Luyao Chen

Prevalence and Characterization of Somatic Mutations in Chinese Aldosterone-Producing Adenoma Patients

AbstractRecently somatic mutations of KCNJ5, ATP1A1, ATP2B3, and CACNA1D have been identified in patients with aldosterone-producing adenoma (APA). The present study sequenced the DNA in the tissues and blood samples from Chinese patients with APA for KCNJ5, ATP1A1, ATP2B3, and CACNA1D gene mutations.Among the 114 patients, 86 (75.4%) were identified with KCNJ5 somatic mutations, including 3 previously reported (G151R, L168R, T158A) and 2 other unreported mutations. One patient presented with both a point mutation (E147) and an insertion mutation, whereas another had a 36-base duplication, G153_G164dup. No mutation of ATP1A1 and ATP2B3 in the known hotspots was identified and only 1 male patient was detected with a novel CACNA1D mutation, V748I. Unlike other studies, male and female patients had similar KCNJ5 mutation rates (76.9% vs 74.2%). Mutation carriers were younger and had lower preoperative potassium level, whereas male (but not female) mutation carriers had higher preoperative plasma aldosterone concentration and preoperative blood pressures. Mutation carriers also had higher LV mass index (LVMI) than nonmutation carriers. After surgery, LVMI improved significantly in the KCNJ5 mutation group but not in the nonmutation group. The mRNA expression of KCNJ5, CYP11B2, and ATP2B3 was higher in the KCNJ5-mutated APA tissues. Functional characterization of the 2 novel KCNJ5 mutations showed that they were associated with decreased proliferation, membrane depolarization, elevated secretion of aldosterone, and increased expression of CYP11B1 and CYP11B2.In conclusion, Chinese APA patients appear to have a high frequency of somatic KCNJ5 mutation. Mutation prevalence rates are similar among men and women and 2 novel mutations are identified. KCNJ5-mutated patients benefit more from surgical resection of APA than nonmutated patients.

The Impact of Diabetes Mellitus on Renal Cell Carcinoma Prognosis: A Meta-Analysis of Cohort Studies

AbstractPrevious studies that investigated the relationship between DM and survival in renal cell carcinoma (RCC) patients reported inconsistent findings. Hence, we conducted a meta-analysis to obtain a more precise evaluation of the prognostic significance of DM in RCC. A systematic review was conducted with PubMed, Embase, and Web of Science to identify relevant articles that evaluated the effect of DM on RCC patients. Based on the inclusion and quality assessment criteria, 18 studies were eligible for the meta-analysis. Pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) for overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were calculated by standard meta-analysis techniques. The results suggested that DM was associated with poor OS (HR 1.56, 95% CI, 1.35–1.81, Pu200a<u200a0.001), poor CSS (HR 2.03, 95% CI, 1.37–3.01, Pu200a<u200a0.001), and poor RFS (HR 1.73, 95% CI, 1.25–2.39, Pu200a=u200a0.012). In addition, for patients with localized RCC, patients with clear cell RCC, or patients receiving nephrectomy, DM was associated with both poor OS and CSS by subgroup analyses. Our study revealed that there was a significant negative impact of DM on OS, CSS, and RFS in RCC patients. Therefore, more attention should be paid to RCC patients with preexisting DM because of their poor prognosis.

Prognostic value of CD44 expression in renal cell carcinoma: a systematic review and meta-analysis.

CD44 is a marker of cancer stem-like cells in renal cell carcinoma (RCC). However, the prognostic value of CD44 in RCC remains controversial. This study evaluated the correlation of CD44 expression with the clinicopathological features of RCC through a meta-analysis. We systematically searched PubMed, ISI Web of Science and Embase for relevant studies until February 2015. We collected and analysed data on clinical stage, Fuhrman grade, microvascular invasion, recurrence, five-year overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS). Twenty studies involving 1672 patients satisfied the inclusion criteria. Results showed that high CD44 expression in RCC was a poor prognostic marker for five-year OS (RRu2009=u20090.69, 95% CI 0.60–0.78) in a fixed-effects model and for five-year DSS (RRu2009=u20090.46, 95% CI 0.27–0.80) and five-year DFS (RRu2009=u20090.63, 95% CI 0.43–0.93) in a random-effects model. CD44 expression also correlated with Furhman grade (RRu2009=u20090.61, 95% CI 0.48–0.77), tumour recurrence (RRu2009=u20097.42, 95% CI 3.74–14.70) and MVI (Microvascular invasion) (RRu2009=u20093.63, 95% CI 1.97–6.71). This meta-analysis suggests that CD44 is a prognostic marker in RCC. High CD44 expression correlates with high Fuhrman grade, recurrence, MVI and poor prognosis.

Prognostic Significance of Hypoxia-Inducible Factor Expression in Renal Cell Carcinoma: A PRISMA-compliant Systematic Review and Meta-Analysis.

AbstractThe prognostic value of hypoxia-inducible factor (HIF) in renal cell carcinoma (RCC) has been evaluated in a large number of studies, but the reports were inconsistent and remained inconclusive. Therefore, we conducted a systematic review and meta-analysis to clarify the significance of HIF expression in RCC prognosis.PubMed, Embase, Web of Science, Cochrane Library, EBSCO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Biological Abstracts were searched for eligible studies. Hazard ratio (HR) data for overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) with 95% confidence interval (CI) related to the expression status of HIF-1&agr; or HIF-2&agr; detected by immunohistochemistry were all extracted. Data were combined using a random- or fixed-effects model based on the corresponding inter-study heterogeneity. Subgroup analyses were also performed.A total of 14 studies composed of 1258 patients for HIF-1&agr; evaluation and 619 patients for HIF-2&agr; evaluation were included for further analysis. When initially analyzed as a whole, the HIF-1&agr; expression was not significantly correlated with OS (HR 1.637, 95% CI 0.898–2.985, Pu200a=u200a0.108), CSS (HR 1.110, 95% CI 0.595–2.069, Pu200a=u200a0.744), and PFS (HR 1.113, 95% CI 0.675–1.836, Pu200a=u200a0.674). Similarly, HIF-2&agr; expression was not significantly correlated with CSS (HR 1.597, 95% CI 0.667–3.824, Pu200a=u200a0.293) and PFS (HR 0.847, 95% CI 0.566–1.266, Pu200a=u200a0.417). However, subgroup analyses concerning subcellular localization of HIFs revealed that the high nuclear expression of HIF-1&agr; was significantly associated with poor OS (HR 2.014, 95% CI 1.206–3.363, Pu200a=u200a0.007) and the high cytoplasmic expression of HIF -2&agr; was significantly associated with poor CSS (HR 2.356, 95% CI 1.629–3.407, Pu200a=u200a0.000).The increased nuclear expression of HIF-1&agr; and cytoplasmic expression of HIF-2&agr; indicate unfavorable prognosis in RCC patients, which may serve as biomarkers for disease management.

MicroRNAs with prognostic significance in bladder cancer: a systematic review and meta-analysis.

The aim of this study was to systematically review articles that investigated the prognostic significance of different microRNAs in bladder cancer (BC). We systematically searched PubMed, Web of Science, and Embase to identify relevant studies until March 2016. After screening, 26 studies that involved 2753 patients were included. Results suggested that many miRs expression aberration may predict prognosis in patients with BC. There are six miRs (miR-21, miR-143, miR-155, miR-200, miR-214, and miR-222) were reported by at least two studies, and we performed meta-analysis in the corresponding studies. Accordingly, we found that high miR-21 expression was associated with poor overall survival [OS; hazard ratio (HR)u2009=u20093.94, 95% CI 2.08–7.44]. High miR-143 expression was associated with poor progression-free survival (PFS; HRu2009=u20093.78, 95% CI 1.61–8.89). High miR-155 expression was associated with poor PFS (HRu2009=u20098.10, 95% CI 2.92–22.48). High miR-222 expression was associated with poor OS (HRu2009=u20093.39, 95% CI 1.10–10.41). Meanwhile, low miR-214 expression was correlated with poor RFS(HRu2009=u20090.34, 95% CI 0.22–0.53). Our comprehensive systematic review concluded that microRNAs, particularly miR-21, miR-143, miR-155, miR-214, and miR-222, could serve as meticulous follow-up markers for early detection of progression or recurrence and even useful therapeutic targets for the treatment in patients with BC.

Prognostic value of preoperative inflammatory response biomarkers in patients with sarcomatoid renal cell carcinoma and the establishment of a nomogram

To examine the prognostic role of inflammatory response biomarkers in sarcomatoid renal cell carcinoma (sRCC). From January 2004 to May 2015, 103 patients with sRCC were enrolled in this study. Preoperative neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR) were analyzed. Besides well-established clinicopathological prognostic factors, we evaluated the prognostic value of this four markers using Kaplan-Meier method and Cox regression models. Additionally, a nomogram was established to predict the prognosis of sRCC patients. Elevated NLR, dNLR and PLR were significantly associated with worse overall survival (OS), nevertheless, elevated LMR showed an adverse effect on reduced OS. Multivariate analysis revealed that NLR (HRu2009=u20094.07, 95% CIu2009=u20091.50–11.00, Pu2009=u20090.006) retained as independent factor. Incorporation of the NLR into a prognostic model including T stage, M stage, tumor necrosis and percentage of sarcomatoid generated a nomogram, which accurately predicted OS for sRCC patients. Preoperative NLR may serve as a potential prognostic biomarker in patients with sRCC and may help with clinical decisions about treatment intervention in clinical practice. The proposed nomogram can be used for the prediction of OS in patients with sRCC.

Prognostic role of urinary collecting system invasion in renal cell carcinoma: a systematic review and meta-analysis.

The relationship between urinary collecting system invasion (UCSI) and oncological outcomes in renal cell carcinoma (RCC) patients has attracted extensive attention recent years. However, the reports were inconsistent and remain controversial. Thus, we performed a systematic literature search of PubMed, Embase, Web of Science and The Cochrane Library databases to identify relevant studies up to June 2015 and conducted a standard meta-analysis of survival outcomes. 17 studies containing 9012 RCC patients satisfied the inclusion criteria. Pooled HRs for overall survival (OS) and recurrence-free survival (RFS) were 1.45 (95%u2009CI, 1.26–1.66, Pu2009<u20090.001) and 2.27 (95%u2009CI, 1.54–3.34, Pu2009<u20090.001), respectively. Further subgroup analysis suggested that UCSI was significant associated with poor cancer-specific survival (CSS) in stage T1–T2 RCC (HRu2009=u20092.05, 95%u2009CI: 1.43–2.96, Pu2009<u20090.001) but not in stage T3–T4 tumors (HRu2009=u20091.08, 95%u2009CI: 0.63–1.85, Pu2009=u20090.771). Current evidence revealed that UCSI has a significant negative impact on OS and RFS in RCC patients and could be used to predict CSS especially in localized RCC. Thus, RCC patients with UCSI should be paid more attention by clinician and pathologist and require close follow up for their poor prognosis.

Prognostic and Clinicopathological Significance of Survivin Expression in Renal Cell Carcinoma: A Systematic Review and Meta-Analysis

Previous studies have elevated the prognostic value of survivin in renal cell carcinoma (RCC). To increase statistical power and improve translation, we systematically searched PubMed, Web of Science, and Embase to identify relevant studies until December 2015 and conducted a standard meta-analysis. Based on the inclusion and exclusion criteria, a total of 12 studies, including 2051 patients, were eligible for further analysis. Results showed that high survivin expression in RCC was associated with poor OS (HRu2009=u20092.84, 95% CI 1.68–4.79), CSS (HRu2009=u20092.36, 95% CI 1.41–3.95), and PFS (HRu2009=u20092.20, 95% CI 1.58–3.08). Survivin expression was also correlated with TNM stage (RRu2009=u20092.75, 95% CI 2.21–3.44), pathological T stage (RRu2009=u20092.19, 95% CI 1.75–2.75), lymph node metastasis (RRu2009=u20092.28, 95% CI 1.61–3.25), distant metastasis (RRu2009=u20091.56, 95% CI 1.16–2.08), Fuhrman grade (RRu2009=u20092.81, 95% CI 2.29–3.45), tumor size (RRu2009=u20091.49, 95% CI 1.24–1.78). Our study suggested that survivin was a prognostic marker in RCC. High survivin expression was correlated with poor prognosis and more advanced clinicopathological features, and it could serve as a biomarker for disease management.

GSTA1 Expression Is Correlated With Aldosterone Level in KCNJ5-Mutated Adrenal Aldosterone-Producing Adenoma

ContextnKCNJ5 mutation is a major cause of aldosterone-producing adenomas (APAs). The development of APA apart from KCNJ5 mutation is less investigated.nnnObjectivenTo investigate other mechanisms affecting aldosterone secretion apart from KCNJ5.nnnPatients and MethodsnSix pairs of KCNJ5-mutated, high and low aldosterone-secreting APAs, five non-KCNJ5-mutated APAs, and four normal adrenal glands were assayed by Affymetrix GeneChip Human Transcriptome Array 2.0. A total of 113 APA samples were investigated to explore the expression of glutathione-S-transferase A1 (GSTA1). H295R cells were used to verify the function of GSTA1.nnnResultsnGSTA1 was the top gene downregulated in high-aldosterone KCNJ5-mutated APAs. GSTA1 was also downregulated in KCNJ5-mutated APAs compared with wild-type KCNJ5 APAs. Accordingly, mutant KCNJ5 decreased GSTA1 messenger RNA and protein expression levels. GSTA1 overexpression suppressed aldosterone secretion whether in wild-type or mutant KCNJ5 H295R cells. Adding ethacrynic acid or silencing of GSTA1 increased aldosterone secretion by increasing reactive oxygen species (ROS), superoxide, H2O2 levels, and Ca2+ influx. The expression of the transcription factors NR4A1, NR4A2, and CAMK1 and intracellular Ca2+ were significantly upregulated by GSTA1 inhibition. The reduced form of NAD phosphate oxidase inhibitor or H2O2 scavenger or blocking calmodulin or calcium channels could significantly reduce aldosterone secretion in GSTA1-inhibited cells.nnnConclusionsn(1) GSTA1 expression is reversely correlated with aldosterone level in KCNJ5-mutated APAs, (2) GSTA1 regulates aldosterone secretion by ROS and Ca2+ signaling, and (3) KCNJ5 mutation downregulates GSTA1 expression, and overexpression of GSTA1 reverses increased aldosterone in KCNJ5-mutated adrenal cells.

Postoperative Adjuvant Sorafenib or Sunitinib for Nonmetastatic Renal Cell Carcinoma with Venous Tumor Thrombus: a Prospective Cohort Study

PURPOSE: To evaluate the efficacy and safety of antiangiogenic agents (sorafenib and sunitinib) as postoperative adjuvant therapy in patients with nonmetastatic renal cell carcinoma (RCC) and venous tumor thrombus (VTT). MATERIAL AND METHODS: From March 2006 to January 2016, 147 patients who met the inclusion criteria were enrolled; 27 patients received sorafenib, and 17 patients received sunitinib. After radical nephrectomy and thrombectomy, the duration of maintenance targeted medication treatment was approximately 1 year. The primary objective was to compare disease-free survival (DFS) between each experimental group and control. Secondary end points included overall survival (OS) and toxic effects. RESULTS: The three groups were well balanced in terms of age, body mass index, gender, performance status, medical history, American Society of Anesthesiologists score, surgical approach, and tumor side and size. However, more patients receiving adjuvant therapy had inferior vena cava tumor thrombus. DFS and OS did not differ significantly between groups (P = .459 and .871, respectively). After adjusting for potential confounding factors, results of multivariate analysis proved that postoperative adjuvant therapy was not an independent factor for predicting DFS and OS (P > .05 for both). The subgroup analyses for inferior vena cava tumor thrombus found similar results. The common adverse events were hand-foot syndrome, diarrhea, fatigue, and neutropenia. The adverse effects were mild in both groups, and the incidence was not significantly different between sorafenib and sunitinib. CONCLUSIONS: Adjuvant treatment postoperatively with sorafenib or sunitinib showed no survival benefit relative to control for patients with nonmetastatic RCC and VTT in a prospective cohort study.