Optimal sequencing strategy using docetaxel and androgen receptor axis-targeted agents in patients with castration-resistant prostate cancer: utilization of neutrophil-to-lymphocyte ratio.

PURPOSE: To investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) for the selection of the optimal sequencing strategy using docetaxel and androgen receptor axis-targeted (ARAT) agents in patients with M0 or M1 castration-resistant prostate cancer (CRPC). Currently, there is a need to identify biomarkers to guide optimal sequential treatment in CRPC. METHODS: This multicenter, retrospective analysis included 303 consecutive patients initially diagnosed with M0 or M1 CRPC between September 2009 and March 2017. Of these, 52 (17.2%) patients received pre-docetaxel ARAT agents and 189 (62.4%) patients received post-docetaxel ARAT agents. The prognostic ability of NLR at CRPC diagnosis regarding radiographic progression-free survival (rPFS) and cancer-specific survival (CSS) were investigated. For the analysis, the NLR level was dichotomized at 2.5, and evaluated according to sequencing strategy. RESULTS: Multivariate analysis revealed NLR ≥ 2.5 as an independent predictor of a lower risk for CSS. During the median follow-up of 18.5 months, patients with NLR ≥ 2.5 exhibited significantly lower 1-year rPFS (p = 0.011) and 2-year CSS rates (p = 0.005) compared to patients with NLR < 2.5. Among patients with NLR < 2.5, the post-docetaxel ARAT agent sequencing group exhibited higher 1-year rPFS (p = 0.031) and 2-year CSS (p = 0.026) rates compared to the pre-docetaxel ARAT agent sequencing group. Among patients with NLR ≥ 2.5, rPFS and CSS rates were comparable regardless of ARAT agent sequencing. CONCLUSION: NLR ≥ 2.5 at CRPC diagnosis is associated with a lower risk for CSS. Patients with NLR < 2.5 should primarily be offered docetaxel considering the survival benefit of docetaxel-to-ARAT agent sequencing.

Impact of clinical trial participation on survival in patients with castration-resistant prostate cancer: a multi-center analysis.

BACKGROUND: Clinical trial (CT) participation may confer access to new, potentially active agents before their general availability. This study aimed to investigate the potential survival benefit of participation in investigational CTs of novel hormonal, chemotherapeutic, and radiopharmaceutical agents in patients with castration-resistant prostate cancer (CRPC). METHODS: This multi-center, retrospective analysis included 299 consecutive patients with newly diagnosed, non-metastatic or metastatic CRPC between September 2009 and March 2017. Of these, 65 (21.7%) patients participated in CTs pertaining to systemic treatment targeting CRPC and 234 (78.3%) patients received pre-established, standard systemic treatment outside of a CT setting. The survival advantage of CT participation regarding cancer-specific survival (CSS) was investigated. RESULTS: An Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 at CRPC diagnosis was found in a lower proportion CT participants than in non-participants (4.6% vs. 14.9%; p = 0.033). During the median follow-up period of 16.0 months, CT participants exhibited significantly higher 2-year CSS survival rates (61.3% vs. 42.4%; p = 0.003) than did non-participants. Multivariate analysis identified prostate-specific antigen and alkaline phosphatase levels at CRPC onset, Gleason score ≥ 8, ECOG PS ≥2, less number of docetaxel cycles administered, and non-participation in CTs as independent predictors for a lower risk of CSS. CONCLUSIONS: Patients diagnosed with CRPC who participated in CTs exhibited longer CSS durations than non-participants who received pre-established, standard systemic therapy outside of a CT setting. Our findings imply that CT participation is associated with CSS, and that CT participation should be offered to patients with CRPC whenever indicated.

Subcutaneous Fat Distribution is a Prognostic Biomarker for Men with Castration Resistant Prostate Cancer.

PURPOSE: The relationship between body fat distribution and survival remains unclear in patients with castration resistant prostate cancer treated with docetaxel and androgen receptor axis targeted agents. We investigated whether body composition parameters could predict radiographic progression-free and cancer specific survival in patients with castration resistant prostate cancer. MATERIALS AND METHODS: In this multicenter retrospective study we evaluated data on 282 consecutive patients diagnosed with castration resistant prostate cancer between September 2009 and March 2017. The subcutaneous fat index, the visceral fat index and the skeletal muscle index at the diagnosis of castration resistant prostate cancer were determined by computerized tomography data. Survival analyses were performed using the subcutaneous fat, visceral fat and skeletal muscle indexes dichotomized at 39.9, 58 and 52.4 cm2/m2, respectively. RESULTS: At the diagnosis of castration resistant prostate cancer, cancer specific survival was independently predicted using prostate specific antigen levels, Gleason score 8 or greater, performance status, a shorter interval from androgen deprivation therapy to castration resistant prostate cancer and a subcutaneous fat index of less than 39.9 cm2/m2. During the median followup of 16.0 months patients with a subcutaneous fat index of 39.9 cm2/m2 or greater received more docetaxel cycles than patients with a subcutaneous fat index of less than 39.9 cm2/m2. Compared to patients with a subcutaneous fat index of less than 39.9 cm2/m2 those with an index of 39.9 cm2/m2 or greater had better 1-year progression-free and 2-year cancer specific survival (p = 0.009 and 0.021, respectively). CONCLUSIONS: Patients with a subcutaneous fat index of 39.9 cm2/m2 or greater at the diagnosis of castration resistant prostate cancer showed higher progression-free and cancer specific survival rates than those with a subcutaneous fat index of less 39.9 cm2/m2 at diagnosis. The subcutaneous fat index determined by computerized tomography data could serve as a useful objective prognostic factor to discuss patient therapeutic options. Further studies are needed to define the roles of each body composition parameter in relation to pharmacokinetics and oncologic outcome.

Cyto-/genotoxic effects of the ethanol extract of Chan Su, a traditional Chinese medicine, in human cancer cell lines.

ETHNOPHARMACOLOGICAL RELEVANCE: Chan Su, an ethanolic extract from skin and parotid venom glands of the Bufo bufo gargarizans Cantor, is widely used as a traditional Chinese medicine for cancer therapy. Although the anti-cancer properties of Chan Su have been investigated, no information exists regarding whether Chan Su has genotoxic effects in cancer cells. The aim of the present study was to examine the cyto-/genotoxic effect of Chan Su in human breast carcinoma (MCF-7 cells), human lung carcinoma (A-549 cells), human T cell leukemia (Jurkat T cells), and normal human lymphocytes. MATERIALS AND METHODS: Effects on the viability of MCF-7, A-549, Jurkat T cells, and normal lymphocytes were evaluated by Trypan blue exclusion assays. The DNA content in the sub-G1 region was detected by propidium iodide (PI) staining and flow cytometry. The genotoxicity of Chan Su was assessed by single-cell gel electrophoresis (comet assay) and the cytokinesis-block micronucleus assay (CBMN assay). RESULTS: Chan Su significantly inhibited the viability of MCF-7, A-549, and Jurkat T cells dose dependently, but had no effect on normal human lymphocytes. Apoptotic death of the cancer cells was evident after treatment. Chan Su also induced genotoxicity in a dose-dependent manner, as indicated by the comet and cytokinesis-block micronucleus assays. CONCLUSIONS: These findings suggest that Chan Su can induce apoptotic death of, and exert genotoxic effects on, MCF-7, A-549, and Jurkat T cells.

Extract of Artemisia lavandulaefolia Inhibits In Vitro Angiogenesis in Human Umbilical Vein Endothelial Cells.

Angiogenesis is important processes for tumor growth and metastasis. Anti-angiogenesis target therapy has recently been known to be new anti-cancer therapeutic strategies. Natural products such as traditional medicine comprise a major source of angiogenesis inhibitors. Artemisia lavandulaefolia has been known to use in the traditional medical practices. However, its molecular mechanism on the tumor protection and therapy was not clearly elucidated. In this study, we investigated the possibility that extract of A. lavandulaefolia inhibits in vitro angiogenesis. Therefore, we examined the effect of extract of A. lavandulaefolia on the vascular network formation of human umbilical vein endothelial cells (HUVECs). We found that the treatment of A. lavandulaefolia extract suppressed the tube formation of HUVECs without any influence on the viability of HUVECs. In addition, extract of A. lavandulaefolia inhibited the migration and invasion of HUVECs. These results suggest that extract of A. lavandulaefolia could be act for an angiogenic inhibitor.

Reverse transcriptase-polymerase chain reaction and immunohistochemical studies for detection of prostate stem cell antigen expression in prostate cancer: potential value in molecular staging of prostate cancer.

OBJECTIVES: To determine whether detection of prostate stem cell antigen (PSCA) expression has potential for molecular staging in prostate cancer (PCa), we examined the relationship between established prognostic factors, biochemical recurrence (BCR) and PSCA expression. METHODS: This study was comprised of 66 patients who underwent radical prostatectomy for the treatment of PCa. We employed reverse transcriptase-polymerase chain reaction (RT-PCR) to detect PSCA mRNA-bearing cells in peripheral blood, and used immunohistochemical (IHC) techniques to identify PSCA protein expression in microarrayed tissue. RESULTS: PSCA-mRNA was detected in the peripheral blood of nine (13.6%) patients by RT-PCR. Whereas 3.2% of patients with low-grade disease were PSCA positive, 22.9% of patients with high-grade disease were PSCA positive (P = 0.030). There was also a significant relationship of RT-PCR PSCA positivity to whether or not the tumor was confined to the prostate. Whereas only 6.8% of patients with prostate-confined disease were RT-PCR PSCA positive, 27.3% of extraprostatic diseases were RT-PCR PSCA positive (P = 0.022). IHC studies of tumor tissue microarrays demonstrated that PSCA expression intensity was related to both extraprostatic extension (P = 0.014) and positive surgical margin (P = 0.053). Whereas 23.8% of prostate-confined diseases were high intensity, 54.5% of extraprostatic diseases were high intensity. BCR developed in seven patients (10.6%) during the follow-up period (median, 16.2 months; range, 9-25 months). Prognostic factors increasing the risk of BCR included: seminal vesicle invasion (P = 0.004), extraprostatic disease (P = 0.019), lymphovascular emboli (P = 0.036) and RT-PCR PSCA positivity (P = 0.004) in univariate analysis. CONCLUSIONS: We were able to detect PSCA mRNA-bearing cells in peripheral blood by RT-PCR, and also identify PSCA protein expression in tumors by IHC analysis of tissue microarrays. RT-PCR PSCA positivity in peripheral blood may be a potential modality for molecular staging of PCa.