Purpose: Asbestos-induced chronic inflammation is implicated in the pathogenesis of malignant mesothelioma (MM). We have investigated blood neutrophil-to-lymphocyte ratio (NLR), an index of systemic inflammation, as a prognostic factor in MM patients.Experimental Design: Patients with MM who had systemic therapy at participating institutes were studied. Potential prognostic factors such as age, gender, performance status, histologic subtype, and baseline laboratory parameters, including NLR, were analyzed. Overall survival from commencement of therapy was determined by the Kaplan-Meier method. Multivariate analyses using Cox Regression model were performed with significant factors (P 0.05) to determine their independent effect.Results: A total of 173 MM patients undergoing systemic therapy including 119 patients receiving firstline therapy and 54 patients receiving second-or third-line therapy were included in this retrospective evaluation. Forty-two percent of patients had an elevated NLR at baseline. The following variables were predictive of survival: female gender (P ¼ 0.044), epithelioid histologic subtype (P < 0.001), baseline white blood cell count less than 8.3 Â 10 9 /L (P ¼ 0.008), baseline platelet count 400 Â 10 9 /L or less (P ¼ 0.05), and NLR of 5 or less (P < 0.001). After multivariate analysis, histologic epithelioid subtype [hazard ratio (HR) ¼ 2.0; 95% confidence interval (CI) ¼ 1.3-2.9; P ¼ 0.001], and NLR less than 5 (HR ¼ 2.7; 95% CI ¼ 1.8-3.9; P < 0.001) remained independent predictors. The 1-year survival rate was 60% versus 26%, whereas the 2-year survival rate was 34% versus 10% for NLR less than 5 and 5 or greater, respectively. In the separate analyses of chemotherapy-naive and previously treated patient groups, NLR was an independent predictor of survival in both groups.Conclusion: Our results indicate that NLR is an independent predictor of survival for patients with MM undergoing systemic therapy. Clin Cancer Res; 16(23); 5805-13. Ó2010 AACR.

BackgroundDose rate variation is a critical factor affecting radionuclide therapy (RNT) efficacy. Relatively few studies to date have investigated the dose rate effect in RNT. Therefore, the aim of this study was to benchmark 90Y RNT (at different dose rates) against external beam radiotherapy (EBRT) in vitro and compare cell kill responses between the two irradiation processes.ResultsThree human colorectal carcinoma (CRC) cell lines (HT29, HCT116, SW48) were exposed to 90Y doses in the ranges 1–10.4 and 6.2–62.3 Gy with initial dose rates of 0.013–0.13 Gy/hr (low dose rate, LDR) and 0.077–0.77 Gy/hr (high dose rate, HDR), respectively. Results were compared to a 6-MV photon beam doses in the range from 1–9 Gy with constant dose rate of 277 Gy/hr. The cell survival parameters from the linear quadratic (LQ) model were determined. Additionally, Monte Carlo simulations were performed to calculate the average dose, dose rate and the number of hits in the cell nucleus.For the HT29 cell line, which was the most radioresistant, the α/β ratio was found to be ≈ 31 for HDR–90Y and ≈ 3.5 for EBRT. LDR–90Y resulting in insignificant cell death compared to HDR–90Y and EBRT. Simulation results also showed for LDR–90Y, for doses ≲ 3 Gy, the average number of hits per cell nucleus is ≲ 2 indicating insufficiently delivered lethal dose. For 90Y doses  3 Gy the number of hits per nucleus decreases rapidly and falls below ≈ 2 after ≈ 5 days of incubation time. Therefore, our results demonstrate that LDR–90Y is radiobiologically less effective than EBRT. However, HDR–90Y at ≈ 56 Gy was found to be radiobiologically as effective as acute ≈ 8 Gy EBRT.ConclusionThese results demonstrate that the efficacy of RNT is dependent on the initial dose rate at which radiation is delivered. Therefore, for a relatively long half-life radionuclide such as 90Y, a higher initial activity is required to achieve an outcome as effective as EBRT.

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