Yi Jun Shen

Serum miRNA-21: elevated levels in patients with metastatic hormone-refractory prostate cancer and potential predictive factor for the efficacy of docetaxel-based chemotherapy.

miR‐21 has been recognized as an “onco‐microRNA” with the activity of negatively modulating the expression of tumor‐suppressor genes. However, its role in prostate cancer (CaP) has not been well‐documented. We designed this study to assess the potential function of serum miR‐21 in the progression of CaP.

Involvement of microRNA-21 in mediating chemo-resistance to docetaxel in androgen-independent prostate cancer PC3 cells.

AbstractAim:To investigate whether microRNA-21 was involved in mediating the chemoresistance of prostate cancer cells to docetaxel.Methods:A microarray technique was used to determine the miRNA profile in docetaxel-resistant PC3 cells. Real-time PCR was used to confirm the array results. miR-21 mimics and inhibitors were synthesized and introduced to cells using Lipofectamine 2000. Cell proliferation was examined with the CCK-8 assay. Luciferase reporter containing PDCD 3′UTR was constructed and the activity was detected by a dual luciferase assay. PDCD4 protein expression was evaluated using Western blot.Results:A docetaxel-resistant prostate cancer PC3 cell line (PC3R) was established . Using microarrays, miR-21 was found to be up-regulated in PC3R cells. Ectopic expression of miR-21 increased the resistance to docetaxel in PC3 wild type cells. In contrast, silencing of miR-21 in PC3R cells sensitized the cells to docetaxel. The IC50 values for miR-21-silencing cells and control cells were 28.31 and 35.89 nmol/L, respectively. PDCD4, a direct target gene of miR-21, could mediate chemoresistance to docetaxel in PC3 cells.Conclusion:Our findings suggest that miR-21 contributed to the resistance of PC3 cells to docetaxel, and that targeting miR-21 may offer a promising therapeutic approach in sensitizing prostate cancer to docetaxel treatment.

External validation of a nomogram using RENAL nephrometry score to predict high grade renal cell carcinoma.

PURPOSE A novel nomogram using the RENAL ([R]adius maximal diameter in cm, [E]xophytic/endophytic properties, [N]earness of the tumor to the collecting system or sinus in mm, [A]nterior/Posterior, [L]ocation relative to the polar lines and [H]ilar) nephrometry score was developed to predict high grade renal cell carcinoma. It showed good performance in internal evaluation. We externally validated the prediction model. MATERIALS AND METHODS We identified a cohort of 391 Chinese patients in whom renal cell carcinoma was surgically resected at our institution from 2008 to 2011. Fuhrman grade was reviewed by an experienced genitourinary pathologist and radiological images were independently assessed by 2 senior urologists. Using a 2-tiered system high grade disease was defined as Fuhrman grade III/IV. The statistical performance of the prediction model was evaluated by discrimination, calibration and clinical usefulness. RESULTS Of the 391 patients 45.5% were considered to have high grade tumors. External validation of the nomogram revealed an AUC of 0.73. The calibration plot showed that the predicted probability of high grade disease had concordance comparable to the observed frequency. On decision curve analysis the prediction model provided a superior net benefit and reduction at a greater than 20% probability threshold. CONCLUSIONS We confirm the predictive value of the nomogram using the RENAL nephrometry score to identify high grade renal cell carcinoma in an independent cohort. Further research is required to evaluate its performance using a head-to-head comparison with renal biopsy results.

Visceral Obesity and Risk of High Grade Disease in Clinical T1a Renal Cell Carcinoma

PURPOSE Accurate assessment of disease characteristics is a prerequisite for treatment decision making regarding small renal masses. In this study we evaluate the association between visceral obesity and Fuhrman grade in patients with cT1a renal cell carcinoma. MATERIALS AND METHODS We retrospectively collected data on 186 patients with surgically treated cT1a renal cell carcinoma. Single slice computerized tomography was used to measure the area of visceral and subcutaneous adipose tissue. Visceral obesity was calculated as the proportion of visceral adipose tissue to overall adipose tissue. Other analyzed factors included clinical characteristics (age, gender, body mass index and tumor size) and anatomical features of the tumor defined by the R.E.N.A.L. nephrometry score. The association between predictors and high grade disease (Fuhrman grade III or IV) were assessed using logistic regression analyses. RESULTS A total of 47 (25.3%) tumors were classified as high grade. The percentage of visceral adipose tissue was higher in male participants but did not correlate with body mass index, age or tumor size. In univariate analyses the percentage of visceral adipose tissue and tumor size were significantly associated with higher Fuhrman grade. Multivariate analysis showed that the percentage of visceral adipose tissue (OR 1.06, p = 0.0018) and tumor size (OR 1.91, p = 0.047) were independent predictors of high grade cancer. Addition of the percentage of visceral adipose tissue to a model including clinical characteristics and anatomical features of the tumor remarkably improved its discriminatory ability (p = 0.0010). CONCLUSIONS Increased visceral obesity was found to be strongly associated with higher Fuhrman grade in patients with cT1a renal cell carcinoma. Further studies are needed to confirm these findings and discover the underlying biological mechanism.

Tumor cytoreduction results in better response to androgen ablation-a preliminary report of palliative transurethral resection of the prostate in metastatic hormone sensitive prostate cancer

OBJECTIVES To investigate the oncologic influence of transurethral resection of the prostate (TURP) as a cytoreductive surgery in metastatic hormone sensitive prostate cancer (mHSPC), in the setting of continuous complete androgen blockade (CAB). MATERIALS AND METHODS Medical histories of 146 consecutive Chinese males with newly diagnosed mHSPC, registered in our institution in 2006 and 2007, were reviewed. All of these patients received CAB as initial systematic therapy. Demographics and cancer control outcomes from 39 mHSPC patients who underwent TURP for a relief of bladder outlet obstruction were compared with those of the other 107 who received CAB only when they were still hormone-sensitive. Median follow-up was 15 months (3 to 27 months). RESULTS Age at diagnosis, baseline PSA, and biopsy Gleason score were comparable between the 2 groups. Patients who underwent a TURP had lower PSA nadir (median 0.15 ng/ml vs. 0.82 ng/ml, P = 0.015) and longer time to PSA nadir (11.2 months vs. 6.4 months, P < 0.001). More patients in the non-TURP group developed hormone refractory prostate cancer (P = 0.007). The TURP group had a tendency towards longer disease-specific survival and overall survival (24.4 months vs. 24.1 months and 24.4 months vs. 22.9 months, respectively), though this did not reach statistical significance. CONCLUSIONS TURP resulted in a better and more prolonged response to hormone therapy in mHSPC, with a trend towards positive influence in disease specific survival and overall survival. To date, our preliminary report is the first study regarding long-term survival of cytoreductive surgery in mHSPC, and further investigations are warranted.

Development and Evaluation of a Nomogram to Predict Inguinal Lymph Node Metastasis in Patients With Penile Cancer and Clinically Negative Lymph Nodes

PURPOSE Optimal management for penile cancer in patients with clinically negative lymph nodes is still under debate. We developed and evaluated a nomogram to stratify patients who are suitable candidates for further treatment. MATERIALS AND METHODS This study included 110 men with penile cancer and clinically negative lymph nodes from 1990 to 2008. All patients underwent primary tumor resection and regional lymphadenectomy. We retrospectively reviewed medical records and tumor slides. Statistical analysis was done in R with library rms. RESULTS The lymph node metastasis rate in the entire cohort was 23.6%. The final model, presented as a nomogram, included T stage, grade, lymphovascular invasion and p53 expression. Only lymphovascular invasion showed independent prognostic value on multivariate analysis (p = 0.024). The model also showed good calibration (bootstrap corrected concordance index 0.79). To determine the clinical usefulness of the nomogram we compared it with the European Association of Urology risk classification using decision curve analysis. At a 10% probability threshold our nomogram led to 1 positive result per 100 patients without an increase in the number of false-positive results. At this probability threshold the model also decreased 13 unnecessary interventions per 100 patients without missing more metastatic disease. CONCLUSIONS We generated a nomogram in patients with clinically node negative penile cancer based on readily available pathological factors. The clinical usefulness of the nomogram was evidenced by decision curve analysis.

Downregulation of DAB2IP results in cell proliferation and invasion and contributes to unfavorable outcomes in bladder cancer

The DOC‐2/DAB2 interactive protein (DAB2IP) is a member of the Ras GTPase‐activating protein family. It has been shown to be often downregulated and a poor prognostic factor in several human malignancies. In this study, we analyzed the clinicopathological features and outcomes of DAB2IP expression in 135 patients with urothelial carcinoma of the bladder (UCB) treated by radical cystectomy plus bilateral lymph node dissection, and evaluated the effect of DAB2IP knockdown in vitro using the MTT method, colony formation assay, cell cycle assay, and cell migration and invasive assay. We found low expression of DAB2IP was significantly associated with high pathological stage (P = 0.002), high pathological grade (P = 0.02), tumor size more than 3 cm (P = 0.04), and presence of histological variants (P = 0.01). DAB2IP was an independent prognostic factor of disease recurrence (hazard ratio, 2.67; P = 0.034) and cancer‐specific survival (hazard ratio, 2.79; P = 0.038). Knockdown of DAB2IP could promote cell proliferation, migration, and invasion. Downregulation of DAB2IP could activate the ERK and Akt pathways and was correlated with the expression of epithelial–mesenchymal transition markers, such as E‐cadherin and vimentin. In conclusion, downregulation of DAB2IP is associated with features of biologically aggressive UCB and results in cell proliferation, migration, and invasion of bladder cancer. DAB2IP may serve as a promising biomarker in patients with UCB treated by radical cystectomy and bilateral lymph node dissection.

Prospectively Packaged Ilioinguinal Lymphadenectomy for Penile Cancer: The Disseminative Pattern of Lymph Node Metastasis

PURPOSE We prospectively evaluated the disseminative pattern of lymph node metastasis in penile cancer cases using packaged lymphadenectomy. In addition, we analyzed prognostic factors of the extent of lymph node metastasis. MATERIALS AND METHODS Packaged inguinal lymphadenectomy was performed in 46 patients. A total of 24 patients with 1 or more positive inguinal lymph nodes underwent packaged iliac lymphadenectomy. Inguinal lymphadenectomy was divided into 3 packages, including medial inguinal, lateral inguinal and Cloquets node packages. Medial and lateral inguinal packages were separated by the lateral surface of the femoral artery and the saphenous vein. Iliac lymphadenectomy was divided into 3 packages, including external iliac, obturator and common iliac packages. Clinicopathological features of the primary tumor and lymph nodes were correlated with the extent of lymph node metastasis. RESULTS Of 92 groin basins 27 cases of inguinal lymphadenectomy and 7 of iliac lymphadenectomy had lymph node metastasis. Medial inguinal and external iliac packages were the most common involved regions in inguinal and iliac lymphadenectomy cases, respectively. No extended lymph node metastasis was observed in the absence of positive lymph nodes in the medial inguinal package. In groin basins with lymph node metastasis in the medial inguinal package extranodal extension was a significant predictor of extended lymph node metastasis. Cloquets node was associated with iliac lymph node metastasis on univariate analysis. However, it was of limited predictive value in patients with 1 or 2 positive inguinal lymph nodes. CONCLUSIONS The medial inguinal package defined in our study was the first involved lymph node region in penile cancer cases. Extranodal extension was an important predictor of extended lymph node metastasis beyond the medial inguinal package.

Prostate-specific antigen half-life: A new predictor of progression-free survival and overall survival in Chinese prostate cancer patients

We investigated the potential value of prostate-specific antigen half-life (PSAHL) and decreasing velocity (PSAVd) to predict progression-free survival (PFS) and overall survival (OS) in Chinese patients with prostate cancer. A total of 153 patients treated with hormonal therapy were included in the study. Of these, 78 patients progressed to hormone-refractory prostate cancer (HRPC) and 24 patients died by the end of follow-up. PSAHL was defined as the time during which prostate-specific antigen (PSA) concentration became half of the initial value during the first hormonal therapy. PSAVd reflected the decreasing velocity of PSA during the first hormonal therapy. PFS was defined as the interval from the beginning of hormonal therapy to HRPC. Cox proportional hazards regression analysis was used to evaluate whether PSAHL and PSAVd were significantly associated with PFS and OS. The median PSAHL and PSAVd were 0.50 months and 33.8 ng mL(-1) per month. The median PFS and OS were 22.7 months (95% confidence interval [CI], 22.0-29.6 months) and 43.5 months (95% CI, 37.9-48.4 months), respectively. On univariate and multivariate analysis, long PSAHL (> 0.5 months), metastatic disease, high biopsy Gleason scores (>or= 8) and high nadir PSA (> 0.4 ng mL(-1)) were all found to be significantly associated with short PFS. Long PSAHL, high nadir PSA and short PSA doubling time (PSADT <or= 2.0 months) were significantly associated with short OS. There were no significant relationships between PSAVd and either PFS or OS. Thus, PSAHL is a promising new independent predictor of survival. Patients with long PSAHL were identified as those at high risk for a relatively short PFS and OS.

The Value of Squamous Cell Carcinoma Antigen in the Prognostic Evaluation, Treatment Monitoring and Followup of Patients With Penile Cancer

PURPOSE We examined whether squamous cell carcinoma antigen has significant value for prognostic evaluation, treatment monitoring and followup in patients with penile cancer. MATERIALS AND METHODS Serum squamous cell carcinoma antigen was prospectively measured in 63 patients with penile squamous cell carcinoma from 2005 to 2007. The normal range of squamous cell carcinoma antigen was set as less than 1.50 mug/l. Statistical data analysis was done by the nonparametric method. Survival analysis was performed with the log rank test and the Cox proportional hazard model. RESULTS Of all patients 23.8% had a value of squamous cell carcinoma antigen that was greater than the upper limit of normal. Increased values correlated positively with lymph node metastasis (p = 0.005). However, squamous cell carcinoma antigen could not accurately predict occult inguinal lymph node metastasis in clinically node negative cases. Preoperatively squamous cell carcinoma antigen was an independent prognostic factor for disease-free survival in patients with node positive penile cancer (OR 0.13, p = 0.006). Combining pretreatment squamous cell carcinoma antigen and the percent of decrease after surgery was informative for predicting disease recurrence. The prognostic value of squamous cell carcinoma antigen was also observed in a small number of patients treated with chemotherapy. During followup continuously increasing squamous cell carcinoma antigen indicated tumor progression without a significant lead time effect. CONCLUSIONS Squamous cell carcinoma antigen is not a sensitive marker of tumor burden. However, it has prognostic significance for disease-free survival in patients with penile cancer treated with surgery.