Poorer outcome of elderly patients treated with extended-field radiotherapy compared with involved-field radiotherapy after chemotherapy for Hodgkin's lymphoma: an analysis from the German Hodgkin Study Group

Background: The optimal treatment of elderly patients with Hodgkin's lymphoma (HL) is still a matter of debate. Since many of these patients receive combined modality treatment, we evaluated the impact of different radiation field sizes, that is extended-field (EF) or involved-field (IF) technique when given after four cycles of chemotherapy. Patients and methods: In the multicenter HD8 study of the German Hodgkin Study Group, 1204 patients with early-stage unfavorable HL were randomized to receive four cycles of chemotherapy followed by either radiotherapy (RT) of 30 Gy EF + 10 Gy to bulky disease (arm A) or 30 Gy IF + 10 Gy to bulky disease (arm B). A total of 1064 patients were assessable for the analysis. Of these, 89 patients (8.4%) were 60 years or older. Results: Elderly patients had a poorer risk profile. Acute toxicity from RT was more pronounced in elderly patients receiving EF-RT compared with IF-RT [World Health Organization (WHO) grade 3/4: 26.5% versus 8.6%)]. Freedom from treatment failure (FFTF, 64% versus 87%) and overall survival (OS, 70% versus 94%) after 5 years was lower in elderly patients compared with younger patients. Importantly, elderly patients had poorer outcome when treated with EF-RT compared with IF-RT in terms of FFTF (58% versus 70%; P = 0.034) and OS (59% versus 81%; P = 0.008). Conclusion: Elderly patients with early-stage unfavorable HL generally have a poorer risk profile and outcome when compared with younger patients. Treatment with EF-RT instead of IF-RT after chemotherapy has a negative impact on survival of elderly patients and should be avoide

An early history of T cell-mediated cytotoxicity.

After 60 years of intense fundamental research into T cell-mediated cytotoxicity, we have gained a detailed knowledge of the cells involved, specific recognition mechanisms and post-recognition perforin-granzyme-based and FAS-based molecular mechanisms. What could not be anticipated at the outset was how discovery of the mechanisms regulating the activation and function of cytotoxic T cells would lead to new developments in cancer immunotherapy. Given the profound recent interest in therapeutic manipulation of cytotoxic T cell responses, it is an opportune time to look back on the early history of the field. This Timeline describes how the early findings occurred and eventually led to current therapeutic applications

Functional and biochemical characterization of a calcium-ionophore-induced state of unresponsiveness in a cytolytic T cell clone

To characterize the requirements for the induction of an anergic state in immunocompetent cells we examined the effect of an increase in intracellular calcium concentration on the subsequent responsiveness of cytolytic T cells to antigenic stimulation in vitro. Pretreatment of a murine cytolytic T cell clone with the calcium-ionophore A23187 resulted in the induction of an anergic state characterized by a decrease in cytolytic activity and granule exocytosis upon Ag-specific stimulation. Furthermore, IFN-gamma synthesis declined whereas de novo synthesis of a yet unidentified protein with a molecular mass of 33 kDa as well as proliferative response of cells in response to exogenous IL-2 were unaffected. This state of partial unresponsiveness 1) could be prevented by concomitant pretreatment of cells with cyclosporin A or protein synthesis inhibitors and 2) was reversible within 48 h. Biochemical analysis of TCR-induced intracellular activation revealed a block in signal transduction before the activation of protein kinase C because cellular unresponsiveness could be bypassed by the phorbol ester PMA plus the calcium-ionophore A23187. However, phosphatidylinositol turnover was markedly inhibited in unresponsive cells that also did not show a calcium influx on stimulation with concanavalin A. We conclude that a rise in intracellular calcium in cytolytic T cells might not only be necessary for cellular activation but may also trigger the induction of a partial unresponsiveness to antigenic stimulation due to an inhibition in the early phase of signal transductio

Dissociation between phytohaemagglutinin-stimulated generation of inositol phosphates and Ca2+ increase in human mononuclear leucocytes.

We have tested whether phytohaemagglutinin (PHA)-stimulated generation of inositol phosphates (IP) and increases in intracellular Ca2+ can be dissociated in human mononuclear leucocytes. Lowering the incubation temperature from 37 degrees to 25 degrees C decreased PHA-stimulated IP generation by more than 80%, but only marginally affected PHA-stimulated Ca2+ increases. In the absence of extracellular Ca2+, PHA did not stimulate IP generation or Ca2+ increases, although PHA binding to its acceptor sites was not impaired. Increasing extracellular Ca2+ up to 0.15 mM enhanced PHA-stimulated PHA generation but this increase was attenuated by further increasing extracellular Ca2+ to 2.6 mM. Increasing extracellular Ca2+ to 0.3 mM also enhanced PHA-stimulated Ca2+ increases, and further increasing extracellular Ca2+ did not affect it. Co-treatment with 100 microM-prostaglandin E2 completely abolished PHA-stimulated IP generation, but inhibited Ca2+ increases by only 20-30%. These results could be explained by IP-generation-independent Ca2+ increases or by non-linear coupling of IP generation to Ca2+ increases. Since the PHA concentrations required to increase Ca2+ were greater than those required for IP generation, the latter hypothesis can be excluded. Furthermore, the Ca2+ ionophore ionomycin increased intracellular Ca2+ and weakly stimulated IP generation, but with very similar concentration-response relationships. Our data suggest that PHA-stimulated IP generation and Ca2+ increases in human mononuclear leucocytes mainly occur independently of one another rather than sequentially