Immunomodulatory Effects of Perioperative Dexmedetomidine in Ovarian Cancer: An In Vitro and Xenograft Mouse Model Study.

BACKGROUND: The surgical stress response (SSR) causes immunosuppression which may cause residual tumor growth and micrometastasis after cancer surgery. We investigated whether dexmedetomidine affects cancer cell behavior and immune function in an ovarian cancer xenograft mouse model. METHODS: The effect of dexmedetomidine on cell viability and cell cycle was assessed using SK-OV-3 cells at drug concentrations of 0.5, 0.1, 5, and 10 µg mL-1. BALB/c nude mice were used for the ovarian cancer model with the Dexmedetomidine group (n=6) undergoing surgery with dexmedetomidine infusion and the Control group (n=6) with saline infusion for 4 weeks. Natural killer (NK) cell activity, serum proinflammatory cytokines, and cortisol were measured at predetermined time points and tumor burden was assessed 4 weeks after surgery. RESULTS: Dexmedetomidine had no effect on cell viability or cell cycle. Following a sharp decrease on postoperative day (POD) 1, NK cell activity recovered faster in the Dexmedetomidine group with significant difference vs. the Control group on POD 3 (P=0.028). In the Dexmedetomidine group, cortisol levels were lower on POD 3 (P=0.004) and TNF-α levels were lower at 4 weeks after surgery (P<0.001) compared to the Control group. The Dexmedetomidine group showed lower tumor burden at 4 weeks vs. the Control group as observed by both tumor weight (P<0.001) and the in vivo imaging system (P=0.03). CONCLUSIONS: Dexmedetomidine infusion may improve ovarian cancer surgery outcome by suppressing the SSR and stress mediator release. Further studies are needed to elucidate the mechanisms by which dexmedetomidine acts on cancer and immune cells.

Comparison of Biochemical Recurrence After Robot-assisted Laparoscopic Radical Prostatectomy with Volatile and Total Intravenous Anesthesia.

Aims: Recurrence after cancer surgery is a major concern in patients with cancer. Growing evidence from preclinical studies has revealed that various anesthetics can influence the immune system in different ways. The current study compared the long-term biochemical recurrence of prostate cancer after robot-assisted laparoscopic radical prostatectomy (RALP) in terms of selection of anesthetic agent between total intravenous anesthesia (TIVA) with propofol/remifentanil and volatile anesthetics (VA) with sevoflurane or desflurane/remifentanil. Methods: We followed up oncologic outcomes of patients who underwent RALP from two previous prospective randomized controlled trials, and the outcomes of those who received TIVA (n = 64) were compared with those who received VA (n = 64). The follow-up period lasted from November 2010 to March 2019. Results: Both TIVA and VA groups showed identical biochemical recurrence-free survivals at all-time points after RALP. The following predictive factors of prostate cancer recurrence were determined by Cox regression: colloid input [hazard ratio (HR)=1.002, 95% confidence interval (CI): 1.000-1.003; P = 0.011], initial prostate-specific antigen level (HR=1.025, 95% CI: 1.007-1.044; P = 0.006), and pathological tumor stage 3b (HR=4.217, 95% CI:1.207-14.735; P = 0.024), but not the anesthetic agent. Conclusions: Our findings demonstrate that both TIVA with propofol/remifentanil and VA with sevoflurane or desflurane/remifentanil have comparable effects on oncologic outcomes in patients undergoing RALP.

Body fluid MMP-2 as a putative biomarker in metastatic breast cancer.

In the present study, we investigated the role of matrix metalloproteinase (MMP)-2 and -9 as novel biomarkers in the body fluid of patients with metastatic breast cancer. We measured the expression of MMPs in 37 samples of body fluid (10 peritoneal and 27 pleural fluids) from metastatic breast cancer patients between 2000 and 2009. Zymography and ELISA assays were used to determine the cut-off level and to quantify MMP expression from a positive control, HT-1080 conditioned media. MMP expression in patient samples was measured with ELISA and compared with other clinical parameters. Ascitic carcinoembryonic antigen (CEA) and pleural CEA were measured in patient samples with a chemiluminescent enzyme immunoassay. Body fluid cytology had a positivity of 45% (9/20) for pleural fluid and 28.6% (2/7) for ascites. However, MMP-2 had a positivity of 85.2% (23/27) in 27 pleural fluid samples and 100% (10/10) in ascitic fluid with cut-off levels of 8.6 and 0.14 ng/ml for MMP-2 and -9, respectively. When body fluid CEA and MMP-2 were combined, the positivity improved to 96% in pleural fluid and 100% in ascites. MMP-2 expression in body fluid did not show any significant differences, but MMP-9 expression was lower in ascites than in pleural fluids (p<0.005). Our results suggest that MMP-2 expression in body fluid be used as an additive diagnostic marker for metastatic breast cancer patients.

MMP-2 as a putative biomarker for carcinomatosis in gastric cancer.

BACKGROUND/AIMS: We evaluated matrix metalloproteinase (MMP)-2 and -9 as novel biomarkers in the body fluid of advanced gastric cancer with peritoneal and pulmonary metastasis. METHODOLOGY: MMPs activity from zymography was quantified with ELISA to determine the cut-off expression levels of MMPs. The expression of MMPs in patient samples were evaluated with ELISA and compared with clinical parameters. Ascitic CEA (aCEA) and pleural CEA (pCEA) were measured by chemiluminescent enzyme immunoassay. RESULTS: MMP-2 and -9 cut-off levels were 8.6ng/mL and 0.14ng/mL, respectively. Ascitic fluid cytology of 93 patients revealed a positivity of 55.9% while for MMP-2 it was 93.3%, for MMP-9 35.2% and for aCEA 86.7%. Combining biomarkers, the positivity increased to 99.1% in patients with MMP-2 or aCEA expression. We found a negative correlation between MMP-2 expression and survival when a new prognostic cut-off of 22.6ng/mL was used. Patients with high MMP-2 expression (≥22.6ng/mL) had a median survival of 45 days and those with low MMP-2 expression (<22.6ng/mL) had a median survival of 69 days (p<0.01). CONCLUSIONS: These results suggest that MMPs could be used as diagnostic markers in body fluid and MMP-2 might be a prognostic marker in ascites of advanced gastric patients with disseminated metastasis.

Chemokine growth-regulated oncogene 1 as a putative biomarker for gastric cancer progression.

Gastric cancer (GC) is a heterogeneous disease that is not well detected by current tumor markers. Identifying molecular markers that can predict the potential for tumor progression is important for appropriate individualized therapy. Using the Cancer Metastasis Research Center microarray database (17K cDNA microarray), we identified genes that were differentially expressed between 96 cancer and 98 normal gastric tissues using significant analysis of microarrays. From these, we selected genes that were overexpressed more than twofold in tumor tissues that encode secreted proteins. The selected genes were validated with ELISA using the sera of 96 GC patients and 48 healthy donors. Our first round of selection included 6510 genes that were differentially expressed between 96 cancer and 98 normal gastric tissues with a minimal false discovery rate of 0.005%. Out of those genes, we picked 386 that encoded secreted proteins based on the SOURCE database. Of these genes, we focused on 55 that were overexpressed more than twofold in GC compared to normal tissues. With Ingenuity Pathway Analysis, we found 34 genes related to cancer. One in particular, chemokine growth-regulated oncogene 1, CXCL1, has been linked to cancer progression in various cancer types, but not yet to GC. Levels of CXCL1 in serum samples of GC patients were significantly higher compared with healthy donors (P < 0.05). Within GC patients, CXCL1 serum levels increased according to tumor stage and lymph node metastasis. The CXCL1 gene appears to be a candidate marker for GC progression.