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Leukemic T-LGL (large granular lymphocyte) composed of clonal CD3+ TCR alphabeta+ CD8+ CD57+ cells were compared with oligoclonally CD3+ CD8hi+ CD57- lymphocytes expanded after BMT. Leukemic CD3+ CD8hi+ CD57+ LGL showed several phenotypic differences such as an upregulation of CD16 and adhesion molecules (mainly CD11c, CD58 and CD54), activation markers and an exclusive CD45RA isoform expression. Unstimulated CD3+ CD8+ CD57+ LGL from both leukemic and BMT donors spontaneously developed an ex vivo CTL-like CD3-redirected cytotoxicity but no NK cell activity. Different stimuli (PHA, PMA or rhIL-2) induced similar cytotoxic profiles after a 6-day culture involving a CD3-redirected lysis predominating over a low NK cell activity. However, culture of leukemic LGL with these stimuli allowed either a 2 week persistence (PMA or rhIL-2) of CD8+ CD57+ LGL or their disappearance after 3 days (PHA). Furthermore, leukemic CD8hi+ CD57+ T lymphocytes produced an inhibitor of cytotoxic functions as previously described for BMT recipients' CD8+ CD57+ cells. Thus, despite some phenotypic differences between both cell sources, leukemic CD57+ T-LGL display the same functional characteristics of cytotoxic effector and immunoregulatory T cells as CD8+ CD57+ T cells from BMT recipients which might represent their normal counterpart. [ABSTRACT FROM AUTHOR]

Although widely used, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a high incidence of gastrointestinal (GI) side-effects. Inhibition of the cyclooxygenase (COX) enzyme is the basis for both the efficacy and toxicity of NSAIDs. The discovery of two COX isoforms, constitutive COX-1 and inducible COX-2, has led to the hypothesis that selective inhibition of COX-2 will minimize the potential for GI toxicity without compromising efficacy. The Meloxicam Large-scale International Study Safety Assessment (MELISSA) trial reported here was therefore set up to investigate the tolerability of meloxicam, a preferential inhibitor of COX-2, compared to diclofenac. MELISSA was a large-scale, double-blind, randomized, international, prospective trial, conducted over 28 days in patients with symptomatic osteoarthritis. Patients received either meloxicam 7.5 mg or diclofenac 100 mg slow release, the recommended doses for the treatment of osteoarthritis. Evaluation of the profile of adverse events was the main aim of the trial, together with assessment of efficacy. A total of 9323 patients received treatment (4635 and 4688 in the meloxicam and diclofenac groups, respectively). Significantly fewer adverse events were reported by patients receiving meloxicam. This was attributable to fewer GI adverse events (13%) compared to diclofenac (19% P<0.001). Of the most common GI adverse events, there was significantly less dyspepsia (P<0.001), nausea and vomiting (P<0.05), abdominal pain (P<0.01) and diarrhoea (P<0.001) with meloxicam compared to diclofenac. Five patients on meloxicam experienced a perforation, ulcer or bleed vs seven on diclofenac (not significant). No endoscopically verified ulcer complication was detected in the meloxicam group compared to four with diclofenac. There were five patient days of hospitalization in patients on meloxicam compared to 121 with diclofenac. Adverse events caused withdrawal from the study in 254 patients receiving meloxicam (5.48%) compared to 373 (7.96%) on diclofenac (P<0.001). These differences were attributable to differences in reported GI adverse events (3.02% on meloxicam vs 6.14% on diclofenac; P<0.001). Differences in efficacy, as assessed by visual analogue scales, consistently favoured diclofenac. In all instances, 95% confidence intervals did not cross zero, suggesting a statistically significant effect. However, differences were small (4.5-9.0% difference) and did not reach pre-determined levels of clinical significance. Nevertheless, significantly more patients discontinued meloxicam because of lack of efficacy (80 out of 4635 vs 49 out of 4688; P<0.01). The MELISSA trial confirms earlier studies suggesting that meloxicam has a significantly improved GI tolerability profile in comparison with other NSAIDs, including diclofenac. These results may be important. These results may provide support for the hypothesis that selective inhibition of COX-2 relative to COX-1 might be an effective approach towards improved NSAID therapy. [ABSTRACT FROM PUBLISHER]

S&ELECT is a large-scale, prospective, international, multicentre, double-blind, double-dummy, randomized, parallel-group trial. Patients with exacerbation of osteoarthritis were treated with the recommended dose of meloxicam (7.5 mg) or piroxicam (20 mg) once daily for 28 days; 4320 patients were administered meloxicam and 4336 piroxicam. The incidence of adverse events was significantly lower in the meloxicam group (22.5%) compared with the piroxicam group (27.9%; P<0.001), mainly due to the significantly lower incidence of gastrointestinal (GI) adverse events in the meloxicam than in the piroxicam group (10.3% vs 15.4%; P<0.001), while the efficacy of both drugs was equivalent. Individual GI events occurred significantly less often with meloxicam than piroxicam: dyspepsia (3.4% vs 5.8%; P<0.001), nausea/vomiting (2.5% vs 3.4%; P<0.05) and abdominal pain (2.1% vs 3.6; P<0.001). There were 16 patients with perforations, ulcerations or bleeding (PUBs) of the upper GI tract in the piroxicam group compared with seven in the meloxicam group (relative risk piroxicam:meloxicam = 1.4). Four PUBs were complicated (perforations or bleedings); none of these occurred in the meloxicam group (relative risk piroxicam:meloxicam = 1.9). the outcome of SELECT is consistent with that of the large-scale clinical trial of similar design and size which compared 7.5 mg meloxicam with 100 mg diclofenac in patients with osteoarthritis, and with a previous global analysis of the safety of meloxicam. It adds further data to the proposed relationship between selective inhibition of cyclooxygenase-2 and improved GI tolerability of non-steroidal anti-inflammatory drugs. [ABSTRACT FROM PUBLISHER]

Background: Based on the national register of new cases of aplastic anaemia (AA) begun in France in 1984, a case-control study was conducted to explore the aetiology of the disease.Methods: Cases were all included in the French national register of AA. Two different groups of controls were derived with individual matching; one group from hospitalized patients in the same hospital; the other group from neighbours named by the case. A 15-year occupational history was collected through interview and then grouped into exposure categories by jobs done for one year or more. The study included 98 cases, 181 hospitalized controls, and 72 neighbours aged 18-70 years.Results: No differences appeared between the cases and both groups of controls relative to any group of occupation investigated. However, a borderline non-significant small excess for exposure to pesticides was observed among the cases when compared to hospitalized controls. Whatever the control group, no association was found between AA and exposure to solvents, ionizing radiation, fuel, oils and grease. A positive relationship between exposure to glues and AA was observed, as well as a trend towards an increased risk after exposure to paints.Conclusions: This large-scale case-control study confirmed the vanishing role of previously known toxic substances in the aetiology of AA. However, a higher proportion of AA patients reported exposure to paints and to glues, a relationship which needs further investigation because of the diversity of compounds included in these products. [ABSTRACT FROM AUTHOR]

The bone marrow karyotypes of three patients with acute myelocytic leukemia (AML) or myelodysplastic syndrome (MDS) were studied at diagnosis and revealed, multiple copies of the same chromosomal anomaly, considered as psu idic(21)(q22) associated with other rearrangement(s). The karyotype of a fourth patient with MDS in transformation showed one copy of a dicentric marker presumably derived from a similar psu idic(21) by (tandem?) interstitial amplification of part of its structure, resembling a "homogeneous staining region", and described as der(21)psu idic(21)(q22)hsr(21)(q22). This rearrangement, previously described in isolated cases only, might be considered as recurrent in AML/MDS and associated with an unfavorable prognosis. It is most probably a secondary change, because it was never observed as sole abnormality and the main association, as for trisomy 21, was with del(5q). In the four cases, the number of partial supernumerary segmental 21pter-->21q22 copies, ranged from 2 to 10. The AML1 gene did not appear to be the common target of this amplification because this locus had been lost by the psu idic(21) in one patient

Purpose: To conduct a prospective study of primary lymphoma of bone (PLB) comparatively with extraskeletal non-Hodgkin's lymphomas (ESNHLs) and secondary lymphoma of bone (SLB)., Patients and Methods: The 28 cases of PLB, 2932 cases of ESNHL, and 219 cases of SLB included between April 1, 1993, and October 1, 1997, in a treatment protocol for NHL developed by the Adult Lymphoma Study Group, were studied prospectively., Results: Of the 28 PLB patients, 17 were men and 11 women; median age was 48 years (range, 18-69). The disease was monostotic in 17 cases (involving the peripheral skeleton in 14) and polyostotic in nine cases. The proportion of patients younger than 60 years was 86% in the PLB group, 59% in the ESNHL group, and 55% in the SLB group. The Ann Arbor stage distribution (I-II/III-IV) was as follows: 54%/46% in the PLB group, 50%/50% in the ESNHL group, and 20%/80% in the SLB group. Performance status was 0 or 1 in 100% of the PLB patients, 50% of the ESNHL patients, and 20% of the SLB patients. The phenotype was B in 89% of the PLBs and 85% of the ESNHLs and SLBs. In the PLB group, 54% of patients had diffuse large cell tumors and 11% diffuse mixed tumors; in the ESNHL group, 39% had diffuse large cell, 13% diffuse mixed, and 8% diffuse immunoblastic tumors; and in the SLB group, 45% had diffuse large cell, 10% diffuse mixed, and 12% diffuse immunoblastic tumors. A complete or partial response to induction therapy was noted in 86% of PLB patients, 84% of ESNHL patients, and 78% of SLB patients. Overall five-year survival was 65% in the PLB group, 50% in the ESNHL group, and 40% in the SLB group., Discussion: Survival was better in the PLB group. Further studies are needed to determine the effect of radiation therapy at completion of the treatment protocol and to look for prognostic factors associated with bone involvement.

Purpose: The impact of treatment options on survival and late neurologic toxicity was investigated in a series of patients with primary cerebral lymphoma (PCL) and no known cause of immunosuppression., Patients and Methods: Prognostic factors for survival and treatment-induced late neurotoxicity were investigated in a retrospective series of 226 patients with PCL., Results: With a median follow-up of 76 months, the median overall survival was 16 months and 5-year survival was 19%. In a univariate analysis, age greater than 60 years, performance status, CSF protein level greater than 0.6 g/L, involvement of corpus callosum or subcortical grey structures, detectable lymphoma cells in CSF, increased serum lactate dehydrogenase (LDH), but not histological subtype, were significantly correlated with a poor survival. Treatment with chemotherapy versus radiotherapy alone (P = .05), high-dose methotrexate (HDMTX; P = .0007), and cytarabine (P = .04) correlated with a better survival in univariate analysis. Using the Cox model, age, performance status, and CSF protein were independently correlated with survival. After adjustment of these factors, treatment with an HDMTX-containing regimen remained the only treatment-related factor independently correlated with survival (P = .01). The projected incidence of treatment-induced late neurotoxicity was 26% at 6 years in this series, with a median survival from the diagnosis of late neurotoxicity of 12 months. Treatment with radiotherapy followed by chemotherapy was the only parameter correlated with late neurotoxicity in multivariate analysis (relative risk, 11.5; P = .0007)., Conclusion: Patients with PCL treated with regimens that included HDMTX followed by radiotherapy have an improved survival, but not a higher risk of late neurotoxicity as compared with other treatment modalities in this series.

Among non-Hodgkin's lymphomas, primary mediastinal large B-cell lymphoma (PMLCL) has been considered a separate entity that has specific clinical and histological aspects and a poor prognosis. In this study, we reexamined the clinicopathologic features and the response to current treatment of 141 PMLCL and compare them with 916 nonmediastinal large B-cell lymphomas (NMLCL) recorded in the same period and treated with similar combined chemotherapy. The clinical features of PMLCL at diagnosis were largely homogeneous and distinct from NMLCL, with a predilection for young women (59% with a mean age of 37 years versus 42% with a mean age of 54 years), bulky tumor (77% versus 7%, p < 10(4)), high serum lactic dehydrogenase (LDH) level 76% versus 51%, p < 10(4)), and frequent intrathoracic extension to adjacent organs such as pleura, pericardium, and lung. By contrast, extrathoracic or hematologic dissemination was uncommon (2% of bone marrow involvement versus 17%). All patients had diffuse large B-cell nonimmunoblastic, nonanaplastic lymphomas. Histological analysis of the 141 PMLCL evaluated two common patterns: the presence of large cells with clear cytoplasm (found in 38% of cases) and the presence of fibrosis (marked in 25% of cases). The presence of clear cells or intense fibrosis did not constitute prognostic indicators. Immunologic and molecular analysis assessed the profile of bcl-2 expression and the presence of Epstein-Barr virus (EBV) in PMLCL: 30% expressed a high level of bcl-2 protein; EBER RNAs were detected by in situ hybridization in only two of the 41 cases tested. Monotypic light chain restriction could be demonstrated in seven of the 41 PMLCL tested on fixed-section. Treated with polychemotherapy regimens without radiotherapy, 79% of PMLCL patients achieved a complete remission compared with 68% in the NMLCL patient group (p = 0.01). Overall, 3-year survival rates were estimated at 66 and 61%, respectively (p = 0.05), and disease-free survival rates were not significantly different (61 versus 64%). Stratified analysis on the International Prognostic Index (based on age, tumor stage, serum LDH level, and performance status) showed no difference in the overall and disease-free survivals between the two lymphoma groups. In conclusion, PMLCL can be combined with other diffuse large B-cell lymphomas on morphologic grounds; it is not associated with EBV. It responds favorably to treatment and should be managed like other high-grade lymphomas of equivalent histology. However, the uncommon clinical presentation makes it a distinct entity.

The cause of the rare and severe condition of aplastic anaemia is largely unknown, although certain drugs have been implicated as possible aetiological factors, mostly through the evidence of case reports. A case-control study was conducted in metropolitan France between 1985 and 1988 to investigate aetiological factors in aplastic anaemia. It was conducted in parallel with the establishment of a national register of the incidence of aplastic anaemia, which started in May 1984. The controls used in the study consisted of 2 hospitalized controls (i.e. patients admitted to hospital at the same time as the case) and a neighbour control named by the case. All three controls were matched for age and sex, and were interviewed by the same investigator as the case. A total of 147 cases, 287 hospitalized controls and 108 neighbour controls were interviewed. An association of varying degrees was noted between aplastic anaemia and the following conditions or treatments: clinical hepatitis during the past 6 months; history of chronic immune disorder (mainly rheumatoid arthritis); gold salts and D-penicillamine; colchicine and allo-thiopurinol; acetaminophen and salicylates. This survey confirmed the vanishing role of previously known toxic agents in the aetiology of aplastic anaemia. Some differences observed between the results of the present study and those published previously suggest that targeted studies on each category of drug according to specific disease areas should be initiated.

Monosomy 7 was detected in bone marrow cells from three patients, one with myeloid leukemia, and two others with myelodysplastic syndrome following previous chemotherapy. Fluorescence in situ hybridization (FISH), carried out with an alphoid DNA probe specific for chromosome 7 centromere, showed that a small marker chromosome present in the tumor cells' karyotype of the three patients, was derived from the missing chromosome 7. In two cases, the marker was a ring chromosome, whereas in the third case it was a tiny dot-like chromosome, unnoticed at first examination on R-banded metaphases. In the three cases, the marker was lost in a proportion of tumor cells. FISH experiments suggested that the marker centromere had undergone structural alterations, with a fluorescence pattern distinct from a normal one. On the whole, these data suggest that: firstly, leukemia-associated monosomy 7 results, in a proportion of cases, from a structural event rather than from simple loss of a whole chromosome 7; secondly, interpretation of interphase FISH must be cautious in monosomy 7 evaluation; and thirdly structural alteration of the chromosome 7 derivative alphoid DNA could explain its propensity to segregate unequally and to be lost at mitosis.

Sixteen adult patients with relapsed (7 patients) or refractory (9 patients) acute leukemia received mitoxantrone (10 mg/m2 per day for 3 days) and etoposide (200 mg/m2 per day for 3 days) with escalating dose of cyclosporin A (CsA) from a loading dose of 2 mg to 6.5 mg/kg per 2 h followed by 3 days continuous infusion of 5-15 mg/kg per day. The major toxicities were stomatitis and prolonged aplasia, occurring for 15 mg/kg per day of CsA. Transient conjugated hyperbilirubinemia occurred in all patients, and was CsA dose-dependent (r = 0.7). Adequate serum levels of CsA (> 1 microgram/ml) were obtained in 3/6 patients treated with 10 mg/kg per day and 4/4 patients with 15 mg/kg per day. The pharmacokinetic of mitoxantrone showed an unusual increase of carboxylic metabolites, parallel to CsA levels. We observed six responses (two complete and four partial remissions), and eight resistances. Two patients died at days 3 and 8 from sepsis. Before treatment, 7/16 patients tested for P-gp with C219 were positive (> 10% positive cells). 3/6 responders were P-gp-positive. At time of leukemic regrowth, cells expressing P-gp before therapy reverted to P-gp-negative cells.

Forty-eight cases of acquired aplastic anemia in children were analyzed in comparison to 26 cases of genetic aplastic anemia and 483 cases of aplastic anemia in adults. All were gathered from similar institutions and all were similarly followed and treated with androgens. The following conclusions were drawn: 1) Initial severity is greater in children than in adults, and is greater in acquired than in genetic aplastic anemia; 2) even in cases of similar initial severity, the early death rate is higher in children than in adults; 3) a multiparametric index allows the correct prediction of short-term evolution in 70% of the cases and thus aids in providing an indication for bone marrow graft; its sensitivity is similar to that of the classical parameters proposed by Camitta, et al., but its specificity significantly higher; 4) most deaths occurred during the first 3-4 months and the chance for long-term improvement appears similar in the more severe than in the less severe cases if they survive this delay; 5) some data (relapse after androgen withdrawal and androgen-dependence and failure of corticoid therapy alone) suggest that androgen therapy in children is useful, as it is in adults, and that corticosteroids do not modify the course of the disease at its usual dosage (1 mg/kg/day); and 6) very few side effects, particularly concerning height, of androgens were noted in the survivors at adult age after long-term androgen therapy prescribed before puberty.