Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma.

PURPOSE: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha). PATIENTS AND METHODS: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. RESULTS: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. CONCLUSION: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.     

In vivo percutaneous absorption of arsenic from water and CCA-treated wood residue.

This study was conducted to evaluate the dermal absorption of arsenic from residues present on the surface of wood preserved with chromated copper arsenate (CCA). The research reported herein used methods parallel to those of earlier research on the dermal absorption of radiolabeled arsenic (R. C. Wester et al., 1993, Fund. Appl. Toxicol. 20, 336-340), with modifications to allow use of environmental matrices that are not radiolabeled. These modifications include the surface area of application and dietary intake of arsenic, thus maximizing the potential for detection of dermally absorbed arsenic in exposed animals above diet-associated background levels of exposure. Two forms of arsenic were administered in this work. The first, arsenic in solution, was applied to the skin of monkeys to calibrate the model against prior absorption research and to serve as the basis of comparison for absorption of arsenic from CCA-treated wood residues. The second substrate was residue that resides on the surface of CCA-treated wood. Results from this research indicate that this study methodology can be used to evaluate dermally absorbed arsenic without the use of a radiolabel. Urinary excretion of arsenic above background levels can be measured following application of soluble arsenic, and absorption rates (0.6-4.4% absorption) are consistent with prior research using the more sensitive, radiolabeled technique. Additionally, the results show that arsenic is poorly absorbed from CCA-treated wood residues (i.e., does not result in urinary arsenic excretion above background levels).     

Health related quality of life and cognitive status in patients with glioblastoma multiforme receiving escalating doses of conformal three dimensional radiation on RTOG 98-03

The Radiation Therapy Oncology Group (RTOG) embarked on a phase I/II study of patients suffering from glioblastoma multiforme (protocol 98-03) to assess the impact of dose escalation with 3-D conformal techniques. The primary endpoints were feasibility and survival. This report describes the outcome of secondary endpoints (quality of life and neurocognitive function). Patients with supratentorial GBM were treated with a combination of carmustine (BCNU) and conformal irradiation (dose levels: 66, 72, 78, 84 Gy, respectively). Quality of Life was assessed with the Spitzer Quality of Life Index. Neurocognitive function was determined by the Mini Mental Status Examination. The latter tests were administered at the start of irradiation, at the end of irradiation and then at 4 month intervals. Relatively high compliance was achieved with both of the tools (SQLI; MMSE). Overall rates of survival between baseline SQLI scores <7 and 7–10 were statistically significantly different [HR = 1.72, 95% CI (1.22, 2.4), P = 0.0015]. The significant impact of high SQLI score on survival was preserved in multivariate analysis. The component of this index which made the greatest contribution was the patient’s independence. There was continual deterioration of neurocognitive function within the populations studied. No correlation was seen between dose escalation and the secondary endpoints studied. Radiation dose escalation and assessment of its impact on life quality and neurocognition can be carried out in a large international trial. Baseline SQLI is a statistically significant determinant of survival. Those who maintain independence have superior survival to those who are reliant on others.     

Modulation of IL-8 and RANTES release in human conjunctival epithelial cells: primary cells and cell line compared and contrasted

PURPOSE: Recent research indicates that epithelial cells of the ocular surface can contribute to the allergic reaction by the release of inflammatory and/or chemotactic mediators. In this study, the role of two inflammatory mediators, previously identified in the tear film of ocular allergy subjects, TNF-alpha and IFN-gamma, were evaluated for their effect on the release of two chemotactic mediators, IL-8 and RANTES, from cultured human conjunctival epithelial cells. METHODS: Human conjunctival epithelial cells (primary cells or HC0597 cell line) were grown to confluence and stimulated with various concentrations of TNF-alpha, IFN-gamma, or a combination of both. Supernatants were collected at 6, 24, and 48 hours and stored frozen for subsequent ELISA analyses of RANTES and IL-8. RESULTS: RANTES and IL-8 release from HC0597 cells was stimulated in a dose- and time-dependent manner following treatment with TNF-alpha. However, only RANTES release was modulated by IFN-gamma treatment. Treatment of HC0597 cells with both TNF-alpha and IFN-gamma resulted in a synergistic increase in the release of RANTES. This synergistic effect was confirmed using primary cultures of human conjunctival epithelial cells. CONCLUSIONS: Stimulation of conjunctival epithelium with proinflammatory mediators, TNF-alpha and/or IFN-gamma, generated the release of the chemotactic factors IL-8 and RANTES, which could act to prolong inflammation. These two chemokines may prolong inflammation by recruiting eosinophils to the ocular surface. This is the first study to compare chemokine release in a cell line and primary cells; similar chemokine release after mediator stimulation was demonstrated, indicating that the two cell types are phenotypically similar.     

HBcrAg Predicts Hepatocellular Carcinoma Development in Chronic B Hepatitis Related Liver Cirrhosis Patients Undergoing Long-Term Effective Anti-Viral

Hepatitis B core-related antigen (HBcrAg) is a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Studies on anti-viral therapy have shown that the use of NUC therapy in HBV patients could reduce the incidence of HCC. However, the incidence of HCC continues to increase after long-term anti-viral therapy. The relationship between HBcrAg and HCC development in CHB-related liver cirrhosis (LC) patients undergoing long-term anti-viral therapy is still unclear. This study enrolled 1108 treatment-naïve CHB patients diagnosed with HBV-related LC receiving NUC therapy from April 1999 to February 2015. The baseline biomarkers, disease history, and following results were collected by the hospital. Among the 1108 patients, 219 developed HCC within a median follow-up period of 6.85 years. A multivariable Cox regression model was used, with adjustment for age, gender, FIB-4, DM, and HBsAg-HQ. The adjusted hazard ratios for the HBcrAg tertile levels were 1.70 (95%CI: 1.21, 2.39) and 2.14 (95%CI: 1.50, 3.05) for levels 3.4–4.9 and >4.9 logU/mL, respectively, compared with levels ≤3.4. The effect of the HBcrAg level on HCC incidence was found to be significantly modified by HBsAg-HQ, where lower HBsAg-HQ (≤ 3) values were associated with a significantly higher risk, but HBsAg-HQ levels >3 were not. Our results highlight that, after adjustment for potential confounding factors, patients with CHB-related LC and higher HBcrAg levels are at significant risk for HCC development, even while undergoing long-term effective anti-viral therapy. The HBcrAg level is therefore an independent risk factor for HCC development, especially for patients with HBsAg-HQ levels <3.