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To clarify the impact of body mass index (BMI) on treatment outcomes including survival, tumor response, and adverse events (AEs) in patients with advanced renal cell carcinoma (RCC) or urothelial carcinoma (UC) treated with immune checkpoint inhibitors (ICIs) in an Asian population.We retrospectively evaluated 309 patients with advanced RCC or UC who received ICIs between September 2016 and July 2021. The patients were divided into high- (i.e., ≥25 kg/mOverall, 57 patients (18.4%) were classified into the high-BMI group. In RCC patients treated with ICIs as first-line therapy or UC treated with pembrolizumab, progression-free survival (PFS) (p = 0.309; p = 0.842), overall survival (OS) (p = 0.701; p = 0.983), and objective response rate (ORR) (p = 0.163; p = 0.553) were comparable between the high- and low-BMI groups. In RCC patients treated with nivolumab monotherapy as later-line therapy, OS (p = 0.101) and ORR (p = 0.102) were comparable, but PFS was significantly longer in the high-BMI group (p = 0.0272). Further, multivariate analysis showed that BMI was not an independent factor of PFS or OS in all the treatment groups (any, p0.05). As for AE profiles, in nivolumab monotherapy, the rate was significantly higher in the high-BMI group (p = 0.0203), whereas in the other two treatments, the rate was comparable.BMI was not associated with survival or response rates of advanced RCC or UC patients treated with ICIs in an Asian population. AEs might frequently develop in high-BMI patients with RCC in nivolumab monotherapy.

Robot-assisted radical prostatectomy with previous holmium laser enucleation of the prostate is challenging, and few studies have analyzed its perioperative, functional, and oncological outcomes. Here we retrospectively evaluated 298 robot-assisted radical prostatectomies, including 25 with and 273 without previous holmium laser enucleation of the prostate, performed in 2015–2022. Regarding perioperative outcomes, operative and console times were significantly longer in the previous holmium laser enucleation of the prostate group. In contrast, the estimated blood loss was similar between groups, and there were no transfusions or intraoperative complications. Multivariable Cox hazard regression analysis of the functional outcomes of postoperative urinary continence showed that body mass index, intraoperative bladder neck repair, and nerve sparing were independently associated factors, whereas a history of holmium laser enucleation of the prostate was not. Similarly, a history of holmium laser enucleation of the prostate was not associated with biochemical recurrence; however, positive surgical margins and seminal vesicle invasion were independent risk factors of biochemical recurrence. Our findings revealed that robot-assisted radical prostatectomy after holmium laser enucleation of the prostate was safe and raised no concerns of postoperative urinary incontinence or biochemical recurrence. Therefore, robot-assisted radical prostatectomy may be a treatment option for patients with prostate cancer after holmium laser enucleation of the prostate.

Disasters could jeopardize breast cancer care, and the 2011 Japan’s triple disaster (earthquake, tsunami, and nuclear accident) has been no exception. However, the information is lacking regarding its details, including that concerning breast cancer-related lymphedema (BCRL). We aimed to explore the process of becoming aware of BCRL among the local patients and the problems faced and the support needed by them. We also aimed to clarify any effects of the 2011 disaster on the experiences related to lymphedema among the target population. Patients who developed BCRL following the breast cancer treatment were recruited in Iwaki City, a municipality located in the southern coastal Fukushima (N = 16). In-depth semi-structured interviews were conducted face-to-face, and the obtained data were appraised with thematic analysis. Five themes related to BCRL were identified: 1) process of becoming aware of BCRL, 2) troubles or worries/concerns due to BCRL, 3) information source regarding BRCA management, 4) strategies to cope with BCRL, 5) adverse impacts of the 2011 disaster on BCRL management. This qualitative analysis clarified the five themes related to BCRL. The themes except for the disaster context were in line with the previous studies conducted in the non-disaster context. There were limited but non-neglectable adverse impacts of the 2011 disaster on the long-term local BCRL management.

Background Prognostic impact of sex in patients with malignancies treated with immune checkpoint inhibitors has been intensively discussed but remains unclear, especially in advanced renal cell carcinoma. Methods We retrospectively evaluated a total of 184 patients with advanced renal cell carcinoma treated with either nivolumab plus ipilimumab combined treatment as first-line therapy (n = 73) or nivolumab as later-line therapy (n = 111) at our affiliated institutions. Progression-free survival, overall survival and objective response rate as well as adverse event profile were compared between sexes. Results Of the total 184 patients, 48 (26%) were female. Female patients had a significantly shorter progression-free survival than male patients (median: 3.8 vs. 8.3 months, P = 0.0005), but overall survival (median: 39.2 vs. 45.1 months, P = 0.283) and objective response rate (29% vs. 42%, P = 0.119) were not different between them. Similar findings were observed when analyzing within each treatment; in both patient groups treated with nivolumab plus ipilimumab combined therapy and nivolumab monotherapy, progression-free survival was significantly shorter in female than in male patients (P = 0.007, P = 0.017), but overall survival (P = 0.914, P = 0.117) and objective response rate (P = 0.109, P = 0.465) were comparable between them. Moreover, in a more restricted cohort consisting of patients with clear-cell renal cell carcinoma, a shorter progression-free survival in female patients was also observed (3.8 vs. 11.0 months, P Conclusions This retrospective study showed that immune checkpoint inhibitors-based treatment for renal cell carcinoma exhibited less marked effects in female than in male patients. Thus, sex may be an important factor for decision-making on systemic therapy as renal cell carcinoma treatment, although further studies are required to validate the present findings.

Objectives: Post-operative urinary incontinence (PUI) after robotic-assisted radical prostatectomy (RARP) is an important complication; PUI occurs immediately after postoperative urethral catheter removal, and, although approximately 90% of patients improve within one year after surgery, it can significantly worsen their quality of life. However, information is lacking on its nature in community hospital settings, particularly in Asian countries. The purposes of this study were to investigate the time required to recover from PUI after RARP and to identify its associated factors in a Japanese community hospital. Methods: Data were extracted from the medical records of 214 men with prostate cancer who underwent RARP from 2019 to 2021. We then calculated the number of days elapsed from the surgery to the initial outpatient visit confirming PUI recovery among the patients. We estimated the PUI recovery rate using the Kaplan–Meier product limit method and evaluated associated factors using the multivariable Cox proportional hazards model. Results: The PUI recovery rates were 5.7%, 23.4%, 64.6%, and 93.3% at 30, 90, 180, and 365 days following RARP, respectively. After an adjustment, those with preoperative urinary incontinence experienced significantly slower PUI recovery than their counterparts, while those with bilateral nerve sparing experienced recovery significantly sooner than those with no nerve sparing. Conclusion: Most PUI improved within one year, but a proportion of those experiencing recovery before 90 days was smaller than previously reported.

Purpose To clarify the efficacy and safety profile of immune checkpoint inhibitors (ICIs) for elderly patients with metastatic renal cell carcinoma (mRCC). Methods We retrospectively evaluated 149 mRCC patients treated with nivolumab monotherapy as subsequent therapy (n = 89) and nivolumab plus ipilimumab as first-line therapy (n = 60) at 5 affiliated institutions. The patients were divided according to age: > 70 (elderly) vs. ≤ 70 years (young). Efficacy was analyzed by comparing progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) between elderly and young patients. Safety was assessed by comparing the incidence rates of immune-related adverse events (irAEs). Results In the nivolumab monotherapy group, 34/89 patients (38%) were classified as elderly. There was no significant difference in PFS (p = 0.607), OS (p = 0.383), ORR (p = 0.0699), or DCR (p = 0.881) between elderly and young patients. In the nivolumab plus ipilimumab group, 20/60 patients (33%) were classified as elderly. There was no significant difference in PFS (p = 0.995), OS (p = 0.714), ORR (p = 0.763), or DCR (p = 1.000) between the two groups. The incidence rate of irAEs was not significantly different in the nivolumab (any grade: p = 0.121; grade ≥ 3: p = 0.542) or in the nivolumab plus ipilimumab (any grade: p = 0.666; grade ≥ 3: p = 0.576) group; a higher rate of gastrointestinal irAEs was observed in elderly than in young patients (any grade 15% vs. 3%). Conclusions The efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab were comparable between elderly and young patients. Thus, chronological age alone should not be a contraindication in the use of ICIs for mRCC.

Objectives To investigate the prognostic impact of tumor burden in patients receiving nivolumab plus ipilimumab as first-line therapy for previously untreated metastatic renal cell carcinoma (mRCC). Methods We retrospectively evaluated 62 patients with IMDC intermediate- or poor-risk mRCC, treated with nivolumab plus ipilimumab as first-line therapy at five affiliated institutions. Tumor burden was defined as the sum of diameters of baseline targeted lesions according to the RECIST version.1.1. We categorized the patients into two groups based on the median value of tumor burden (i.e., high vs. low). The association of tumor burden with progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) with nivolumab plus ipilimumab treatment was analyzed. Results The median tumor burden was 63.0 cm (interquartile range: 34.2–125.8). PFS was significantly shorter in patients with high tumor burden (n = 31) than in those with low tumor burden (n = 31) (median: 6.08 [95% CI: 2.73–9.70] vs. 12.5 [4.77–24.0] months, P = 0.0134). In addition, OS tended to be shorter in patients with high tumor burden; however, there was no statistically significant difference (1-year rate: 77.3 vs. 96.7%, P = 0.166). ORR was not significantly different between patients with high and low tumor burden (35 vs. 55%, P = 0.202). Multivariate analysis of PFS further showed that tumor burden was an independent factor (HR: 2.22 [95% CI: 1.11–4.45], P = 0.0242). Conclusions Tumor burden might be a useful factor for outcome prediction, at least for PFS prediction, in patients receiving nivolumab plus ipilimumab for mRCC. Further prospective studies are warranted to confirm our findings.

Koichi Nishimura,1,2,* Jinichi Mori,1– 3,* Takahiro Sawada,1,2 Shuhei Nomura,1,4 Alexander Kouzmenko,1 Kaori Yamashita,5 Yoshiaki Kanemoto,1,2 Tomohiro Kurokawa,1,2 Akira Hayakawa,1 Suguru Tokiwa,5 Michihisa Ochi,5 Hiroaki Shimmura,5 Shigeaki Kato1,2 1Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki, Japan; 2Graduate School of Life Science and Engineering, Iryo Sosei University, Iwaki, Japan; 3Department of Hematology, Jyoban Hospital, Iwaki, Japan; 4Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 5Department of Urology, Jyoban Hospital, Iwaki, Japan*These authors contributed equally to this workCorrespondence: Shigeaki Kato Email uskato0525@gmail.comIntroduction: Although the ability of androgens to promote prostate cancer development has been known for decades, the molecular mechanisms of androgen receptor (AR) signaling in the tumorigenesis remain unclear. Enhancer RNAs (eRNAs) transcribed from strong enhancers, or super-enhancers (SEs), have recently emerged as a novel class of regulatory non-coding RNAs (ncRNAs) that facilitate transcription, including that of androgen target genes, through chromatin looping to position enhancers proximate to the promoters. The aim of this study was to assess androgen-dependent transcription in prostate tumors of eRNAs (designated as KLK3eRNAs) from the SE of the KLK3 gene encoding the prostate-specific antigen (PSA) protein, a clinical marker of prostate carcinogenesis.Materials and Methods: The androgen-induced KLK3eRNAs were identified in the LNCaP human prostate cancer cell line. The expressions of these KLK3eRNAs together with KLK3 and AR mRNA transcripts were assessed by qRT-PCR in prostate tumor samples from five prostate cancer patients.Results: Androgen-induced KLK3eRNAs have been identified in the LNCaP cells, and their expression was further analyzed in tumors of prostate cancer patients. Transcripts of the tested KLK3eRNAs have been detected in all clinical samples, but their expression patterns differed between individual tumor specimens. We found a statistically significant correlation between the levels of the KLK3 and AR mRNAs with those of the previously reported KLK3eRNAs, while such correlation was not observed for novel KLK3eRNAs described in our recent report.Conclusion: Presented data suggest that prostate tumor development may associate with epigenetic reorganization in the KLK3 genomic regulatory elements reflected by changes of the KLK3eRNA expression. Our findings support a potential of eRNAs profiling to be used as diagnostic marker.Keywords: enhancer RNA, prostate cancer, androgen receptor, PSA, non-coding RNA, epigenetic modification

The prognostic impact of immune-related adverse events during immune checkpoint inhibitor-based combination therapy for advanced renal cell carcinoma remains unclear, especially in terms of differences between regimens.We aimed to clarify the prognostic impact of immune-related adverse events in patients with advanced renal cell carcinoma receiving immune checkpoint inhibitor dual combination therapy (IO-IO) or immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy (IO-TKI).We retrospectively evaluated the data of 148 patients who received immune checkpoint inhibitor-based combination therapy as first-line therapy. Patients were divided into two groups based on regimens, namely IO-IO and IO-TKI. The associations between immune-related adverse event development and outcomes, such as progression-free survival, overall survival, and objective response rate, were compared between the two groups.In the IO-IO and IO-TKI groups, 67 of 91 (74%) and 31 of 57 (54%) patients, respectively, experienced at least one immune-related adverse event and the rate was significantly higher in the IO-IO group (p = 0.0204), where immune-related adverse events development was significantly associated with longer progression-free survival (p0.0001) and overall survival (p = 0.0102), and a higher objective response rate (p = 0.0028). A multivariate analysis revealed immune-related adverse event development as an independent factor for longer progression-free survival (hazard ratio, 0.25; p0.0001) and overall survival (hazard ratio, 0.42; p = 0.0287). There were no significant associations between immune-related adverse events and progression-free survival, overall survival, or objective response rate in the IO-TKI group.The development of immune-related adverse events was positively associated with the outcome of patients with advanced renal cell carcinoma treated with IO-IO combination therapy; no such correlation was observed for IO-TKI combination therapy.

Androgen induces the binding of its receptor (AR) to androgen-responsive elements (AREs), while genome-wide studies showed that most androgen-induced AR binding sites on chromatin were unrelated to AREs. Enhancer RNAs (eRNAs), a class of noncoding RNAs (ncRNAs), are transcribed from superenhancers (SEs) and trigger the formation of large ribonucleoprotein condensates of transcription factors. By in silico search, an SE is found to be located on the locus of KLK3 that encodes prostate specific antigen. On the KLK3 SE, androgen-induced expression of ncRNAs was detected and designated as KLK3eRNAs in LNCaP cells, and androgen-induced association of AR and FOXA1 on the KLK3eRNA coding regions was detected. Such androgen-induced association of an AR mutant lacking DNA binding activity on the KLK3eRNA coding regions was undetectable on an exogenous ARE. Thus, the present findings suggest a molecular basis of androgen-induced association of AR with chromatin on ARE-unrelated sequences.

It remains unclear how early treatment interruption of nivolumab plus ipilimumab due to immune-related adverse events affects the outcome of previously untreated metastatic renal cell carcinoma (mRCC). To investigate the prognostic impact of the early interruption of nivolumab plus ipilimumab, used as first-line therapy for mRCC. We retrospectively evaluated 59 intermediate- or poor-risk mRCC patients who received nivolumab plus ipilimumab as first-line therapy. Based on whether early treatment interruption was implemented within the initial four treatment cycles (i.e., 3 months) or not, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were compared. The prognostic association was further compared with that of 186 patients treated with tyrosine kinase inhibitors (TKIs) as first-line therapy. Twenty-three of the 59 patients (39%) experienced interruption of nivolumab plus ipilimumab therapy. The patients with interruption had longer PFS (p = 0.0055), similar OS (p = 0.366), and likely higher ORR (p = 0.0660) than those without interruption. Of the patients treated with TKIs, 60 of 186 (32%) experienced interruption, with shorter PFS (p = 0.0121), similar OS (p = 0.378), and similar ORR (p = 0.738) than those without interruption. In the 23 patients with nivolumab plus ipilimumab interruption, high-dose corticosteroids were administered in seven patients (30%). PFS (p = 0.638), OS (p = 0.968), or ORR (p = 0.760) did not differ based on corticosteroid administration. Early treatment interruption, which exerted a negative effect for TKIs, was a preferable event for nivolumab plus ipilimumab when considering PFS. Furthermore, early administration of high-dose corticosteroids did not diminish the anti-tumor effect of nivolumab plus ipilimumab.

Objectives To explore the therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Patients and methods Forty-one patients with synchronous metastatic renal cell carcinoma who received nivolumab plus ipilimumab as first-line systemic therapy at our affiliated institutions were retrospectively evaluated. We focused on the prognosis, including tumor responses in primary kidney and metastatic lesions in patients treated with deferred cytoreductive nephrectomy. In addition, the overall survival according to nephrectomy status (i.e. deferred cytoreductive nephrectomy vs. upfront cytoreductive nephrectomy vs. without cytoreductive nephrectomy) was compared. Results During a median follow-up period of 12.0 months, seven (30%) patients received deferred cytoreductive nephrectomy at a median time of 10.4 months after nivolumab plus ipilimumab initiation. All the patients showed tumor shrinkage in their primary kidney lesions, including six (86%) patients with ≥30% of shrinkage. Metastatic lesions were also shrunk by ≥30% in six (86%) patients, including two (29%) obtaining complete response. At the last time of follow-up, three (43%) patients were disease-free. The overall survival rate after nivolumab plus ipilimumab initiation tended to be higher in patients with deferred cytoreductive nephrectomy compared with those with upfront cytoreductive nephrectomy (1-year survival rate: 100% vs. 72.4%, P = 0.0587) and those without cytoreductive nephrectomy (vs. 58.2%, P = 0.0613). Conclusions The present retrospective data showed that deferred cytoreductive nephrectomy had the potential to exert a therapeutic effect in a subset of patients who obtained favorable tumor responses to nivolumab plus ipilimumab for a certain period. Prospective randomized clinical trials are needed to confirm the prognostic impact of deferred cytoreductive nephrectomy after frontline immunotherapy in synchronous metastatic renal cell carcinoma.

Data regarding the efficacy and safety profiles of immune checkpoint inhibitors (ICIs) for metastatic renal cell carcinoma (mRCC) trial-ineligible patients in the real world remain unclear.The aim of this study was to clarify the impact of trial eligibility on ICI-based combination therapy for mRCC.We collected clinical data of mRCC patients receiving ICIs since 2016, and 222 patients were registered. Among these patients, we evaluated 93 patients treated with ICI-based combination therapy, including nivolumab plus ipilimumab, pembrolizumab plus axitinib, or avelumab plus axitinib, as first-line therapy. Patients were classified into the trial-ineligible group when they had at least one of the following factors at the time of treatment initiation: Karnofsky performance status (KPS) 70%, hemoglobin level 9.0 g/dL, estimated glomerular filtration rate (eGFR) 40 mL/min/1.73 mForty-eight patients (52%) were classified into the trial-ineligible group. The frequency of patients with trial-ineligible factors was highest for low eGFR (n = 20, 45%), followed by non-clear cell histology (n = 17, 36%) and low KPS score (n = 12, 25%). There was no significant difference in progression-free survival (median: 24.0 vs. 11.0 months, p = 0.416), overall survival (1-year rate: 87.0% vs. 85.3%, p = 0.634), or objective response rate (52% vs. 42%, p = 0.308) between the trial-eligible and -ineligible patients. The incidence rate of adverse events was higher in the trial-eligible patients than in the trial-ineligible patients (91% vs. 75%, p = 0.0397); however, the rate of grade 3 or higher adverse events was comparable between the two groups (42% vs. 40%, p = 0.796).There are many trial-ineligible patients in the real world. Nevertheless, the efficacy and safety of ICI-based combination therapy in trial-ineligible patients were non-inferior compared with those of trial-eligible patients.

Knowledge of changes in the outcome in patients with metastatic renal cell carcinoma from the molecular-targeted therapy era to the immune checkpoint inhibitor (ICI) era remains limited in the real-world setting.We aimed to clarify outcome changes from the previous molecular-targeted therapy era to the current ICI era in patients with metastatic renal cell carcinoma using multi-institution real-world data.We retrospectively evaluated 415 patients with metastatic renal cell carcinoma who received first-line systemic therapy at five Japanese institutions between January 2008 and August 2021. We divided the patients into two groups based on the treatment era: molecular-targeted therapy era (January 2008-August 2018) and ICI era (September 2018-August 2021). According to the era, progression-free survival, overall survival, and objective response rate from first-line systemic therapy were compared.Overall, 304 (73.3%) and 111 (26.7%) patients were categorized into the molecular-targeted therapy and ICI eras, respectively. The proportion of patients without prior nephrectomy (p = 0.0030) or those with low Karnofsky Performance Status scores [≤ 70] (p = 0.0258) were significantly higher in the ICI era group. The patients in the ICI era group had significantly longer overall survival (median: not reached vs 23.2 months, p = 0.0001) and a higher objective response rate (47.8% vs 24.7%, p 0.0001) than those in the molecular-targeted therapy era group, and progression-free survival tended to be longer in the ICI era group (median: 13.3 vs 8.75 months, p = 0.0579). Multivariate analysis further showed that the treatment era (ICI vs molecular-targeted therapy) was an independent factor for overall survival and objective response (both, p 0.0001).The present multi-institution real-world data showed the improved outcome of previously untreated patients with metastatic renal cell carcinoma in the ICI era group compared with that in the molecular-targeted therapy era group. These findings strongly encourage the use of ICI-based treatment for patients with metastatic renal cell carcinoma in the real-world setting. Further studies with extended follow-up periods are needed to confirm our findings.

Holmium laser enucleation of the prostate is well-established and effective for bladder outlet obstruction due to benign prostatic hyperplasia. The objective of this study was to examine the detection rate of incidental prostate cancer by holmium laser enucleation of the prostate and variables associated with them.A total of 612 patients were enrolled. We retrospectively examined the detection rate of incidental prostate cancer and perioperative variables associated with them.Forty-nine of 612 patients were diagnosed with incidental prostate cancer. Univariate logistic regression analysis showed that higher prostate-specific antigen density (odds ratio 3.34, 95% confidence interval 1.02-10.94, P = 0.05), higher prostate-specific antigen density of the transition zone (odds ratio 2.28, 95% confidence interval 1.02-5.09, P = 0.04), and findings of the prostate cancer on magnetic resonance imaging (peripheral zone: odds ratio 4.71, 95% confidence interval 1.70-13.1, P = 0.003; transition zone: odds ratio 3.46, 95% confidence interval 1.74-6.86, P 0.001; peripheral and transition zones: odds ratio 6.00, 95% confidence interval 1.51-23.8, P = 0.01) were significantly associated with incidental prostate cancer. Multivariate logistic regression analysis showed that findings of the prostate cancer on magnetic resonance imaging (peripheral zone: odds ratio 4.36, 95% confidence interval 1.49-12.8, P = 0.001; transition zone: odds ratio 3.54, 95% confidence interval 1.75-7.16, P 0.001; peripheral and transition zones: odds ratio 6.14, 95% confidence interval 1.53-24.5, P = 0.01) was an independent risk factor for incidental prostate cancer.The detection rate of incidental prostate cancer was 8.0%, and findings of the prostate cancer on magnetic resonance imaging were an independent predictive factor for incidental prostate cancer.

Objective:There has been little research on the health consequences of evacuation in the disaster context. A comparative analysis of survival between evacuated and nonevacuated hospital dialysis patients was conducted following Japan’s Fukushima Dai-ichi nuclear power plant incident, which occurred on March 11, 2011.Methods:The study included 554 patients (mean age: 70.9) receiving dialysis therapy at one of the Tokiwakai Group hospitals—all of which are located in and around Iwaki City, approximately 50 km from the Fukushima nuclear plant—as of the incident date. The patients’ survival after the incident was tracked until March 3, 2017. Significant differences in mortality rates between postincident evacuees and nonevacuees were tested using the Bayesian survival analysis with Weibull multivariate regression.Results:Out of 554 dialysis patients, 418 (75.5%) were evacuated after the incident. The postincident mortality rate (adjusted for covariates) of evacuees was not statistically significantly different from that of nonevacuees. The hazard ratio was 1.17 (95% credible intervals: 0.77-1.74).Conclusions:If performed in a well-planned manner with satisfactory arrangements for appropriate selection of evacuees and their transportation, evacuation could be a reasonable option, which might save more lives of vulnerable people.

Suguru Tokiwa,1 Hiroaki Shimmura,1 Shuhei Nomura,2–4 Ryota Watanabe,1 Minoru Kurita,1 Naoto Yoshida,1 Kaori Yamashita,1 Yoshitaka Nishikawa,5 Alexander Kouzmenko,6 Shigeaki Kato4 1Department of Urology, Jyoban Hospital, Tokiwa Foundation, Iwaki, Fukushima, Japan; 2Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK; 3Department of Global Health Policy, Graduate School of Medicine, The University of Tokyo, Tokyo, 4Research Institute of Innovative Medicine, Tokiwa Foundation, Iwaki, 5Department of Health Informatics, School of Public Health, Kyoto University, Kyoto, Japan; 6Department of Life Sciences, Alfaisal University, Riyadh, Kingdom of Saudi Arabia Introduction: Therapeutically induced androgen deficiency (AD) is a standard treatment for patients with prostate cancer, but it is often associated with various adverse effects (AEs) that may lead to discontinuation. Some AEs may depend on the patient’s health condition, while others may be due to complications of the drug delivery method. Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist widely used for the treatment of androgen-dependent prostate cancer. This study aimed to ascertain the following: 1) the compatibility of degarelix treatment with diabetes and 2) any specific causal associations of degarelix injections with increased blood clotting and antithrombotic therapy requirements.Patients and methods: The medical records of 162 patients with prostate cancer who had undergone degarelix treatment were retrospectively examined. The association of a medical history of diabetes and anticoagulant co-treatment with degarelix treatment discontinuation was analyzed statistically.Results: Rapid and significant decreases in prostate-specific antigen (PSA) levels during the course of degarelix treatment were detected for patients with prostate cancer regardless of clinical state. During the 27months of treatment, 68 subjects (48%) ceased degarelix treatment, owing to several reasons, mainly financial issues. Among these subjects, 19 had diabetes, while 35 were treated with antithrombotics. Extensive statistical analysis indicated that there were no causal associations between degarelix treatment discontinuation and preexisting diabetes or antithrombotic therapy.Conclusion: Our study suggests that preexisting diabetes and antithrombotic therapy were not significant factors for the discontinuation of degarelix treatment in patients with prostate cancer. Keywords: GnRH antagonists, prostate cancer, degarelix, discontinuation, diabetes, antithrombotic treatment

Both Breast and prostate cancers are dependent on the actions of sex hormones mediated through their nuclear receptors in onset and development of the cancers. Nuclear estrogen and androgen receptors(ER and AR)are DNA-binding transcription factors and regulate expressions of the target mRNA genes by modulating chromatin structure and function. In this short review, the function of nuclear sex hormone receptors in sex hormone-depend cancers are overviewed in the chromatin reorganization for target gene regulations. Moreover, the role of enhancer RNA(eRNA), one of the non-coding RNAs, in chromatin reconfiguration is discussed for enhancer function in tumor development.

www.thelancet.com Vol 387 June 4, 2016 2291 6 Rubini Gimenez M, Twerenbold R, Jaeger C, et al. One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I. Am J Med 2015; 128: 861–70. 7 Jaff e AS. TRAPID or Trapped? Ann Emerg Med 2016; published online Feb 10. doi:10.1016 /j.annemergmed.2016.01.009. 8 Shah AS, Newby DE, Mills NL. High sensitivity cardiac troponin in patients with chest pain. BMJ 2013; 347: f4222.

BABYSCAN, a whole body counter (WBC) for small children was developed in 2013, and units have been installed at three hospitals in Fukushima Prefecture. Between December, 2013 and March, 2015, 2707 children between the ages of 0 and 11 have been scanned, and none had detectable levels of radioactive cesium. The minimum detectable activities (MDAs) for $^{137}$Cs were $\leq 3.5$ Bq kg$^{-1}$ for ages 0-1, decreasing to $\leq 2$ Bq kg$^{-1}$ for ages 10-11. Including the $^{134}$Cs contribution, these translate to a maximum committed effective dose of $\sim 16 \mu$Sv y$^{-1}$ even for newborn babies, and therefore the internal exposure risks can be considered negligibly small. Analysis of the questionnaire filled out by the parents of the scanned children regarding their families' food and water consumption revealed that the majority of children residing in the town of Miharu regularly consume local or home-grown rice and vegetables, while in Minamisoma, a majority avoid tap water and produce from Fukushima. The data show, however, no correlation between consumption of locally produced food and water and the children's body burdens., Comment: 8 pages, 7 figures, 1 table

The mechanism responsible for accommodation in renal transplantations across the blood barrier remains unclear. We recently encountered two patients with accommodated status after living-related kidney transplantations across the blood barrier. Both developed elevations of anti-blood-group antibodies to titers over 128x after transplantation, despite excellent renal function. We investigated the serum samples after the establishment of accommodation bound to the erythrocyte membrane of the donors or the third party with the same blood group. After the establishment of accommodation, the serum samples from both accommodated patients demonstrated a significant decrease in binding to the donors' erythrocyte membrane, but did not show any decrease in binding to the erythrocyte membrane of the third party. By contrast, serum samples from patients with graft loss after unsuccessful accommodation showed high anti-blood-type antibody activity directed towards both the donor's and the third party's erythrocytes. The result of this study suggests the difference of quality in antibodies produced by accommodated and nonaccommodated recipients.

Previously, we reported that allogeneic skin grafts were rapidly rejected by CD28 and CD40 ligand double deficient mice mediated by CD8+ T cells. These results indicated that some elements in addition to CD28- and CD40-mediated costimulation provide stimulatory signals for the activation of donor-specific CD8+ T cells. In this report, we investigated the role of inflammation associated with transplantation on costimulation-independent priming of CD8+ T cell during graft rejection. B6 RAG1 KO mice were transplanted with BALB/c-skin and adoptively transferred with syngeneic CD8+ T cells the same day or 50 days after transplantation. When blockade of CD28- and CD40-mediated costimulation failed to prevent acute rejection of freshly transplanted skin grafts, it efficiently delayed rejection of well-healed skin grafts. These results showed that factors associated with transplantation have essential roles in inducing costimulation blockade-resistant allograft rejection. Costimulation blockade failed to prevent acute graft-infiltration of NK cells and increasing expression of intragraft IL-12 and IL-15. These factors may trigger the graft-infiltration and priming of CD8+ T cells to induce costimulation blockade-resistant allograft rejection.

In Japan, the complement-dependent cytotoxicity (CDC-crossmatch) test and the anti-donor antibody flow cytometric assay (FCXM) are used to evaluate presensitization among transplantation candidates. We introduced the flow cytometric panel reactive antibody method (FlowPRA) at our institution, and in this paper, we compared the results of FCXM and FlowPRA. Sera of a total of 238 patients receiving the first graft were analyzed by FlowPRA retrospectively. Specimens from 125 of these patients were also analyzed by FCXM, and the results obtained using the two methods were compared. In addition, postoperative pathological findings by graft biopsy were examined in patients with PRA class 1(+) or PRA class 2(+). (i) Class 1 antibodies were detected in 36 of the 238 patients (15%), class 2 antibodies in six patients (3%), and both class 1 and class 2 antibodies in five patients (2%). (ii) Totally 125 patients analyzed by both FCXM and FlowPRA, 28 patients (22%) who tested negative by FCXM were, however, found to be positive by FlowPRA, and 16 of these 28 patients (57%) had shown evidence of humoral rejection suspected of antibody-mediated in the early postoperative stage. A large proportion of patients who tested negative by FCXM but positive by FlowPRA experienced rejection. Thus, for detecting 'high responders' in patients receiving the first graft, use of FlowPRA to detect antibodies may be superior to that of FCXM.

Introduction Delayed graft function due to acute tubular necrosis (ATN) is frequently seen in kidney transplants from non–heart-beating donors. However, only a biopsy can be used to assess the severity of ATN. Therefore, we studied the validity of microscopic findings in tubular epithelial cells (TECs) from urine as a means to monitor ATN. Materials and methods The first voided urine in the morning was examinedfor the appearance and nuclear cytoplasmic (N/C) ratio of the TECs, using a murine staining withURO-3monoclonal antibody to detect proximal tubular cells (PTCs). Case A 58-year-old man underwent cadaveric kidney transplantation in January, 2003 using tacrolimus, mycophenolate mofetil, and prednisone following basiliximab induction therapy. His graft did not function immediately; needle biopsy was performed on day 17. The pathological findings showed severe ATN without evidence of acute rejection. A large quantity of TECs was seen in his urine between days 7 and 14. After day 28, TECs with a large N/C ratio and that were URO-3 antibody–positive were detected. Urine volume increased gradually and hemodialysis was not necessary after day 36. Conclusion The presence of URO-3–positive TECs with large N/C ratios suggests the reconstruction of PTCs. Therefore, it may be useful to monitor TEC findings to assess the severity ATN after cadaveric kidney transplantation.

We used an enzyme linked immunosorbent assay (ELISA) to investigate the presence of subtypes of anti-blood-type antibodies in patients with biopsy-proven humoral rejection after ABO-incompatible renal transplantation. High agglutinin IgG and IgM anti-blood type antibodies from 12 ABO-incompatible recipients with vascular rejection were separately assessed using an ELISA. Patients who exhibited excellent renal function despite high agglutinin titers of anti-blood-type antibodies(n = 8) were also examined. All 12 rejection patients exhibited highly elevated titers of IgG and IgM, while the eight stable patients exhibited only slightly elevated IgG titers, but not IgM. IgG and IgM titers did not change after plasmapheresis and steroid pulse therapy, whereas IVIg treatment significantly blocked both IgG and IgM, with IgM being blocked to a larger extent than IgG. Blocking of IgM seems to play an important role in improving ABO-incompatible grafts.

It has been shown that simultaneous blockade of CD28- and CD40-mediated costimulatory signals significantly prolongs allograft survival. Although these results led to an expectation of the establishment of specific immunotolerant therapy for organ transplantation, it became evident that these treatments rarely resulted in indefinite allograft survival. To uncover the mechanisms underlying these costimulation blockade-resistant allograft rejections, we studied the process of allogenic skin graft rejection in CD28 and CD40 ligand (L) double-deficient (double-knockout [dKO]) mice.Skin grafts from BALB/c or BALB.B mice were transplanted to C57BL/6 background dKO mice. The frequency of CD4+ and CD8+ T cells responding to alloantigens presented by direct or indirect pathways were defined by the use of a cytostaining assay.BALB/c skin grafts were rapidly rejected by dKO mice. This CD28 and CD40L independent allograft rejection was inhibited by the depletion of CD8+ T cells. In vitro studies indicated that CD8+ T cells from BALB/c skin-grafted dKO mice responded to donor antigen presented only by the direct pathway. Unlike major histocompatibility complex (MHC)-mismatched donors, allogenic skin grafts from MHC-matched donors were accepted by dKO mice.In the absence of CD28 and CD40 costimulatory signals, CD8+ T cells recognize MHC antigens by the direct pathway, resulting in the rejection of skin grafts from MHC-mismatched donors. In contrast, MHC-matched and non-MHC-mismatched donor skin grafts indefinitely survive in dKO mice. These results indicated that donor-host MHC matching may still be critical to costimulation blockade therapy for organ transplantation.

We examined histological features of allograft biopsies in ABO minor-mismatched kidney transplantation. Forty-five patients who underwent ABO minor-mismatched kidney transplantation between September 1999 and December 2001 at our institute. The mean age was 32.6 years, with 28 males and 17 females. We divided them into five groups based on the donor and recipient ABO blood groups. Group 1, O renal allografts given to A patients (13 patients); Group 2, O to B (9). Group 3, O to AB (2); Group 4, A to AB (9); and Group 5, B to AB (12). From September 1999 to April 2002, we performed 127 allograft biopsies in these 45 ABO minor-mismatched kidney transplant recipients. Among a total of 127 biopsy specimens, 47 specimens were taken as 0- or 1-h biopsies and 6 were protocol biopsies. Pathological analysis of 74 episode biopsy specimens showed: acute humoral rejection (AHR) in 13 (18%); acute cellular rejection (ACR) in 17 (23%); combined AHR and ACR in eight (11%); borderline change in six (8%); chronic rejection in 10 (12%); cyclosporin or tacrolimus nephrotoxicity in seven (10%) and chronic allograft nephropathy in three (4%). In total, some form of acute rejection (AR) was seen histologically in 38 biopsy specimens (48%) from 19 patients (42%). When we investigated AR in two separate categories, i.e. AHR and ACR, AHR was diagnosed in 21 biopsy specimens (26%) from IS patients (33%) and ACR was seen in 25 biopsy specimens (31 %) from 13 patients (29%). We compared the incidence rate of acute rejection in the cases of ABO minor-mismatched renal transplantation with ABO-incompatible and ABO-compatible cases between January 1989 and December 1999. The incidence rate of AR in ABO minor-mismatched cases (42%) was statistically lower than that in ABO-incompatible cases (63%). There was no statistical difference in the incidence rate of AR between ABO minor-mismatched cases and ABO-compatible cases (49%). There was statistical difference in the incidence of AR among the donor and recipient ABO blood groups. Group 4 (A allografts given to AB patients) had the statistically highest rate of AR (89%), followed by Group 1 (54%), Group 5 (33%) and Group 2 (11%), and there was no AR case in Group 3 (O to AB). In conclusion, the incidence rate of AR in ABO minor-mismatched kidney transplantation is statistically lower than ABO-incompatible cases and is not statistically different from that in ABO-compatible cases. The incidence cases of AHR are slightly higher than that of ACR in ABO minor-mismatched kidney transplantation and this finding is similar to findings of ABO incompatible kidney transplantation. Finally, there is a statistical difference in AR incidence among the donor and recipient ABO blood groups.

Background Kidney grafts with multiple renal arteries have been considered a relative contraindication because of the increased risk of complications. In the present study, we retrospectively reviewed multiple renal artery reconstruction in kidney transplantation to elucidate the usefulness of these grafts. Methods. From January 1997 until August 2001, 431 recipients underwent kidney transplantation at our institution; 393 patients are reviewed. The surgical techniques of vascular reconstruction and short-term outcome are reported. The living kidney transplant recipients were divided into vascular reconstructed and nonreconstructed groups, and mean serum creatine levels, warm and total ischemic times, and incidences of acute rejection and posttransplantation hypertension were compared. Results. We noted multiple renal arteries in 96 (2404%) of the 393 grafts. Arterial reconstruction was performed on 53 (13.5%) grafts, whereas 43 (109%) small polar arteries were simply ligated. Surgical management of the multiple arteries was variable. The most common reconstruction was conjoined anastomosis (17 cases) between two arteries of equal size and end-to-side anastomosis (14 cases) of smaller arteries to larger arteries. In nine cases, autogenous hypogastric or epigastric artery grafts were used to reconstruct multiple renal arteries. Multiple anastomosis was performed in six cases. In seven cases, complicated surgical vascular reconstruction was performed. The mean total ischemic times in the reconstructed and nonreconstructed groups were 102.6 and 71.0 min, respectively (P

A 61-year-old-woman with end-stage renal disease caused by IgA nephropathy received living unrelated kidney transplantation from her husband in February 2001. Pre-transplant donor-specific T- and B-cell cross-match was negative. Immunosuppressive treatment consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), methylprednisolone (MP) and antilymphocyte globulin (ALG). The kidney functioned immediately after kidney transplantation. On post-operative day 9, the level of serum creatinine (S-Cr) rose from 1.1 to 1.5 mg/dL. The allograft biopsy specimen taken on the day revealed moderate accumulations of polymorphonuclear leucocytes in peritubular capillaries (PTCs), dilatation of PTCs and transplant glomerulitis, moderate to severe. Immunofluorescent study of a frozen section of the allograft biopsy specimen showed a strong, diffusely distributed endothelial staining pattern in PTCs for the stable complement split product C4d. Post-transplant donor-specific T- and B-cell cross-matches performed on post-operative day 13 were positive. From the allograft biopsy and the positive post-transplant donor-specific T- and B-cell cross-matching, acute humoral rejection (AHR) associated with the development of antidonor antibodies (ADA) was diagnosed. Plasma exchange (PE) treatment was initiated on day 11. After a total of 13 treatments of PE, donor-specific T- and B-cell cross-matches became negative and the biopsy performed on day 72 revealed mild transplant glomerulopathy without accumulation of polymorphonuclear leucocytes in PTCs or a C4d staining pattern in PTCs of immunofluorescence. The allograft functioned well and the creatinine level was 1.1 mg/dL 7 months post-transplant. This was a case of AHR after renal transplantation associated with the development of ADA, which was triggered by spousal-donor antigens. The presence of widespread C4d deposition in PTCs in renal allograft biopsies played a role in the diagnosis of AHR and the diagnosis was confirmed by positive donor-specific T- and B-cell cross-matches at the time of rejection, which were negative at pre-transplantation. Several treatments of PE were effective for resolving AHR in this case and the effect of PE in the treatment of AHR could be assessed by the degree of peritubular capillaritis (PTCitis) and C4d deposits in PTCs.

A 46-yr-old Japanese male who underwent a second cadaveric kidney transplantation on 31 October 1996 after suffering Type II diabetic mellitus for 25 yr was admitted to our institute on 23 January 1999, because of colickyabdominal pain and abdominal discomfort. Elevated levels of serum creatinine, severe proteinuria and microscopic haematuria were observed. The allograft biopsy specimen disclosed crescentic glomerulonephritis. Immunofluorescence showed granular deposits of mainly IgA and C3 along glomerular capillary walls and mesangial areas. Electron microscopy showed extensive subepithelial and mesangial electron dense deposits. Rapid and irreversible worsening of graft function led to resumption of haemodialysis on 31 May 1999. We speculated that this case was an atypical form of de novo Henoch-Schonlein purpura nephritis (HSPN) in transplanted kidney because of the histopathological findings of the allograft biopsy and clinical symptoms.

Background Our previous studies showed that the incidence of humoral rejection was extremely high in ABO-incompatible living kidney transplantation. This result suggests that anti-A/B antibody titers directly influence the graft survival of ABO-incompatible kidney transplantation. In this study, we examined the impact of preoperative anti-A/B antibody titers on the results of ABO-incompatible living kidney transplantation. Methods Sixty-seven patients underwent ABO-incompatible living kidney transplantation at our institution between January 1989 and December 1995. The mean age was 34.9 years with 38 males and 29 females. Sixty-one of the 67 recipients were included in an analysis of the impact of anti-A/B antibody titer in long-term graft survival. The remaining six patients were excluded because of death with a functioning graft (three patients) and withdrawal of immunosuppression due to nonimmunological reasons (three patients) within 1 year after renal transplantation. Results The graft survival rate for the level of less than 1:16 in maximum IgG antibody before transplantation (n=21) at 1, 5, and 8 years was 81.0, 66.8, and 66.8%, respectively. The corresponding values for the level of 1:32-1:64 (n=33) and higher than 1:128 (n=7) were 93.9, 90.5, and 79.7%, and 42.9, 28.6, and 28.6%, respectively (log-rank test, P=0.0007). There was no significant association between maximum anti-A/B IgM titers, minimum anti-A/B IgM titers, minimum anti-A/B IgG titers, and graft survival. Conclusions Preoperative maximum anti-A/B IgG titers correlated with the long-term graft survival in ABO-incompatible living kidney transplantation. Thus, preoperative maximum levels of anti-A/B IgG titers are one of the good predictors of the results of ABO-incompatible living kidney transplantation.