Failure of Costimulatory Blockade-induced Regulatory T Cells to Sustain Long-term Survival of High Ischemic Allografts.

BACKGROUND: Costimulatory blockade-induced allograft tolerance has been achieved in rodent models, but these strategies do not translate well to nonhuman primate and clinical transplants. One confounder that may underlie this discrepancy is the greater ischemic inflammation imposed on the transplants. In mice, cardiac allografts subjected to prolonged cold ischemic storage (CIS) before transplant have increased ischemia-reperfusion injury, which amplifies infiltrating endogenous memory CD8 T-cell activation within hours after transplantation to mediate acute graft inflammation and cytotoxic lymphocyte-associated molecule-4 immunoglobulin-resistant rejection. This study tested strategies inhibiting memory CD8 T-cell activation within such high ischemic allografts to achieve long-term survival. METHODS: A/J (H-2 a ) hearts subjected to 0.5 or 8 h of CIS were transplanted to C57BL/6 (H-2 b ) recipients and treatment with peritransplant costimulatory blockade. At 60 d posttransplant, regulatory T cells (Treg) were depleted in recipients of high ischemic allografts with anti-CD25 monoclonal antibody (mAb) or diphtheria toxin. RESULTS: Whereas peritransplant (days 0 and +1) anti-lymphocyte function-associated antigen-1 mAb and anti-CD154 mAb prolonged survival of >60% allografts subjected to minimal CIS for >100 d, only 20% of allografts subjected to prolonged CIS survived beyond day 80 posttransplant and rejection was accompanied by high titers of donor-specific antibody. Peritransplant anti-lymphocyte function-associated antigen-1, anti-tumor necrosis factor-α, and anti-CD154 mAb plus additional anti-CD154 mAb on days 14 and 16 obviated this donor-specific antibody and promoted Treg-mediated tolerance and survival of 60% of high ischemic allografts beyond day 100 posttransplant, but all allografts failed by day 120. CONCLUSIONS: These studies indicate a strategy inducing prolonged high ischemic allograft survival through Treg-mediated tolerance that is not sustained indefinitely.

[A Case of Strangulated Bowel Obstruction Caused by Barbed Suture Following Laparoscopic Sacrocolpopexy].

A 63-year-old woman underwent laparoscopic sacrocolpopexy for pelvic organ prolapse. Four days postoperatively, she underwent an abdominal computed tomography scan because she developed a stomachache, and a strangulated bowel obstruction was suspected. The patient then underwent an emergency laparotomy which revealed strangulation of the small intestine caused by a band formed between the stump of a barbed suture and the mesentery. The strangulation was released by resecting the stump, and intestinal resection was not necessary. Nine days following the re-intervention, the patient was discharged from our hospital. As of four months after the surgery, she has not experienced any recurrence of pelvic organ prolapse or other postoperative complications. We need some ingenuity when using barbed suture in situations where the thread and the intestine come into contact.

Efficacy of combined androgen blockade therapy in patients with metastatic hormone-sensitive prostate cancer stratified by tumor burden.

OBJECTIVE: To determine the effect of combined androgen blockade with a first-generation anti-androgen on the prognoses of metastatic hormone-sensitive prostate cancer patients stratified by tumor burden. METHODS: We retrospectively analyzed the cases of metastatic hormone-sensitive prostate cancer patients who were treated with androgen deprivation therapy in 2008-2017 at 30 institutions in Japan. To compare the overall survival and progression-free survival rates of the patients treated with castration monotherapy and combined androgen blockade, we carried out a Cox proportional hazards regression analysis using both inverse probability of treatment weighting and instrumental variables methods. High-burden disease was defined as the presence of four or more bone metastases and/or visceral metastasis. RESULTS: Of 2048 patients, 702 (34.3%) and 1346 (65.7%) patients were classified as the low- and high-burden groups, respectively. In each group, >80% of the patients were treated with combined androgen blockade. Although there was no significant between-group difference in the overall survival according to the androgen deprivation therapy method, in the high-burden group the progression-free survival of the combined androgen blockade-treated patients was significantly better than that of patients treated with castration monotherapy: inverse probability of treatment weighting method, hazard ratio 0.49, 95% confidence interval 0.34-0.71; instrumental variables method, hazard ratio 0.80, 95% confidence interval 0.60-0.98. CONCLUSION: In the high-burden group, combined androgen blockade with a first-generation anti-androgen resulted in superior progression-free survival compared with castration monotherapy. For well-selected metastatic hormone-sensitive prostate cancer patients, the use of combined androgen blockade might still have some suitable scenarios.

Novel metastatic burden-stratified risk model in de novo metastatic hormone-sensitive prostate cancer.

The metastatic burden is a critical factor for decision-making in the treatment of metastatic hormone-sensitive prostate cancer (HSPC). This study aimed to develop and validate a novel risk model for survival in patients with de novo low- and high-burden metastatic HSPC. The retrospective observational study included men with de novo metastatic prostate cancer who were treated with primary androgen-deprivation therapy at 30 institutions across Japan between 2008 and 2017. We created a risk model for overall survival (OS) in the discovery cohort (n = 1449) stratified by the metastatic burden (low vs high) and validated its predictive ability in a separate cohort (n = 951). Based on multivariate analyses, lower hemoglobin levels, higher Gleason grades, and higher clinical T-stage were associated with poor OS in low-burden disease. Meanwhile, lower hemoglobin levels, higher Gleason grade group, liver metastasis, and higher extent of disease scores in bone were associated with poor OS in patients with high-burden disease. In the discovery and validation cohorts, the risk model using the aforementioned parameters exhibited excellent discriminatory ability for progression-free survival and OS. The predictive ability of this risk model was superior to that of previous risk models. Our novel metastatic burden-stratified risk model exhibited excellent predictive ability for OS, and it is expected to have several clinical uses, such as precise prognostic estimation.

External validation of the albumin, C-reactive protein and lactate dehydrogenase model in patients with metastatic renal cell carcinoma receiving second-line axitinib therapy in a Japanese multi-center cohort.

PURPOSE: To externally validate the utility of the albumin, C-reactive protein and lactate dehydrogenase model to predict the overall survival of previously treated metastatic renal cell carcinoma patients. PATIENTS AND METHODS: The ability of the albumin, C-reactive protein and lactate dehydrogenase model to predict overall survival was validated and compared with those of other prognostication models using data from 421 metastatic renal cell carcinoma patients receiving second-line axitinib therapy at 36 hospitals belonging to the Japan Urologic Oncology Group. RESULTS: The following factors in this cohort were independently associated with poor overall survival in a multivariate analysis: a low Karnofsky performance status, <1 year from diagnosis to targeted therapy, a high neutrophil count, and low albumin, elevated C-reactive protein, and elevated lactate dehydrogenase, and the Japan Urologic Oncology Group model was newly developed based on the presence/absence of these independent factors. In this cohort, 151 (35.9%), 125 (27.7%) and 145 (34.4%) patients were classified into the favorable, intermediate and poor risk groups, respectively, according to the albumin, C-reactive protein and lactate dehydrogenase model; however, the proportions of patients in the intermediate risk group stratified by the Japan Urologic Oncology Group, Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium models were >50%. The superiority of the albumin, C-reactive protein and lactate dehydrogenase model to the Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium models, but not the Japan Urologic Oncology Group model, was demonstrated by multiple statistical analyses. CONCLUSIONS: The utility of the albumin, C-reactive protein and lactate dehydrogenase model as a simple and objective prognostication tool was successfully validated using data from 421 metastatic renal cell carcinoma patients receiving second-line axitinib.

[A Case of Advanced Bladder Carcinoma Treated by Third-Line Gemcitabine and Paclitaxel Chemotherapy].

A 77-year-old man underwent robot-assisted laparoscopic radical cystectomy with pelvic lymph node dissection and ileal conduit for bladder carcinoma. Six months postoperatively, multiple lung metastases and a sacral bone metastasis were detected on computed tomography (CT). The patient then received gemcitabine-carboplatin (G-CBDCA) because he had renal dysfunction, which is a contraindication for cisplatin. After two courses of G-CBDCA, pembrolizumab was started because the lung metastases showed progression. The patient then underwent gemcitabine-paclitaxel (GP) chemotherapy (G : 1,000 mg/m² on days 1, 8, and 15 ; P : 180 mg/m² on day 1 ; every 4 weeks) as third-line treatment because of further progression after two courses of pembrolizumab. The lung metastases showed an almost complete response after two courses of GP. Additionally, after two courses, the lung metastases showed a complete response, and no abnormal fluorodeoxyglucose uptake in the sacral bone metastasis was seen on positron emission tomography-CT. The patient suffered neutropenia and anemia as adverse effects ; however, these disappeared after discontinuing gemcitabine. Chemotherapy was discontinued after the four courses in accordance with the patient's wishes, and he has remained free from recurrence for 2 months after discontinuing therapy.

Differential prognostic factors in low- and high-burden de novo metastatic hormone-sensitive prostate cancer patients.

Metastatic burden is a critical factor for therapy decision-making in metastatic hormone-sensitive prostate cancer. The present study aimed to identify prognostic factors in men with high- or low-metastatic burden treated with primary androgen-deprivation therapy. The study included 2450 men with de novo metastatic prostate cancer who were treated with primary androgen-deprivation therapy at 30 institutions across Japan between 2008 and 2017. We investigated the prognostic value of various clinicopathological parameters for progression-free survival (PFS) and overall survival (OS) in patients stratified by low- or high-metastatic burden. Among the 2450 men, 841 (34.3%) and 1609 (65.7%) were classified as having low- and high-metastatic burden, respectively. Median PFS of the low- and high-burden groups were 44.5 and 16.1 months, respectively, and the median OS was 103.2 and 62.7 months, respectively. Percentage of biopsy-positive core, biopsy Gleason grade group, T-stage, and N-stage were identified to be differentially prognostic. M1a was associated with worse PFS than was M1b in the low-burden group, whereas lung metastasis was associated with better PFS and OS than was M1b in the high-burden group. Differential prognostic factors were identified for patients with low- and high-burden metastatic prostate cancer. These results may assist in decision-making to select the optimal therapeutic strategies for patients with different metastatic burdens.

[A Case of Bladder Cancer Treated with Arterial Stent-Grafting to Prevent Uretero-Arterial Fistula Due to Radiation Therapy for Metastasis].

A 66-year-old male with bladder cancer underwent radical cystectomy and ileal conduit construction. The pathological diagnosis was urothelial carcinoma with squamous differentiation (pT3b). Computed tomography (CT) 18 months postoperatively revealed a right external iliac lymph node metastasis. He was treated with systemic chemotherapy after placement of bilateral ureteral stents, but CT following chemotherapy revealed an increase in the size of the metastasis, and the patient was diagnosed with progressive disease. Radiotherapy to the metastasis was selected as local therapy, but the patient was at risk of an uretero-arterial fistula because the right external iliac artery and the right ureter adjacent to the metastasis were involved in the irradiated field. The right external iliac lymph node metastasis was irradiated with a dose of 50 Gy after stent grafting for the right external iliac artery to prevent an ureteroarterial fistula. He had no adverse events, including hematuria after radiotherapy, but died of cancer cachexia 12 months after radiotherapy.

Oncological outcomes of a multicenter cohort treated with axitinib for metastatic renal cell carcinoma.

The present study aimed to evaluate the efficacy of the real-world use of axitinib and to develop a prognostic model for stratifying patients who could derive long-term benefit from axitinib. This was a retrospective, descriptive study evaluating the efficacy of axitinib in patients with metastatic renal cell carcinoma that had been treated with 1 or 2 systemic antiangiogenic therapy regimens at 1 of 36 hospitals belonging to the Japan Urologic Oncology Group between January 2012 and February 2019. The primary outcome was overall survival (OS). Using a split-sample method, candidate variables that exhibited significant relationships with OS were chosen to create a model. The new model was validated using the rest of the cohort. In total, 485 patients were enrolled. The median OS was 34 months in the entire study population, whereas it was not reached, 27 months, and 14 months in the favorable, intermediate, and poor risk groups, respectively, according to the new risk classification model. The following 4 variables were included in the final risk model: the disease stage at diagnosis, number of metastatic sites at the start of axitinib therapy, serum albumin level, and neutrophil : lymphocyte ratio. The adjusted area under the curve values of the new model at 12, 36, and 60 months were 0.77, 0.82, and 0.82, respectively. The efficacy of axitinib in routine practice is comparable or even superior to that reported previously. The patients in the new model's favorable risk group might derive a long-term survival benefit from axitinib treatment.

Potential effectiveness of local radiotherapy for extending survival and reducing symptomatic local events in patients with de novo metastatic prostate cancer.

Objectives: To evaluate the association between the use of local radiotherapy (RT) with the survival of patients with de novo metastatic prostate cancer and symptomatic local events (SLEs). Patients and methods: Patients were initially diagnosed with metastatic prostate cancer between 2008 and 2017 at 30 institutes in Japan. Prostate-specific antigen (PSA) progression-free survival (PSA-PFS) under initial androgen deprivation therapy and overall survival (OS) was compared between patients receiving local RT (RT group) and no RT (no-RT group) by multivariate Cox proportional hazard analyses. The occurrence rate of grade ≥2 SLEs was compared by multivariate logistic regression analyses. Propensity score matching (PSM) analyses were performed to compare PSA-PFS and OS of the groups in the high and low metastatic burden cohort. Results: Two hundred and five (7%) of 2829 patients received RT before PSA progression. Median PSA-PFS and OS were significantly longer in the RT group than in the no-RT group and the difference was significant in multivariate analyses (HR = 0.44, 95% CI = 0.33-0.57 and HR = 0.40, 95% CI = 0.27-0.60, respectively). The occurrence rate of grade ≥2 SLEs was significantly lower in the RT group (2%) than the no-RT group (9%) and the difference was significant in multivariate analyses (HR = 0.28, 95% CI = 0.10-0.76). Using PSM analyses, PSA-PFS and OS remained significantly different (HR = 0.64, 95% CI = 0.46-0.89 and HR = 0.47, 95% CI = 0.30-0.72, respectively), between the RT (n = 182) and the no-RT (n = 182) groups. The difference in OS was significant in the high metastatic burden cohort (HR = 0.55, 95% CI = 0.37-0.81). Conclusions: Addition of local RT to standard treatment for de novo metastatic prostate cancer patients tends to have the potential to extend survival, even in patients with high metastatic burden, and to reduce SLEs.

Supposed pituitary-production of human chorionic Gonadotropin induced by androgen deprivation therapy

ABSTRACT Introduction: The main cause of slightly elevated human chorionic gonadotropin (HCG) after successful treatment of male germ cell tumors is considered to be pituitary-derived HCG. It is well known that pituitary-derived HCG is frequently detected in postmenopausal women. We evaluated the status of serum HCG in men with elevated gonadotropins, which were induced by androgen deprivation therapy, using commercially available assays. Materials and Methods: We enrolled 44 patients with prostate cancer, who underwent luteinizing-hormone releasing hormone agonist treatment. We measured serum follicle-stimulating hormone (FSH), serum luteinizing hormone (LH), serum total HCG, serum free HCG-β subunit, and urine total HCG 3 times per patient, on the day of treatment initiation, the next day, and 3 months after. Results: On the day after treatment initiation, serum and urine HCG was detected in 61% and 73% of patients, respectively. Markedly strong correlations were observed between serum/urine HCG and FSH/LH. In particular, receiver operating characteristic curve analysis indicated excellent area under the curve (0.977, 95% confidence interval 0.951-1.003)) for serum HCG-detectable LH. At the cutoff value of 21.07 mIU/mL for serum HCG-detectable LH, the sensitivity and specificity were 96.7% and 95.3%, respectively. Serum HCG-β was not detectable at any times in any patients. Conclusions: Suggested pituitary-derived HCG can be frequently detected in patients with elevated gonadotropins, and there is a firm association between HCG detection and gonadotropin levels.

Small bowel obstruction due to internal hernia caused by the ureter after laparoscopic radical cystectomy and ileal conduit: A case report.

A 74-year-old man presented at our hospital with complaints of abdominal pain, nausea, and vomiting. He had undergone laparoscopic radical cystectomy and ileal conduit for urinary bladder cancer 1 month earlier. The patient had abdominal distention, resonant sounds on percussion, and diffuse abdominal tenderness without rebound or guarding. Abdominal CT revealed dilated jejunal loops herniated through a cord-like structure. Based on these findings, emergency surgery was performed, and intestinal dilatation into the space between the ureter, the ileal conduit, and the sacral bone was detected. The loops were released manually and were not resected. To the best of our knowledge, this is the first case report of small bowel obstruction due to internal hernia caused by the ureter after laparoscopic radical cystectomy and ileal conduit. Retroperitonealization and the minimum required mobilization of the ureters may be necessary when urinary diversion is constructed, especially in laparoscopic or robotic surgeries.

Supposed pituitary-production of human chorionic Gonadotropin induced by androgen deprivation therapy.

INTRODUCTION: The main cause of slightly elevated human chorionic gonadotropin (HCG) after successful treatment of male germ cell tumors is considered to be pituitary-derived HCG. It is well known that pituitary-derived HCG is frequently detected in postmenopausal women. We evaluated the status of serum HCG in men with elevated gonadotropins, which were induced by androgen deprivation therapy, using commercially available assays. MATERIALS AND METHODS: We enrolled 44 patients with prostate cancer, who underwent luteinizing-hormone releasing hormone agonist treatment. We measured serum follicle-stimulating hormone (FSH), serum luteinizing hormone (LH), serum total HCG, serum free HCG-ß subunit, and urine total HCG 3 times per patient, on the day of treatment initiation, the next day, and 3 months after. RESULTS: On the day after treatment initiation, serum and urine HCG was detected in 61% and 73% of patients, respectively. Markedly strong correlations were observed between serum/urine HCG and FSH/LH. In particular, receiver operating characteristic curve analysis indicated excellent area under the curve (0.977, 95% confidence interval 0.951-1.003)) for serum HCG-detectable LH. At the cutoff value of 21.07 mIU/mL for serum HCG-detectable LH, the sensitivity and specificity were 96.7% and 95.3%, respectively. Serum HCG-ß was not detectable at any times in any patients. CONCLUSIONS: Suggested pituitary-derived HCG can be frequently detected in patients with elevated gonadotropins, and there is a firm association between HCG detection and gonadotropin levels.

[A Case of Rectum-Infiltrating Prostate Cancer Mimicking Prostate-Infiltrating Rectal Cancer].

A 71-year-old man was admitted to the department of general surgery at our hospital due to constipation. A large bowel endoscopic examination revealed a stenosis of the rectum near the anus. The pathological diagnosis of the biopsy was poorly differentiated adenocarcinoma. After a computed tomography/magnetic resonance imaging examination, rectal cancer infiltrating the prostate was the diagnosis. External beam radiation therapy and chemotherapy were performed. After those neoadjuvant therapies, an abdominoperineal resection of the rectum (Miles) and a retropubic radical prostatectomy were performed. The final pathological diagnosis was prostate cancer infiltrating the rectum. Prostate cancer infiltrating the rectum is rare because of the Denonvillier's fascia barrier. However, it is difficult to distinguish prostate cancer infiltrating the rectum from rectal cancer infiltrating the prostate. Thus, when we see rectal cancer infiltrating the prostate, prostate cancer infiltrating the rectum should be suspected, serum prostate specific antigen (PSA) level should be determined, and PSA immunostaining should be performed.

Impact of relative dose intensity in gemcitabine-cisplatin chemotherapy for metastatic urothelial carcinoma.

OBJECTIVES: To evaluate the impact of relative dose intensity for gemcitabine-cisplatin chemotherapy in patients with metastatic urothelial carcinoma. METHODS: We retrospectively reviewed the medical records of 18 patients with metastatic urothelial carcinoma, who received gemcitabine-cisplatin regimen as the first-line chemotherapy between 2009 and 2015. The doses of gemcitabine and cisplatin were reduced or the intervals between treatment cycles were prolonged according to the treatment efficacy and adverse events during the first and second cycles. The individually optimal relative dose intensity was set as the actual dose per the standard dose in the first and second cycles. From the third course onward, patients received the gemcitabine-cisplatin chemotherapy with the same relative dose intensity. Overall survival was compared with the groups according to the value of relative dose intensity. RESULTS: The median age was 72.5 (range, 56-79) years and 15 men and 3 women were enrolled in the study. The median number of cycles of first-line gemcitabine-cisplatin chemotherapy was 8 (range, 2-17), and the median survival time from initiation of first-line chemotherapy was 20.1 (range, 3.5-32.8) months. The total median relative dose intensity of gemcitabine-cisplatin chemotherapy was 56.1%. The median survival time of 10 patients in the group with the relative dose intensity of less than 60% was significantly longer than that of 8 patients in the group with the relative dose intensity of more than 60% (19.2 and 11.0 months, respectively, p = 0.04). CONCLUSION: Individual low relative dose intensity management in the first-line gemcitabine-cisplatin chemotherapy may be an acceptable option for patients with metastatic urothelial carcinoma.

Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia.

Prolonged cold ischemia storage (CIS) is a leading risk factor for poor transplant outcome. Existing strategies strive to minimize ischemia-reperfusion injury in transplanted organs, yet there is a need for novel approaches to improve outcomes of marginal allografts and expand the pool of donor organs suitable for transplantation. Aquaporins (AQPs) are a family of water channels that facilitate homeostasis, tissue injury, and inflammation. We tested whether inhibition of AQP4 improves the survival of fully MHC-mismatched murine cardiac allografts subjected to 8 hours of CIS. Administration of a small molecule AQP4 inhibitor during donor heart collection and storage and for a short-time posttransplantation improves the viability of donor graft cells, diminishes donor-reactive T cell responses, and extends allograft survival in the absence of other immunosuppression. Furthermore, AQP4 inhibition is synergistic with cytotoxic T lymphocyte-associated antigen 4-Ig in prolonging survival of 8-hour CIS heart allografts. AQP4 blockade markedly reduced T cell proliferation and cytokine production in vitro, suggesting that the improved graft survival is at least in part mediated through direct effects on donor-reactive T cells. These results identify AQPs as a promising target for diminishing donor-specific alloreactivity and improving the survival of high-risk organ transplants.

[Spontaneous Infection of an Atrophic Ureter with an Ectopic Ureteral Opening after Living-Donor Renal Transplantation in a Patient with Kabuki Syndrome].

A 24-year-old woman with a high fever presented at our hospital. She had been diagnosed with Kabuki syndrome at the age of 4 years because she had the typical facial features of the condition ; she had undergone living donor renal transplantation 12 years prior. She was prescribed a course of antibiotics to treat pyelonephritis of the transplanted kidney and the high fever disappeared, but the fever developed again 3 days after the discharge. Abdominal computed tomography revealed a tubular structure of recent onset running from the left dorsal side to the lower part of the bladder. This structure was filled with pus, which we drained. We also performed laparoscopic ureterectomy of the left ureter to achieve a complete cure. No complication was observed after the surgery and the graft renal function did not deteriorate further.

Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts.

While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) mice were transplanted with complete MHC-mismatched A/J kidney grafts, and intragraft inflammatory components were followed to rejection. B6.CCR5(-/-) and B6.CD8(-/-)/CCR5(-/-) recipients rejected kidney allografts by day 35, whereas 65% of allografts in wild-type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8(-/-)/CCR5(-/-) recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts.

Sulfoquinovosylacylpropanediol is a novel potent radiosensitizer in prostate cancer.

OBJECTIVES: To examine the effects of combined treatment with sulfoquinovosylacylpropanediol and X-ray irradiation on the remodeling of the prostate cancer microenvironment, including angiogenic and hypoxic characteristics. METHODS: Human prostate cancer cells (DU145 and PC3) were implanted subcutaneously into the right hind legs of athymic nude mice. After the tumor volume reached 100-300mm(3) , 2mg/kg/day sulfoquinovosylacylpropanediol was given intravenously from day0 to day4, and cells were exposed to 4Gy X-ray irradiation on days0 and 3 (for a total of 8Gy). Tumors were fixed and stained for pathological analyses and immunohistochemical evaluations. To analyze vascular normalization, 60mg/kg pimonidazole dissolved in saline was injected intraperitoneally. RESULTS: Combined treatment with sulfoquinovosylacylpropanediol plus X-ray irradiation enhanced growth inhibition in DU145 xenografts. The tumor vessel density in DU145 cells significantly decreased after the combined treatment. Staining for αsmooth muscle actin in vessels was significantly increased. Pimonidazole staining, showing hypoxic lesions, was negative from 72h, but positive at 6 and 24h after the first combined treatment. In contrast, no enhancement of the microenvironment in PC3 xenografts was observed with sulfoquinovosylacylpropanediol plus X-ray irradiation. CONCLUSION: Sulfoquinovosylacylpropanediol could be a novel potent radiosensitizing agent targeting angiogenesis in prostate cancer.

Influence of dialysis duration on the outcome of living kidney transplantation.

Previous studies have reported negative impacts of long-term dialysis on kidney transplantation (KTx) outcomes. However, advances in surgical techniques, immunosuppressive therapies, and post-transplant monitoring have led to an impressive increase in patient and allograft survival. Thus, the number of KTx among patients on long-term dialysis is increasing. We evaluated the influence of dialysis duration on the outcome of living donor KTx. Between January 2000 and October 2011, we performed 1098 first KTx from living donors in adults (>18 years). We divided the patients into six groups, A group: pre-emptive kidney transplantation, B group: <24 months duration of dialysis, C group: 25-60 months duration, D group: 61-120 months duration, E group: 121-240 months duration, and F group: ≥ 241 months duration. The 5-year patient survival rates were 95.7, 98.8, 99.0, 99.0, 97.3, and 100% in groups A-F, respectively. The 5-year graft survival rates were 91.3, 95.6, 94.2, 96.3, 90.7, and 100% in groups A-F, respectively. No significant differences were observed in patient or graft survival among the six groups. Longer dialysis duration was correlated with lower rates of preoperative hypertension and diabetes mellitus. Survivors of long-term dialysis tended to be in good compliance with self-management. If recipients of living KTx have few complications, good prognoses are expectable even if dialysis periods are very long.