Diffuse large B-cell lymphoma in the young in Japan: a study by the Osaka Lymphoma Study Group.

Clinicopathological and immunophenotypical characteristics in 24 patients with diffuse large B-cell lymphoma (DLBCL) under 30 years of age in Osaka, Japan were examined, and the results compared to those of DLBCL patients aged over 40 years in Osaka and of young DLBCL patients in Western countries. The level of LDH and IPI score at initial diagnosis were significantly lower in young than older patients. The sex ratio (M:F) and age range (median) in the young and older groups were 1.18 and 11-30 (24.8) years and 1.59 and 42-87 (62.4) years, respectively. Extranodal presentation was higher in the young group (83.3% versus 60.0%, P < 0.05). Based on immunophenotyping with anti-CD10, bcl-6, and MUM1 antibodies, the cases were categorized as germinal center B-cell (GCB) (CD10+ or CD10-, bcl-6+, MUM1+) or non-GCB phenotype. The frequency of GCB type was significantly lower in the young group than older group (25% vs. 54%, P < 0.05), and much lower than that reported for young patients in Western countries. In situ hybridization revealed one of the young patients to be positive for Epstein-Barr virus (EBV). In the older group, none of 31 cases showed EBV positivity. Three year event-free and overall survival rates of young patients were better than those of the older patients, although not significantly different. DLBCL in the young in Japan is characterized by a much lower frequency of the GCB phenotype compared to that in Western countries.

A phase II study of VEPA/FEPP chemotherapy for aggressive lymphoma in elderly patients: Japan Clinical Oncology Group Study JCOG9203.

The Lymphoma Study Group (LSG) of the Japan Clinical Oncology Group conducted a phase II trial of LSG12 therapy for 45 elderly patients with aggressive lymphoma to clarify whether LSG12 reduces severe infection without lowering the complete response (CR) rate in comparison with LSG4. LSG12, which consisted of a regimen of vincristine, cyclophosphamide, prednisolone, doxorubicin, vindesine, etoposide, and procarbazine (VEPA/FEPP), excluded bleomycin and methotrexate of LSG4 therapy, reduced the dosages of doxorubicin and cyclophosphamide, and increased etoposide and procarbazine dosages instead. Inclusion criteria consisted of a patient age of 70 to 75 years, a World Health Organization performance status of 0 to 2, and acceptable organ function. The treatment was completed in 47% of the patients and terminated early for disease progression in 20% and for toxicity in 16%. The CR rate was 60% (95% confidence interval [CI], 44%-74%). The 5-year overall survival (OS) rate was 42% (95% CI, 27%-57%), and the median OS time was 4.3 years. Leukopenia of grade 3 to 4 occurred in 98% of the patients, and severe infection occurred in 9%. Eight patients with hepatitis C virus (HCV) antibody showed no severe hepatic toxicity and had a better CR or OS rate than the 37 HCV-negative patients. Although the outcomes of LSG12 met our expectations with a reduction in severe infection and equivalent CR and OS outcomes compared with LSG4 and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), the possibility of a regimen more beneficial than LSG12 for aggressive lymphoma in the elderly patient should be explored because of frequent hematologic toxicity and poor compliance in LSG12.

Massive telomere loss and telomerase RNA expression in dexamethasone-induced apoptosis in mouse thymocytes.

Apoptosis is a well-recognized process of cell death occurring under several physiological and pathological conditions and represents the principal mechanism involved in cell selection in the thymus. Glucocorticoids are well known to stimulate apoptosis in rat thymocytes. However, it is unclear whether the same changes occur after in vivo glucocorticoid treatment in mice. Chromosomal stability and cell viability require a proficient telomeric end-capping function. Cells with critical telomere shortening and telomerase dysfunction undergo increased apoptosis. In turn, the change in telomere function in cells undergoing apoptosis is not fully characterized. In order to investigate this, we studied the changes in thymocytes after dexamethasone administration in BALB/c mice. The loss of normal thymocytes coincided with the appearance of small dense cells with characteristic features of apoptosis including condensed chromatin, internucleosomal DNA cleavage, and a "hypodiploid" peak on flow cytometry, which suggested that dexamethasone-induced thymocyte apoptosis in BALB/c mice could be considered a well-defined experimental model for studying apoptotic processes. Dexamethasone-treated thymocytes exhibited rapid and dynamic loss of telomeric sequences and up-regulation of telomerase RNA as an early event in the apoptotic process. Telomerase activity was unchanged in this event. Thereafter, telomere gain associated with an increase in telomerase activity occurred in the regenerative process of the thymus. These results suggest a role of telomere loss and up-regulation of telomerase RNA as key apoptosis sensors.