Instillation Strategies for Non-Muscle-Invasive Bladder Cancer in the Bacillus Calmette-Guerin Shortage Era: A Simple Solution for BCG Discontinuation.

Objective: Among intravesical instillation protocol in patients with non-muscle-invasive bladder cancer (NMIBC), chemotherapy agents have been widely used during the bacillus Calmette-Guérin (BCG) shortage era since the patient might under the risk of BCG discontinuation. This study evaluates the efficacy of incomplete BCG instillation compared with pure chemotherapy instillation protocol. Materials and Methods: Patients newly diagnosed with intermediate- and high-risk NMIBC who received incomplete BCG intravesical instillation or chemotherapy instillation were retrospectively included. Patients were divided into three groups according to different intravesical instillation schedules: [BCG only], [BCG + Chemo], and [Chemo only]. Comparisons between these three groups were performed. Bladder recurrence-free survival (RFS) was analyzed as the primary endpoint. Results: A total of 475 patients who received intravesical instillations were enrolled. Compared to the [Chemo only] group, the [BCG + Chemo] group had significantly better bladder RFS (p = 0.027). Multivariate analysis of recurrence revealed the [BCG + Chemo] regimen has a hazard ratio 0.381 (95% CI 0.154-0.941, p = 0.037). The total instillation number >12 was associated with better RFS (p = 0.001) compared with other instillation numbers. Conclusion: For NMIBC patients facing the risk of unexpected BCG instillation interruption, instead of starting instillation with chemotherapy agents, receiving BCG first till stoppage then shifting to chemotherapy agents is recommended.

Promoter Gene Methylation Regulates Clooxygenase-2 Expression in Androgen-Dependent and Independent Prostate Cancer Cells.

Background: Clooxygenase-2 (COX-2) expression is overexpressed in human prostate cancer, and aberrant methylation of the COX-2 promoter has also been elucidated. However, how the methylation of CpG islands at COX-2 regulates its expression in prostate cancer is still unclear. We will determine the methylated 5' CpG island of the COX-2 gene and its role in the expression of COX-2 in prostate androgen-dependent and androgen-independent cancer cells, LNCaP and DU145. Methods: We used western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to confirm the COX-2 expression in prostate cancer cell lines, including LNCaP (androgen-dependent) and DU145 (androgen-independent) cells. To investigate whether the COX-2 expression was regulated by the methylation status of the 5' CpG island, we treated LNCaP and DU145 cells with the DNA methylation inhibitor, 5-aza-2'-deoxycytidine, and determined COX-2 expression in the treated/untreated cells by western blotting and qRT-PCR. Subsequently, bisulfite sequencing was performed to study the methylation sites in the treated/untreated cells. The effects of 5-aza-2'-deoxycytidine to cell proliferation, cell migration and cell cycle process in DU145 and LNCaP cells were determined using Cell Counting Kit-8 (CCK-8) assay, transwell assay and flow cytometry, respectively. Results: The results revealed that the expression of COX-2 in androgen-dependent LNCaP cells was 5.44-fold (in protein level) and 2.46-fold (in mRNA level) higher than that in androgen-independent DU145 cells. After 5-aza-2'-deoxycytidine treatment, COX-2 expression in DU145 cells was elevated significantly, but no change was found in LNCaP cells. The A and C regions of the COX-2 CpG island exhibited reduced methylation along with that an increased expression of COX-2 was noted in DU145 cell after 5-aza-2'-deoxycytidine treatment. Also, the treatment with 5-aza-2'-deoxycytidine inhibited cell proliferation, cell migration and influenced the cell cycle progression in both DU145 and LNCaP cells. Conclusions: Our results reveal that androgen receptor (AR)-dependent/independent prostate cancer cell lines exhibit different regulation of methylation in COX-2 that regulate its expression. Additionally, 5-aza-2'-deoxycytidine treatment of DU145 and LNCaP cells inhibits their ability of tumor progression.

Clinical predictors for biochemical failure in patients with positive surgical margin after robotic-assisted radical prostatectomy.

OBJECTIVE: Patients with positive surgical margins (PSMs) after radical prostatectomy for localized prostate cancer have a higher risk of biochemical failure (BCF). We investigated the risk factors of BCF in patients with PSMs after robotic-assisted radical prostatectomy (RARP). METHODS: We evaluated 462 patients who underwent RARP in a single medical center from 2006 through 2013. Of them, 61 with PSMs did not receive any treatment before BCF. Kaplan-Meier curve and Cox regression analysis were used to compare patients with (n = 19) and without (n = 41) BCF. RESULTS: Overall, 13.2% of patients had PSMs, and of those, 31.7% experienced BCF during follow-up. The mean follow-up duration was 43.7 months (42.4 [non-BCF] vs 46.35 (BCF], p = 0.51). In univariant analyses, the platelet to lymphocyte ratio (6.26 [non-BCF] vs 8.02 [BCF], p = 0.04) differed statistically. When patients were grouped by pathologic grade ≦2 or ≧3 (p = 0.004), the BCF-free survival rates differed significantly. Seminal vesicle invasion also differed significantly (5 [non-BCF] vs 7 [BCF], p = 0.005). Patients with undetectable nadir prostate-specific antigen (PSA) after RARP (BCF rate 4/34) differed statistically from those with detectable PSA after RARP (BCF rate 15/26) (p < 0.001). In the multivariate analysis, the platelet/lymphocyte (P/L) ratio, pathologic grade, and undetectable nadir PSA remained statistically significant. CONCLUSIONS: In patients who undergo RARP and have PSMs, P/L ratio >9 preoperatively, pathologic grade ⩾3, and detectable nadir PSA after RARP should be considered adverse features. Early intervention such as salvage radiation therapy or androgen deprivation therapy should be offered to these patients.

Clinical behavior and management of three types of renal angiomyolipomas.

OBJECTIVES: To analyze and present the demography, clinical behavior, especially the risk factors of tumor hemorrhage and management of sporadic angiomyolipoma (SAML), tuberous sclerosis complex associated angiomyolipoma (TSCAML) and epithelioid angiomyolipoma (EAML) in our institution. METHODS: A retrospective study of 587 patients who were diagnosed with renal angiomyolipoma in our institution between January 2000 and May 2015 was done. The AMLs were diagnosed by ultrasonography, CT, or MRI. EAML was confirmed by histopathology. Medical records and follow-up results were analyzed using the SPSS version 22 software. RESULTS: Out of 587 cases of renal AMLs, 87.4% were SAMLs, 8.7% were TSCAMLs and 3.9% were EAMLs. Most of the AML patients were asymptomatic. The most common presenting symptoms included flank pain and abdominal pain. The median tumor size of SAML, TSCAML, EAML were 4.7, 2.7, 10.5 cm respectively. Approximately half of SAMLs were conservatively treated, almost all TSCAMLs were treated conservatively, while all EAMLs were surgically treated. The median tumor size of hemorrhagic SAML cases was 8 cm versus non-hemorrhagic cases of 4.1 cm. The optimal cut-off point on the ROC curve for predicting SAML tumor hemorrhage was 7.35 cm. CONCLUSION: A larger tumor size, younger patient's age and higher BMI value correlated with a higher risk of tumor hemorrhage. For tumor sizes less than 7.35 cm, we recommend active surveillance or TAE for hemorrhage prevention. We also suggest that surgical management should be considered for patients with tumors larger than 7.35 cm, symptomatic and progressive AML, or suspicious EAML.

CCL4 is the only predictor for non-responder in GT-1 CHC patients with favorable IL28B genotype when treated with PegIFN/RBV.

BACKGROUND: Chemokines/cytokines play important roles in the pathogenesis of chronic hepatitis C (CHC). However, their clinical characteristics and implications in treatment responses to pegylated interferon plus ribavirin treatment (PegIFN/RBV) have not been fully illustrated yet. In this study, we intended to investigate the possible predictability of serum chemokines/cytokines on the treatment response in Taiwanese of CHC, genotype-1 (GT-1). METHODS: 60 Patients with GT-1 CHC infection who had been treated with PegIFN/RBV were enrolled, including 27 (45%) with sustained virological response (SVR), 11 (18%) with relapse after 48 weeks of treatment and 22 (37%) non-response (NR). Clinical parameters, seven chemokines/cytokines, CCL3, CCL4, CXCL9, CXCL10, CXCL11, IL-10 and IFN-γ, and genotypes of rs12979860, the single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) were analyzed for their relationship to treatment response. RESULTS: Baseline serum levels of CXCL10, CXCL11, CCL3 and CCL4 were significantly higher in NR group while comparing with non-NR group. (CXCL10: p = 0.001; CXCL11: p < 0.001; CCL3: p = 0.006; CCL4: p = 0.005). However, only rs12979860 CC genotype was the independent factors for NR in GT-1 CHC infection (OR, 8.985; p = 0.008). In addition, baseline serum level of CCL4 was found to be the only independent factor for NR in GT-1 CHC patients with favorable IL28B genotype (OR, 1.134; p = 0.039). CONCLUSIONS: IL28B genotype is the predictor for NR in GT-1 CHC patients treated with PegIFN/RBV, while baseline serum level of CCL4 is the only predictor for NR in GT-1 CHC patients with favorable IL28B genotype.

Blockade of TNF-α signaling benefits cancer therapy by suppressing effector regulatory T cell expansion.

Effector but not naive regulatory T cells (Treg cells) can accumulate in the peripheral blood as well as the tumor microenvironment, expand during tumor progression and be one of the main suppressors for antitumor immunity. However, the underlying mechanisms for effector Treg cell expansion in tumor are still unknown. We demonstrate that effector Treg cell-mediated suppression of antitumor CD8+ T cells is tumor-nonspecific. Furthermore, TNFR2 expression is increased in these Treg cells by Affymetrix chip analysis which was confirmed by monoclonal antibody staining in both hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patients and murine models. Correspondingly, increased levels of TNF-α in both tissue and serum were also demonstrated. Interestingly, TNF-α could not only expand effector Treg cells through TNFR2 signaling, but also enhanced their suppressive activity against antitumor immunity of CD8+ T cells. Furthermore, targeting TNFR2 signaling with a TNF-α inhibitor could selectively reduce rapid resurgence of effector Treg cells after cyclophosphamide-induced lymphodepletion and markedly inhibit the growth of established tumors. Herein, we propose a novel mechanism in which TNF-α could promote tumor-associated effector Treg cell expansion and suggest a new cancer immunotherapy strategy using TNF-α inhibitors to reduce effector Treg cells expansion after cyclophosphamide-induced lymphodepletion.