Expression of p21 protein predicts clinical outcome in DLBCL patients older than 60 years treated with R-CHOP but not CHOP: a prospective ECOG and Southwest Oncology Group correlative study on E4494.

PURPOSE: To prospectively investigate the prognostic significance of p21 and p53 expression in diffuse large B-cell lymphoma in the context of the U.S. Intergroup trial comparing conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy to rituximab-CHOP (R-CHOP) induction, with or without maintenance rituximab. EXPERIMENTAL DESIGN: Immunohistochemical staining of 197 paraffin-embedded biopsy specimens was scored by an independent panel of experts. RESULTS: The cyclin-dependent kinase inhibitor, p21, was expressed in 55% of cases examined. In a multivariable analysis adjusting for International Prognostic Index score and BCL2 status, p21 expression was a significant, independent, favorable predictive factor for failure-free survival (relative risk, 0.3; P = 0.001) and overall survival (relative risk, 0.3; P = 0.003) for patients treated with R-CHOP. Expression of p21 was not predictive of outcome for CHOP-treated patients. Only p21-positive cases benefited from the addition of rituximab to CHOP. Among p21-positive patients, treatment with R-CHOP was associated with a higher failure-free survival rate at 5 years compared with CHOP (61% versus 24%; P = 0.01). In contrast, no significant differences were detected in failure-free survival according to treatment arm for p21-negative patients. Expression of p53, alone or in combination with p21, did not predict for outcome in univariable or multivariable analyses. CONCLUSIONS: In this study, p21 protein expression emerged as an important independent predictor of a favorable clinical outcome when rituximab was added to CHOP therapy. These data suggest that rituximab-related effects on lymphoma survival pathways may be functionally linked to p21 activity.

Morphology of retinal ganglion cells in the ferret (Mustela putorius furo).

The ferret is the premiere mammalian model of retinal and visual system development, but the spectrum and properties of its retinal ganglion cells are less well understood than in another member of the Carnivora, the domestic cat. Here, we have extensively surveyed the dendritic architecture of ferret ganglion cells and report that the classification scheme previously developed for cat ganglion cells can be applied with few modifications to the ferret retina. We confirm the presence of alpha and beta cells in ferret retina, which are very similar to those in cat retina. Both cell types exhibited an increase in dendritic field size with distance from the area centralis (eccentricity) and with distance from the visual streak. Both alpha and beta cell populations existed as two subtypes whose dendrites stratified mainly in sublamina a or b of the inner plexiform layer. Six additional morphological types of ganglion cells were identified: four monostratified cell types (delta, epsilon, zeta, and eta) and two bistratified types (theta and iota). These types closely resembled their counterparts in the cat in terms of form, relative field size, and stratification. Our data indicate that, among carnivore species, the retinal ganglion cells resemble one another closely and that the ferret is a useful model for studies of the ontogenetic differentiation of ganglion cell types.

Follicular lymphoma: today's treatments and tomorrow's targets.

Over the past two decades, the incidence of follicular lymphoma has increased. Contemporary treatments include combinations of chemotherapy and monoclonal antibodies, radioimmunotherapy, new targeted agents and stem-cell transplantation. Prognostic tools are becoming more important in helping clinicians and patients decide on the most appropriate therapeutic regimens. Gene expression profiling and biomarkers are promising additions to this armamentarium. When patients do require therapy, the addition of rituximab to chemotherapy seems to improve remission duration and may improve overall survival. Radioimmunotherapy capitalises on the capacity to target radiation directly to malignant cells, and is currently approved for the treatment of relapsed/refractory follicular lymphoma. Further investigation is needed to clarify the role of stem-cell transplantation in follicular lymphoma. Only well-designed clinical trials can provide answers to the many questions that remain regarding the optimal treatment and sequence of treatments for patients with follicular lymphoma.

Current controversies in follicular lymphoma.

Follicular lymphoma (FL) is characterized by its responsiveness to initial therapy, a pattern of repeated relapses, and a tendency for histologic progression to a process resembling diffuse, large B-cell lymphoma. Treatment decisions are complicated by the many effective options now available including combinations of conventional chemotherapy and monoclonal antibody, radioimmunotherapy, new targeted agents, and autologous and allogeneic stem cell transplantation. For selected patients, "watch and wait" or involved field irradiation may still be the most appropriate strategy. When therapy is required, a combination of rituximab and conventional chemotherapy results in improved outcomes compared to chemotherapy alone. Radioimmunotherapy alone or in combination with chemotherapy is an attractive strategy for patients with relapsed disease and may prove to be appropriate first line therapy. The role of stem cell transplant in FL requires further investigation. Novel agents with varied mechanisms of action continue to be developed. Enrollment of patients into clinical trials designed to address the many unanswered questions in FL is essential to improving clinical outcomes.

Hematologic effects of inactivating the Ras processing enzyme Rce1.

Posttranslational processing of Ras proteins has attracted considerable interest as a potential target for anticancer drug discovery. Rce1 encodes an endoprotease that facilitates membrane targeting of Ras and other prenylated proteins by releasing the carboxyl-terminal 3 amino acids (ie, the -AAX of the CAAX motif). Homozygous Rce1 mutant embryos (Rce1(-/-)) die late in gestation. To characterize the role of Rce1 in hematopoiesis, we performed adoptive transfers and investigated cells from the recipients. Rce1(-/-) fetal liver cells rescued lethally irradiated recipients and manifested normal long-term repopulating potential in competitive repopulation assays. The recipients of Rce1(-/-) cells developed modest elevations in mature myeloid cells (neutrophils + monocytes), but remained well. Bone marrow cells from mice that received transplants of Rce1(-/-) activated extracellular signal-related kinase (ERK) normally in response to granulocyte-macrophage colony-stimulating factor. These data suggest that pharmacologic inhibitors of Rce1 will have minimal effects on normal hematopoietic cells.