Malignant Lymphoproliferative Diseases Research Articles

Severe immunodeficiency in patients treated with fludarabine monophosphate.

Fludarabine monophosphate (FAMP) has been shown to be highly effective against low-grade malignant B-cell lymphoproliferative diseases. Because some opportunistic infections were observed in patients treated with FAMP, we investigated the influence of this drug on several parameters of immunocompetence. For 17 consecutive patients treated with FAMP for CLL or low-grade malignant lymphoma we studied T-cell subpopulations during and after therapy by flow cytometry and our findings were correlated with the clinical course of their disease. A pronounced decrease in the various T-cell subpopulations was seen in all cases, that for CD4+ cells was still present 11-13 months after the end of the therapy. In 7 patients a severe opportunistic infection developed; the outcome was fatal in 2 cases. Only 5 patients did not experience any serious infection. These results show that FAMP therapy in a dose of 25 mg/m2/day for 5 d every 4 weeks might be too toxic for patients with very advanced disease. However, in view of the efficacy of FAMP, the possibility of less intensive schedules for these advanced cases should be explored.

Malignant Lymphoproliferative Diseases in Occupations with Potential Exposure to Phenoxyacetic Acids or Dioxins: A Register-Based Study

Malignant Lymphoproliferative Diseases in Occupations with Potential Exposure to Phenoxyacetic Acids or Dioxins: A Register-Based Study

Malignant Lymphoproliferative Diseases in Occupations with Potential Exposure to Phenoxyacetic Acids or Dioxins: A Register-Based Study

Malignant Lymphoproliferative Diseases in Occupations with Potential Exposure to Phenoxyacetic Acids or Dioxins: A Register-Based Study

Malignant lymphoproliferative diseases (MLD) in patients seropositive for the HIV

Malignant lymphoproliferative diseases (MLD) in patients seropositive for the HIV

T cell receptor and immunoglobulin gene rearrangement analysis as a laboratory aid in the diagnosis of human malignant lymphoproliferative diseases

The identification of clonal rearrangements of the immunoglobulin heavy chain and T cell receptor beta chain gene loci by Southern blot analysis has led to advances in the diagnosis and classification of lymphoproliferative disorders. This paper reviews our experience with this technique over a three and a half year period. Specimens from 99 patients with suspected haematological malignancy were tested for leucocyte immunophenotype and immunoglobulin or T cell receptor gene rearrangement. Genotyping provided evidence of clonality in malignancies from 28 patients and demonstrated malignant cell lineage in eight patients not formally deduced from immunophenotyping alone. Our findings suggest that this technique can be employed in conjunction with immunophenotyping to aid in the determination of malignant cell lineage derivation and identification of malignant cell clonality, as well as potentially estimating the extent of disease, detecting relapse, and monitoring disease progression.

Mime Combination Chemotherapy in Recurrent or Refractory Lymphoproliferative Malignancies: A Phase II Study

Seventy-two patients with recurrent or refractory malignant lymphoproliferative diseases were treated with MIME combination chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide) and concurrent mesna to prevent urothelial toxicity; 41 patients had high/intermediate-grade non-Hodgkin's lymphoma (NHL), 18 low-grade NHL/chronic lymphocytic leukemia (CLL), and 13 Hodgkin's disease (HD). The overall response rates were 56% in high/intermediate-grade NHL, 11% in low-grade NHL/CLL, and 69% in HD respectively. Median survival in the same 3 groups was 7, 2 and 10 months respectively. Neither previous type of response to chemotherapy nor previous amount of treatment predicted the outcome of MIME chemotherapy. Toxicity was modest, hemorrhagic cystitis did not occur, and only one therapy-related death occurred. Although MIME appears to be a safe treatment with considerable activity in recurrent or refractory lymphoproliferative disease very few patients become long-term survivors. However, MIME is well suited for remission induction in patients intended for subsequent autologous bone-marrow transplantation.

Nation-wide study of lethal mid-line granuloma in Japan: frequencies of wegener's granulomatosis, polymorphic reticulosis, malignant lymphoma and other related conditions.

Lethal mid-line granuloma (LMG) is a clinical term, and it is histologically composed of Wegener's granulomatosis (WG), polymorphic reticulosis (PR), and malignant lymphoma (ML). WG is an inflammatory disease, and PR and ML are considered to represent a neoplastic proliferation of lymphoreticular cells. In the present report, a nation-wide study on LMG in Japan is compared with a study from the UK, to examine differences in frequencies of each disease in Eastern and Western countries. A total of 340 cases of LMG were examined. On the basis of histological and clinical findings, these cases were categorized as 68 WG, 129 PR, 92 ML, 44 chronic inflammation not specified, and 7 other related conditions. The crude frequencies of WG, PR, and ML per 100,000 outpatients of ENT clinics in Japan and England were 4, 8 and 6, respectively and 8, 4 and I, respectively. The predominance of malignant lymphoproliferative diseases to WG in Japan (3.5:1) was in marked contrast to the situation in the UK (1:1.6). A review of the pertinent literature suggests a clustering of malignant lymphoproliferative diseases of the nose among Mongolian ethnic groups.

Dipeptidylaminopeptidase IV in lymphocytes of patients with lymphoproliferative diseases

DAP-IV activity (Gly-Pro-MCA hydrolysis, pH 7.8) was found in lysates of peripheral blood lymphocytes of patients with T- and B-cell forms of malignant lymphoproliferative diseases. The highest DAP-IV activity was seen in the cells of patients with a rare variant of T-cell lymphocytic leukemia (T-CLL); these cells expressed simultaneously the antigens of T helpers and T suppressors (Th and Ts) (OKT4+ and OKT8+). The DAP-IV activity about ten times less was found in the pathological cells with a phenotype of mature Th (Sezary disease), as well as in the cells expressing antigens of both Ts and natural killers (a rare variant of T-CLL). The same activity was also found in Ts (T gamma-lymphocytosis). The data obtained show that the differences in DAP-IV expression are connected with the differentiation step rather than with the belonging to a particular subpopulation of T-cells. DAP-IV activity, which was somewhat lower than that of T-cells, was found in B-lymphocytes of patients with B-CLL, hair-cellular leukemia, and non-Hodgkin's lymphoma. No correlation of DAP-IV activity with the level of E-cellular differentiation was observed.

The clinical significance of pure Bence Jones proteinuria at low concentration.

The clinical significance of Bence Jones (BJ) proteinuria at low concentration (less than 0.2 g/24 hours) was investigated in 33 unselected patients who had no intact monoclonal immunoglobulin in their serum. The great majority (79%) of the patients were recognized as having malignant lymphoproliferative diseases, such as chronic lymphocytic leukemia (46%), hairy cell leukemia (6%), and non-Hodgkin's lymphoma (27%), whereas only two patients (6%) had multiple myeloma or systemic amyloidosis. Five patients (15%) had no evidence of definite malignant immunoproliferative disorders at the time of recognition of BJ proteinuria. Three of them, who were excreting steadily low amounts of BJ protein in their urine for 47, 61, and 73 months, respectively, without development of any B-lymphocytic malignancy, were classified as having a monoclonal gammopathy of undetermined significance. In the remaining two patients, BJ protein disappeared spontaneously 14 and 18 months, respectively, after its recognition. The study indicates that pure BJ proteinuria, even when occurring at low concentration, is most consistently associated with malignant proliferations of B-lymphocytic origin. However, the possibility should be considered that the clinical spectrum of the monoclonal gammopathy of the light chain type also includes benign and transient forms.

Differential Diagnosis of Monoclonal Gammopathy

With a large segment of the adult population now undergoing routine screening tests on a periodic basis, findings such as rouleaux when the complete blood count is performed or an elevated total protein and globulin fraction on serum chemistries often lead to the performance of a serum protein electrophoresis. When a monoclonal gammopathy is confirmed, the clinician is faced with a broad differential diagnosis that includes a variety of distinct malignant plasma cell disorders and lymphoproliferative diseases, as well as the high incidence of MGUS in the otherwise healthy adult population. Other benign causes of secondary monoclonal gammopathy, such as underlying inflammatory or infectious disorders or drug reactions, may add to the diagnostic dilemma in some patients. By following a systematic plan of laboratory evaluation such as that described here, however, and always keeping the patient's clinical status as a primary focus, the clinician should be able to arrive at a diagnosis and formulate a therapeutic plan in most instances. The most common differential diagnosis, that of MGUS versus PCM, still is difficult in some cases, and it is emphasized that careful follow up over time remains the best method at present for differentiating these two conditions. Once the basic laboratory evaluation of monoclonal gammopathy has been completed, further work-up will need to be individualized. In some cases, the preliminary evaluation will reveal a key feature, such as a monoclonal gammopathy that is IgM, which will lead to a rapid diagnosis of WMG and alert the clinician to investigate other nonroutine aspects of the laboratory evaluation, such as a serum viscosity or specific tests of hemostatic function. In other patients, the initial laboratory evaluation of monoclonal gammopathy may lead to other recommendations, such as lymph node biopsy for evaluation of possible lymphoma, or tissue biopsy to confirm the suspicion of amyloidosis. Overall, the evaluation of monoclonal gammopathy remains a challenging one, but one in which the clinician usually is rewarded with a diagnosis that will allow him to make appropriate management plans for his patient.

Alteration of beta-2-microglobulin level in malignant lymphoproliferative diseases after a high dose of alpha-2-recombinant interferon

A group of 10 patients with malignant lymphoproliferative diseases resistant to any standard therapeutical modalities were treated with a high dose of alpha- 2-recombinant interferon (alpha- 2-rIF). Alpha- 2-rIF was administered at a total dose of 120 × 10 6 IU in a continuous infusion during 48 h. Two cycles of alpha- 2-rIF immunotherapy were employed with an interval of 1 month in between each. Serum and urinary beta- 2-microglobulin (B 2M) were examined prior to alpha- 2-rIF application and on days 2, 4, 6 afterwards. Alpha- 2-rIF treatment induced an increase in serum B 2M as noted on day 2 followed by a decline to below the normal range. The initial increased value was significantly higher as compared to either the pretreatment value or the normal physiological range. The reduced B 2M serum level was protracted and lasted until the second cycle of treatment. Similar but not so great changes in B 2M serum values were noted during the second application of alpha- 2-rIF. The changes of B 2M level in the urine, although less convincing, mimic those observed in the serum. The present results confirmed the biological activity of alpha- 2-rIF in malignant lymphoproliferative diseases.

A method combining morphological, immunocytochemical and chromosomal examinations of the same cell in the study of lymphoproliferative diseases.

6 cases of different lymphoproliferative diseases were studied with the new MAC (Morphology-Antibody-Chromosome) method in order to find out 1) if the abnormal karyotype is confined to the monoclonal cell population, 2) if there are, within this clone, also cells with a normal karyotype, and 3) if the method can help the pathologist to diagnose malignant lymphoproliferative diseases. The MAC method allows a simultaneous study in the same metaphase cell of the karyotype, surface markers, and some morphological features. In all cases in which a monoclonal cell proliferation was detected immunohistologically, the MAC examination showed a chromosomal abnormality for the same light chain as was detected in immunohistology, but not in other cells. In all but a single case, all mitotic cells belonging to the clonal cell proliferation had an abnormal karyotype. In this case with lambda clonality, 2/8 lambda-positive mitoses had a normal karyotype. However, all the normal mitoses occurred in small lymphocytes whereas the abnormal mitoses were seen in large blastic cells. In 1 case, the MAC method helped in confirming the diagnosis of malignant lymphoma (nodular small cleaved cell type). Especially in lymphomas composed of a mixed cell population, the MAC method makes it possible to find out which cell types have an abnormal karyotype and which have a normal karyotype.

Increased Porphobilinogen Deaminase Activity in Patients With Malignant Lymphoproliferative Diseases

Patients with malignant lymphoproliferative diseases, ie, chronic lymphocytic leukemia and lymphoma, were found to have higher porphobilinogen deaminase (PBGD) activity in their peripheral lymphocytes than normal control subjects, patients with other malignant neoplasms, and patients with various infectious diseases. The specificity and sensitivity of the test were 99% and 87%, respectively. The sensitivity of the test was 100% in patients with chronic lymphocytic leukemia and 82% in patients with lymphoma. The diagnostic value of PBGD determinations was shown in a prospective study of a group of patients evaluated because of fever of unknown origin, anemia, or other constitutional symptoms with or without lymphadenopathy or a mediastinal mass. The positive and negative predictive values in these patients were 91% and 100%, respectively. Nearly all patients who were in remission had normal enzyme activity. Lymphocyte PBGD determinations also may be of value in determining when to terminate or reinitiate drug treatment.

Increased porphobilinogen deaminase activity in patients with malignant lymphoproliferative diseases. A helpful diagnostic test

Increased porphobilinogen deaminase activity in patients with malignant lymphoproliferative diseases. A helpful diagnostic test

"Idiopathic" Bence Jones proteinuria: long-term follow-up in seven patients.

We studied seven patients with idiopathic Bence Jones proteinuria (excretion greater than 1.0 g per 24 hours) who did not have acquired Fanconi's syndrome or an intact monoclonal immunoglobulin in the serum. None had evidence of overt multiple myeloma, of its variants, of systemic amyloidosis, or of malignant lymphoproliferative diseases when the proteinuria was recognized. In three of the seven patients, symptomatic multiple myeloma (associated with systemic amyloidosis in one) developed 8.8 to 21.1 years later. A fourth patient has asymptomatic myeloma and has not been treated. A fifth patient had an evolving myeloma at nine years but died of an unrelated cause. The remaining two patients still have apparently benign Bence Jones proteinuria after 7.7 and 12 years. Plasma-cell labeling indexes were low in all cases tested. This experience shows that although idiopathic Bence Jones proteinuria may remain stable for years, multiple myeloma or amyloidosis often develops, and consequently these patients must be kept under observation indefinitely.

Book Reviews

Book reviewed in this article: Biochemistry of Nonheme Iron. By Anatoly Bezkorovainy Vol. 1 of Biochemistry of the Elements Malignant Lymphoproliferative Diseases. Edited by J. G. van den Twell C. R. Taylor and F. T. Bosman Haematology of Infancy and Childhood, 2nd edn. Edited by David G. Nathan Frank A. Oski Curator of the Dead: Thomas Hodgkin (1798–1866). By Michael Rose Postgraduate Haematology, 2nd edn. Edited by A. V. Hoffbrand S. M. Lewis Haemophilia Home Therapy. Edited by Peter Jones

Immune Deficiency Predisposing to Epstein-Barr Virus-Induced Lymphoproliferative Diseases: The X-Linked Lymphoproliferative Syndrome as a Model

The chapter describes diseases induced by EBV in immune compromised patients. The discussion begins by considering normal immune responses that combat Epstein-Barr virus. Features of infectious mononucleosis (IM) mimicking graft-versus-host response (GVHR) have been illustrated and speculated on. A spectrum of complications of IM, including death from infiltration of vital organs by infected B cells and malignant lymphoma, has been discussed in detail. Phenotypic expressions of the X-linked lymphoproliferative syndrome (XLP) and their immunopathogenesis have been presented to exemplify EBV-induced oncogenesis in immune deficiency. The immunopathogenesis of EBV-induced lymphoproliferative diseases and methods for detecting EBV in immunodeficiency patients have been outlined. These diagnostic monitoring procedures and therapies are being attempted by the lymphoproliferative syndrome and infectious mononucleosis research groups. The results of studies of malignant lymphoproliferative diseases in patients with immune deficiencies such as those accompanying renal transplantation are elaborated. Suggested techniques for documenting EBV infections in immunedeficient patients have been provided to guide diagnosticians and researchers.

Serum selenium levels in malignant lymphoproliferative diseases.

Serum selenium levels were measured in 38 patients with malignant lymphoproliferative diseases (MLD) and in 34 non-hospitalized healthy individuals. Selenium was determined by proton induced x-ray emission. In Hodgkin's disease and non-Hodgkin malignant lymphoma the mean serum levels of selenium were not different from those of the control group. On the contrary lowered mean serum selenium concentrations were observed in the group with chronic lymphocytic leukaemia (5.2 +/- 0.7 microgram/100 ml) as compared to normal individuals (7.9 +/- 0.3 microgram/100 ml). The difference is highly significant (P less than 0.005). A second selenium test was made in 11 out of the 38 patients within 8 weeks from the beginning of radiotherapy or chemotherapy; unchanged levels were found.

B and T lymphocytes in lymphoproliferative diseases of the skin. Effect of a thymic hormone on the immunocompetence of T lymphocytes.

Cell-mediated immunity using the E-rosette technique, the graft-versus-host reaction and intradermal skin tests were investigated in two groups of patients, twenty-two with benign lymphoproliferative diseases of the skin (lymphocytic infiltration of the skin and lymphadenosis benigna cutis) and nine with malignant lymphoproliferative diseases (mycosis fungoides and lymphoma cutis). The effect of thymic hormone upon T lymphocytes which proved to have impaired functional capacity was investigated. Seventeen of the twenty-two patients with benign lymphoproliferative diseases were found to have intact cellular immunity whereas seven of the nine patients with malignant disease proved to be immunodeficient. The determination of immune competence may be of help in establishing the correct diagnosis in doubtful cases and might also be useful in the follow-up of these patients. The improvement in functional capacity of T lymphocytes resulting from their interaction with a thymic hormone indicates that it holds therapeutic promise.

Immunosuppressive Effects of Lymphoproliferative Neoplasms of Chickens

of natural antibody pioneered experimental studies on immunosuppression in tumor systems. It became apparent that hosts bearing progressive malignant disease usually had reduced immunocompetence. Stutman (43) recently reviewed the results of a vast number of experimental studies on the immunosuppressive effect of neoplasia. In the present report, I will discuss some of the information on the effects of Marek's disease (MD), lymphoid leukosis (LL), and reticuloendotheliosis (RE) on the immune competence of chickens. Because some of the earlier data on the subject have been reviewed previously (13,34), this paper emphasizes data that have appeared within the last few years. Marek's disease and LL are the two principal virus-induced malignant lymphoproliferative diseases that occur naturally in chickens. Marek's disease is caused by a herpesvirus that is highly contagious and spreads readily to susceptible chickens through a contaminated environment. Marek's disease is not transmitted vertically (42). It causes the transformation of T-cells in chickens and initiates vigorous humoral and cell-mediated immune responses to virus and tumor-associated antigens. Although the principal terminal lesion in MD is lymphoid cell proliferation, there is initially a severe depletion of lymphocytes in the major lymphoid organs: thymus, bursa, and spleen (35). The lymphoid depletion is probably associated with the lytic infection of lymphocytes with MDV. Lymphoid leukosis, on the other hand, is caused by a group of RNA viruses that are characteristically egg-transmitted and cause gross lymphomas in chickens, usually after a long latent period. The target cells for LL viruses are the B-cells resident in