We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.

The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.

Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas frequently involved other thoracic structures but not extrathoracic sites typical of other DLBCLs. PMBL patients had a relatively favorable clinical outcome, with a 5-yr survival rate of 64% compared with 46% for other DLBCL patients. Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkin lymphoma cells. PDL2, which encodes a regulator of T cell activation, was the gene that best discriminated PMBL from other DLBCLs and was also highly expressed in Hodgkin lymphoma cells. The genomic loci for PDL2 and several neighboring genes were amplified in over half of the PMBLs and in Hodgkin lymphoma cell lines. The molecular diagnosis of PMBL should significantly aid in the development of therapies tailored to this clinically and pathogenetically distinctive subgroup of DLBCL.

We used gene expression profiling to establish a molecular diagnosis of mantle cell lymphoma (MCL), to elucidate its pathogenesis, and to predict the length of survival of these patients. An MCL gene expression signature defined a large subset of MCLs that expressed cyclin D1 and a novel subset that lacked cyclin D1 expression. A precise measurement of tumor cell proliferation, provided by the expression of proliferation signature genes, identified patient subsets that differed by more than 5 years in median survival. Differences in cyclin D1 mRNA abundance synergized with INK4a/ARF locus deletions to dictate tumor proliferation rate and survival. We propose a quantitative model of the aberrant cell cycle regulation in MCL that provides a rationale for the design of cell cycle inhibitor therapy in this malignancy.

Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin's lymphoma.

We analyzed the 2,531-patient Southwest Oncology Group extensive-stage non-small-cell lung cancer (ENSCLC) data base from 1974 to 1988 to (1) assess the interactions of host- or tumor-related prognostic factors and therapy using Cox modeling and recursive partitioning and amalgamation (RPA) to determine whether each independently predicts outcome, and (2) use RPA to define prognostic subsets with different survival potentials. Good performance status (PS), female sex, and age greater than or equal to 70 years were significant independent predictors in a Cox model applied to the entire population. In a second Cox model for patients with good PS enrolled on recent studies, hemoglobin level greater than or equal to 11.0 g/dL, normal lactate dehydrogenase (LDH), normal calcium, and a single metastatic site were significant favorable factors. The use of cisplatin was an additional independent predictor of improved outcome in both Cox models after adjustments for year of accrual and all prognostic variables. The favorable effect of cisplatin was observed in each of six RPA-derived subgroups from the entire population. A second RPA of 904 patients from recent trials (nearly all received cisplatin-based therapy) resulted in three distinct prognostic subsets based on PS, age, hemoglobin, and LDH; greater than or equal to 1-year survivals were 27%, 16%, and 6% (P less than .0001). The best survival occurred for patients with a good PS who had a hemoglobin level greater than or equal to 11 g/dL and who were older than 47 years. This analysis suggests that although several factors were independent variables in the Cox models, three important prognostic subgroups were easily defined through RPA. Together with other analyses, our results suggest the need to modify the stage IV category in NSCLC.

The Leukemia and Lymphoma Molecular Profiling Project recently published results from DNA microarray analyses of 240 diffuse large B-cell lymphomas (DLBCLs). Four gene expression "signatures" were identified as correlated with patient outcome, including the major histocompatibility complex (MHC) class II genes (eg, HLA-DRA) which correlated with better survival. We further analyzed the effects of HLA-DRA on survival and correlated gene expression with protein status and tumor-infiltrating lymphocytes. The 5-year overall survival was 24% in the lowest 10% of HLA-DRA expression, 37% in the 10% to 25% group, 50% in the 25% to 50% group, and 55% for patients in the highest 50%. Further analysis demonstrated that the hazard ratio of death was a nonlinear function of HLA-DRA expression. Adjustment for the International Prognostic Index did not alter the impact of HLA-DRA on survival. Other MHC class II genes were found to predict survival similarly. IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma diagnosed in the United States, accounting for approximately 40% of non-Hodgkin lymphoma (NHL) overall. Patients with DLBCL have an extremely variable clinical outcome using standard adriamycin-containing chemotherapy, ranging from cure to treatment failure, relapse, and death. While the median survival for all patients treated with such regimens is approximately 4 years, survival can range from a few weeks to more than 10 years when the disease is cured. This variability in clinical outcome suggests marked intertumoral heterogeneity. This heterogeneity is reflected, to a limited extent, by the morphologic classification of DLBCL, which has recently evolved to include several subtypes. The new World Health Organization (WHO) classification scheme published in 2001 identifies several morphologic and immunophenotypic variants, including centroblastic, immunoblastic, T-cell/ histiocyte-rich, anaplastic, plasmablastic, and DLBCL with expression of full-length anaplastic lymphoma kinase (ALK). 1 However, even within these defined subtypes, considerable variation in clinical outcome persists, indicating that additional factors are relevant.The major histocompatibility complex (MHC) on chromosome 6p encodes a series of proteins responsible for elicitation of a cellular immune response. MHC class I proteins (human leukocyte antigen-A [HLA-A], HLA-B, and HLA-C) are expressed on all nucleated cells and function in the presentation of antigenic peptides to CD8 ϩ cytotoxic T cells. MHC class II proteins are expressed only on professional antigen-presenting cells such as B lymphocytes, monocytes, and dendritic cells. Class II proteins function in the presentation of antigenic peptides to CD4 ϩ helper T cells. There are 3 classical MHC class II proteins, HLA-DR, HLA-DQ, HLA-DP, and 2 nonclassical molecules, HLA-DM and HLA-DO. Each protein is a heterodimer of an alpha and a beta chain, encoded by the A and B genes, respectively. The classical proteins reside on the cell surface and compose the antig...

A method is developed for obtaining tree-structured relative risk estimates for censored survival data. The first step of a full likelihood estimation procedure is used in a recursive partitioning algorithm that adopts most aspects of the widely used Classification and Regression Tree (CART) algorithm of Breiman et al. (1984, Classification and Regression Trees, Belmont, California: Wadsworth). The performance of the technique is investigated through stimulation and compared to the tree-structured survival methods proposed by Davis and Anderson (1989, Statistics in Medicine 8, 947-961) and Therneau, Grambsch, and Fleming (1990, Biometrika 77, 147-160).