Yijun Shen

Efficacy of sorafenib on metastatic renal cell carcinoma in Asian patients: results from a multicenter study.

BackgroundThe effects of sorafenib in the treatment of advanced renal cell carcinoma (RCC) have been confirmed in an international collaborative phase III trial. This study aims to confirm similar efficacy and treatment-induced toxicities of sorafenib in the treatment of metastatic RCC in ethnic Chinese patients.MethodsNinety-eight consecutive and non-selected patients with pathologically confirmed metastatic RCC were treated according to an institutional treatment protocol. All patients were treated with 400 mg of sorafenib orally twice daily on a continuous basis until disease progression or intolerance to treatment occurred. Dose reduction to 400 mg once daily was required if grade 3 or 4 toxicities occurred. All patients except for 7 received nephrectomy in the course of their disease. All patients were assessed for tumor response, progression-free survival (PFS), overall survival (OS), and treatment-induced toxicities.ResultsThe median follow-up time was 76 weeks (range 2–296 weeks) for the entire group of patients. Radiologically confirmed complete response (CR), partial response (PR), stable disease (SD) of more than 4 months, and disease progression as best objective responses were observed in 1 (1%), 23 (23.5%), 62 (63.3%), and 12 (12.2%) patients, respectively. The tumor control rate (CR+PR+SD of >4 months) was 87.8%. The 1-year estimated PFS and OS were 58.4% and 64.6%, respectively. The median progression-free survival (PFS) time was 60 weeks (95% CI 41–79); and the median overall survival (OS) time was not reached with a follow-up of 76 weeks. Reduction of sorafenib dose was required in 26 patients who developed grade 3 or 4 treatment-cause adverse-effects. An additional 9 patients discontinued sorafenib treatment due to severe adverse-effects. No grade 5 toxicity occurred.Multivariate analysis revealed that independent predictive factors for tumor response to sorafenib treatment included ECOG status, presence of lymph node metastasis, and nephrectomy prior to the development of metastasis.ConclusionSorafenib produced an 87.8% disease control rate for metastatic renal cell carcinoma in Chinese patients, with acceptable rates of toxicity. The medication dosed at 400 mg twice daily is both efficacious and safe in the treatment of metastatic renal cell carcinoma in Chinese patients.

Clinicopathological characteristics, management and outcome of metastatic penoscrotal extramammary Paget's disease.

Backgroundu2002 Metastatic penoscrotal extramammary Paget’s disease (EMPD) has seldom been reported in the literature.

Lower skeletal muscle index and early complications in patients undergoing radical cystectomy for bladder cancer

BackgroundRadical cystectomy (RC) is the standard treatment for patients with muscle-invasive bladder cancer (BC), and it is also a valid option for selected patients with high-risk non-muscle-invasive BC. The purpose of this study was to evaluate the effect on the lower skeletal muscle index (SMI) of short-term postoperative complications of radical cystectomy (RC) in patients with bladder cancer (BC).MethodsA total of 247 patients who received RC for BC and 204 age-matched healthy population-based controls were retrospectively assessed. SMI was measured by preoperative computed tomography scans at the L4 to L5 level. Early complications were graded by Clavien-Dindo classification; severity of grade III or greater was identified as a severe complication. Logistic regression was utilized to determine the relationships between covariables and severe complications.ResultsA total of 125 (50.61%)/19 (7.69%) patients exhibited overall/severe complications during the early postoperative period. SMI was strongly associated with gender (P <0.01), but not age and body mass index (BMI), among patients with BC. Compared with the matched control group, BC patients exhibited lower SMI. The difference was statistically significant in the subgroup of male patients (Pu2009=u20090.03). In the multivariate analysis, SMI was an independent predictor of developing severe complications. Each 1 cm2/m2 increase in SMI was associated with a decrease in the odds of morbidity by 4.8%.ConclusionsA lower SMI is frequently observed in bladder cancer patients undergoing RC and is shown to be strongly associated with early complications following surgery.

Long non-coding RNA LOC572558 inhibits bladder cancer cell proliferation and tumor growth by regulating the AKT-MDM2-p53 signaling axis

Long non-coding RNAs (lncRNAs) have been suggested to play important roles in the progression of many cancers such as bladder cancer. However, the detailed mechanism has not been fully understood. We have previously identified a collection of aberrantly expressed lncRNAs in bladder cancer using microarray gene profiling assay. In the current study, we aim to further explore the expression profile and the function of LOC572558, one of the most deregulated lncRNAs in bladder cancer. A large cohort of human bladder cancer tissue samples with benign controls, as well as established human bladder cancer cell lines, has been examined for the expression of LOC572558. The biological functions of LOC572558 were examined by CCK-8 assay, flow cytometry analysis, and wound healing and transwell assays. Using a high-throughput phospho-proteome array, we identified proteins that were ectopic phosphorylated in bladder cancer cells where LOC572558 expression was upregulated. We demonstrated that LOC572558 expression was markedly decreased in bladder cancer tissues and bladder cancer cell lines. Moreover, ectopic expression of LOC572558 inhibited cell proliferation and motility, induced S phase arrest of the cell cycle and promoted cell apoptosis in T24 and 5637 bladder cancer cell lines. We further verified that overexpression of LOC572558 was associated with dephosphorylation of AKT, MDM2 and phosphorylation of p53 protein. Our data clearly demonstrated that LOC572558 is a tumor suppressor and regulates the p53 signaling pathway in bladder cancer. Thus, it may serve as a promising new diagnostic marker and therapeutic target in bladder cancer.

Expression of dicer and its related MiRNAs in the progression of prostate cancer

Dicer is aberrantly expressed in several types of malignancies. Cleaved by Dicer, the small noncoding microRNAs (miRNAs) are considered potential tools for the diagnosis and prognosis of cancer. This study investigated the expression of miRNAs thought to target Dicer. Expression of 1,205 human miRNAs and miRNA*s were examined in four patients with prostate cancer (PCa) by miRNA array in which the threshold was set as two-fold. Seventy-three miRNAs and miRNA*s were significantly down-regulated while 10 were up-regulated in PCa tissues compared with matched histologically normal glands. Of these, miR-29b-1, miR-200a, miR-370, and miR-31, which were the most down/up-regulated and closely potentially target to the Dicer 3′ UTR, were investigated further. Tissues of primary tumors and matched normal prostate glands from 185 patients with PCa were collected for further investigation. Dicer mRNA levels were negatively correlated with miR-29b-1 (ρs = −0.177, p = 0.017), miR-200a (ρs = -0.489, p < 0.0001) and miR-31 (ρs = −0.314, p < 0.0001) expression. Compared with adjacent normal glands, PCa tissues showed significantly lower miR-200a and miR-31 expression levels. Furthermore, in metastatic PCa, the expression levels of miR-200a, miR-370, and miR-31 were dramatically higher than in localized PCa. Additionally, elevated expression levels of miR-200a and miR-31 appeared to be associated with castration-resistant PCa. These findings suggest possibilities that miR-200a and miR-31 target Dicer and are involved in the carcinogenesis, migration, and behavior of castration-resistant PCa, indicating that they could be potential biomarkers for monitoring PCa progression.

Polymorphisms at long non-coding RNAs and prostate cancer risk in an eastern Chinese population.

Background:Controversial data on the association of single-nucleotide polymorphisms (SNPs, rs3787016G>A and rs10773338G>A) in long non-coding RNA (lncRNA) with prostate cancer risk were emerged. Considering possible genetic differences among populations, we conducted the present study to clarify these discrepancies and re-validate these results in an eastern Chinese population and thus provide clues for new therapeutic targets of prostate cancer.Methods:Genotypes of these two SNPs from 1015 ethnic Han Chinese patients with prostate cancer and 1032 cancer-free controls were determined by Taqman assays. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk associations.Results:The association of rs3787016 A variant genotypes with a significantly higher prostate cancer risk were found (adjusted OR=1.418, 95% CI=1.090–1.844 for AA vs GG). Stratification analysis indicated that the risk of rs3787016 variant AG/AA genotypes was more evident in younger subjects, ever smoking, patients with Gleason score ⩾7(4+3) and highly aggressive status. All these risks were not present for rs10773338G>A.Conclusions:These findings suggested that lncRNA SNPs may contribute to prostate cancer risk in an eastern Chinese population. Larger and well-designed studies with different ethnic populations are warranted to validate our findings.

PD-L1 expression in Xp11.2 translocation renal cell carcinoma: Indicator of tumor aggressiveness

Programmed death ligand-1 (PD-L1), a promising antitumor target, has proven clinical value against many malignancies. However, the PD-L1 content of Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) and its correlation with clinical outcomes remain unclear. This study aimed to investigate PD-L1 expression in Xp11.2 RCC and to assess its prognostic value. Formalin-fixed paraffin-embedded specimens from 36 adult patients that were histologically confirmed (by fluorescence in situ hybridization) were subjected to immunohistochemical analysis. Of the 36 Xp11.2 RCC patients, 9 (25.0%) had tumors with positive PD-L1 expression and 27 (75.0%) had tumors with negative PD-L1 expression. Positive PD-L1 expression correlated with advanced tumor stage (Pu2009=u20090.001), regional lymph node metastasis (Pu2009<u20090.001), and distant metastasis (Pu2009<u20090.001). A multivariate analysis identified positive PD-L1 expression was an independent adverse prognostic factor for both progression free survival (hazard ratio: 3.7, Pu2009=u20090.018) and overall survival (hazard ratio: 4.5, Pu2009=u20090.034). The median PFS and OS for the whole cohort were 13.0 months (95% confidence interval [CI], 9.4–16.6 months) and 36.0 months (95% CI, 23.9–48.1 months), respectively. Our findings suggest that positive PD-L1 expression is indicative of worse clinical outcome in Xp11.2 RCC. Further studies are needed to explore the potential efficacy of targeting PD-L1 in Xp11.2 RCC.

Role of KIT expression in the prognosis of clear cell renal cell carcinomas in Chinese patients

ObjectivesTo investigate the expression of KIT in clear cell renal cell carcinomas, and to reveal the relationships between KIT status and clinicopathological features and survival of clear cell renal cell carcinomas.MethodsThe expression of KIT was tested immunohistochemically in 119 specimens of clear cell renal cell carcinoma. Their correlations to clinicopathological parameters were compared and discussed. Kaplan–Meier method was used to determine the survival between KIT-positive and KIT-negative patients. Multivariate analysis was performed using the Cox-regression model for overall survival.ResultsA total of 13 out of 119 cases of clear cell renal cell carcinomas (10.9%) were demonstrated consistent overexpression of KIT. There was statistical significance in the correlation between KIT expression and tumor size (Pxa0<xa00.01), pathological stage (Pxa0<xa00.01), tumor grade (Pxa0<xa00.01) and P53 (0.01xa0<xa0Pxa0<xa00.05). On multivariate analysis, positive KIT expression presented an independent predictive factor for decreased overall survival (hazard ratio 17.26, Pxa0=xa00.005). The estimated mean survival time was 25.6xa0months for KIT-positive patients and 56.9xa0months for KIT negative patients, Pxa0<xa00.001.ConclusionsThe expression of KIT was significantly associated with tumor size, pathological stage, tumor grade and P53 in clear cell renal cell carcinomas. The expression of KIT is an important survival predicting factor for patients with clear cell renal cell carcinoma.

Outcomes of patients with lymph node metastasis treated with radical prostatectomy and adjuvant androgen deprivation therapy in a Chinese population: results from a cohort study

BackgroundThe aim of this study is to assess the prognosis of prostate cancer (PCa) with lymph node metastases (LNM) detected in pelvic lymph node dissection (PLND) after radical prostatectomy (RP) and adjuvant androgen deprivation therapy (ADT) in a Chinese population.MethodsFrom June 2005 to September 2012, the medical histories of 67 Chinese PCa patients with LNM detected after RP and extended PLND were collected, and all these patients received continuous adjuvant ADT. Postoperative survival was estimated using the Kaplan-Meier method. The impact of various clinicopathological factors on outcome was analyzed using Cox proportional hazard regression models. All tests were two-sided with P < 0.05 considered significant.ResultsMedian follow-up was 46.7 months, and two patients were lost to follow-up. Five-year event-free survival for patients with positive lymph nodes was 93.0%, 83.0%, and 96.0% for local recurrence, systemic progression, and cancer death, respectively. One-year, 2-year, and 3-year biochemical recurrence (BCR)-free survival was 52%, 40%, and 22%, respectively. Postoperative BCR-free survival was 25.7 months. BCR-free survival for patients with a single LNM was longer than those with two or more LNM (median 39.1 months vs. median 17.2 months, P = 0.002). In a multivariate Cox model, only two or more LNM was a significant predictor of BCR (hazard ratio 2.6, P = 0.005).ConclusionsDespite low BCR-free survival, Chinese patients with LNM can benefit from RP and adjuvant ADT. Patients with low nodal metastatic burden had a favorable prognosis.

Upregulation of COL6A1 is predictive of poor prognosis in clear cell renal cell carcinoma patients

Background: The extracellular matrix (ECM) is reported to play an important role in tumorigenesis and progression. Collagen VI is an important ECM protein. In this study, we investigated the potential role of the COL6A1 gene, which encodes the α1 polypeptide of collagen VI, in the biological functions involved in the progression and outcome of clear cell renal cell carcinoma (ccRCC). Materials and methods: A total of 288 ccRCC patients who underwent radical nephrectomy (RN) or nephron sparing nephrectomy (NSS) at Fudan University Shanghai Cancer Center (FUSCC) were enrolled. Total RNA was extracted from frozen samples obtained from the tissue bank of FUSCC and expression of COL6A1 was determined by qRT-PCR. The clinical relationship between COL6A1 expression and ccRCC prognosis was analyzed. These data were then validated in the Cancer Genome Atlas (TCGA) cohort. We also investigated the effect of COL6A1 overexpression in a xenografted tumor model in nude mice in vivo. Results: In multivariate analysis of TCGA cohorts, COL6A1 high expression was predictive of poor prognosis in ccRCC patients’ overall survival (OS) (HR: 2.588 95%CI 1.616–4.146) and disease free survival(DFS) (HR: 3.106 95%CI 1.534–6.288). In FUSCC cohorts, after adjusted for relevant factors, the COL6A1 expression indicates poor prognosis in ccRCC patients’s OS (HR 2.211; 95% CI, 1.360–8.060) and DFS (HR 3.052; 95%CI, 1.500–6.210). COL6A1 overexpression promoted tumor growth in xenografted nude mice. Conclusion: Increased COL6A1 expression correlates with poor prognosis in ccRCC patients. Moreover, COL6A1 stimulates tumor growth in vivo.