm after catheter ablation remains unclear. The aim of the present study was to evaluate the effects of cardiac rehabilitation on exercise capacity, inflammatory status, cardiac function, and safety in patients with persistent atrial fibrillation who had catheter ablation., Methods: In this randomized controlled study, 61 patients treated with catheter ablation for persistent atrial fibrillation (male, 80%; mean age, 66 ± 9 years) were analyzed. Thirty patients underwent cardiac rehabilitation (rehabilitation group), whereas the remaining 31 patients received usual care (usual care group). The rehabilitation group underwent endurance and resistance training with moderate intensity, at least three times per week for six months. Six-minute walk distance, muscle strength, serum high-sensitivity C-reactive protein, plasma pentraxin 3, left ventricular ejection fraction and atrial fibrillation recurrence were assessed at baseline and at six-month follow-up., Results: In the rehabilitation group, significant increases in the six-minute walk distance, handgrip strength, leg strength and left ventricular ejection fraction and significant decreases in high-sensitivity C-reactive protein and plasma pentraxin 3 concentrations were observed at six-month follow-up compared with baseline (all p  < 0.05). No significant changes were observed in the usual care group. During the six-month follow-up period, the number of patients with atrial fibrillation recurrence was six (21.4%) in the rehabilitation group and eight (25.8%) in the usual care group (risk ratio, 0.83; 95% confidence interval, 0.33 to 2.10)., Conclusions: Cardiac rehabilitation improved exercise capacity without increasing the risk for atrial fibrillation recurrence. It may also be effective in managing systemic inflammatory status and systolic left ventricular function in patients with persistent atrial fibrillation treated with catheter ablation.

In the nematode Caenorhabditis elegans , the conserved LIN-41 RNA-binding protein is a translational repressor that coordinately controls oocyte growth and meiotic maturation. LIN-41 exerts these effects, at least in part, by preventing the premature activation of the cyclin-dependent kinase CDK-1 Here we investigate the mechanism by which LIN-41 is rapidly eliminated upon the onset of meiotic maturation. Elimination of LIN-41 requires the activities of CDK-1 and multiple SCF (Skp1, Cul1, and F-box protein)-type E3 ubiquitin ligase subunits, including the conserved substrate adaptor protein SEL-10/Fbw7/Cdc4, suggesting that LIN-41 is a target of ubiquitin-mediated protein degradation. Within the LIN-41 protein, two nonoverlapping regions, Deg-A and Deg-B, are individually necessary for LIN-41 degradation; both contain several potential phosphodegron sequences, and at least one of these sequences is required for LIN-41 degradation. Finally, Deg-A and Deg-B are sufficient, in combination, to mediate SEL-10-dependent degradation when transplanted into a different oocyte protein. Although LIN-41 is a potent inhibitor of protein translation and M phase entry, the failure to eliminate LIN-41 from early embryos does not result in the continued translational repression of LIN-41 oocyte messenger RNA targets. Based on these observations, we propose a model for the elimination of LIN-41 by the SEL-10 E3 ubiquitin ligase and suggest that LIN-41 is inactivated before it is degraded. Furthermore, we provide evidence that another RNA-binding protein, the GLD-1 tumor suppressor, is regulated similarly. Redundant mechanisms to extinguish translational repression by RNA-binding proteins may both control and provide robustness to irreversible developmental transitions, including meiotic maturation and the oocyte-to-embryo transition., (Copyright © 2018 by the Genetics Society of America.)

An extended meiotic prophase is a hallmark of oogenesis. Hormonal signaling activates the CDK1/cyclin B kinase to promote oocyte meiotic maturation, which involves nuclear and cytoplasmic events. Nuclear maturation encompasses nuclear envelope breakdown, meiotic spindle assembly, and chromosome segregation. Cytoplasmic maturation involves major changes in oocyte protein translation and cytoplasmic organelles and is poorly understood. In the nematode Caenorhabditis elegans , sperm release the major sperm protein (MSP) hormone to promote oocyte growth and meiotic maturation. Large translational regulatory ribonucleoprotein (RNP) complexes containing the RNA-binding proteins OMA-1, OMA-2, and LIN-41 regulate meiotic maturation downstream of MSP signaling. To understand the control of translation during meiotic maturation, we purified LIN-41-containing RNPs and characterized their protein and RNA components. Protein constituents of LIN-41 RNPs include essential RNA-binding proteins, the GLD-2 cytoplasmic poly(A) polymerase, the CCR4-NOT deadenylase complex, and translation initiation factors. RNA sequencing defined messenger RNAs (mRNAs) associated with both LIN-41 and OMA-1, as well as sets of mRNAs associated with either LIN-41 or OMA-1 Genetic and genomic evidence suggests that GLD-2, which is a component of LIN-41 RNPs, stimulates the efficient translation of many LIN-41-associated transcripts. We analyzed the translational regulation of two transcripts specifically associated with LIN-41 which encode the RNA regulators SPN-4 and MEG-1 We found that LIN-41 represses translation of spn-4 and meg-1 , whereas OMA-1 and OMA-2 promote their expression. Upon their synthesis, SPN-4 and MEG-1 assemble into LIN-41 RNPs prior to their functions in the embryo. This study defines a translational repression-to-activation switch as a key element of cytoplasmic maturation., (Copyright © 2017 by the Genetics Society of America.)

Objective: To evaluate the efficacy and safety of degarelix 3-month depot in Japanese patients with prostate cancer., Methods: In this Phase II, open-label, parallel-group study, 155 Japanese prostate cancer patients were randomized to treatment with degarelix administered subcutaneously at a maintenance dose of 360 or 480 mg every 84 days for 12 months, after receiving an initial dose of 240 mg. The primary endpoint was the cumulative probability of serum testosterone ≤0.5 ng/ml (Days 28-364). Secondary endpoints included percent change in serum prostate-specific antigen level and proportion of patients with prostate-specific antigen failure at Day 364. For safety, adverse events were evaluated., Results: The cumulative probability of serum testosterone ≤0.5 ng/ml (Days 28-364) was 88.3% (95% confidence interval: 77.9-94.0%) and 97.2% (95% confidence interval: 89.4-99.3%) in the 360 and 480 mg groups, respectively. The median percent change in serum prostate-specific antigen level from baseline to Day 364 was -95.05% and -96.43% in the 360 and 480 mg groups, respectively; the proportion of patients with prostate-specific antigen failure was 2.7% and 1.3%. The most frequent adverse event was injection site reaction; however, this did not cause any patient to discontinue treatment., Conclusions: The 3-month dosing regimen of degarelix 360/480 mg was effective and well tolerated for treatment of Japanese prostate cancer patients. The 480 mg group showed a higher cumulative castration rate than the 360 mg group; thus, 480 mg was considered to be the optimal clinical dosage for future Phase III trials., (© The Author 2017. Published by Oxford University Press.)

Eos (Extensible object-oriented system) is one of the powerful applications for image processing of electron micrographs. In usual cases, Eos works with only character user interfaces (CUI) under the operating systems (OS) such as OS-X or Linux, not user-friendly. Thus, users of Eos need to be expert at image processing of electron micrographs, and have a little knowledge of computer science, as well. However, all the persons who require Eos does not an expert for CUI. Thus we extended Eos to a web system independent of OS with graphical user interfaces (GUI) by integrating web browser.Advantage to use web browser is not only to extend Eos with GUI, but also extend Eos to work under distributed computational environment. Using Ajax (Asynchronous JavaScript and XML) technology, we implemented more comfortable user-interface on web browser. Eos has more than 400 commands related to image processing for electron microscopy, and the usage of each command is different from each other. Since the beginning of development, Eos has managed their user-interface by using the interface definition file of "OptionControlFile" written in CSV (Comma-Separated Value) format, i.e., Each command has "OptionControlFile", which notes information for interface and its usage generation. Developed GUI system called "Zephyr" (Zone for Easy Processing of HYpermedia Resources) also accessed "OptionControlFIle" and produced a web user-interface automatically, because its mechanism is mature and convenient,The basic actions of client side system was implemented properly and can supply auto-generation of web-form, which has functions of execution, image preview, file-uploading to a web server. Thus the system can execute Eos commands with unique options for each commands, and process image analysis. There remain problems of image file format for visualization and workspace for analysis: The image file format information is useful to check whether the input/output file is correct and we also need to provide common workspace for analysis because the client is physically separated from a server. We solved the file format problem by extension of rules of OptionControlFile of Eos. Furthermore, to solve workspace problems, we have developed two type of system. The first system is to use only local environments. The user runs a web server provided by Eos, access to a web client through a web browser, and manipulate the local files with GUI on the web browser. The second system is employing PIONE (Process-rule for Input/Output Negotiation Environment), which is our developing platform that works under heterogenic distributed environment. The users can put their resources, such as microscopic images, text files and so on, into the server-side environment supported by PIONE, and so experts can write PIONE rule definition, which defines a workflow of image processing. PIONE run each image processing on suitable computers, following the defined rule. PIONE has the ability of interactive manipulation, and user is able to try a command with various setting values. In this situation, we contribute to auto-generation of GUI for a PIONE workflow.As advanced functions, we have developed a module to log user actions. The logs include information such as setting values in image processing, procedure of commands and so on. If we use the logs effectively, we can get a lot of advantages. For example, when an expert may discover some know-how of image processing, other users can also share logs including his know-hows and so we may obtain recommendation workflow of image analysis, if we analyze logs. To implement social platform of image processing for electron microscopists, we have developed system infrastructure, as well., (© The Author 2014. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The objective of the present study was to investigate the trends over time in the initial treatment of prostate cancer in Japan., Methods: A total of 8291 patients with newly diagnosed prostate cancer whose treatment started in 2010 were registered in a multi-institutional observational study undertaken nationwide across Japan by the Japan Prostate Cancer Study Group. Each patient's background characteristics and initial treatment were recorded., Results: The median age at diagnosis was 71 years. The proportion of T1c disease was 40.5% and that of M1 disease was 10.4%. The prostate-specific antigen level was <10 ng/ml in 52.0% of the patients. High-, intermediate- and low-risk patients as determined by D'Amico's classification system made up 19.3, 29.8 and 25.9% of the cases, respectively. The initial treatment was androgen depletion therapy in 40.2%, radical prostatectomy in 32.0% (17.3% of these involved laparoscopic prostatectomy), radiation in 21.0% (46.4% of these involved brachytherapy). In cases of organ-confined disease, radical prostatectomy was selected in 39.5%, androgen depletion therapy in 28.0% and radiation in 23.9%. In D'Amico's low-risk group, the proportion treated with radiation was nearly equal to that treated with radical prostatectomy (30.2 and 32.7%, respectively); 73.2% of the radiation treatments involved brachytherapy., Conclusion: Compared with previous Japanese studies, radiation use was increased by ∼10%. This increased proportion of radiation use was a typical trend in initial therapy for newly diagnosed prostate cancer cases in Japan. Although androgen depletion therapy use was decreased, it was selected in a high proportion of the patients irrespective of the disease stage., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In flowering plants, meiocytes develop from subepidermal cells in anthers and ovules. The mechanisms that integrate gene-regulatory processes with meiotic programs during reproductive development remain poorly characterized. Here, we show that Arabidopsis thaliana plants deficient in ACTIN-RELATED PROTEIN6 (ARP6), a subunit of the SWR1 ATP-dependent chromatin-remodeling complex, exhibit defects in prophase I of female meiosis. We found that this meiotic defect is likely due to dysregulated expression of meiotic genes, particularly those involved in meiotic recombination, including DMC1 (DISRUPTED MEIOTIC cDNA1). Analysis of DMC1 expression in arp6 mutant plants indicated that ARP6 inhibits expression of DMC1 in the megasporocyte and surrounding nonsporogeneous ovule cells before meiosis. After cells enter meiosis, however, ARP6 activates DMC1 expression specifically in the megasporocyte even as it continues to inhibit DMC1 expression in the nonsporogenous ovule cells. We further show that deposition of the histone variant H2A.Z, mediated by the SWR1 chromatin-remodeling complex at the DMC1 gene body, requires ARP6. Therefore, ARP6 regulates female meiosis by determining the spatial and temporal patterns of gene expression required for proper meiosis during ovule development., (© 2014 American Society of Plant Biologists. All rights reserved.)

Objective: A planned primary analysis of a Phase II study of S-1 demonstrated that the drug was active and tolerable in Japanese patients with cytokine-refractory metastatic renal cell carcinoma. Furthermore, pharmacogenomic analysis suggested that low expression of thymidylate synthase mRNA may have been associated with clinical outcome in terms of overall response rate and progression-free survival. Here, we report the results of the final analysis assessing the efficacy and safety of S-1 including overall survival., Methods: Patients with renal cell carcinoma were eligible if they had had at least one regimen of cytokine for metastatic disease. S-1 was orally administered on Days 1-28 of a 42-day cycle until disease progression. The primary endpoint was the overall response rate, and the secondary endpoint included progression-free survival, overall survival and safety., Results: A total of 45 patients were treated with S-1 and were fully assessable for efficacy and safety. At the final analysis, a response was seen in 11 patients (overall response rate, 24.4%; 95% confidence interval: 12.9-39.5%), including two patients who achieved a complete response. The final median progression-free and overall survival were 9.2 and 42.8 months, respectively. The safety profile of S-1 was favorable. It was suggested that there was no relation between overall survival and the expression level of thymidylate synthase., Conclusion: This final analysis confirms that S-1 treatment is effective and safe in patients with cytokine-refractory renal cell carcinoma.

Objective: The aim of this study was to clarify the prognostic value and clinical reliability of the 2004 World Health Organization classification system of non-muscle-invasive bladder cancer., Methods: Between January 1995 and November 2010, 153 patients were diagnosed with non-muscle-invasive bladder cancer. We used a substage system that discerns T1-microinvasive (T1m, 42 patients) and T1-extensive-invasive (T1e, 37 patients) cancers., Results: There were 2 (1.3%), 89 (58.2%) and 62 (40.5%) cases of Grade 1-3 urothelial carcinoma, respectively, on the basis of the 1973 World Health Organization classification system. Of these, 37 (24.2%) and 116 (75.8%) were graded as low and high on the basis of the 2004 World Health Organization classification system. All of the cases with progression (15 patients) were diagnosed as high grade at the time of primary transurethral resection of the bladder tumor. Based on the Kaplan-Meier analysis, the 2004 World Health Organization classification system accurately predicted tumor recurrence (P = 0.029) and progression (P = 0.031). The 5-year recurrence-free survival rates in patients with low-grade and high-grade tumors were 68.7 and 47.1%, and the 5-year progression-free survival rates were 100 and 89.0%, respectively. In the high-grade T1 cases, the substage (T1m or T1e) was a significant predictor of tumor recurrence (P = 0.001) and progression (P = 0.020)., Conclusions: The 2004 World Health Organization classification system accurately predicts the risk of recurrence in primary non-muscle-invasive bladder cancer cases and has the same accuracy when predicting the risk of progression as the 1973 World Health Organization classification. Furthermore, the substaging system for high-grade T1 tumors is useful in predicting both recurrence and progression.

Objective: Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated., Methods: A subgroup analysis was conducted in Japanese patients enrolled in the randomized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for metastatic renal cell carcinoma., Results: Twenty-five (of 361) and 29 (of 362) patients randomized to the axitinib and sorafenib arms, respectively, were Japanese and included in this analysis. Median progression-free survival in Japanese patients was 12.1 months (95% confidence interval 8.6 to not estimable) for axitinib and 4.9 months (95% confidence interval 2.8-6.6) for sorafenib (hazard ratio 0.390; 95% confidence interval 0.130-1.173; stratified one-sided P = 0.0401). The objective response rate was 52.0% for axitinib and 3.4% for sorafenib (P = 0.0001). The common all-causality adverse events (all grades) in Japanese patients were dysphonia (68%), hypertension (64%), hand-foot syndrome (64%) and diarrhea (56%) for axitinib, and hand-foot syndrome (86%), hypertension (62%) and diarrhea (52%) for sorafenib. The safety profiles of axitinib and sorafenib in Japanese patients were generally similar to those observed in the overall population, with the exceptions of higher incidences of hypertension, dysphonia, hand-foot syndrome, hypothyroidism and stomatitis., Conclusions: Axitinib is efficacious and well tolerated in Japanese patients with previously treated metastatic renal cell carcinoma, consistent with the results in the overall population, providing a new targeted therapy for these Japanese patients.

Objective: There are few reports investigating the potential benefits of preoperative systemic chemotherapy for patients with node-positive upper tract urothelial carcinoma. The purpose of this study was to examine the impact of preoperative systemic chemotherapy on the clinical outcomes of patients with node-positive upper tract urothelial carcinoma treated by radical nephroureterectomy., Methods: Data were collected on 195 consecutive patients with upper tract urothelial carcinoma treated by radical nephroureterectomy between 1995 and 2010 at a single institute. Of these, 29 patients with node-positive disease but no visceral metastasis were retrospectively evaluated. In patients who underwent preoperative systemic chemotherapy, tumor response, post-therapy pathological downstaging to either residual disease at radical nephroureterectomy or no residual lymph node metastasis (pN0) and toxicity were the endpoints of interest. Overall survival was compared between two groups: those with and without preoperative chemotherapy., Results: All patients underwent regional lymphadenectomy. Overall, 15 patients (52%) underwent preoperative systemic chemotherapy. Pathological downstaging was achieved in 47%, including pN0, but there was no pathological complete response. Eighty-six percent of the patients with pathological downstaging had no evidence of recurrence. The median overall survivals were 38 and 9 months for patients with and without preoperative systemic chemotherapy, respectively (hazard ratio: 0.26, P = 0.015, log-rank test). There was no significant difference in operative morbidity between the two groups, and no operations were delayed because of preoperative chemotherapy., Conclusions: The survival of patients who undergo preoperative systemic chemotherapy following radical nephroureterectomy seems to be superior to that of those undergoing radical nephroureterectomy alone. However, to confirm this, prospective randomized studies are needed.

A Phase III clinical trial has been started in Japan to determine the optimal treatment strategy for patients with high-grade pT1 bladder cancer who have pT0 histology after second transurethral resection. The aim of this trial is to demonstrate the non-inferiority of relapse-free survival (excluding Tis or Ta intravesical recurrence) for watchful waiting compared with intravesical bacillus Calmette-Guérin therapy for pT0 after second transurethral resection. Patients with high-grade pT1 bladder cancer at the first registration and pT0 after second transurethral resection at the second registration are randomized to either a watchful waiting arm or an intravesical bacillus Calmette-Guérin therapy arm. A total of 575 patients at the first registration and 260 patients at the second registration will be accrued for this study from 38 institutions over 5 years. The primary endpoint is relapse-free survival (excluding Tis or Ta intravesical recurrence), and the secondary endpoints are overall survival, metastasis-free survival with bladder preserved, annual proportion of intravesical relapse-free survival, annual proportion of T2 or deeper relapse-free survival, adverse events and serious adverse events.

Introduction: Gender identity and the second-to-fourth finger length ratio (2D : 4D) are discriminative between the sexes. However, the relationship between 2D : 4D and gender identity disorder (GID) is still controversial., Aim: The aim of this study is to investigate the relationship between 2D : 4D and score on the Gender Identity Scale (GIS) in female-to-male (FtM) GID subjects., Methods: Thirty-seven GID-FtM with testosterone replacement therapy from our clinic were included in this study. As controls, 20 male and 20 female volunteers participated from our institution (medical doctors and nurses). We photocopied left and right hands of the participants and measured the second and fourth finger lengths. Gender identity was measured with the GIS., Main Outcome Measures: 2D : 4D digit ratio and GIS in male, female, and GID-FtM subjects., Results: The 2D : 4D (mean ± standard deviation) in male, female, and GID-FtM were 0.945 ± 0.029, 0.999 ± 0.035, and 0.955 ± 0.029 in right hand and 0.941 ± 0.024, 0.979 ± 0.040, and 0.954 ± 0.036 in left hand, respectively. The 2D : 4D was significantly lower in male controls in both hands and GID-FtM in the right hand than in female controls (P < 0.05, analysis of variance). Multiple linear regression analysis revealed that "consistent gender identity" score in the higher domain in GIS and "persistent gender identity" score in the lower domain are statistically significant variables correlating with 2D : 4D in the right hands among biological females., Conclusions: The finger length ratio 2D : 4D in GID-FtM was significantly lower than in female controls in the right hand in this study. 2D : 4D showed a positive correlation with GIS score. Because 2D : 4D influences are assumed to be established in early life and to reflect testosterone exposure, our results suggest a relationship between GID-FtM and perinatal testosterone., (© 2012 International Society for Sexual Medicine.)

Objective: To assess the efficacy and safety of degarelix, a new gonadotropin-releasing hormone antagonist, for achieving and maintaining serum testosterone suppression (≤0.5 ng/ml) during the 12-month treatment of Japanese patients with prostate cancer., Methods: This Phase II study was conducted as a multicentre, randomized, parallel-group, open-label study. A total of 273 patients with adenocarcinoma of the prostate (any stage) were treated. Degarelix was administered subcutaneously at an initial dose of 240 mg followed by monthly maintenance doses of either 80 or 160 mg for a total of 12 doses. The treatment continued for 12 months., Results: Dose regimens of 240/80 and 240/160 mg maintained castrate levels of testosterone in 94.5 and 95.2% of the patients, respectively. After 3 days, 99.3 and 98.5% of the patients, respectively, reached these levels without a testosterone surge. Prostate-specific antigen levels decreased rapidly following degarelix administration and remained low throughout the study. Best overall response rates according to RECIST were 71.4 (20/28) and 72.7% (16/22), respectively. Eighteen patients (6.6%) withdrew from the study due to adverse events. The most common adverse events were injection site reactions; other adverse events included hot flush, nasopharyngitis, weight increase and pyrexia., Conclusions: Both monthly degarelix dosing regimens were found to be effective in testosterone suppression without a testosterone surge, prostate-specific antigen reductions and anti-tumour effect in Japanese patients with prostate cancer, as was shown in the overseas Phase III study. Degarelix was also well tolerated.

Objective: To clarify the survival benefit of immunotherapy for renal cell carcinoma patients with lung metastasis using low-dose interleukin-2 plus interferon-α, we examined survival outcomes and factors associated with prognosis., Methods: This was a multicenter prospective study. Nephrectomized renal cell carcinoma patients with lung metastasis were treated with interleukin-2 (0.7 × 10(6) unit, 5 days a week) and interferon-α (6 × 10(6) IU, 3 days a week) for the first 8 weeks, and then with both interleukin-2 and interferon-α, 2 or 3 days a week for 16 additional weeks., Results: Median follow-up period for 42 patients was 28.3 months (range: 4.2-43.8). Two-year overall survival rate was 82% and the probability of 3 year survival rate was 71%. Median progression-free survival was 10.4 months. While no difference was found in survival among patients assessed as complete response, partial response and no change, survival of patients assessed as NC or better was significantly better than those assessed as progressive disease (P < 0.0001). Furthermore, multivariate analyses identified pre-treatment serum sodium (P = 0.004) as an independent prognostic factor. The sodium level was also statistically associated with tumor response (p = 0.035). Patients with normal sodium level survived significantly longer (P = 0.0005) than those with low sodium level showing median survival of 12.2 months., Conclusions: Combination immunotherapy with low-dose interleukin-2 plus interferon-α showed survival benefit for patients with lung metastasis whose tumor responded as no change or better. This combination immunotherapy could be beneficial for patients selected by metastatic organ and their pre-treatment serum sodium level.

Introduction: The precise mechanisms underlying erectile dysfunction (ED) occurring after cavernous nerve (CN)-sparing surgery remain to be determined. Aim.  To evaluate the expression of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) after CN injury, and the effect of inhibiting IL-6 bioactivity on nerve injury-related ED., Methods: Male Sprague-Dawley rats were divided into three groups: sham operation; bilateral CN dissection without crushing or cutting; and bilateral CN resection. In the interventional experiment, male rats underwent bilateral CN dissection, and anti-rat IL-6 antibody in phosphate-buffered saline (PBS) or vehicle alone was injected intraperitoneally immediately and 24 hours after CN dissection., Main Outcome Measures: One, 3, 7, 28, and 56 days after surgery, the expression of IL-6 and IL-6R in the major pelvic ganglion (MPG) was examined by real-time polymerase chain reaction. In the interventional experiment, erectile function was assessed by determining intracavernous pressure divided by arterial pressure (ICP/AP) during electrical pelvic nerve stimulation at 4 weeks after surgery in the anti-IL-6-injected rats and PBS-injected rats. The degree of nerve injury was also evaluated by retrograde dye tracing with Fluorogold., Results: The expression levels of IL-6 and IL-6R were increased in the early period of CN injury, as compared with the sham group. IL-6 expression on day 1 was particularly enhanced. Four weeks after CN dissection, the anti-IL-6 group had greater ICP/AP and more FG-positive cells than the PBS group., Conclusions: Expression levels of IL-6 in the MPG were increased in the acute phase following CN injury. Inhibition of IL-6 bioactivity attenuated ED following CN dissection. Thus, the suppression of excess inflammatory responses in the acute phase may lead to improvements in ED occurring after nerve-sparing radical prostatectomy., (© 2011 International Society for Sexual Medicine.)

Objective: A post hoc analysis of Asian men in the REDUCE study was conducted to investigate whether the outcomes were in line with those of the overall population., Methods: REDUCE was a 4-year international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Inclusion criteria were men between 50 and 75 years of age, a serum prostate-specific antigen level of 2.5-10.0 ng/ml (50-60 years) or 3.0-10.0 ng/ml (>60 years), and a single, negative prostate biopsy (6-12 cores) within 6 months before enrollment. The primary endpoint was biopsy-detectable prostate cancer. This post hoc analysis included subjects who were recorded as Asian., Results: A total of 134 Asians, including 57 Japanese, were randomized to the study treatment. During the study period, the incidence of prostate cancer in the placebo and dutasteride groups was 19.6% (11/56) and 9.3% (5/54), respectively (relative risk reduction, 54%; 95% confidence intervals, -27 to 83%, P = 0.12), in the Asian subpopulation. Fewer tumors with the Gleason scores of 7-10 and 8-10 were detected among dutasteride-treated men. Although the incidences of drug-related sexual adverse events were higher in the dutasteride group, only in rare occasions did they lead to drug discontinuation., Conclusions: The incidence of prostate cancer in the dutasteride group was lower than that in the placebo group, although the difference was not significant. These results paralleled those for the overall population and support the value of dutasteride for prostate cancer risk reduction in Asian men with an increased risk of prostate cancer.

Objective: We investigated whether serum testosterone after the failure of androgen deprivation monotherapy predicted the efficacy of antiandrogens added to androgen deprivation monotherapy as second-line treatments for patients with castration-resistant prostate cancer., Methods: We reviewed 30 patients with castration-resistant prostate cancer who received maximal androgen blockade with addition of an antiandrogen (delayed maximal androgen blockade) (bicalutamide 80 mg daily for 21 patients and flutamide 375 mg daily for 9 patients) as the second-line treatment. The patients were divided into two groups by serum testosterone before delayed maximal androgen blockade: 22 in the testosterone ≥ 5 ng/dl group and 8 in the testosterone <5 ng/dl group. A prostate-specific antigen response was defined as a prostate-specific antigen decline of ≥ 50% from the pre-treatment level., Results: The response rate was significantly higher in the testosterone ≥ 5 ng/dl group than in the testosterone <5 ng/dl group (77.3 vs. 37.5%, P =0.04). During the median follow-up period of 52.5 months, 24 patients (80.0%) developed prostate-specific antigen progression. A serum testosterone level of <5 ng/dl was an independent factor to predict prostate-specific antigen progression in a reduced and full model setting on multivariate analysis (hazard ratio 6.03, P =0.003 and 5.99, P =0.003, respectively). The 1-year prostate-specific antigen progression-free survival rate was significantly higher in the testosterone ≥ 5 ng/dl group than in the testosterone <5 ng/dl group (52.9 vs. 0%, P =0.002), as was cause-specific survival (5 years: 66.0 vs. 33.3%, P =0.007)., Conclusions: Serum testosterone could play an important role when delayed maximal androgen blockade is indicated as the second-line treatment in patients with castration-resistant prostate cancer. Delayed maximal androgen blockade might be more beneficial in patients with a serum testosterone level of ≥ 5ng/dl.

Objective: To investigate the clinical outcomes of patients who underwent radical cystectomy for bladder cancer at a single institution and compare those who had pT0 specimens with those who had residual cancer., Methods: From January 1990 to December 2006, 186 patients underwent radical cystectomy with or without neoadjuvant chemotherapy for cT2 or higher stage urothelial carcinoma in the bladder in our hospital. We estimated the 5-year disease-free survival, cancer-specific survival and overall survival by the pathological stage., Results: The median follow-up of the 186 patients was 38.5 months (0-194). Of these, 51 received neoadjuvant chemotherapy. For all subjects, the 5-year disease-free survival was 54.9%, cancer-specific survival 61.0% and overall survival 57.1%. Of the 186 patients, 24 (12.9%) had no residual cancer in the bladder specimen at radical cystectomy. Of the 24 patients with pT0, only 1 (4.2%) died of bladder cancer. The 5-year disease-free survival, cancer-specific survival and overall survival rates in patients with pT0 were ∼96.0%. We found pT0 histology in 11 of the 51 patients (21.6%) with neoadjuvant chemotherapy and in 13 of the 135 patients (9.6%) with radical cystectomy alone (P = 0.047)., Conclusions: We demonstrated that the outcomes of patients who underwent radical cystectomy were similar to those in previous reports. Patients with pT0 showed favorable outcomes for disease-free survival, cancer-specific survival and overall survival in our study. However, they should be periodically followed up because pT0 does not always mean cure.

Objective: To assess the efficacy and safety of everolimus in Japanese patients with metastatic renal cell carcinoma., Methods: A subgroup analysis of the pivotal Phase III, randomized, double-blind, placebo-controlled trial of everolimus 10 mg/day in patients with disease progression after treatment with sorafenib, sunitinib or both assessed outcomes in Japanese participants. Results were compared with those for the overall study population., Results: The final trial analysis included 24 Japanese patients (everolimus, n= 15; placebo, n = 9). Median progression-free survival in the Japanese subpopulation was 5.75 months (95% confidence interval, 4.90 months to not reached) with everolimus and 3.61 months (95% confidence interval, 1.91-9.03 months) with placebo (hazard ratio, 0.19; 95% confidence interval, 0.05-0.83). Median overall survival was not reached with everolimus and was 14.9 months (95% confidence interval, 11.0-16.8 months) with placebo (hazard ratio, 0.30; 95% confidence interval, 0.07-1.27). Overall, efficacy and safety were similar when comparing the Japanese and overall populations. In the Japanese subpopulation, the most common adverse events with everolimus were stomatitis, infections and rash. Four Japanese subjects (27%) developed Grade 1 (n = 2) or 2 (n = 2) pneumonitis (all reversible and allowing for continuation of therapy, after interruption, steroids and dose reduction for both Grade 2 cases), with a lower pneumonitis incidence of 14% in the overall population (albeit associated with a Grade 3 incidence of 4%)., Conclusions: These findings suggest that the demonstrated benefits of everolimus in the overall trial population are similar in Japanese patients with metastatic renal cell carcinoma.

Objectives: We analyzed the efficacy of additional antiandrogens as second- and third-line treatments after the failure of initial androgen deprivation monotherapy., Methods: This retrospective study included 53 patients with advanced prostate cancer initially treated with androgen deprivation monotherapy alone. An antiandrogen was added to androgen deprivation monotherapy as the second-line treatment after the failure of the initial androgen deprivation monotherapy. Another antiandrogen, estrogen or steroid was given as the third-line treatment after the second-line treatment failed., Results: The initial androgen deprivation monotherapy was effective in all 53 patients for a median of 9.6 months. Thirty-three (62.3%) patients showed a prostate-specific antigen response to the second-line treatment for a median of 10.7 months. Of the 46 patients who received the third-line treatment, 16 (34.8%) showed a prostate-specific antigen response for a median of 6.0 months. Patients who responded to the second-line treatment had a significantly higher cancer-specific survival rate than those without a response. In multivariate analysis, a nadir prostate-specific antigen of 4.0 ng/ml or greater during androgen deprivation monotherapy and prostate-specific antigen doubling time of less than 10 months after androgen deprivation monotherapy failure were independent risk factors for prostate cancer death after androgen deprivation monotherapy failure, with hazards ratios of 5.59 and 8.00, respectively. The 5-year cancer-specific survival rates were 100%, 65.0% and 15.5% in patients with 0, 1 and 2 risk factors, respectively (P = 0.047)., Conclusions: In this study, the second- and third-line treatments were effective for patients with advanced prostate cancer. Nadir prostate-specific antigen during androgen deprivation monotherapy and prostate-specific antigen doubling time just after the failure of androgen deprivation monotherapy are factors that can predict the prognosis.

Objective: In our previous study, a combination therapy of interleukin-2 and interferon-alpha was found to be more effective than monotherapy, especially for lung metastasis. In order to determine the genetic markers of those who positively responded, a multi-institutional open study was conducted on the patients with lung metastasis. In this paper, the clinical response to our combination therapy is reported., Methods: Untreated patients with lung metastasis were enrolled in this study. Patients received interleukin-2 (0.7 x 10(6) U/day) and interferon-alpha (6 x 10(6) IU/day): interleukin-2, 5 days a week and interferon-alpha, 3 days a week for the first 8 weeks, and then both interleukin-2 and interferon-alpha, 2 or 3 days a week for 16 additional weeks., Results: Forty-two patients were able to be evaluated for response. The overall positive response rate was 35.7% (15 of 42) including 2 patients with complete response. Progression-free patients were observed more frequently in patients with lung metastasis only (80.6%) than those with lung plus other organ metastasis (54.5%). Tumor shrinkage was observed in 81.0% (34 of 42) of patients. Progression-free survival rate at 200 days was 63.6%. Toxicities observed were primarily flu-like symptoms due to the cytokines and were typical of those observed with each single agent., Conclusions: Combination therapy of interleukin-2 and interferon-alpha was confirmed to be effective for renal cell carcinoma patients with lung metastasis. Identification of genetic markers is now ongoing with the tissue samples from this trial.

Objective: We investigated the clinical safety and feasibility of an algorithm we developed for the decision-making on neurovascular bundle preservation in radical prostatectomy to decrease the incidence of positive surgical margins., Methods: We prospectively applied our algorithm to 82 patients (164 prostate sides) with clinically localized prostate cancer who underwent radical prostatectomy at our institution between October 2004 and September 2006. The algorithm was developed using the apical core characteristics, clinical T stage, preoperative prostate-specific antigen level and Gleason sum. All prostate sides were divided into two groups by the algorithm: 115 sides (70.1%) were qualified for neurovascular bundle preservation (favorable algorithm side group) and 49 sides (29.9%) for non-neurovascular bundle preservation (unfavorable algorithm side group)., Results: Median patient age was 66 years (range: 52-77) and median prostate-specific antigen was 7.1 ng/ml (range: 1.4-29.6). Overall, a positive surgical margin was observed in 23 sides (14.0%). The incidence of positive surgical margins at the apex was significantly correlated with the maximal diameter of the tumor in the apex (P < 0.001). The incidence of positive surgical margins was 8.7% in the favorable algorithm group, whereas it was 26.5% in the unfavorable algorithm group (P = 0.003). When this algorithm was combined with surgeons' intraoperative assessments, the incidence of positive surgical margins was 2.1% in neurovascular bundle preservation sides, compared with 25.0% in non-neurovascular bundle preservation sides (P = 0.002)., Conclusions: This simple algorithm is safe and feasible for the decision-making on neurovascular bundle preservation from the aspect of cancer control in radical prostatectomy patients.

Objective: Patients with T1G3 bladder cancer are at high risk of progression to muscle-invasive cancer, and early cystectomy is considered as a treatment option in this particular situation. On the other hand, understaging of T1G3 bladder cancer has been gradually proven as second or repeat transurethral resection (TUR) has been widely applied. To evaluate the real rate of progression, we investigated the prognosis of T1G3 bladder cancer in which a muscle layer was histologically confirmed in the TUR specimens., Methods: We retrospectively reviewed 48 patients with primary T1G3 bladder cancer in which a muscle layer in the TUR specimens was confirmed between 1990 and 2006 in our institute. We investigated recurrence and progression in 45 patients, excluding 3 who were immediately treated with radical cystectomy. Fifteen and 12 patients received intravesical treatment with bacillus Calmette-Guérin (BCG) and anticancer agents just after TUR, respectively. The remaining 18 did not have any such treatment., Results: Recurrence and progression were observed in 21 (47%) and 3 patients (6.7%), respectively, during a median follow-up period of 42.1 months. The 3-year recurrence-free and progression-free survival rates were 54% and 91%, respectively. No significant differences were observed in the rates between the patients with and without BCG treatment in the study., Conclusions: There is a possibility that the progression rate in patients with T1G3 bladder cancer is not as high as previously reported when only patients whose muscle layer was histologically confirmed were analyzed. An adequate technique for TUR that unmistakably collects the muscle layer may be important to predict the outcome accurately.

Tetraploid sour cherry (Prunus cerasus) has an S-RNase-based gametophytic self-incompatibility (GSI) system; however, individuals can be either self-incompatible (SI) or self-compatible (SC). Unlike the situation in the Solanaceae, where self-compatibility accompanying polyploidization is often due to the compatibility of heteroallelic pollen, the genotype-dependent loss of SI in sour cherry is due to the compatibility of pollen containing two nonfunctional S haplotypes. Sour cherry individuals with the S(4)S(6)S(36a)S(36b) genotype are predicted to be SC, as only pollen containing both nonfunctional S(36a) and S(36b) haplotypes would be SC. However, we previously found that individuals of this genotype were SI. Here we describe four nonfunctional S(36) variants. Our molecular analyses identified a mutation that would confer loss of stylar S function for one of the variants, and two alterations that might cause loss of pollen S function for all four variants. Genetic crosses showed that individuals possessing two nonfunctional S(36) haplotypes and two functional S haplotypes have reduced self-fertilization due to a very low frequency of transmission of the one pollen type that would be SC. Our finding that the underlying mechanism limiting successful transmission of genetically compatible gametes does not involve GSI is consistent with our previous genetic model for Prunus in which heteroallelic pollen is incompatible. This provides a unique case in which breakdown of SI does not occur despite the potential to generate SC pollen genotypes.

Objective: We retrospectively evaluated long-term oncological outcomes in patients with germ cell tumors (GCTs) primarily treated at our institution and assessed late recurrence and second primary malignancies., Methods: This study included a total of 139 males with newly diagnosed GCTs of the testis or extragonadal origin who received treatment, including surgery, chemotherapy and radiation therapy, at our hospital between 1980 and 2005. We reviewed late recurrence that occurred at least 2 years after the initial disease-free status and secondary malignancies as well as oncological outcomes., Results: In patients with seminoma, 5-year progression-free survival and cause-specific survival rates were 87.2% and 100% for Stage I, 88.9% and 100% for Stage II, and 50.0% and 50.0% for Stage III, respectively, whereas in those with non-seminomatous GCTs, they were 79.1% and 96.3% for Stage I, 89.5% and 89.4% for Stage II, and 85.7% and 78.4% for Stage III, respectively. Late recurrence was found in five (3.6%) patients and all of them responded to salvage treatment and achieved disease-free status. Second primary hematological neoplasms occurred in three (2.2%), although they had a long-term free of the primary disease. All died of the second primary disease., Conclusions: Late recurrence was successfully managed with appropriate treatments, although its incidence was not negligible. Periodic follow-up may be necessary for >5 years in patients with GCTs for early detection of late recurrence. In addition, care should be taken to watch for the development of life-threatening second primary malignant disease during long-term follow-up.

Objective: We retrospectively assessed long-term outcomes of chemotherapy for advanced germ cell tumors (GCTs) at our institution., Methods: Ninety-five consecutive males with advanced GCTs of the testis or extragonadal origin who received chemotherapy between 1980 and 2006 were enrolled. All patients underwent induction chemotherapy including cisplatin., Results: The median follow-up period was 36.1 months (0 - 288.5) for all patients and 52.6 months (2.2 - 288.5) for the 73 current survivors. Totally, 75 patients (78.9%) achieved complete remission (CR). CR was achieved in 61.1%, 37.9% and 75.0% of the patients after induction therapy, second-line therapy and third-line or more, respectively. As salvage therapy, high-dose chemotherapy was performed in 11 patients (11.7%) and regimens with novel anticancer agents such as paclitaxel and irinotecan were employed for 8 patients (8.5%) from 2003 and later. The era of the treatment, extrapulmonary metastasis and serum alpha-fetoprotein were independent prognostic factors for patients. The 5-year overall survival of patients after 1992 was 83.0%, which was significantly higher than that of those before 1992 (56.3%). CR was never achieved in 20 patients and most of them met the criteria of the poor-prognosis group. Disease recurrence after CR was found in nine patients who were initially classified into the good- or intermediate-prognosis group., Conclusions: Improvement of medical management during chemotherapy and the development of several regimens for salvage chemotherapy seemed to contribute to improving outcomes of patients with advanced testicular cancer. Newly established chemotherapy regimens are needed for improvement of survival of patients in the poor-prognosis group.

Objective: The aim of this study was to assess the surgical outcome of high-grade prostate cancer (PCA) treated with antegrade radical prostatectomy with intended wide resection (aRP) and to establish the risk stratification., Methods: A consecutive 77 Japanese patients with Gleason score 8-10 PCA were treated with aRP alone and excluding patients with persistently elevated prostate-specific antigen (PSA), prospectively observed without any treatment until PSA failure was confirmed. PSA failure-free, cancer-specific and overall survival curves were generated with Kaplan-Meier method and the difference between groups was assessed with log-rank test. Cox's proportional hazards model was used to elucidate predictors of PSA failure., Results: During a median follow-up of 6 years, PSA failure was observed in 41 (53%) of the 77 patients. Five- and 10-year PSA failure-free survival rates of the entire cohort were 44.6% and 40.1%, respectively. Both overall and cancer-specific survival rates of the entire cohort at 5 and 10 years were 96.8% and 87.9%, respectively. In a multivariate analysis, PSA (P = 0.008), specimen confinement (SC) (P = 0.006) and persistently elevated PSA after aRP were identified as significant and independent predictors of PSA failure. When stratifying patients into three risk groups according to PSA level and SC status, PSA failure-free survival rate in patients with PSA < 10 ng/ml and specimen-confined disease (SCD) was significantly better than that in those of any other groups., Conclusions: Good prognosis can be expected in patients with high-grade PCA treated with aRP alone when PSA < 10 ng/ml and the tumor was removed as an SCD.

The real-time translocation of iron (Fe) in barley (Hordeum vulgare L. cv. Ehimehadaka no. 1) was visualized using the positron-emitting tracer (52)Fe and a positron-emitting tracer imaging system (PETIS). PETIS allowed us to monitor Fe translocation in barley non-destructively under various conditions. In all cases, (52)Fe first accumulated at the basal part of the shoot, suggesting that this region may play an important role in Fe distribution in graminaceous plants. Fe-deficient barley showed greater translocation of (52)Fe from roots to shoots than did Fe-sufficient barley, demonstrating that Fe deficiency causes enhanced (52)Fe uptake and translocation to shoots. In the dark, translocation of (52)Fe to the youngest leaf was equivalent to or higher than that under the light condition, while the translocation of (52)Fe to the older leaves was decreased, in both Fe-deficient and Fe-sufficient barley. This suggests the possibility that the mechanism and/or pathway of Fe translocation to the youngest leaf may be different from that to the older leaves. When phloem transport in the leaf was blocked by steam treatment, (52)Fe translocation from the roots to older leaves was not affected, while (52)Fe translocation to the youngest leaf was reduced, indicating that Fe is translocated to the youngest leaf via phloem in addition to xylem. We propose a novel model in which root-absorbed Fe is translocated from the basal part of the shoots and/or roots to the youngest leaf via phloem in graminaceous plants.

Objective: No previous study has reported the numbers of prostate cancer (PC) patients existing among a normal Japanese population with prostate-specific antigen (PSA) < 4 ng/ml. The aim of this study was to elucidate the performance of %free PSA as a screening tool for a normal Japanese population with PSA of 2-4 ng/ml and to examine the characteristics of cancer detected using this criterion., Methods: We conducted a prospective, multi-center study to evaluate the performance of %free PSA among a normal Japanese population. We decided on a %free PSA cutoff value of 12% according to the preliminary results. A total of 5548 consecutive screening volunteers aged 50-79 years were enrolled in the project. Men with total PSA > 4 ng/ml, or men with total PSA of 2-4 ng/ml and %free PSA of < or =12% were indicated to undergo 12 core biopsies., Results: There were 826 (14.9%) men with PSA of 2-4 ng/ml. Among them, those with %free PSA of < or =12% numbered 100 (12.1%). Forty-nine out of 100 men (49%) received biopsy, and 16 PC patients were detected. Among 10 patients undergoing radical prostatectomy, seven were associated with extra-prostatic extension (pT3) or high-grade cancer (Gleason score > or = 8)., Conclusions: We confirmed the ability of %free PSA and demonstrated that there are considerable numbers of PC patients among the normal Japanese population with PSA of 2-4 ng/ml. We ascertained that cancers detected in this study had a variety of tumor characteristics, including those of an aggressive nature.

Introduction: Recent studies have highlighted the influence of alpha1-adrenoceptor antagonists on ejaculatory function., Aim: We evaluated the effect of a new, highly selective alpha1A-blocker, silodosin, on ejaculatory function of normal volunteers., Methods: The study included 15 healthy male urologists who voluntarily participated in the study. They took 4 mg of silodosin or a placebo twice daily for 3 days in a randomized, double-blind crossover design., Main Outcome Measures: We investigated the ejaculatory volume, sperm count in urine after ejaculation, and fructose concentration in seminal plasma before and after administration of the agents., Results: All volunteers on silodosin had a complete lack of ejaculation. Three days after completion of silodosin, the mean ejaculatory volume recovered to the baseline level. There was no sperm in urine after ejaculation under silodosin administration in any volunteer., Conclusions: All volunteers on silodosin had anejaculation and did not show post-ejaculate sperm in their urine. The mechanism of ejaculatory dysfunction caused by silodosin is a loss of seminal emission.