Impact of sex on the outcomes of deceased donor liver transplantation.

BACKGROUND: Data examining the impact of sex on liver transplant (LT) outcomes are limited. It is clear that further research into sex-related differences in transplant patients is necessary to identify areas for improvement. Elucidation of these differences may help to identify specific areas of focus to improve on the organ matching process, as well as the peri- and post-operative care of these patients. AIM: To utilize data from a high-volume Eurotransplant center to compare characteristics of male and female patients undergoing liver transplant and assess asso ciation between sex-specific variables with short- and long-term post-transplant outcomes. METHODS: A retrospective review of the University of Essen's transplant database was performed with collection of baseline patient characteristics, transplant-related data, and short-term outcomes. Comparisons of these data were made with Shapiro-Wilk, Mann-Whitney U, χ2 and Bonferroni tests applied where app ropriate. A P value of < 0.05 was accepted as statistically significant. RESULTS: Of the total 779 LT recipients, 261 (33.5%) were female. Female patients suffered higher incidences of acute liver failure and lower incidences of alcohol-related or viremic liver disease (P = 0.001). Female patients were more likely to have received an organ from a female donor with a higher donor risk index score, and as a high urgency offer (all P < 0.05). Baseline characteristics of male and female recipients were also significantly different. In multivariate hazard regression analysis, recipient lab-Model for End-Stage Liver Disease score and donor cause of death were associated with long-term outcomes in females. Pre-operative diagnosis of hepatocellular carcinoma, age at time of listing, duration of surgery, and units transfused during surgery, were associated with long-term outcomes in males. Severity of complications was associated with long-term outcomes in both groups. Overall survival was similar in both males and females; however, when stratified by age, females < 50 years of age had the best survival. CONCLUSION: Female and male LT recipients have different baseline and transplant-related characteristics, with sex-specific variables which are associated with long-term outcomes. Female recipients < 50 years of age demonstrated the best long-term outcomes. Pre- and post-transplant practices should be individualized based on sex-specific variables to optimize long-term outcomes.

Efficacy of avelumab plus axitinib versus sunitinib by numbers of IMDC risk factors and target tumor sites at baseline in advanced renal cell carcinoma: long-term follow-up results from JAVELIN Renal 101.

BACKGROUND: In the phase III JAVELIN Renal 101 trial, first-line avelumab + axitinib improved progression-free survival (PFS) and objective response rate versus sunitinib in patients with advanced renal cell carcinoma across all International Metastatic RCC Database Consortium (IMDC) risk groups (favorable, intermediate, and poor); analyses of overall survival (OS) remain immature. Here, we report post hoc analyses of efficacy from the third interim analysis (data cut-off, April 2020) by the numbers of IMDC risk factors and target tumor sites at baseline. METHODS: Efficacy endpoints assessed were PFS, objective response, and best overall response per investigator assessment (RECIST v1.1) and OS. Best percentage change and percentage change from baseline in target tumor size over time during the study were also assessed. RESULTS: In patients with 0, 1, 2, 3, or 4-6 IMDC risk factors, hazard ratios [HRs; 95% confidence interval (CIs)] for OS with avelumab + axitinib versus sunitinib were 0.660 (0.356-1.223), 0.745 (0.524-1.059), 0.973 (0.668-1.417), 0.718 (0.414-1.248), and 0.443 (0.237-0.829), and HRs (95% CIs) for PFS were 0.706 (0.490-1.016), 0.709 (0.540-0.933), 0.711 (0.527-0.960), 0.501 (0.293-0.854), and 0.395 (0.214-0.727), respectively. In patients with 1, 2, 3, or ≥4 target tumor sites, HRs (95% CIs) for OS with avelumab + axitinib versus sunitinib were 0.912 (0.640-1.299), 0.715 (0.507-1.006), 0.679 (0.442-1.044), and 0.747 (0.346-1.615), and HRs (95% CIs) for PFS were 0.706 (0.548-0.911), 0.552 (0.422-0.723), 0.856 (0.589-1.244), and 0.662 (0.329-1.332), respectively. Across all subgroups, analyses of objective response rate and complete response rate favored avelumab + axitinib versus sunitinib, and a greater proportion of patients treated with avelumab + axitinib had tumor shrinkage. CONCLUSIONS: In post hoc analyses, first-line treatment with avelumab + axitinib was generally associated with efficacy benefits versus treatment with sunitinib in patients with advanced renal cell carcinoma across subgroups defined by different numbers of IMDC risk factors or target tumor sites.

Novel Screening Tool Using Non-linguistic Voice Features Derived from Simple Phrases to Detect Mild Cognitive Impairment and Dementia.

Appropriate intervention and care in detecting cognitive impairment early are essential to effectively prevent the progression of cognitive deterioration. Diagnostic voice analysis is a noninvasive and inexpensive screening method that could be useful for detecting cognitive deterioration at earlier stages such as mild cognitive impairment. We aimed to distinguish between patients with dementia or mild cognitive impairment and healthy controls by using purely acoustic features (i.e., nonlinguistic features) extracted from two simple phrases. Voice was analyzed on 195 recordings from 150 patients (age, 45-95 years). We applied a machine learning algorithm (LightGBM; Microsoft, Redmond, WA, USA) to test whether the healthy control, mild cognitive impairment, and dementia groups could be accurately classified, based on acoustic features. Our algorithm performed well: area under the curve was 0.81 and accuracy, 66.7% for the 3-class classification. Thus, our vocal biomarker is useful for automated assistance in diagnosing early cognitive deterioration.

Factors Associated With Growth After Deceased and Live Donor Pediatric Liver Transplantation.

BACKGROUND: There are limited data on predictors of growth after pediatric liver transplantation. METHODS: We reviewed the impact of graft type, ethnicity, and biliary complications (BC) on growth after pediatric liver transplantation (LT). We compared preoperative and 6-, 12-, and 24-month weight, height, and body mass index (BMI) percentiles between living donor (LD), deceased donor full-size (DD-full), and deceased donor split (DD-split) graft recipients. We also compared length of stay (LOS) between groups. RESULTS: We had 98 patients (DD-split: 32; DD-full: 43, LD: 23). The Median Pediatric End-stage Liver Disease (PELD) scores, exception points, albumin, bilirubin, failure to thrive, and presence of ascites were similar among groups. The DD-full group had the lowest preoperative percentiles in all categories and exceeded these at 24 months. The DD-split group was at preoperative percentiles at 24 months. The LD group had parallel weight curves compared to the DD-full group and exceeded only the preoperative weight percentile at 24 months. Black patients had the lowest percentiles in all categories (P < .01). The BC group caught up weight and BMI percentile at 24 months but had persistent decrease in height percentiles. Patients without BC exceeded preoperative height percentiles. The longer LOS group had lower height and BMI percentiles at 24 months; however, there was no statistical difference. CONCLUSION: DD-full and black patients seem to benefit the most from LT in terms of growth. BC seems to affect height percentiles. Patients with longer LOS had lower height and BMI percentiles (P>.05). Longer follow up and larger cohorts are necessary to improve the power of these findings.

Advances in targeted alpha therapy for prostate cancer.

Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.

Comparison of glycemic control after pancreas transplantation for Type 1 and Type 2 diabetic recipients at a high volume center.

INTRODUCTION: The number of pancreas transplants (PTX) in patients with Type 2 diabetes (T2DM) has increased in response to excellent outcomes in appropriately selected patients. Not all pancreas transplant centers share an enthusiasm for performing PTX for T2DM out of concern for increased complication rates. This study aims to clarify the characteristics of T2DM recipients with successful outcomes to clarify which candidates are more suitable for PTX as means of maximizing access to this highly effective therapy for Type 2 patients. METHODS & RESULTS: At MedStar Georgetown Transplant Institute, 50 patients underwent pancreas transplant between 2013 and 2016. Based on patient characteristics, 38 (78%) were categorized as T1DM, and 11 (22%) were considered T2DM. One case was excluded due to early graft loss. The estimated age of diabetes onset was significantly different between T1DM and T2DM cohorts (13 years vs. 29 years, P < .001). T2DM patients had significantly higher preoperative C-peptide levels (4.11 vs. 0.05, P < .001). Preoperative HbA1c, preoperative Body Mass Index (BMI), number of diabetic complications, and hemodialysis status were similar between both groups. At 2-year follow-up, there was no statistical difference in glycemic control between the two groups (T1DM vs. T2DM). Infectious complications and readmission rates were similar. Other trends that did not meet statistical significance included T1DM group with a slightly higher mortality and re-intervention rate. The T2DM group demonstrated higher BMI, higher rejection rates, and higher short-term postoperative insulin requirements. Graft survival was 95% and 82% for T1 and T2DM at 2 years post-transplant, respectively. CONCLUSION: Successful PTX in T1DM and T2DM recipient groups resulted in comparable glycemic control at 2-year post-transplant follow-up. T2DM group had a trend toward higher BMI as well as higher rates of rejection, temporary insulin requirement and graft failure, although none of these trends reached statistical significance. These results suggest that strict classification of T1 and T2DM by itself may not be relevant to achieving excellent outcomes in pancreas transplantation and, therefore, patient selection for PTX should not be based primarily on this classification.

Transplant nephrectomy with peritoneal window: Georgetown University experience.

OBJECTIVES: Transplant nephrectomy is a technically challenging procedure with high complication rates. Morbidity and mortality are mostly due to hemorrhage or infection and are reported to be 17-60% and 1-39%, respectively. The most common surgical technique for transplant nephrectomy is sub-capsular, extraperitoneal approach which may result in fluid accumulation and subsequent super-infection. We report that intraperitoneal approach, after assuring hemostasis of the transplant pedicle, allows for passive drainage, decreases hematoma formation and minimizes the subsequent infection risk in the nephrectomy bed. MATERIAL AND METHODS: From July 2009 to July 2014 a total of 38 transplant nephrectomies were performed using the intraperitoneal window technique at Georgetown University MedStar Transplant Institute (MGTI). Data was collected retrospectively. RESULTS: Average age at the time of transplant nephrectomy was 43.9 ± 14.3, and the majority were male (55.3%). Mean time to nephrectomy was 71.7 ± 67.4 months following transplantation. Indications for nephrectomy included pain, hematuria, fever, and recalcitrant rejection. Average operative time was 97.1 ± 28.9 minutes, average blood loss was 172.5 ± 213.6 mL. A total of 9 (24%) complications occurred. Postoperative blood transfusion was the most common complication (15.7%) followed by 2 (5.3%) re-interventions; one take back for hematoma and one percutaneous drain placement for symptomatic fluid collection. We had no infection, postoperative sepsis, ICU admissions, or mortality. CONCLUSION: Transplant nephrectomy with peritoneal window is a technique with better results compared to the literature. An opening between the transplant cavity and the peritoneum allows for passive drainage of fluid and minimizes the risk of hematoma and abscess formation. This approach does not add significant time to the operation, furthermore it may decrease morbidity and mortality by reducing overall complications, namely hematoma formation and infection, which overall decreases rates of re-interventions and length of hospital stay.

The Role of PD-1 Positivity in the Tumour Nest on Clinical Outcome in Upper Tract Urothelial Carcinoma Patients Treated with Radical Nephroureterectomy.

AIMS: The role of PD-1 (programmed cell death 1) expression on the clinical outcome of upper tract urothelial carcinoma has not yet been elucidated in detail. MATERIALS AND METHODS: PD-1 expression was immunohistochemically examined in 181 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy. A part of PD-1 protein expression in the tumour periphery and tumour nest was evaluated separately. The PD-1-positive cells were counted in the area showing the highest density of PD-1 expression at a magnification of 400×. RESULTS: PD-1 staining in the tumour nest was low in 137 (75.7%) and high in 44 (24.3%) patients. PD-1 staining in the tumour periphery was low in 78 (43.1%) and high in 103 (56.9%) patients. The 5 year progression-free survival rates in patients with the high PD-1 expression in the tumour nest and in the tumour periphery were 54.6% and 67.7%, respectively, which were significantly lower than those in their counterparts (79.4%, P < 0.001; 80.0%, P = 0.04). The 5 year cancer-specific survival rates in patients with the high PD-1 expression in the tumour nest and the tumour periphery were 69.1% and 75.7%, respectively, which were significantly lower than those in their counterparts (84.7%, P = 0.007; 87.8%, P = 0.01). A multivariate Cox regression analysis identified the high PD-1 expression in the tumour nest (hazard ratio 3.07, P < 0.001; hazard ratio 2.44, P = 0.011) and positive lymphovascular invasion (hazard ratio 4.86, P < 0.001; hazard ratio 4.03, P < 0.001) as independent predictors of disease progression and of cancer death, respectively. CONCLUSIONS: PD-1 positivity in the tumour nest could be a strong predictor for a worse clinical outcome and may be a useful indicator for selecting appropriate candidates for adjuvant therapy such as chemotherapy in upper tract urothelial carcinoma patients treated with radical nephroureterectomy.

Probiotics to prevent necrotising enterocolitis and nosocomial infection in very low birth weight preterm infants.

The aim of the study was to determine whether routine probiotic supplementation (RPS) with Lactobacillus rhamnosus GG (LGG) or Lactobacillus acidophilus +Lactobacillus bifidum is associated with reduced risk of necrotising enterocolitis (NEC)≥Stage II in preterm neonates born at ≤32 weeks' gestation. We conducted a retrospective cohort study on the effect of probiotic supplementation in very low birth weight infants in our neonatal unit by comparing two periods: before and after supplementation. The incidence of NEC≥Stage II, late-onset sepsis and all-cause mortality was compared for an equal period 'before' (Period I) and 'after' (Period II) RPS with LGG or L. acidophillus+L. bifidum. Multivariate logistic regression analysis was conducted to adjust for relevant confounders. The study population was composed of 261 neonates (Period I v. II: 134 v. 127) with comparable gestation duration and birth weights. In <32 weeks, we observed a significant reduction in NEC≥Stage II (11·3 v. 4·8 %), late-onset sepsis (16 v. 10·5 %) and mortality (19·4 v. 2·3 %). The benefits in neonates aged ≤27 weeks did not reach statistical significance. RPS with LGG or L. acidophillus+L. bifidum is associated with a reduced risk of NEC≥Stage II, late-onset sepsis and mortality in preterm neonates born at ≤32 weeks' gestation.

Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma.

BACKGROUND: In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among axitinib exposure, BP change, and efficacy. PATIENTS AND METHODS: Patients received axitinib 5 mg twice daily during a lead-in period. Patients who met dose-titration criteria were randomized 1:1 to stepwise dose increases with axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients. RESULTS: Area under the plasma concentration-time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the ≥10 and ≥15 mmHg groups had longer progression-free survival. CONCLUSIONS: Optimal axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor.

High tracking of apolipoprotein B levels from the prepubertal age to adolescence in Spanish children.

AIM: To assess tracking of lipid and apolipoproteins from the prepubertal age (baseline, 6-8 years old) to adolescence (follow-up, 13-16 years old) in Spanish children. METHODS: The sample population included 385 healthy children (179 boys and 206 girls). Tracking was estimated by correlations between baseline and follow-up levels, multiple regression models in which the follow-up lipid was the dependent variable and analysing the percentage of individuals who remained in the same lipid levels status from prepubertal age to adolescence. RESULTS: Correlations between baseline and follow-up levels for low density lipoprotein (LDL)-cholesterol and apolipoprotein B (apo B) were stronger in boys and for high density lipoprotein-cholesterol and apo A-I stronger in girls. Regression analyses showed that, after adjusting by body mass index (BMI), baseline LDL-cholesterol and apo B levels explain 23% and 39% of the variation of follow-up LDL-cholesterol and apo B levels, respectively, in boys and 13% and 22%, respectively, in girls. The strength of tracking for LDL-cholesterol and apo B was 79% and 89%, respectively, in boys and 72% and 82%, respectively, in girls. CONCLUSION: Apolipoprotein B showed the strongest tracking in both sexes, stronger than for LDL-cholesterol, which supports the importance of determining apo B levels as a marker of dyslipidaemia in children.

Prognostic significance of Bcl-xL expression and efficacy of Bcl-xL targeting therapy in urothelial carcinoma.

BACKGROUND: Bcl-xL has an important role in the control of cell death through its inhibition of apoptosis. The aim of this study was to investigate the clinicopathological significance of Bcl-xL in upper urinary tract urothelial carcinoma (UTUC) and the therapeutic effect of targeting Bcl-xL protein in urothelial carcinoma (UC) cells. METHODS: We evaluated the immunohistochemical expression of Bcl-xL in 175 UTUC patients to determine the clinical role of Bcl-xL expression in clinical outcome. We used bafilomycin A1 (BMA) as a specific inhibitor of Bcl-xL to examine the biological effects in UC cells in vitro and in vivo. RESULTS: Immunohistochemical analysis of Bcl-xL expression revealed that patients with a high Bcl-xL score had a significantly lower 5-year cancer-specific survival (CSS) rate (53.2%) than those with a low Bcl-xL score (77.2%) (P=0.0011). Multivariate analysis indicated that a high Bcl-xL score was an independent prognostic factor of CSS (P=0.023). BMA inhibited UMUC-3 cell proliferation in vitro by induction of apoptosis. Treatment with BMA significantly inhibited tumour growth in UMUC-3 tumours in this mouse xenograft model accompanied by an elevated apoptosis induction. CONCLUSION: Bcl-xL appears to be a significant molecular marker for the prognosis of UTUCs. Targeting Bcl-xL may be a promising therapeutic strategy for patients with UC.

The prognostic significance of vasohibin-1 expression in patients with prostate cancer.

BACKGROUND: We recently isolated vasohibin-1 (VASH1), a novel angiogenic molecule that is specifically expressed in activated vascular endothelial cells (ECs), and the status of VASH1 expression has been documented in various cancer angiogenesis. The aim of this study was to assess the prognostic value of VASH1 expression in prostate cancer (PCa). METHODS: In this study, we retrospectively analysed the clinical records and evaluated the VASH1 expression of tumour microvessels in 167 patients with PCa who underwent radical prostatectomy. We immunohistochemically examined the microvessels positive for anti-CD34 as microvessel density (MVD) and the microvessels with activated ECs positive for VASH1 density. RESULTS: We found that the VASH1 expression was restricted to ECs in the tumour stroma. VASH1 density was significantly associated with pathological T stage, Gleason score and MVD. The 5-year PSA recurrence-free survival rate was 58.8% in patients with higher VASH1 density (≧12 per mm(2)) and 89.1% in patients with lower VASH1 density (<12 per mm(2)), respectively (P<0.001). Microvessel density was not an independent predictor of PSA recurrence. Multivariate analysis revealed that high VASH1 density was an independent prognostic indicator of PSA recurrence (P=0.007, HR=2.950). CONCLUSION: VASH1 density represents a clinically relevant predictor of patient prognosis and can be a new biomarker that would provide additional prognostic information in PCa.

Enhancement of radiosensitivity by a unique novel NF-κB inhibitor, DHMEQ, in prostate cancer.

BACKGROUND: Inducible activation of nuclear factor (NF)-κB is one of the principal mechanisms through which resistant prostate cancer cells are protected from radiotherapy. We hypothesised that inactivation of inducible NF-κB with a novel NF-κB inhibitor, DHMEQ, would increase the therapeutic effects of radiotherapy. METHODS: PC-3 and LNCaP cells were exposed to irradiation and/or DHMEQ. Cell viability, cell cycle analysis, western blotting assay, and NF-κB activity were measured. The antitumour effect of irradiation combined with DHMEQ in vivo was also assessed. RESULTS: The combination of DHMEQ with irradiation resulted in cell growth inhibition and G2/M arrest relative to treatment with irradiation alone. Inducible NF-κB activity by irradiation was inhibited by DHMEQ treatment. The expression of p53 and p21 in LNCaP, and of 14-3-3σ in PC-3 cells, was increased in the combination treatment. In the in vivo study, 64 days after the start of treatment, tumour size was 85.1%, 77.1%, and 64.7% smaller in the combination treatment group than that of the untreated control, DHMEQ-treated alone, and irradiation alone groups, respectively. CONCLUSION: Blockade of NF-κB activity induced by radiation with DHMEQ could overcome radio-resistant responses and may become a new therapeutic modality for treating prostate cancer.

Urinary excretion of phenolic acids by infants and children: a randomised double-blind clinical assay.

OBJECTIVES: The present study, which is part of the ISRCTN16968287 clinical assay, is aimed at determining the effects of cranberry syrup or trimethoprim treatment for UTI. METHODS: This Phase III randomised clinical trial was conducted at the San Cecilio Clinical Hospital (Granada, Spain) with a study population of 192 patients, aged between 1 month and 13 years. Criteria for inclusion were a background of recurrent UTI, associated or otherwise with vesico-ureteral reflux of any degree, or renal pelvic dilatation associated with urinary infection. Each child was randomly given 0.2 mL/Kg/day of either cranberry syrup or trimethoprim (8 mg/mL). The primary and secondary objectives, respectively, were to determine the risk of UTI and the levels of phenolic acids in urine associated with each intervention. RESULTS: With respect to UTI, the cranberry treatment was non-inferior to trimethoprim. Increased urinary excretion of ferulic acid was associated with a greater risk of UTI developing in infants aged under 1 year (RR 1.06; CI 95% 1.024-1.1; P = 0.001). CONCLUSIONS: The results obtained show the excretion of ferulic acid is higher in infants aged under 1 year, giving rise to an increased risk of UTI, for both treatment options.

Prognonstic impact of renin-angiotensin system blockade in localised upper-tract urothelial carcinoma.

BACKGROUND: The potential role of the renin-angiotensin system (RAS) in the promotion of tumour growth has been investigated, and the administration of RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), may improve disease control in malignancy. We investigated the prognostic impact of RAS inhibitors by analysing data from patients with upper-tract urothelial carcinoma (UTUC). METHODS: A total of 279 patients who underwent nephroureterectomy for localised UTUC (pTa-3N0M0) were identified at our three institutions. We retrospectively investigated the prognostic outcomes following nephroureterectomy in patients administered or not administered ACEIs or ARBs. RESULTS: The median follow-up period was 3.4 years. RAS inhibitors were administered to 48 patients (17.2%). Multivariate analysis showed that the appearance of pathological T3, positive lymphovascular invasion, and no RAS inhibitor administration (P=0.027 HR=3.14) were independent risk factors for a decrease in subsequent metastasis-free survival. The 5-year metastasis-free survival rate was 93.0% in patients who administered RAS inhibitors, and 72.8% in their counterparts who did not (P=0.008). CONCLUSION: The absence of RAS inhibitor administration was an independent risk factor for subsequent tumour metastasis in patients with localised UTUC. We propose RAS inhibitors may be a potent choice as an effective treatment following nephroureterectomy.

Acquired platinum resistance enhances tumour angiogenesis through angiotensin II type 1 receptor in bladder cancer.

BACKGROUND: We investigated the changes in reactive oxygen species (ROS) and angiogenesis through angiotensin II (Ang II) type 1 receptor (AT1R) after the development of acquired platinum resistance in bladder cancer. METHODS: Four invasive human bladder cancer cell lines, T24, 5637, T24PR, and 5637PR, were used in vitro, whereas in vivo, T24 and T24PR cells were used. T24PR and 5637PR cells were newly established at our institution as acquired platinum-resistant sublines by culturing in cisplatin (CDDP)-containing conditioned medium for 6 months. RESULTS: Ang II induced significantly higher vascular endothelial growth factor (VEGF) production in T24PR and 5637PR cells than in their corresponding parent cells in vitro, whereas Ang II induced a further increase in VEGF production. These platinum-resistant cells also showed significantly higher AT1R expression than their corresponding parent cells. ROS was also significantly upregulated in T24PR and 5637PR cells, whereas increased AT1R expression was significantly downregulated by scavenging free radicals. We also demonstrated the efficacy of AT1R blockade at suppressing the growth of platinum-resistant xenograft model. CONCLUSION: Our findings indicate a new molecular mechanism for upregulated AT1R signalling through increased ROS when tumours progressed after the CDDP-based regimens, and shed light on the importance of AT1R blockade for platinum-resistant bladder cancers.

Association of the Q223R polymorphism with age at menarche in the leptin receptor gene in humans.

Although genetics clearly influences the onset of menarche, the association of age at menarche (AAM) with variants in genes related to energy homeostasis remains unexplored. Our aim was to analyze the relationship of the Q223R polymorphism in the leptin receptor gene (LEPR(Q223R)) with AAM in a population-based sample of healthy pubertal girls. The study included 338 Spanish girls aged between 11 and 17 yr. Data were collected on AAM. The Q223R polymorphism in LEPR was detected by TaqMan allelic discrimination assays. Girls carrying the RR genotype had a significantly younger AAM (11.5 yr) than those carrying the QR (11.9 yr) or QQ (12.0 yr) genotype (P < 0.05). Furthermore, we found a significantly higher frequency of the RR genotype in girls with an AAM of 11 yr or younger than in girls with an AAM older than 12 yr (23.9% vs. 7.8%, χ(2) = 11.17, P = 0.0008). Also, the RR genotype frequency in girls with an AAM between 11 and 12 yr was significantly higher than in girls with an AAM older than 12 yr (16.8% vs. 7.8%, χ(2) = 3.97, P = 0.0046). The Q223R polymorphism in the LEPR gene is associated with variations in AAM among Spanish girls, with the RR genotype being related to earlier onset.