Karyotype abnormalities in non-Hodgkin lymphomas

Karyotype anomalies were found in 9 of 13 non-Hodgkin lymphomas. The observed non-random involvement of chromosomes was non-specific and was associated with chromosome breakpoints rather than recurrent markers. The recurrent markers which were found were similar to those of previously published studies. An attempt to correlate histological classification and chromosome anomalies in published series indicated that there were limited histological associations, the frequency of abnormalities of chromosomes 14 and 18 showing the largest disparity between disease types. Among the breakpoints and translocations found are those known to be associated with oncogene location, and the possibility is raised of an oncogene on 18.     

c-myc mRNA expression in non-Hodgkin’s lymphomas

Steady state c-myc mRNA levels determined by Northern blot analysis were examined in non-Hodgkin's lymphomas (NHL) of both high (n = 29) and low malignancy (n = 18), and in non-specific chronic lymphadenitis (n = 6). High grade NHL, classified according to the updated Kiel classification, revealed significantly larger amounts of c-myc mRNA compared with low grade NHL and lymphadenitis. mRNA levels in non-specific lymphadenitis were lower than in low grade NHL, but the differences were not statistically significant. No correlation between c-myc mRNA levels and the immunologic phenotype was discernible. Growth fractions of the NHL were determined by immunostaining with the monoclonal antibody Ki-67. Significant correlations between the percentages of Ki-67-positive cells, as well as the amounts of c-myc mRNA, and classification into high or low grade NHL were found. However, the percentage of Ki-67 positive cells and c-myc mRNA levels in individual cases and in the various histologic entities of NHL did not correlate. Our results indicate the overexpression of the c-myc gene in NHL, and a highly significant correlation of steady state c-myc mRNA levels with the prognosis-related histomorphologic Kiel classification of NHL into different subgroups of low and high grade malignancy.     

Computer aided cytometry in high grade malignant non-Hodgkin’s lymphomas and tonsils

The aim of the study is to establish quantitative cytological criteria for reliable diagnoses in high grade malignant non-Hodgkin’s lymphomas (NHL). For this purpose Pappenheimstained cytologic imprints from 15 cases of high grade malignant NHL and ten cases of chronic tonsillitis have been analysed using a TV-microscope system, high resolution color scanning (13.3 pixel/μm), and image processing on a computer. The highly reliable computer-extracted cell features can be used to discriminate the different cell types of malignant NHL. Because of a considerable overlap, no feature on its own is sufficient to discriminate all the different cells. Only multivariate analysis of a suitable combination of features allows reliable discrimination. The results show that the different cells defined by subjective morphological criteria in the Kiel-classification of malignant NHL also form distinctive subpopulations with regard to their objective mathematical cell features and show distinctive differences when compared with their benign counterparts derived from reactive lymphatic tissue. Supported by the Wilhelm Sander-Stiftung, Neustadt a. d. Donau, FRG. Presented in part at the 72. Congress of the German Pathological Society, Hannover, June 1988     

Progress in the treatment of non-Hodgkin's lymphomas

The authors analyze the progress achieved in the treatment of low-grade as well as of high-grade non-Hodgkin's lymphomas. The challenging task in the treatment of low-grade or indolent lymphomas still is to decide whether watchful waiting is sufficient or whether chemotherapy is necessary and how aggressive this treatment should be. Among the new chemotherapeutic agents the role of purine analogues should be emphasized, fludarabin is especially important in the treatment of chronic lymphocytic leukemia and follicular lymphoma, while pentostatin and cladribine have revolutionized the treatment of hairy cell leukemia. Treatment with monoclonal antibodies, radioimmunoconjugates as well as autologous or allogeneic stem cell transplantation are potential new therapeutic options in the treatment of low-grade non-Hodgkin's lymphomas. In the case of aggressive non-Hodgkin's lymphomas risk-adapted strategies help the choice between standard or more intensive treatment options. In patients with relapsed high-grade lymphomas stem cell transplantation is indicated. In patients with marginal zone lymphoma the combination of hyperCVAD protocol + stem cell transplantation greatly improves prognosis.     

Vaccine strategies in the treatment of low-grade non-Hodgkin lymphoma

Recent years have witnessed the development of a variety of promising immunotherapies for treating patients with B-cell non-Hodgkin's lymphomas. Each B lymphocyte expresses an immunoglobulin molecule that is the product of a unique combination of gene segments. B cell malignancy arises from one original B lymphocyte, and therefore all the members of a given lymphoma tumor population have the same unique immunoglobulin, which can serve as a target for immune therapy. When the idiotype (Id), or unique portion, of each immunoglobulin is used as a vaccine, antibodies and T cells can be induced and each can cause rejection of the tumor by the host. This special opportunity for tumor specificity is accompanied by the challenge of constructing a different vaccine for each patient. The first clinical trial of Id vaccination for lymphoma was initiated at Stanford University in 1988. Tumor cells obtained from lymph node sampling were fused with a myeloma cell line to generate a "hybridoma" producing large quantities of idiotype protein. Purified Id protein was then chemically coupled to keyhole limpet hemocyanin (KLH) and emulsified in an "oil-in-water" type immunologic adjuvant. The initial trial included patients with low-grade, follicular lymphoma, in first remission following chemotherapy. Among the first 32 vaccinated patients, roughly half (14/32) developed anti-Id immune responses. These were principally humoral responses rather than cellular responses. Long-term follow-up of these 32 patients has revealed that the development of an immune response is strongly correlated with prolonged freedom from disease progression interval and overall survival. Further trials have confirmed significant clinical benefit following Id vaccination. There is reason for excitement about the prospects for effective vaccine therapies for lymphoma as randomized Id vaccine trials commence and newer cell-based vaccine trials enter the clinic. As the clinical activity of lymphoma vaccines becomes established, it will be important to determine how to best integrate active vaccination approaches with standard therapeutic approaches.     

Genetic analysis of chemoresistance in primary murine lymphomas

Understanding the basis of chemoresistance is a principal goal of molecular oncology. We have exploited a murine lymphoma model and retroviral gene transfer to rapidly generate a series of spontaneous tumors differing only in a gene of interest, and subsequently studied the impact of the test gene on the treatment sensitivity of tumors at their natural site. We demonstrate that the Bcl-2 oncoprotein produces multi-drug resistance when assessed in primary lymphomas in vivo. In contrast, this effect was dramatically reduced when the primary lymphomas were subjected to long-term culture, and completely missed in the standard clonogenic survival assay. This model highlights the importance of physiological test systems to address the complexity of clinical drug resistance and provides a novel strategy to evaluate compounds targeting specific genetic lesions.     

Evaluation of the circulating and splenic lymphocyte subpopulations in patients with non-Hodgkin lymphomas and Hodgkin's disease using monoclonal antibodies

The number of B lymphocytes, T lymphocytes and their helper/inducer, cytotoxic/suppressor and NK/K subpopulations was measured in peripheral blood and spleen cell suspensions from patients with Hodgkin's disease (HD) in the active stage of the disease and in remission status, as well as in Non-Hodgkin lymphomas (NHL) in active stage of the disease. B lymphocytes were determined by direct immunofluorescence and T lymphocytes with the E rosette technique. Helper/inducer, cytotoxic/suppressor, and NK/K T lymphocytes were determined by indirect immunofluorescence with the monoclonal antibodies OKT4, OKT8 and Leu 7 (HNK1). In the same way, Lyt3 was used for determination of the total T lymphocytes. Whereas in peripheral blood of the NHL group an increase of B lymphocytes and a slight reduction of T lymphocytes could be observed, with normal distribution of the subpopulations, in patients with active HD as well as in those in remission, a marked absolute and relative decrease of T helper/inducer cells was found with normal cytotoxic/suppressor and NK/K proportion. In contrast to this, a significant increase of helper/inducer T lymphocytes with decreased cytotoxic/suppressor T proportion was found in spleen cell suspensions of patients with HD.