High expression of miR-17-5p in tumor epithelium is a predictor for poor prognosis for prostate cancer patients

MicroRNAs (miRs) are small non-coding RNA molecules, which are involved in the development of various malignancies, including prostate cancer (PCa). miR-17-5p is considered the most prominent member of the miR-17-92 cluster, with an essential regulatory function of fundamental cellular processes. In many malignancies, up-regulation of miR-17-5p is associated with worse outcome. In PCa, miR-17-5p has been reported to increase cell proliferation and the risk of metastasis. In this study, prostatectomy specimens from 535 patients were collected. Tissue microarrays were constructed and in situ hybridization was performed, followed by scoring of miR-17-5p expression on different tumor compartments. High expression of miR-17-5p in tumor epithelium was associated with biochemical failure (BF, p < 0.001) and clinical failure (CF, p = 0.019). In multivariate analyses, high miR-17-5p expression in tumor epithelial cells was an independent negative prognostic factor for BF (HR 1.87, 95% CI 1.32–2.67, p < 0.001). In vitro analyses confirmed association between overexpression of miR-17-5p and proliferation, migration and invasion in prostate cancer cell lines (PC3 and DU145). In conclusion, our study suggests that a high cancer cell expression of miR-17-5p was an independent negative prognostic factor in PCa.

Tumor-stromal IL-1β/ NFκB / ESE3 Signaling Axis Drives Pancreatic Cancer Fibrosis, Chemoresistance, and Poor Prognosis

Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis and pancreatic ductal adenocarcinoma (PDAC) progression. The mechanisms controlling PSC activation is not completely understood. Here we investigated the role of ESE3 (Epithelium-Specific ETS factor 3) in PSC activation. We discovered that in PDAC patients ESE3 expression was increased in PSC while decreased in tumor cells. ESE3 overexpression in PSC promoted PSC activation. Condition medium from ESE3-overexprssing PSC promotes PDAC cell migration, chemoresistance, tumor growth and fibrosis. ESE3 directly induced the transcription of α-SMA, Collagen 1 and IL-1β by binding to ESE3 binding sites on their promoters to activate PSC. On the other hand, IL-1β upregulates ESE3 in PSC through NFκB activation and ESE3 is required for PSC activation by tumor cell derived IL-1β. Clinical data showed ESE3 upregulation in PSC was positively correlated with tumor size, pTNM stage, CA19-9, CEA and CA242 level in serum. ESE3 overexpression in PSC was an independent negative prognostic factor for disease-free survival and overall survival among PDAC patients. Inhibition of the IL-1β/ ESE3 (PSC)/ IL-1β positive feedback loop represents a promising therapeutic strategy to reduce tumor fibrosis and increase chemotherapeutic efficacy in PDAC.

Cut-Off Analysis of CTC Change under Systemic Therapy for Defining Early Therapy Response in Metastatic Breast Cancer

Detection of circulating tumor cells (CTC) can distinguish between aggressive and indolent metastatic disease in breast cancer patients and is thus considered an independent, negative prognostic factor. A clear decline in CTCs is observed in patients who respond to systemic therapy. Nevertheless, CTCs can decrease in patients experiencing disease progression during systemic therapy, too. This study aims to determine the differences between CTC decline in patients responding to therapy and those in whom disease is progressing. Therefore, CTC values were compared at the start and after one cycle of a new line of systemic therapy. In all, 108 initially CTC-positive patients (with ≥5 intact CTCs in 7.5 mL blood) were enrolled in this study and intact and apoptotic CTCs were measured via the CellSearch® system. A cut-off analysis was performed using Youden’s J statistics to differentiate between CTC change in the two groups. Here, 64 (59.3%) patients showed stable disease or partial response vs. 44 (40.7%) presenting disease progression. Median overall survival was 23 (range: 4–92) vs. 7 (2–43) months (p < 0.001). Median intact CTC count at enrollment was 15.0 (5–2760) vs. 30.5 (5–200000) cells (p = 0.39) and 2.5 (0–420) vs. 8.5 (0–15000) cells after one cycle of systemic therapy (p = 0.001). Median apoptotic CTC count at enrollment was 10.5 (0–1500) vs. 9 (0–800) cells (p = 0.475) and 1 (0–200) vs. 3 (0–250) cells after one cycle of systemic therapy (p = 0.01). A 50% reduction in baseline apoptotic CTC count represents the optimal cut-off to differentiate between therapy response and disease progression. An apoptotic CTC reduction of ≤10% is 74% specific for early disease progression.

Circulating Tumor Cells Counting Act as a Potential Prognostic Factor in Cervical Cancer

Background: Circulating tumor cells (CTCs) hold huge potential for both clinical applications and basic research into the management of cancer, but the relationship between CTC count and cervical cancer prognosis remains unclear. Therefore, research on this topic is urgently required. Objective: This study investigated whether CTCs were detectable in patients with cervical cancer and whether CTC count was an indicator of prognosis. Methods: We enrolled 107 patients with pathologically confirmed cervical cancer. CTCs were detected after radiotherapy or concurrent cisplatin-containing chemotherapy in all patients. We evaluated all medical records and imaging data as well as follow-up information to calculate progression-free survival (PFS). PFS was defined as the time until first diagnosis of tumor progression or death. We also analyzed the relationship between CTC count and patient age, disease stage, histological differentiation, tumor size, and pathological type. Results: CTCs were identified in 86 of 107 patients (80%), and the CTC count ranged from 0 to 27 cells in 3.2 mL blood. The median progression-free survival (PFS) was 43.1 months. Patients in which CTCs were detected had a significantly shorter PFS than CTC-negative patients (P = 0.018). Multivariate analysis indicated that CTC count was an independent negative prognostic factor for survival. However, no correlation was observed between CTC count and patient age, disease stage, histological differentiation, tumor size, and pathological type. Conclusion: CTC count is an independent negative prognostic factor for cervical cancer.

Expression Analysis of Autophagy Related Markers LC3B, p62 and HMGB1 Indicate an Autophagy-Independent Negative Prognostic Impact of High p62 Expression in Pulmonary Squamous Cell Carcinomas

Autophagy is involved in maintaining cellular homeostasis under stress conditions. It also plays an important role in various diseases including cancer. Pulmonary squamous cell carcinomas (pSQCC) at present lack targetable molecular alterations, and demand alternative therapeutic options. We assessed the expression levels of autophagy related proteins LC3B, p62, and HMGB1 in 271 primary resected pSQCC by immunohistochemistry, in correlation with clinical and pathological parameters, as a rationale for a potential autophagy directed therapy. LC3B, p62, and HMGB1 staining showed various patterns. LC3Bhighp62low levels, suggested to indicate intact activated autophagy, were associated with prolonged disease specific survival (DSS) and LC3Bhighp62high levels, indicating activated but late stage impaired autophagy, with shorter DSS (p = 0.024). p62high expression regardless of LC3B, however, showed an even stronger association with shorter DSS (p = 0.015) and was also an independent negative prognostic factor in multivariate analysis (HR = 2.99; 95% CI 1.38–6.52; p = 0.006). HMGB1 expression correlated neither with the expression of LC3B and p62, nor with patients’ outcome. Different states of autophagy characterized by distinct p62 and LC3B expression patterns may be linked to patient’s prognosis in pSQCC. Our results, however, point also to an autophagy independent role of p62 with an even more pronounced prognostic impact compared to autophagy related p62.

Plasma biomarker analysis of ramucirumab in Japanese patients with advanced gastric cancer.

81 Background: Ramucirumab, anti-VEGFR2 receptor antibody, showed significantly improved survivals of gastric cancer in the second line with paclitaxel or single use. Recently we reported early elevation of plasma VEGF-A was associated with shorter survival as a preliminary result. We will report the results of final analysis. Methods: Patients with advanced gastric cancer who received ramucirumab combined with paclitaxel or single use were enrolled. Plasma samples were collected at pre-treatment and day 8 after administration. Nine kinds of plasma biomarker involved in angiogenesis, VEGF-A, C, D, PlGF, VEGFR1, 2, Angiopoietin 1, stromal cell derived factor-1α (SDF1α), and Neuropirin-1, were measured by means of ELISA. Patients were dichotomized by optimal cut-off value. Univariate and multivariate analysis were done by Cox proportion hazard model. Results: Forty-one patients were enrolled. Thirty-nine patients (95.1%) received ramucirumab with paclitaxel. Plasma VEGF-A, D, PlGF, and VEGFR2 levels were significantly increased one week after administration compared with baseline levels, while plasma VEGFR1 and NRP1levels were significantly decreased. Median PFS and OS were 5.6 (95% CI 4.66-6.54) and 9.8 (95% CI 5.41-14.19) months, respectively. In univariate analysis, higher baseline SDF1α and PlGF levels resulted in shorter OS with HR 2.71 95% CI 1.23-6.00, p =0.013 for SDF1α and HR 2.78 95% CI 1.16-6.65, p =0.022 for PlGF. Higher D8 VEGF-A was associated with shorter PFS with HR 2.77 95% CI 1.39-5.51, p =0.004. While higher D8 VEGF-D was associated with better PFS with HR 0.39 95% CI 0.20-0.77, p =0.007. In multivariate analysis, higher baseline SDF1α and PlGF were independent negative prognostic factor for OS with HR 2.45 95% CI 1.10-5.42, p =0.028 for SDF1α and HR 2.48 95% CI 1.03-5.96, p =0.043. With respect to PFS, higher D8 VEGF-A was also independent negative prognostic factor with HR 2.32 95% CI 1.13-4.77, p =0.022, while higher D8 VEGF-D was favorable predictor for PFS with HR 0.47 95% CI 0.23-0.96, p =0.038. Conclusions: Higher base line SDF1α and PlGF levels may be negative prognostic marker. While early VEGF-A and D elevation after ramucirumab administration may be predictive marker of ramucirumab.