Neoadjuvant radiochemotherapy for locally advanced gastric cancer: a phase I-II study

Background: To study in a phase I-II trial the maximum tolerated dose, the toxicity, and the tolerance of adding radiotherapy to systemic chemotherapy administered preoperatively in patients with locoregionally advanced gastric adenocarcinoma. Patients and methods: Patients with adenocarcinoma of the stomach (T3-4Nany or TanyN+), performance status ≤1, normal hematological, hepatic and renal functions received two cycles of cisplatin 100 mg/m2 on day 1, 5-FU 800 mg/m2 on days 1 to 4 and leucovorin 60 mg b.i.d. on days 1 to 4 q3w, concomitantly with radiation therapy escalated in three dose tiers (31.2, 38.4 and 45.6 Gy). Results: Nineteen patients were accrued and 18 completed neoadjuvant therapy. Major toxicity consisted of grade 3/4 leucopenia and mucositis in 89% and 36% of the patients, respectively. Only one episode of febrile neutropenia was recorded. Dose level number 2 (38.4 Gy) with the chemotherapy given q4w is the recommended dose level. All patients were subsequently operated and no fatalities occurred. Pathological assessment showed one complete and eight partial responses. Two- and 3-year relapse-free survival rates were 57% and 50%, respectively. Only one patient relapsed locally. The peritoneum was the most frequent site of relapse. Conclusions: This neoadjuvant therapeutic program is relatively well tolerated, does not seem to increase the operative risk, and might increase the locoregional control of the disease. The frequency of peritoneal involvement in relapsing patients underscores the need for a more effective systemic treatmen

Cyclin D1, cyclin E, and p21 have no apparent prognostic value in anal carcinomas treated by radiotherapy with or without chemotherapy

The purpose of this study was to assess the potential prognostic and/or predictive value of the expression of cyclin D1, cyclin E, and p21 protein in a series of 98 anal carcinomas (T1-4, N0-3) treated by radiotherapy with (51) or without (47) chemotherapy in one institution. Correlation with Mib1 index and p53 expression was also investigated. Median follow-up for surviving patients was 124 months (range: 30-266). Immunohistochemical staining was performed on pretreatment biopsies, applying a standard ABC technique for cyclin D1 (clone DSC6, DAKO, 1 : 300), cyclin E (clone 13A3, Novocastra, 1 : 100), p21(WAF/CIP1) (clone SX118, DAKO, 1 : 50), p53 (clone DO7, DAKO, 1 : 200), and Mib1 (Ki-67, Dianova, 1 : 20). Tumours were classified into low- or high-expression groups according to the expression level of the protein considered. High expression was found in 51% of tumours for cyclin E, in 33.7% for cyclin D1, and in 65% for p21. None of those factors were significantly associated with clinical variables such as advanced T or N categories. In a monovariate analysis, advanced T and N categories and longer overall treatment time were the only variables that correlated significantly with low rate of local control (LC) and disease-free survival. However, in a subgroup analysis, high p21 expression correlated with a trend for significantly higher 5-year LC (87 vs 68%, P=0.07) in the N0 patients. The results of this study suggest that the cell-cycle proteins investigated are unlikely to be clinically useful in predicting treatment response or prognosis in patients with anal carcinomas

Immunity to viruses in B cell-deficient mice: influence of antibodies on virus persistence and on T cell memory.

Mice rendered B cell deficient by targeted disruption of the immunoglobulin mu chain gene (IgM-/- mice) were used to analyze the role of antibodies and B cells in viral infections; homozygous IgM-/- mice were bred in a way to avoid transmission of maternal antibodies. After infection with vesicular stomatitis virus (VSV), IgM-/- mice developed paralytic disease and subsequently died, whereas C57BL/6 control mice or IgM-/- mice passively protected with VSV-neutralizing antibodies survived. Furthermore, IgM-/- mice showed increased natural killer (NK) activity upon exposure to either lymphocytic choriomeningitis virus (LCMV) or to poly(I).poly(C), while NK activity in untreated IgM-/- mice was within normal ranges. Cytotoxic T cell responses were comparable in IgM-/- and control mice infected either with VSV or with vaccinia virus or with low doses of LCMV (10(2) infectious focus-forming units [ifu]). After intracerebral infection with LCMV-Armstrong, CD8+ T cell-mediated lethal lymphocytic choriomeningitis developed independently of the presence of B cells and antibodies. After infection with high doses (2 x 10(6) - 5 x 10(6) ifu) of LCMV-WE or LCMV-Docile, IgM-/- mice exhibited a reduced capacity to control these primary infections and had elevated virus titers for prolonged times (> 60 days). Nevertheless, the cytotoxic T cell response against LCMV in the early phase of infection was comparable in IgM-/- and control mice, but disappeared in those IgM-/- mice which had a persistent viral infection. Cytotoxic T cell memory was apparently unimpaired in low-dose-primed IgM-/- mice, which were able to control the primary virus infection; both IgM-/- and control mice cleared a high intravenous dose of virus within 2 days after challenge infection. This indicates that an efficient T cell memory against LCMV was established in the absence of B cells

CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production

B cells are essential for antiviral immune defence because they produce neutralizing antibodies, present antigen and maintain the lymphoid architecture. Here we show that intrinsic signalling of CEACAM1 is essential for generating efficient B-cell responses. Although CEACAM1 exerts limited influence on the proliferation of B cells, expression of CEACAM1 induces survival of proliferating B cells via the BTK/Syk/NF-kappaB-axis. The absence of this signalling cascade in naive Ceacam1(-/-) mice limits the survival of B cells. During systemic infection with cytopathic vesicular stomatitis virus, Ceacam1(-/-) mice can barely induce neutralizing antibody responses and die early after infection. We find, therefore, that CEACAM1 is a crucial regulator of B-cell survival, influencing B-cell numbers and protective antiviral antibody responses