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Waldenström's macroglobulinemia associates a serum monoclonal IgM and a lymphoplasmacytic infiltration of bone marrow, spleen, lymph nodes and various organs. Clinical symptoms are related either to the lymphoid disorder or to the physico-chemical characteristics or antibody activity of the monoclonal IgM. Visceral infiltration may target stomach small bowel, lungs, exocrine glands or skin. Major complications include bone marrow failure, auto-immune cytopenia, occurrence of large cell lymphoma and infections (related either to the humoral immunodeficiency or to chemotherapy). Asymptomatic macroglobulinemia does not deserve any treatment. Otherwise, alkylating agents or nucleoside analogues are first line agents. The benefit of monoclonal antibodies, high dose chemotherapy followed by auto or allogenic stem cell graft is currently assessed.

Monoclonal IgM associated with a peripheral neuropathy often feature an antibody activity directed against the myelin-associated-glycoprotein. The main characteristics of the structure of these IgM are reviewed: the variable gene repertoire used by these antibodies is rather large. The VH genes belong to the different variability subgroups; this also holds true for the VL repertoire although the single V kappa 4 gene may be used quite often. These variable segments often exhibit somatic mutations clustered in the CDR regions suggesting an antigen driven process. The monoclonal IgM is produced by a B cell clone which may be undetectable in the majority of patients. Nevertheless, it is possible to detect clonal B cells in the blood which have the remarkable capacity to differentiate spontaneously in vitro to plasma cells. This process is dependent upon an IL6-autocrine differentiation pathway which may be modulated by some drugs such as interferons or all trans retinoic acid.

Objectives: Legitimate efforts to reduce health care costs, especially of intensive protocols including transplantation for haematological diseases, require realistic economic evaluations. We determined the direct cost of intensive chemotherapy associated with total body irradiation and autologous blood stem cell transplantation in patients with multiple myeloma., Methods: Ten consecutive patients (7 males, 3 females) with Stage II or II multiple myeloma, who had received no prior treatment and were under the age of 55, were included in the study. Peripheral blood stem cells were collected by successive cytaphereses after a short period of aplasia induced by a CHOP protocol. During this period, the patients were in normal hospital rooms. A VAMP protocol was then administered in three 4-day sessions. Intensive therapy was started 1 month later with CCNU, etoposide, cyclophosphamide and melphalan. Total body irradiation (12 Gy) was performed on days -3, -2, -1. Autologous grafting was done on day 0. The intensive therapy was followed by a period of aplasia and the patients were protected in laminar flow rooms. Regular antibiotic and haematologic protocols were applied. Growth hormone was not given. The patients were seen regularly for follow-up and interferon alpha 2b was prescribed for 5., Results: The mean cost of the two year treatment was 468,392 +/- 167,467 French francs. Personnel accounted for 36% of the total cost, marrow collection 13%, blood products 9.8%, laboratory tests 8.2% and drugs 7.2%. Little data are available in the literature of comparable cost analyses in other French hospitals or in other countries., Conclusion: Controlled cost/benefit studies should be conducted to enable a rigorous comparison between different therapeutic strategies.

The NH2-terminal structure of serum abnormal protein, as well as the sequence of the corresponding mRNA, were determined in a new case of alpha heavy chain disease. The patient presented with typical clinical features of the disease. Intestinal and mesenteric lymphoplasmic infiltration was monoclonal as assessed by the study of the configuration of heavy and light chain genes. The serum abnormal alpha chains included two molecular species: one starting at the beginning of the hinge region and the other being two amino acids shorter, missing the two first amino acids of the hinge region. The sequence of the mRNA displayed a leader exon, a 93 bp sequence of unknown origin and the second and third constant exons of human alpha 1 chain. These data are discussed in the light of previously reported molecular studies in heavy chain diseases.

The various chemotherapeutic regimens in multiple myeloma allow only a mean survival of less than three years. Polychemotherapy has at best a minor advantage over monochemotherapy. High dose chemotherapy followed by hematopoietic stem cell grafts yields a notable percentage of apparent complete remission. The best therapeutic choices as well as the introduction of new drugs such as alpha interferon still needs prospective evaluation.

Peripheral neuropathy is often associated with a monoclonal IgM and occurs in about 3% of authentic Waldenström macroglobulinemias. In at least as many cases, the neuropathy is associated with a monoclonal IgM although lymphoplasmocyte proliferation is not detected, at least initially. In about 2/3 of the cases, the monoclonal IgM is a specific antibody against a myelin associated glycoprotein (MAG), two peripheral nerve glycolipids (SGPG and SGLPG), the peripheral nerve protein P0, other smaller molecular weight molecules of the peripheral nerves, or finally certain adhesion proteins such as N-CAM. All these IgM have a fine specificity against an epitope of the glucuronyl sulfate determinant present on the carbohydrate moiety of these proteins. The clinical manifestations are similar in all patients with sensorimotor polyneuropathy, with frequent sensory dominance and demyelinization. Atypical symptoms including motor dominance, paralysis of the cranial nerves, asymmetric forms, are rare. On histological examination, there is demyelinization and monoclonal IgM deposit along the nerve fibers. Passive in vivo and in vitro transfer experiences suggest that these monoclonal antibodies can play a role in triggering or maintaining the peripheral neuropathy. Despite identical or nearly identical antibody specificities of the monoclonal IgMs, the regions of the heavy or light chains involved vary from one patient to another, indicating that the glucoronyl sulfate determinant is quite variable. This variability is not found in other monoclonal autoantibody models with autoantibody activity such as the rheumatoid factor or cold agglutinins. These data would suggest the need for different therapeutic approaches using chemotherapy, plasmapheresis, high dose intravenous immunoglobulins and other immunomodulator treatments. Two therapeutic trials are discussed.

Serum immunoglobulins abnormalities may be qualitative or quantitative. So called benign IgG or IgA monoclonal gammopathy may be associated with certain rare clinical entities such as mucinar papulosis or leakage syndrom. Monoclonal IgM are mostly observed in patients with lymphoplasmacytic malignant proliferation; monoclonal IgM frequently posess a defined antibody activity which may be related to clinical symptoms such as hemolysis, cryoglobulinemic purpura or peripheral neuropathy. When a lymphoplasmacytic disease can be excluded, hypogammaglobulinemia is usually genetic, although rare causes of acquired hypogammaglobulinemia exist. Selective humoral deficiencies mostly of IgA or IgG2 may be missed on routine study of the serum. A marked hypergammaglobulinemia is observed in infectious or parasitic diseases, autoimmune disorders or certain lymphoid proliferation such as angioimmunoblastic lymphadenopathy. The presence of a monoclonal IsG or IsA morrate the need of a careful evaluation to second a malignand localized or gone marrow plasmacytic proliferation.

Interleukin 6 has pleiotropic effects on cells from various lineages. Several data indicate that it may play a critical role in the development of multiple myeloma by an autocrine or paracrine stimulation pathway. For instance, we showed that oligodeoxynucleotides antisens of IL6 mRNA were capable to decrease the proliferation of two different myeloma cell lines. In Waldenström's macroglobulinemia, at the initial stage of the disease, there is an autocrine differentiation pathway which is dependant of the secretion of IL6 by tumor cells. IL6 may also be implicated in the pathogenesis of some other lymphoid malignancies such as follicular lymphomas or large cell lymphomas. Its role in the systemic symptoms of Castleman disease has been clearly established.

The incidence of malignancies is strikingly high in patients with primary immunodeficiency diseases. Analysis of clinical data and the types of neoplastic proliferations raise several hypothesis. Occurrence of cancers does not seem to be favored by secondary immunodeficiencies related to lymphoma or immunosuppressive therapy.

In two patients with Waldenström's macroglobulinaemia complicated with peripheral neuropathy, purified monoclonal immunoglobulin M showed antibody activity specifically directed against vimentin, a major polypeptide of mesenchymal cell cytoskeleton and therefore in Schwann's cell. The neuropathy was of the sensory-motor type. It was improved in one case by plasma exchanges combined with chemotherapy. The relevance of this original antibody activity to the pathogenesis of neuropathy is discussed.

The authors report the chance discovery in a man aged 53 years with serum positive rheumatoid arthritis, of gamma 3 heavy chain disease. The originality of this case depended on the absence of any detectable lymphoid proliferation and on the transient character of the pathological protein. Only the course after a long follow up will determine whether there is no incipient lymphoid proliferation and whether the heavy chain disease has disappeared permanently.

In a 66-year old man without previous major disease the unexpected finding of pancytopenia on routine blood count during an acute respiratory infection led to the diagnosis of IgG-producing myeloma without radiological bone lesions, associated with partial blastocytosis and abnormalities in granulocyte maturation. No treatment was given. Within 15 days, the circulating blastocytes became more numerous and type M1 acute myeloblastic leukaemia was diagnosed. A combined rubidazone and cytosine arabinoside treatment failed, and the patient died rapidly.

Although recently identified, this disease is by no means exceptional. It is characterized by the deposition in various organs of an amorphous substance which differs from the amyloid substance and contains monoclonal immunoglobulin determinants: either a light kappa or lambda chain, or a light and a heavy chain. The severity of the disease is due to various organs being involved, notably the kidneys. There is in every case a monoclonal plasmocytic or lymphoplasmocytic proliferation which may appear as benign. In almost one-third of the cases no monoclonal immunoglobulin can be detected in the serum. In a study of immunoglobulin biosynthesis, 6 out of 8 patients showed striking structural abnormalities. The relationship between these very unusual lg's and tissue deposition is discussed in detail.

Monoclonal antibody analysis of peripheral blood T-cell subsets was performed in 23 multitransfused haemophiliacs, 5 children and 10 adults. Although none of the patients exhibited symptoms of acquired immune deficiency, 5 of them showed an abnormally low proportion of T-cells with reversal of the OKT4 (helper/inducer) to OKT8 (cytotoxic/suppressor) ratio. No evidence of cytomegalovirus infection was found. A search for antibodies to human leukaemia virus antigen P24 gave negative results. The relationship between this abnormality and transfusions is discussed.

The occurrence of malignant proliferative diseases in patients with primary immune deficiencies is far more frequent than in normal individuals. These malignant proliferations may supervent in all types of immune deficiencies but are more frequent in the Wiskott-Aldrich syndrom, ataxia telangiectasia and variable immunodeficiencies. The incidence of malignant lymphomas is striking since they account for two thirds of the malignancies. This fact does not support the hypothesis of a faulty immunological surveillance and would be in accordance with the hypothesis of a direct role of antigenic stimulations occurring on an immune system devoid of regulatory mechanisms.

A case of systemic lupus erythematosus associated with an homozygous deficiency in the second fraction of complement is reported and compared to previous reports of the literature. The high incidence of infections in these patients is outlined. The defective gene in this family was associated with the HLA A10B18 haplotype and the propositus was homozygous at the HLA-D locus. Familial study allowed the detection of 3 heterozygous individuals two of them being symptomatic (vascular purpura, high incidence of bacterial infections).

Bleeding episodes in hemophiliacs with inhibitor to factor VIII are often dramatic situations. High level inhibitors do not respond to massive amount of factor VIII and are often refractory to immunosuppressive drugs such as cyclophosphamide. In this situation it has been proposed to use "activated prothrombin complex" to control bleeding in hemophilic patients with inhibitors. A plasmatic fraction "Auto IX" has been used successfully for the treatment of an intestinal hemorrhage in a patient with an inhibitor to F. VIII. Possible mechanisms of action as well as potential thrombotic danger of such concentrate are discussed.

The authors describe a case which demonstrates that nephrotic syndromes occuring during the course of a myeloma are not always of the amyloid type. They emphasize the possibility of a dysglobulinemia being involved in a glomerular nephropathy syndrome, especially when there are histological lesions of a glomerulosclerosis. The published literature is reviewed and the possible pathogenesis of these nephropathies briefly discussed: either protein deposits, the nature of which has not been fully determined, or mesangial modifications induced by the filtered light chains.

Two cases of infantile acute lymphoblastic leukaemia, Burkitt type, are reported. The cytogenetic study revealed a translocation t(8;14) similar to that of Burkitt's lymphoma. This chromosomal rearrangement is considered as a further argument which favours uniqueness of the two diseases.

Cryoglobulins are serum proteins which precipitate at 4 degrees C and redissolve during warming. When purified, they can be divided by immunochemical analysis into three main groups: monoclonal cryoglobulin, mixed cryoglobulin containing a monoclonal immunoglobulin, and polyclonal mixed cryoglobulins. There is a close correlation between the immunochemical composition of cryoglobulins and the symptoms or diseases associated with their presence.

The case of a 60 year old man in whom diarrhea, steatorrhea and protein losing enteropathy developed one year after the diagnosis of Waldenström's macroglobulinemia is reported. Histological study of multilevel peroral biopsies of the small bowel mucosa showed the following features: a) lymphangiectasia, b) intralymphatic and interstitial deposits composed of lipids and immunoglobulin M of the kappa type (as demonstrated by specific histoimmunofluorescence), c) a mild lymphoplasmocytoid infiltrate, corresponding to the location of Waldenström's macroglobulinemia. The patient died six months later, in spite of improvement of his digestive tract functional abnormalities by a low-fat diet. Sixteen cases of small intestinal involvement have been reported during the course of Waldenström's macroglobulinemia, of which only one showed features similar to those found in our case. Lymphangiectasia appear to be due to mesenteric lymph node involvement by the tumoral process, and/or to increased blood viscosity; in turn the lymphangiectasia seem to be responsible for steatorrhea and plasma protein losses, since in our case both lipids and the immunoglobulin M-kappa were shown to cross the villous epithelium by immunohistochemistry.

The immunological analysis of the membrane phenotype of the leukemic cells, by studies of various markers and antigens unmasks some degree of heterogeneity of chronic lymphocytic leukemias and of acute lymphoblastic leukemias. This analysis gives indications of the nature and origin of the proliferating cells. The analysis gives indications of the nature and origin of the proliferating cells. The data provided by these studies are useful for a modern classification of these diseases and allow new nosologic groupings.