Influence of prostate size on the perioperative and postoperative outcome of transurethral plasmakinetic enucleation of the prostate: Results of 892 patients with 3 years of follow-up.

To explore the influence of prostate size on the outcome of Plasmakinetic enucleation of the prostate (PkEP) for the treatment of benign prostate hyperplasia (BPH), The data of 892 patients with symptomatic BPH who underwent PkEP were retrospectively reviewed. Among them, 199 (22.31%) had the prostate size smaller than 40 g (Group 1), 409 (45.85%) between 40 and 79 g (Group 2), 197 (22.09%) between 80 and 120 g (Group 3), and 87 (9.75%) larger than 120 g (Group 4). Perioperative variables, perioperative and postoperative complications were recorded. Patients were followed up for 36 months postoperatively. The efficiency of the surgery increased as the prostate size increased. Greater decreases in hemoglobin were noted in groups with larger prostates, while the duration of catheterization after the operation was similar across all groups. During the 3-year follow-up, the postoperative improvement in International Prostate Symptom Score (IPSS), Quality of Life (QOL), maximal flow rate (Qmax) and post-void residual urine volume (PVR), as well as longterm complications including urethral stricture and bladder-neck contracture were comparable across the 4 groups. These findings revealed that PkEP is more efficient for large prostate and can treat all prostates regardless of the size with equivalent symptom relief and micturition improvement.

MiR-134, epigenetically silenced in gliomas, could mitigate the malignant phenotype by targeting KRAS.

Gliomas are characterized by a malignant phenotype with proliferation, cell cycle arrest and invasion. To explore the biological consequences of epigenetically regulated miRNAs, we performed a microarray-based screening (whose expression was affected by 5-AZA treatment) followed by bisulfite sequencing validation. We found that miR-134 as an epigenetically regulated suppressor gene with prognostic value in gliomas. MicroRNA-134 was downregulated in high-grade gliomas, especially in GBM samples. Functional studies in vitro and in vivo in mouse models showed that overexpression of miR-134 was sufficient to reduce cell cycle arrest, cell proliferation and invasion. Target analysis and functional assays correlated the malignant phenotype with miR-134 target gene KRAS, an established upstream regulator of ERK and AKT pathways. Overall, our results highlighted a role for miR-134 in explaining the malignant phenotype of gliomas and suggested its relevance as a target to develop for early diagnostics and therapy.

Signal Peptide Peptidase, Encoded by HM13, Contributes to Tumor Progression by Affecting EGFRvIII Secretion Profiles in Glioblastoma.

BACKGROUND AND AIMS: EGFRvIII is the most prevalent glioblastoma mutation, occurring in more than 25% of glioblastomas. EGFRvIII cells release microvesicles that contain proteins, miRNAs, and mRNAs that enhance the growth and survival of surrounding tumor cells. However, little is known about the maturation process and regulatory mechanisms of secreted vesicles in EGFRvIII cells. METHODS: Signal peptide peptidase (SPP) provides a fascinating mechanism for protein cleavage and subsequent dislocation in the endoplasmic reticulum transmembrane domain. RESULTS: In this study, we reported that SPP facilitates the secretion of cytokines in vitro and promotes tumor progression in mice. Human cytokine antibody arrays revealed that EGFRvIII secreted higher levels of cytokines, but these levels were significantly reduced following SPP knockdown, suggesting that cytokines in EGFRvIII secretion profiles play important roles in GBM development. Identical results were confirmed in intracellular maturation tracking of TGF-ß1 in mouse serum. Clinically, analyses of GBM patient data from the database revealed that HM13 expression was closely related to patient prognosis and survival, suggesting an influence by the secreted vesicles of EGFRvIII tumor cells. CONCLUSIONS: Collectively, our study identifies that SPP affects EGFRvIII secretion profiles and thus promotes tumor progression, providing further understanding of the formation of secreted vesicles and driving role of EGFRvIII in GBM.

Evolving Molecular Genetics of Glioblastoma.

OBJECTIVE: To summary the recent advances in molecular research of glioblastoma (GBM) and current trends in personalized therapy of this disease. DATA SOURCES: Data cited in this review were obtained mainly from PubMed in English up to 2015, with keywords "molecular", "genetics", "GBM", "isocitrate dehydrogenase", "telomerase reverse transcriptase", "epidermal growth factor receptor", "PTPRZ1-MET", and "clinical treatment". STUDY SELECTION: Articles regarding the morphological pathology of GBM, the epidemiology of GBM, genetic alteration of GBM, and the development of treatment for GBM patients were identified, retrieved, and reviewed. RESULTS: There is a large amount of data supporting the view that these recurrent genetic aberrations occur in a specific context of cellular origin, co-oncogenic hits and are present in distinct patient populations. Primary and secondary GBMs are distinct disease entities that affect different age groups of patients and develop through distinct genetic aberrations. These differences are important, especially because they may affect sensitivity to radio- and chemo-therapy and should thus be considered in the identification of targets for novel therapeutic approaches. CONCLUSION: This review highlights the molecular and genetic alterations of GBM, indicating that they are of potential value in the diagnosis and treatment for patients with GBM.

Integrated analysis of genome-wide DNA methylation, gene expression and protein expression profiles in molecular subtypes of WHO II-IV gliomas.

BACKGROUND: Glioma is the most common malignant primary brain tumor among adults, among which glioblastoma (GBM) exhibits the highest malignancy. Despite current standard chemoradiation, glioma is still invariably fatal. A further insight into the molecular background of glioma is required to improve patient outcomes. METHOD: Previous studies evaluated molecular genetic differences through comparing different grades of glioma. Here, we integrated DNA methylation, RNA sequencing and protein expression data sets of WHO grade II to IV gliomas, to screen for dysregulated genes in subtypes during malignant progression of glioma. RESULTS: We propose a list of universal genes (UG) as novel glioma biomarkers: 977 up-regulated genes and 114 down-regulated genes, who involved in cell cycle, Wnt receptor signaling pathway and fatty acid metabolic process. Poorer survival was associated significantly with the high expression of 977 up-regulated genes and low expression of 114 down-regulated in UG (P <0.001). CONCLUSION: To our knowledge, this was the first study that focused on subtypes to detect dysregulated genes that could contribute to malignant progression. Furthermore, the differentially expressed genes profile may lead to the identification of new therapeutic targets for glioma patients.

Identification of high risk anaplastic gliomas by a diagnostic and prognostic signature derived from mRNA expression profiling.

Anaplastic gliomas are characterized by variable clinical and genetic features, but there are few studies focusing on the substratification of anaplastic gliomas. To identify a more objective and applicable classification of anaplastic gliomas, we analyzed whole genome mRNA expression profiling of four independent datasets. Univariate Cox regression, linear risk score formula and receiver operating characteristic (ROC) curve were applied to derive a gene signature with best prognostic performance. The corresponding clinical and molecular information were further analyzed for interpretation of the different prognosis and the independence of the signature. Gene ontology (GO), Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA) were performed for functional annotation of the differences. We found a three-gene signature, by applying which, the anaplastic gliomas could be divided into low risk and high risk groups. The two groups showed a high concordance with grade II and grade IV gliomas, respectively. The high risk group was more aggressive and complex. The three-gene signature showed diagnostic and prognostic value in anaplastic gliomas.

Isocitrate dehydrogenase 1 Gene Mutation Is Associated with Prognosis in Clinical Low-Grade Gliomas.

Isocitrate dehydrogenase 1 gene mutations are found in most World Health Organization grade II and III gliomas and secondary glioblastomas. Isocitrate dehydrogenase 1 mutations are known to have prognostic value in high-grade gliomas. However, their prognostic significance in low-grade gliomas remains controversial. We determined the predictive and prognostic value of isocitrate dehydrogenase 1 status in low-grade gliomas. The association of isocitrate dehydrogenase 1 status with clinicopathological and genetic factors was also evaluated. Clinical information and genetic data including isocitrate dehydrogenase 1 mutation, O 6-methylguanine DNA methyltransferase promoter methylation, 1p/19q chromosome loss, and TP53 mutation of 417 low-grade gliomas were collected from the Chinese Glioma Genome Atlas database. Kaplan-Meier and Cox proportional hazards regression analyses were performed to evaluate the prognostic effect of clinical characteristics and molecular biomarkers. Isocitrate dehydrogenase 1 mutation was identified as an independent prognostic factor for overall, but not progression-free, survival. Notably, isocitrate dehydrogenase 1 mutation was found to be a significant prognostic factor in patients with oligodendrogliomas, but not in patients with astrocytomas. Furthermore, O 6-methylguanine DNA methyltransferase promoter methylation (p = 0.017) and TP53 mutation (p < 0.001), but not 1p/19q loss (p = 0.834), occurred at a higher frequency in isocitrate dehydrogenase 1-mutated tumors than in isocitrate dehydrogenase 1 wild-type tumors. Younger patient age (p = 0.041) and frontal lobe location (p = 0.010) were significantly correlated with isocitrate dehydrogenase 1 mutation. Chemotherapy did not provide a survival benefit in patients with isocitrate dehydrogenase 1-mutated tumors. Isocitrate dehydrogenase 1 mutation was an independent prognostic factor in low-grade gliomas, whereas it showed no predictive value for chemotherapy response. Isocitrate dehydrogenase 1 mutation was highly associated with O 6-methylguanine DNA methyltransferase promoter methylation and TP53 mutation.

[Use of limited sampling strategy for estimating area under concentration-versus-time curve of mycophenolate sodium in renal allograft recipients].

OBJECTIVE: To establish a formula for estimating area under the concentration-versus-time curve (AUC) of mycophenolate sodium in Chinese renal allograft recipients with a limited sampling model. METHODS: A total of 35 renal allograft recipients were recruited from 2010 to 2013 to receive enteric-coated mycophenolate sodium (EC-MPS), calcineurin (CNI) and prednisone as immunosuppressive triple therapy. The serum concentration of mycophenolic acid (MPA) was assayed by enzyme multiplied immunoassay technique (EMIT) at pre-dose (C0), 0.5 (C0.5), 1.0 (C1), 1.5 (C1.5), 2.0 (C2), 3.0 (C3), 4.0 (C4), 6.0 (C6), 8.0 (C8) and 12.0 (C12) h post-dose respectively. Pharmacokinetic parameters of MPA (C0, C12, Cmax, Tmax, AUC0-12 h) were calculated by software WINNOLIN. Simplified formulae for estimation of MPA-AUC in tacrolimus (Tac) group or cyclosporin A (CsA) group were established by multiple stepwise regression analysis. RESULTS: There were variable MPA AUC0-12 h levels between 14 and 67 mg×h/L (mean: 37 ± 14). The MPA trough level (C0) had no correlations with MPA AUC0-12 h (r(2) = 0.090) . The simplified MPA AUC formula for Tac group was AUC = 5.678+1.718×C4+2.853×C6+1.812×C8+3.413×C12 with four sampling points (C4, C6, C8, C12). Estimated AUC with the formula had correlations with AUC0-12 h (r(2) = 0.890). The mean absolute predict error (APE) was 3.45% (0.41%-24.71%) and the proportion of APE above 15% stood at 11.1% (2/18) . In CsA group, the simplified MPA AUC formula was AUC = 7.072+1.525×C3+1.558×C4+ 1.573×C6+2.285×C8. The correlation was r(2) = 0.952, mean APE was 6.50% (0.02%-12.91%) and proportion of APE above 15% stood at 0. The above formulae were observed to have agreement with AUC0-12 h by Bland-Altman analysis. CONCLUSION: The simplified MPA AUC formulae with 4-point sampling provide an effective approach for estimating full MPA AUC0-12 h in Chinese renal recipients on EC-MPS plus tacrolimus or cyclosporin A.

Digital subtraction angiography and computed tomography angiography of predominant artery feeding pancreatic body and tail.

BACKGROUND: Recently a considerable number of promising clinical trials have been designed to perform infusion of stem cells by pancreatic arterial intervention to improve the endocrine function of the pancreas for better diabetes control. It is necessary to investigate the pancreatic body and tail (PBT) arterial system for human islets located mostly in the PBT and identify the predominant artery or arteries. However, the arterial system in the PBT is complicated and variable. In this study we comprehensively investigated the anatomical characteristics of arteries feeding the PBT. RESEARCH DESIGN AND METHODS: One hundred two patients with diabetes underwent 64-slice computed tomography angiography (CTA) and digital subtraction angiography (DSA). The target artery was catheterized, and DSA was performed to show the PBT. All images were documented for later analysis. RESULTS: DSA demonstrated that the feeding arteries for the PBT included the dorsal pancreatic artery (DPA) alone (n = 51 [50%]), combined DPA and great pancreatic artery (GPA) (n = 22 [21.6%]), GPA alone (n = 16 [15.7%]), and transverse pancreatic artery (TPA) (n = 11 [10.8%]). DPA was observed to originate from the initial segment of the splenic artery (n = 34 [46.6%]), common hepatic artery (n = 17 [23.3%]), or superior mesenteric artery (n = 14 [19.2%]). The GPA was mostly from the middle (n = 36 [94.7%]), and only two were found to originate from the initial segment of the splenic artery. The TPA (n = 11) was from either the pancreatoduodenal artery (n = 5 [54.5%]) or the gastroduodenal artery (n = 4 [36.4%]). In most case, the predominant artery of the PBT (95.1%, 97 of 102) could be revealed by 64-slice CTA. CONCLUSIONS: The origins and identities of the predominant artery in the PBT are variable. DSA is superior to CTA for preoperative imaging in arterial intervention therapy.

Factors influencing second renal allograft survival: a single center experience in China.

Second renal transplants are historically associated with a poor prognosis. The aim of the present study was to assess long-term survival of second renal grafts from deceased donors performed at our center and to analyze risk factors associated with long-term graft outcome. Sixty-five second renal grafts were enrolled into this study, and compared to primary ones performed during the same period. Kaplan-Meier curve showed a graft survival rate of 89.2% at 1 year, 80% at 3 years, and 63.1% at 5 years, which were similar to that of primary graft. Univariate analysis showed that time to first graft loss, cold ischaemia time, HLA mismatch, primary maintenance immunosuppressant, acute rejection episodes, and serum creatinine at 1 year were significantly associated with regraft survival. Cox regression demonstrated the dominant effect of acute rejection episodes, primary maintenance immunosuppressant, serum creatinine at 1 year, and time to first graft loss as predictor of second graft outcome. However, when long-term survival of second graft was examined on the basis of Kaplan-Meier estimates, HLA mismatch was found to be significant. The second graft had more benefits of improved pre-transplant screening and post-transplant management, and its survival rate was satisfactory and similar to that of primary one. Immunologic factors such as acute rejection and primary immunosuppressant are the main determinants of long-term renal transplantation outcome.

The long-term outcomes of pediatric kidney transplantation: a single-centre experience in China.

To explore the long-term outcomes of paediatric kidney transplantation and the effects of renal allograft on growth, education, employment, marriage and procreation. Twenty-seven children with ESRD received the renal allograft from 1985 to 2001. The patient and kidney survival rate, renal function, growth and employment, etc., were reviewed retrospectively. The average follow-up period was 10.3 +/- 4.4 yr. The one-, three-, five- and 10-yr graft survival rates were 96.3%, 88.9%, 81.5% and 66.7%, respectively, and the corresponding patient survival rates were 100%, 92.6%, 85.2% and 68.8%. The body weight gain was 4-10 kg in one-yr post-operative and the height increased 0-2 cm for girls and 2-5 cm for boys. A total of 44.4% of the recipients accomplished their education above junior high school. The employment rate was 46.2% in males, and 57.2% in females. Twelve patients were married. Non-adherence occurred in 30% of the recipients. Forty percent of the surviving recipients developed complications. Seven patients died. More attention should be paid to non-adherence of medications and more supports from the society are required to improve the life quality of paediatric recipients, especially in employment and education.

Comparison of single bolus ATG and Basiliximab as induction therapy in presensitized renal allograft recipients receiving tacrolimus-based immunosuppressive regimen.

Presensitized renal allograft recipients require special management to improve their outcome, and there is no consensus on the optimal immunosuppressive strategy. We retrospectively analyzed clinical data of 82 patients, who were PRA positive pre-transplant (above 10%) and received single bolus ATG and basiliximab as induction therapy, and assessed safety and efficacy of two kinds of induction therapies. Patients of ATG group (n=40) received single bolus ATG (Fresenius, 9 mg/kg preoperatively) and those of basiliximab group (n=42) were given two doses of basiliximab (Simulect, Novartis, 20 mg) on days 0 and 4 post-transplant. All patients received standard triple immunosuppressive therapy with tacrolimus (FK-506), mycophenolate mofetil (MMF), and steroids. The follow-up time was 12 months. There was no hyperacute rejection in two groups, and delayed graft function occurred in two patients of ATG group and three of basiliximab group. After 12-month follow-up, more acute rejection (AR) episodes were observed in basiliximab group than ATG group (35.7% vs. 15%, P=0.032). Although highly significant differences were observed between ATG group and basiliximab group with respect to the incidence of thrombocytopenia (P=0.001), single bolus ATG was well tolerated. Incidences of other adverse events and infection episodes did not differ between two groups (P>0.05). One-year patient and graft survival was 95%, 92.5% and 95.2%, 88.1% in ATG and basiliximab group respectively (P>0.05). Both single bolus ATG and basiliximab induction therapy achieved similar one-year graft/patient survival. However, single bolus ATG yielded much lower AR rate than basiliximab without increase in infection episodes and severe adverse events.

[Study of the effects of immunosuppressive agents on human islet cells in vitro].

OBJECTIVE: To investigate the effects of immunosuppressive agents on insulin secretion of human islet cells in vitro. METHODS: Human islet cells were isolated by the solution of the liberase and purified by Ficoll's density gradient centrifugation and then were exposed to various concentrations of four immunosuppressive agents for 24 hr respectively. Glucose-stimulated insulin secretion during subsequent static incubation was measured using the human insulin ELISA kit. RESULTS: Glucose-stimulated insulin secretion from human islet cells was significantly reduced after exposed to high concentrations of MMF and FK506 (both P < 0.05). No significant reduction in insulin secretion was observed from human islet cells after exposed to FTY720 and rapamycin (both P > 0.05). CONCLUSION: (1) High concentrations of MMF and FK506 have deleterious effects on insulin secretion in human islet cells. Low-dose FK506 + MMF is available for clinical use. (2) FTY720 and rapamycin have no adverse effects on insulin secretion in human islet cells. FTY720 and rapamycin may become useful immunosupressants for future clinical islet allotransplantation.