Prognostic and predictive value of circulating tumor cells and CXCR4 expression as biomarkers for a CXCR4 peptide antagonist in combination with carboplatin-etoposide in small cell lung cancer: exploratory analysis of a phase II study.

Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4+ tumor, ≥7% CTCs with CXCR4 expression (CXCR4+ CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4+ tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS

Rapid helium isotopic variability in Mauna Kea shield lavas from the Hawaiian Scientific Drilling Project

Author Posting. © American Geophysical Union, 2004. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 5 (2004): Q04G14, doi:10.1029/2002GC000439.This paper presents new magmatic helium isotopic compositions in a suite of lavas from phase II of the Hawaiian Scientific Drilling Project (HSDP2) core, which sampled Mauna Kea volcano to a maximum depth of 3098 m below sea level. Most of the measurements were performed by in vacuo crushing of olivine phenocrysts, but include submarine pillow glasses from the 2200 to 2500 meter depth interval, and orthopyroxene phenocrysts from an intrusive at 1880 m. The magmatic 3He/4He ratios range from 6 to 24.7 times atmospheric (Ra), which significantly extends the range of values for Mauna Kea volcano. The 3He/4He ratios are lowest (i.e., close to MORB values of ∼8 Ra) near the top of the Mauna Kea section and rise slowly, to 10–12 Ra, at 1000 m below sea level, consistent with results from the HSDP1 core. At depths greater than 1000 m in the core, primarily in the submarine lavas, there are brief periods when the 3He/4He ratios are higher than 14.5 Ra, always returning to a baseline value. Twelve such excursions were identified in the core; all but one are in the submarine section, and most (7) are in the deepest section, at depths of 1950 to 3070 m. The baseline 3He/4He value rises from 10–12 Ra near 1000 m depth to 12–14 Ra at 3000 m. The helium spikes are found only in lavas that are older than 380 Ka in age, based on an age model derived from Ar-Ar data (W. D. Sharp et al., manuscript in preparation, 2003). Excluding the excursions defined by single lava flows (3) and intrusive units (3), the average spike duration is approximately 15 (±9) Ka (n = 6). The high 3He/4He spikes are interpreted as pulses of magma from the center of the actively upwelling Hawaiian hot spot. The short duration of the high 3He/4He excursions suggests that Mauna Kea was never directly over high the 3He/4He component of the plume (during the HSDP2 eruptive period), presumed to be the plume center. Assuming that the Mauna Kea helium spikes result from melting of heterogeneities within the plume, their short duration implies that the length scales of heterogeneities in the solid upwelling mantle are between 60 m and 12 km (for upwelling rates of 2 to 40 cm/yr). The high 3He/4He are associated with high 208Pb/204Pb, and relatively low 143Nd/144Nd, Zr/Nb, and SiO2. The correlations with major elements, trace elements and isotopes demonstrate that helium is coupled to the other geochemical variations, and that the Mauna Kea isotopic variability is caused by heterogeneities within the upwelling plume.This work was supported by EAR/NSF through the Continental Dynamics and Instrumentation and Facilities programs