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To investigate the occupational and environmental risk factors related to non-Hodgkin's lymphoma (NHL).A case-control study was performed during the 1992-1996 period in Languedoc-Roussillon, southern France. Four hundred and forty-five cases of histologically diagnosed NHL were declared. One thousand and twenty-five randomly selected population controls were interviewed about their medical histories; occupational exposures, such as chemicals, pesticides, and electromagnetic radiation; and toxic habits.The following factors were independently and significantly related to NHL as a result of the multivariate analysis: a previous hematopoietic malignancy (ORa = 11.5, 95% CI 2.4-55.4), a history of hives (ORa = 1.7, 95% CI 1.2-2.2), benzene exposure810 days (ORa = 4.6, 95% CI 1.1-19.2), daily welding (ORa = 2.5, 95% CI 1.2-5.0), and activity of radio operator (ORa = 3.1, 95% CI 1.4-6.6). To be an agricultural professional seemed slightly related to NHL in reference to non-professionals (ORa = 1.5, 95% CI 1.0-2.1). All of these results have also been adjusted for age, gender, education level, and urban setting.As some of the reported associations were based on a very small proportion of exposed subjects, further investigations are necessary to confirm our results. However, the findings suggest that factors related to altered immune functions such as a history of hematopoietic malignancy, history of hives, occupational exposure to benzene, or being an agricultural professional might increase the risk of NHL. Currently, underlying mechanisms for these associations are still unclear, and further investigations focused on interactions between immunity alterations and different chemicals would be of great interest.

Subcutaneous recombinant interleukin-2 (rIL-2) and recombinant interferon alfa-2a (rIFNalpha-2a) have been used extensively in the treatment of metastatic renal cancer. Most results, coming from noncontrolled phase II trials, showed inconsistent rates of response. More recently, the addition of fluorouracil (FU) was proposed to improve the efficacy of these regimens.The role of a subcutaneous combination of rIL-2 and rIFNalpha-2a with or without FU was investigated. Patients were randomly assigned to receive a combination of rIL-2 and rIFNalpha-2a at weeks 1, 3, 5, and 7 or the same combination together with a continuous infusion of FU at weeks 1 and 5. The major end points of this multicenter, randomized trial were progression-free survival, response rate, and toxicity. Overall survival was a secondary end point. Tumor responses were reviewed by an independent committee. Analysis of the results was performed on an intention-to-treat basis.One hundred thirty-one patients were enrolled. There was no difference in toxicity between the arms, and no toxic death was observed. One partial response was observed in arm A and five in arm B. Progression-free survival did not differ between the arms, and rates at 1 year were 12% and 15% in arms A and B, respectively. No statistically significant differences were detected in any end point.The subcutaneous combination of rIL-2 and rIFNalpha-2a with or without FU does not benefit patients with metastatic renal carcinoma. Neither of these regimens can be recommended as standard treatment. The results of the subcutaneous cytokine regimen seem disappointing.

Peripheral blood from patients with multiple myeloma (MM) contains a small number of plasma cells related to the bone marrow tumour cells by their cytoplasmic immunoglobulin (Ig), their cell membrane antigen expression and/or their gene rearrangements, but hitherto the monoclonal Ig (M-Ig) production by circulating cells has not been reported. Using a two-colour ELISPOT assay, Ig-secreting cells (Ig-SCs) were detected in the blood of 28 MM and five Waldenstrom's macroglobulinaemia (WM) patients. The number of cells that spontaneously produced an Ig isotype similar to that of the M-Ig in serum was greater than that of the other Ig-SCs. MM patients presented an excess of circulating heavy-chain (alpha or gamma) Ig-SCs (0.38% of the PBMC) with kappa or lambda light chains (0.48%) compared with the number of cells secreting the other heavy- (0.02%) and light-chain isotypes (0.03%). WM patients also presented high numbers of cells secreting the mu-heavy-chain isotype (0.66%). The Ig synthesized in vitro was characterized as monoclonal, and the M-Ig secretory capacity of the peripheral blood cells was similar to that observed for Ig-SCs from polyclonal activated B cells in vivo. The number of these monoclonal cells was significantly increased in patients in an advanced stage of MM (I/II vs. III, P0.001) and correlated with the serum beta-2 microglobulin concentration (r = 0. 69; P0.0003). The number of M-Ig-SCs in MM patients could be a useful marker for evaluating the progression of multiple myeloma.

We studied the role of interleukin (IL)-1beta in patients with multiple myeloma. By in situ hybridization and immunochemistry, myeloid and megakaryocytic cells expressed high levels of the IL-1beta gene and produced IL-1beta. Myeloma cells less potently expressed the IL-1beta gene and IL-1beta protein. IL-1beta gene expression was not constitutive since it was detected in the bone marrow myeloma cells of two patients, unlike circulating tumoural cells. In addition, nine myeloma cell lines failed to express the IL-1beta gene and this expression could not be induced by 12 different cytokines. We demonstrated that IL-1 was mainly responsible for IL-6 production in the tumoural environment through a PGE2 loop. In fact, an IL-1 receptor antagonist (IL-1RA) blocked PGE2 synthesis and IL-6 production by 80%; this blockage could be reversed by adding synthetic PGE2. Similar findings were found with indomethacin, an inhibitor of cyclooxygenase that blocks PGE2 synthesis. Taken together, these data emphasize the possibility of blocking IL-1 by using IL-1RA or other antagonists in order to block IL-6 production, which is a major tumoural survival and proliferation factor.

AIMS: Interleukin 6 (IL-6) is expressed in the majority of renal cell carcinomas and has an important role in the proliferation of some renal cell carcinoma cell lines. This action is mediated by two membrane proteins, gp80 (the IL-6 receptor; IL-6R), which binds IL-6, and gp130, which transduces the signal. The soluble form of gp80 (sIL-6R) is able to activate gp130 when complexed to the IL-6 molecule. These considerations prompted an investigation of IL-6R expression in this malignancy. IL-6, C reactive protein (CRP), and sIL-6R were also measured in serum and correlated to clinical and pathological features. METHODS: Immunostaining was performed on cryostat sections from renal cell carcinoma tumours with M91, an anti-IL-6R monoclonal antibody, using the alkaline phosphatase antialkaline phosphatase technique. The proliferation index was measured using the KI-67 monoclonal antibody. CRP, IL-6, and sIL-6R were measured in serum before nephrectomy, using an immunoenzymatic or immunoradiometric assay. RESULTS: There were significant differences in survival in patients with tumours larger than 8 cm, metastasis at diagnosis, high nuclear grade tumours, detectable serum concentrations of IL-6 (correlated to CRP serum concentration), more than 4% proliferating cells, and the presence of the IL-6R in situ. Furthermore, the serum IL-6 concentration correlated with tumour size and stage. The mean serum sIL-6R concentration was not significantly different from that observed in 40 normal subjects. Tumour IL-6R expression was present in 10 samples. There was a significant association between the presence of the IL-6 receptor in tumours and tumour stage, nuclear grade, proliferation index, and serum IL-6. CONCLUSIONS: This study revealed the importance of IL-6/CRP and IL-6R expression in situ as potential new prognostic factors and opens the way to new therapeutic strategies in renal cell carcinoma.

MCL is a well-described clinicobiological entity that presents the worst prognosis of the small-cell lymphomas. No treatment is known as the reference treatment. On the basis, first, of clinicobiological similarities between MCLs and multiple myelomas and, second, of our experience of chlorambucil in high intermittent dose in MCLs, we have treated MCL with the VAD regimen both with and without chlorambucil.Thirty disseminated MCL patients from three institutions, most in relapse (70%), were treated with the classical VAD regimen: 4 weeks VAD for 12 patients and VAD with 12 mg chlorambucil (d20-d29) for 5 weeks (VAD+C) for 18 patients. Five patients received complementary high-dose therapy (Alkeran or cyclophosphamide HD with TBI) and peripheral blood stem-cell transplantation.Complete response was achieved in 43% of the patients in which 84.5% were treated by VAD+C. The median overall survival from the diagnosis was 52 months, and from the first VAD +/- C (OSvad) was 22.5 months, with a 20.5 month (0-75) median follow-up between diagnosis and the first VAD +/- C. The OSvad was significantly better for patients with fewer than two prognostic factors (ECOG, lymphocytosis, blastic variant, LDH level, and Ki-67 score). Four of five patients treated with HDT and PBSCT were alive in CR 12.5 months (7-22) after the first VAD +/- C regimen.The VAD regimen appears effective in disseminated MCL patients and even better when associated with chlorambucil. HDT and PBSCT appear promising in younger patients in CR before HDT. A multicenter prospective study is in preparation to confirm these encouraging results.

The objective of this study was to assess the expression of a multidrug resistance (MDR) phenotype, implicated in the cellular resistance of tumor to chemotherapy, in rheumatoid synovial membrane. Synovial membrane from 16 rheumatoid (RA) patients was studied. Six patients with osteoarthritis constituted the control group. The cell membrane expression of the glycoprotein Pgp 170, encoded by the MDR 1 gene, was determined by an immunoperoxidase technique using two different monoclonal antibodies (JSB 1, C 219). The polymerase chain reaction (PCR) methods were used in parallel to detect the presence of the MDR 1 gene mRNA in the synovial cells. Pgp 170 was expressed on the cell membrane of five RA patients and MDR 1 cellular transcription was detected in one other RA patient. We did not observe any association between synovial glycoprotein expression and age, disease activity, and a specific treatment with a long-acting drug. However, MDR protein expression was associated with the successive treatment with more than three disease-modifying antirheumatic drugs (DMARDs). We concluded that the synovial membrane expresses a glycoprotein recognized by the antibodies JSB 1 and C 219. The absence of concomitant MDR 1 transcription suggests the expression of an atypical MDR phenotype in the synovial membrane, distinct from the Pgp 170 encoded by the MDR 1 gene. The implications of the MDR phenotype and the resistance of RA to DMARDs is further discussed.

To evaluate the prevalence, the incidence and clinical presentation of non-Hodgkin's lymphoma associated with primary Sjögren's syndrome.Sixty-two patients with primary Sjögren's syndrome were analyzed retrospectively in an open investigation.Of 62 patients with primary Sjögren's syndrome, 4 of them (6.4%) developed non-Hodgkin's lymphoma (6.9 cases per 1000 per year). All of them were women. Non-Hodgkin's lymphoma always developed after the onset of primary Sjögren's syndrome with a time interval ranging from 3 to 27 years. Pathological findings showed two diffused mixed small and large cell cleaved lymphomas and two diffused large cell cleaved lymphomas. Three cases had extra-nodular localizations. All of these 4 patients are still alive and in complete remission 2 to 8 years after the diagnosis of non-Hodgkin's lymphoma.This study confirms the association of non-Hodgkin's lymphoma in primary Sjögren's syndrome. These non-Hodgkin's lymphomas frequently had extra-nodal localizations. Good sensitivity to treatment, when necessary, provided good prognosis.

Pneumocystis carinii (PC) pneumonia was reported with increased frequency in patients presenting with acquired immunodeficiency syndrome (AIDS) or in patients receiving immunosuppressive chemotherapy for hemopathies. Extrapulmonary dissemination of PC is rare. In this study, three patients had PC infection of the bone marrow. Two of them presented with malignant lymphoma that had apparent immunosuppression, and the third patient presented with AIDS. In all three cases, such an infection was observed before or concomittantly with PC pneumonia. A bone marrow biopsy, bone marrow aspirate, or both can be useful, readily available tools for the diagnosis of a PC infection and especially its dissemination in patients with malignant lymphoma after intensive treatment or in patients with AIDS. The appreciation of such a dissemination may have some implications in the treatment of PC infection.

Midline granuloma includes diverse clinicopathological entities, such as Wegener granulomatosis, polymorphic reticulosis, lethal midline granuloma and conventional malignant lymphoma of the nose usually of B-cell origin. The authors describe five patients with LMG clinically and pathologically typical. Using an extensive panel of monoclonal antibodies, they demonstrate an "activate" T-cell phenotype observed on the initial lesion of the face in one patient, similar to that found in two patients with LMG but studied after dissemination in peripheral T-cell lymphoma. Furthermore, many atypical cells were found in LMG, and stained with the Ki-67 monoclonal antibody, a marker of proliferating cells. These findings support the view that LMG is closely related to T-cell malignancies. Two of them were treated with recombinant Interferon alpha 2a followed by a response rapidly objective. Immunohistologic studies are very important for confirming the T-cell origin of such a disease and for selecting patients to be treated with Interferon alpha.

Data concerning the presentation and response to treatment of 73 patients with multiple myeloma who survived for 5 years or more were reviewed. At the time of diagnosis, the proportion of patients with hypercalcaemia (4%), severe anaemia (9%), renal failure (10%) or high beta 2-microglobulin levels (25%) was low. Less than one-third of our patients belonged to a "high risk" group, as defined by the three classification systems adopted: the lowest percentage of such patients (18%) was observed with the Medical Research Council classification. In all patients, but even more in those with an initially aggressive disease (P less than 0.05), obtaining a plateau (70% of the cases) or even an optimal tumoral regression with complete disappearance of monoclonal immunoglobulin (26% of the cases) seems to be a highly favourable factor. The same applies, though to a lesser degree, to slow response to chemotherapy (18 months on average). In all responders whether the remission was maintained or not by chemotherapy seemed to have no influence on the frequency (70%) and delay of relapses (4 1/2 years on average from the time of diagnosis). The risk of secondary blood disease (2 AML 1, 1 AML4, 1 RAEB, 1 ASIA, four of which were directly responsible for death) after 4 years on average of chemotherapy must be taken into consideration.

Pneumocystis carinii is observed in the bone marrow of two adults immuno-compromised; the initial diseases are on the one hand a Hodgkin's disease, on the other hand a malignant lymphoma for immunocytoma type, which necessitate heavy and invalidating treatments. A Pneumocystis carinii pneumonia with respiratory distress seems to have carrying away two patients death. Eventually pathogenic part of the parasite in the bone marrow localization.

Nine unusual cases of B cell malignancies presenting with lytic bone lesions on radiography and/or hypercalcemia, and mimicking multiple myeloma are reported in this study. These cases included acute lymphoblastic leukemia (one patient), non-Hodgkin's lymphoma (five patients), chronic lymphocytic leukemia (two patients), and Waldenström's disease (one patient). Quantitative bone biopsy performed in two patients (one with non-Hodgkin's lymphoma and one with Waldenström's disease) demonstrated a dramatic increase in osteoclastic resorption close to tumor cells in both cases, similar to or even more marked than that observed in multiple myeloma. Finally, significant production of bone resorbing activity was found in short-term liquid culture specimens of tumor cells in eight of the nine cases. These observations clearly indicate that in B cell disorders other than multiple myeloma, the malignant B cells can produce significant bone resorbing activity in vitro and result in excessive osteoclastic resorption and lytic bone lesions, frequent hypercalcemia, and an overall disease picture clinically mimicking multiple myeloma.