End Of First Cycle Research Articles

Effects of celecoxib on vascular endothelial growth factor (VEGF) gene expression in squamous cell carcinoma of head and neck (SCCHN) patients receiving 5-fluorouracil and cisplatin

5603 Background: Induction of cyclooxygenase-2 (COX-2) gene expression in SCCHN cells results in an increase in VEGF expression. Several phase II studies using celecoxib, a selective COX-2 inhibitor, in combination with chemotherapy have shown to increase chemotherapy efficacy in patients with non-small cell lung and colorectal cancers. The purpose of this pilot study is to examine VEGF gene expression in SCCHN patients receiving celecoxib and chemotherapy with an intention to develop a novel therapeutic regimen. Methods: This is an open-label one-arm phase II study with ongoing accrual. Recurrent or metastatic SCCHN patients who meet the eligibility criteria are given celecoxib 400mg po bid starting 3 days before first course of chemotherapy and continuing through out study period. Chemotherapy is repeated every 28 days with cisplatin 100 mg/m2 IV infusion 2 hours on day 1, then 5-fluorouracil 1000 mg/m2 IV infusion 24 hours daily for 5 days. Evaluation of treatment response is conducted after 3 cycles of chemotherapy. Twenty ml blood sample and 24-hour urine are collected on 4 days prior to 1st cycle of chemotherapy (before taking celecoxib), day 1 and day 5 of each chemotherapy cycle, and are subject to VEGF and PGE2 measurement by enzyme immunoassay kits from Amersham. Additionally, peripheral blood mononuclear cells are used for VEGF RT-PCR. Results: We have analyzed the first 3 patients’ blood samples for VEGF gene expression. One patient’s VEGF gene expression remained unchanged during the first and second cycles of treatment. Two patients’ VEGF gene expression increased 1.5- to 2-fold by the end of first cycle, and increased to four-fold by the end of 2nd cycle. All three patients were found to have progression of disease. Analysis of serum prostaglandin E2 is ongoing. Further results will be presented. Conclusions: Celecoxib can not effectively suppress induction of VEGF gene expression in SCCHN patients receiving chemotherapy with cisplatin and 5-fluorouracil, and may not enhance chemotherapy efficacy in this setting. Future study using celecoxib and VEGF inhibitor in combination with chemotherapy in SCCHN is planned. No significant financial relationships to disclose.

Short- and long-term effects of a dietary yeast β-glucan (Macrogard) and alginic acid (Ergosan) preparation on immune response in sea bass ( Dicentrarchus labrax)

The present study investigated the immunomodulatory activity of Ergosan, an algal extract containing alginic acid, and Macrogard, a yeast extract containing β-glucans, on innate and specific immunity in sea bass ( Dicentrarchus labrax). Four cycles of experimental feeding using normal fish feed formulation (control group) supplemented with Ergosan (0.5%) or Macrogard (0.1%) were performed at 60-day intervals (15 days of treatment + 45 days of suspension). Serum complement, lysozyme, total proteins and heat shock protein (HSP) concentrations were measured at 15, 30 and 45 days from the end of the first 15-day feeding cycle (short term) and 45 days after the end of each feeding cycle over a 35-week period (long term). The percentage of B- and T-lymphocytes in peripheral blood leucocytes and gut were measured over long-term trial. Significant elevation ( P < 0.05) in serum complement activity occurred in sea bass fed with alginic acid and glucans, at 15 days from the end of first cycle of treatment. Significant elevation ( P < 0.05) in serum lysozyme, gill and liver HSP concentration were observed in the same experimental groups at 30 days from the end of treatment, whereas a significant increase ( P < 0.05) of complement activity was only observed in fish that received an Ergosan diet. At 45 days from the end of treatment, complement, lysozyme and HSP concentration did not differ among groups. Over the long-term period, no significant differences were observed in innate and specific immune parameters, survival, growth performances and conversion index in treated and control fish. A dramatic decrease of both innate and acquired immune parameters was observed during the winter season in all groups, followed by a partial recovery when water temperature increased. Reduction in complement and lysozyme activities was significatively correlated ( p < 0.01) to water temperature variation. The results suggested the potential of alginic acid and β-glucans to activate some innate immune responses in sea bass, and particularly under conditions of immunodepression related to environmental stress.

Viral and host factors in determining response of relapsers with chronic hepatitis C to retreatment with interferon.

In chronic hepatitis C the rate of relapse after an end-of-treatment response to interferon may exceed 50%. The usefulness of retreatment of relapsers with interferon in obtaining a complete sustained response and the role of clinical, virological and immunological features in determining long-term efficacy of retreatment are unclear. We aimed to assess the efficacy of interferon retreatment in obtaining a complete sustained response, to evaluate whether increasing the dose may enhance responsiveness, and to identify possible predictors of sustained response. We enrolled 42 patients with biopsy-proven chronic hepatitis C without cirrhosis who had previously responded to a six-month course of Interferon-alpha2b (total dose: group A, 22 patients, 234 MU; group B, 20 patients, 468 MU) and then relapsed. All, except one, were HCV-RNA negative at the end of first cycle of interferon; most (31/42, 74%) were infected by HCV 1b. Subjects were randomly allocated to receive another cycle of interferon either at the original dose (group A1: 234 MU, 11 patients; group B1 468 MU, 10 patient) or twice the original dose (group A2: 468 MU, 11 patients; group B2: 936 MU, 10 patients). At the end of the second cycle of interferon, 24 subjects (57%) had normal ALT and were HCV-RNA negative, and 16 (39%) had normal ALT, but were HCV-RNA positive. A complete sustained response was obtained in eight patients (19%), at a similar rate in all treatment groups. Complete sustained responders were different from the other patients in terms of age (35.9 +/- 10.4 vs 44.1 +/- 8.8, P = 0.027), rate of infection with non-1b HCV (6/8 vs 5/34, P = 0.0005), serum HCV-RNA (74,016 vs 321,428 median copies/ml, P = 0.037) and serum levels of 90K/MAC-2 BP (5.76 +/- 3.01 vs 10.25 +/- 5.16 units/ml, P = 0.02), an N-glycoprotein implicated in cellular defense functions. Multivariate logistic analysis validated age and HCV genotype as independent predictors of CSR. Among noncirrhotic relapsers who received a total interferon dose > or = 234 MU in the first cycle, retreatment usually induced end-of-treatment response. A complete sustained response was obtained in only one of every five subjects. Increasing the dose of interferon above that of the first cycle did not enhance the rate of sustained response. In conclusion we might assert that young subjects infected by non-1b HCV and with low levels of HCV-RNA and of 90K/MAC-2 BP are the best candidates for retreatment.

Degradation model for one-way cyclic lateral load on piles in soft clay

Abstract The analysis of laterally loaded piles in soft clay is carried out idealising the pile as beam elements and the soil by nonlinear inelastic spring elements modeled with elasto-plastic sub-elements. The nonlinear hyperbolic model for static load condition is developed based on the undrained shear strength and modulus of subgrade reaction. An iterative procedure is adopted to perform a nonlinear finite element analysis and the effect of static lateral load on deflection is studied. Based on the lateral deflection at the end of first cycle (static load), the degradation factor is assumed and the p-y curve is modified. The cyclic load analysis is carried out using the static analysis program idealising the soil by modified p-y curve, which considers the effect of number of cycles and magnitude of cyclic lateral load. The results of the proposed analytical model compare well with the published experimental results, on piles subjected to one-way cyclic loading for different magnitude of cyclic lateral load and number of cycles.