Xiu-Wu Pan

Sunitinib dosing schedule 2/1 improves tolerability, efficacy, and health-related quality of life in Chinese patients with metastatic renal cell carcinoma

PURPOSE To assess the efficacy and tolerability of sunitinib dosing schedule of 2 weeks on and 1 week off (schedule 2/1) vs. the traditional schedule of 4 weeks on and 2 week off (schedule 4/2) and its influence on health-related quality of life (HRQoL) in Chinese patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS A retrospective analysis of 108 patients with mRCC who were treated with sunitinib regimens (50mg daily) between January 2009 and July 2013 was undertaken. Overall, 3 groups of patients were studied according to the dosing schedule they received: schedule 4/2 (n = 50), transitional schedule 2/1 (T2/1; patients switched from schedule 4/2 to 2/1; n = 26), and initial schedule 2/1 (I2/1; n = 32). The tumor response, progression-free survival (PFS) time, adverse events, and HRQoL were assessed and compared among the groups. RESULTS The incidences of diarrhea, fatigue, hand-foot syndrome, and neutropenia induced by the treatment of sunitinib were all significantly less common with schedule I2/1 and T2/1 than with schedule 4/2 (P<0.05). Although there was no statistically significant difference in the tumor response among the 3 groups, the median PFS time was significantly longer with schedule I2/1 than with schedules T2/1 and 4/2 (11.2 vs. 9.4 and 9.5mo, respectively, P = 0.030), and HRQoL (as determined by 19-item Functional Assessment of Cancer Therapy Kidney Symptom Index scores) was better. CONCLUSIONS Treatment with sunitinib 50mg daily using a 2/1 dosing schedule can provide better tolerability and a longer PFS with better HRQoL in Chinese patients with mRCC than the traditional schedule 4/2.

The oncogenic role of EIF3D is associated with increased cell cycle progression and motility in prostate cancer

EIF3 is the largest multi-protein complex, and several studies have revealed the oncogenic roles of its subunits in many human cancers. However, the roles of EIF3D in the development and progression of PCa remain uncovered. In the present study, the expression of EIF3D in prostate cancer and paracarcinoma tissues, as well as PCa cell lines, was examined. In PCa tissues, the expression of EIF3D was up-regulated compared to that in paracarcinoma tissues. In order to investigate whether EIF3D could serve as potential therapeutic target for prostate cancer, EIF3D was knocked down to verify its functional role in prostate cancer cells. After EIF3D knockdown in PC-3 and DU145 cells, cell proliferation, invasion and colony formation were significantly inhibited; meanwhile, cell cycle analysis revealed cell cycle arrest at G2/M phase. EIF3D is associated with PCa, and silencing EIF3D will result in decreased proliferation, and migration, as well as G2/M arrest in DU145 and PC-3 cells. These results suggest that EIF3D plays an oncogenic role in PCa development and progression.

Icaritin acts synergistically with epirubicin to suppress bladder cancer growth through inhibition of autophagy

Bladder cancer is one of the most commonly diagnosed urological malignancies. Acquired resistance to chemotherapy is a great barrier for achieving successful treatment of bladder cancer. In the present study, we investigated the effect and mechanisms of icaritin, a flavonol glycoside derived from genus Epimedium, against human bladder cancer cells. It was found that despite the low cytotoxicity in normal human HEK293 cells, icaritin significantly inhibited the proliferation and colony formation of BT5637 and T24 bladder cancer cells time- and dose-dependently compared to the DMSO vehicle control. Moreover, cell viability monitored through mitochondrial membrane potential was inhibited markedly after icaritin treatment. Further investigation indicated that icaritin may inhibit epirubicin (EPI)-induced autophagy, and acted synergistically with EPI to suppress the proliferation of BT5637 and T24 cells. These findings suggest that icaritin may prove to be a novel potent therapeutic agent for the treatment of bladder cancer.

Radiofrequency ablation versus partial nephrectomy for treatment of renal masses: A systematic review and meta-analysis

Our study was to collect the data available in the literature on radiofrequency ablation (RFA) and partial nephrectomy (PN) and conduct a cumulative analysis on perioperative outcomes, renal function outcomes, and survival to evaluate the overall safety and efficacy of RFA versus PN for small renal cell cancer (SRCC). A literature search was carried out using various electronic databases. Data including age, tumor size, comorbid disease, operation duration, hospital stay, pre‐ and postoperative estimated glomerular filtration rate (eGFR), major and minor complications, and local tumor recurrence and metastasis were collected for meta‐analysis. Sixteen studies were included for this meta‐analysis. The age of patients treated with RFA was significantly older than that of patients treated with PN [weighted mean difference (WMD) = 5.07 years]. There were more patients with cardiovascular disease in RFA group as compared with PN group [odds ratio (OR) = 4.24] before treatment. RFA was associated with a shorter length of hospital stay compared with PN (WMD = −2.02 days). No significant difference was found in major and minor complications between the two groups (major: OR = 0.74; minor: OR = 0.45). Preoperative eGFR and eGFR decline in RFA patients was significantly lower than that in PN patients (WMD = −7.27 and −4.82, respectively), whereas there was no significant difference in postoperative eGFR (WMD = −1.18). The local tumor recurrence rate in RFA group was higher than that in PN group (OR = 1.81). However, the distant metastasis rate was no statistical difference between the two groups (OR = 1.63). RFA is a suitable therapeutic option for older patients and those at high risk for SRCC because of a low risk of operation and better preservation of renal function.

Overexpression of USP39 predicts poor prognosis and promotes tumorigenesis of prostate cancer via promoting EGFR mRNA maturation and transcription elongation

Castration resistance is a serious problem facing clinical treatment of prostate cancer (PCa). The underlying molecular mechanisms of acquired proliferation ability of tumor cells upon androgen deprivation are largely undetermined. In the present study, we identified that ubiquitin specific peptidase 39 (USP39) was significantly upregulated in PCa samples and cell lines. Elevated USP39 expression was positively correlated with Gleason score, predicted a poor outcome, and functioned as an independent risk factor for biochemical recurrence (BCR) especially in patients with a Gleason score ≤7. Our cell-based study showed that the expression level of USP39 was the highest in AR-negative PCa cell lines. Knockdown of USP39 in PCa cells inhibited cancer colony formation and tumor cell growth, and induced G2/M arrest and cell apoptosis. Microarray analysis suggested that knockdown of USP39 caused a reduced expression of EGFR. Silencing of USP39 inhibited the expression of EGFR 3′-end, and presented a remarkable block to the maturation of EGFR mRNA, suggesting that silencing of USP39 decreased the transcriptional elongation and maturation of EGFR mRNA. Oncomine datasets analysis showed that USP39 expression was positively correlated with EGFR level. The above findings suggest that USP39 plays a vital oncogenic role in the tumorigenesis of PCa and may prove to be a potential biomarker for predicting the prognosis of PCa patients.

Knockdown of GPR137,G protein‐coupled receptor 137, inhibits the proliferation and migration of human prostate cancer cells

GPR137 belongs to the G protein‐coupled receptor family involving the regulation of transmembrane signal transduction that launches pivotal cellular functions. However, its function in prostate cancer (PCa) has been rarely reported. It was found in this study that GPR137 was upregulated in PCa tissues as compared with that in paracancerous tissues. To see whether GPR137 could serve as a potential therapeutic target for PCa, GPR137 was knocked down to verify its biological function in PCa cells. Lentivirus‐introduced short hairpin RNA (shRNA) was designed to silence GPR137 gene. It was found that silencing of GPR137 gene suppressed the proliferation and colony formation of PCa cell lines PC‐3 and DU145. Further study indicated that growth inhibition by GPR137 knockdown was associated with cell cycle arrest at G0/G1 phase. Furthermore, silencing of GPR137 repressed the invasion and migration abilities of PC‐3 cells via downregulating slug and snail and upregulating E‐cadherin. Collectively, these findings imply that GPR137 plays an important role in the occurrence and progression of PCa and may prove to be a potential therapeutic target for the treatment of advanced PCa.

The prognostic value of lymphovascular invasion in radical prostatectomy: a systematic review and meta-analysis

To systematically evaluate the prognostic value of lymphovascular invasion (LVI) in radical prostatectomy (RP) by a meta-analysis based on the published literature. To identify relevant studies, PubMed, Cochrane Library, and Web of Science database were searched from 1966 to May 2014. Finally, 25 studies (9503 patients) were included. LVI was found in 12.2% (1156/9503) of the RP specimens. LVI was found to be correlated with higher pathological tumor stages (greater than pT3 stage) (risk ratio [RR] 1.90, 95% confidence interval [CI] 1.73-2.08, P< 0.00001), higher Gleason scores (greater than GS = 7) (RR 1.30, 95% CI 1.23-1.38, P< 0.00001), positive pathological node (pN) status (RR 5.67, 95% CI 3.14-10.24, P< 0.00001), extracapsular extension (RR 1.72, 95% CI 1.46-2.02, P< 0.00001), and seminal vesicle involvement (RR 3.36, 95% CI 2.41-4.70, P< 0.00001). The pooled hazard ratio (HR) was statistically significant for Biochemical Recurrence-Free (BCR-free) probability (HR 2.05, 95% CI 1.64-2.56; Z = 6.30, P< 0.00001). Sensitivity analysis showed that the pooled HR and 95% CI were not significantly altered by the omission of any single study. Begg′s Funnel plots showed no significant publication bias (P = 0.112). In conclusion, LVI exhibited a detrimental effect on the BCR-Free probability and clinicopathological features in RP specimens, and may prove to be an independent prognostic factor of BCR.

Selection of personalized laparoscopic partial nephrectomy based on tumor characteristics: A preliminary study in a single center

OBJECTIVES To evaluate the feasibility and therapeutic outcome of a personalized laparoscopic partial nephrectomy (LPN) selection scheme designed according to tumor characteristics. METHODS We included 187 patients in this study with clinical T1 renal tumors who were diagnosed between March 2012 and February 2014. 93 patients underwent the personalized LPN on the basis of tumor characteristics (Group A, n = 93), including no renal arterial clamping LPN, selective renal arterial clamping LPN and main renal arterial clamping LPN, and the other 94 patients underwent LPN with main renal arterial clamping (Group B, n = 94). Patient characteristics, tumor characteristics, perioperative data and renal function parameters were collected prospectively. RESULTS 85 patients in Group A and 90 patients in Group B completed the designed surgery without conversion. Compared with Group B, the operation time was longer in Group A (110.2 vs. 122.3 min, p = 0.001), intraoperative blood loss was increased (127.8 vs. 151.1 ml, p = 0.017), and there was less reduction in GFR 12 months postoperative (7.6 vs. 5.1 ml/min, p < 0.001). The study was limited by the relatively small sample size and long-term postoperative renal function is still awaited. CONCLUSIONS The result of our study showed that, although the intraoperative blood loss was greater, there was a less decrease in GFR 12 months postoperative in personalized LPN group.

Frizzled 8 promotes the cell proliferation and metastasis of renal cell carcinoma

Recent reports have shown a rapid rise in the incidence of renal cell carcinoma (RCC), and Wnt (Wingless-related integration site) signaling pathway is important in RCC. Frizzled 8 (FZD8) is a member of Frizzled (FZD) receptor family which could activate canonical or non-canonical Wnt/β-catenin pathways. Nevertheless, the role of FZD8 in RCC is poorly investigated. The immunohistochemical analysis showed high expression of FZD8 in RCC tissues compared with peri-tumor tissues. FZD8 knockdown decreased the ability of proliferation and metastasis of RCC cells. Research revealed that the FZD8 regulated the transcription of Cyclin D1, c-Myc, and could promote the epithelial to mesenchymal transition (EMT) by mediating Vimentin and Snail through the Wnt/β-catenin signaling pathway. In addition, the results of our experiment revealed that FZD8 is involved in the regulation of non-canonical Wnt signaling pathway. These data suggested that the expression of FZD8 may play an important role in the proliferation and metastasis of RCC, and serve as a putative promising drug target for human RCC therapy.

High expression of PDLIM5 facilitates cell tumorigenesis and migration by maintaining AMPK activation in prostate cancer

PDZ and LIM domain 5 (PDLIM5) is a cytoskeleton-associated protein and has been shown to bind to a variety of proteins through its specific domain, thereby acting to regulate cell migration and tumor progression. Here, we found that PDLIM5 was abnormally upregulated in prostate cancer (PCa) tissues as compared with that in normal prostate tissue. ONCOMINE microarray data mining showed that PDLIM5 was closely correlated with the prognosis of PCa in terms of Gleason score, tumor metastasis and biochemical recurrence. Lentivirus-mediated short hairpin RNA (shRNA) knockdown of PDLIM5 inhibited cell proliferation and colony formation, arrested hormone independent PCa cells DU145 and PC-3 in G2/M phase, and induced apoptosis. Meanwhile, silencing PDLIM5 inhibited migration and invasion of tumor cells by reversing the mesenchymal phenotype and a similar result was confirmed in a xenograft nude mouse model. Finally, we found PDLIM5 plays a crucial role in regulating malignant tumor cell proliferation, invasion and migration by binding to AMPK and affecting its activation and degradation, and may therefore prove to be a potential oncogenic gene in the development and progression of PCa.