High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series.

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.

Fluorescence in situ hybridization analysis of minute marker chromosomes in leukemia with monosomy 7.

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.

Cyclosporin A as a modifier agent in the salvage treatment of acute leukemia (AL).

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.

Leukemic CD3+ LGL share functional properties with their CD8+ CD57+ cell counterpart expanded after BMT.

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.

Primary mediastinal large B-cell lymphoma. A clinicopathologic study of 141 cases compared with 916 nonmediastinal large B-cell lymphomas, a GELA ("Groupe d'Etude des Lymphomes de l'Adulte") study.

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.

A case-control study of aplastic anaemia: occupational exposures. The French Cooperative Group for Epidemiological Study of Aplastic Anaemia.

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.

Primary lymphoma of bone: a prospective study of 28 cases.

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.

[Clinical trials in oncology: specific methodology problems]. / Essais cliniques en cancérologie: problèmes méthodologiques spécifiques.

Clinical benefit in oncology patients can only be derived from coordinated and successive experimental trials. The following consensus thus emerged from the working party: The assessment of tolerance during clinical trials requires the actuarial rate of acute adverse events (AE) to be registered and the development of epidemiological structures involved in long-term assessment of AE. Experimental trials have to be assessed according to descriptive epidemiological data (generated in France and Europe) and completed with observational studies on post-marketing medical practice. The principle of an a priori authorization given by the Afssaps for gene and cell therapy trials was legalised in October 2001. The working group spoke strongly in favour of authorizing early trials only validating the process, and for reasonable objectives in terms of viral security assessment of annex therapeutic products. With regard to the development of new antiproliferative agents, the active dose (or optimal biological dose) replaces the maximal tolerable dose. Early efficacy criteria could be biological and specific. With cumulative subacute rather than acute toxicity, these agents can not be properly evaluated with a short term benefit/risk ratio as is done for cytotoxic drugs. Elderly people constitute a fragile, heterogeneous and increasing population, in whom adequate assessment of anticancer agents is mandatory. It is important to promote controlled clinical trials in children and to systematically monitor them over a very long period of time. Only rare tumours may be considered as orphan situations. Finally, a list of all clinical trials conducted in oncology should be made by the Afssaps, with the help of the FNLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) who have already begun this work.

[Merkel cell carcinoma: primary cutaneous neuroendocrine tumor]. / Carcinome à cellules de Merkel: tumeur neuroendocrine cutanée primitive.

Merkel cell carcinoma is a neuroendocrine primitive tumor of the skin. We report a case who develops node and visceral metastasis, and dead. The clinical presentation, diagnosis, histology, immunocytochemistry, treatment and prognosis of this tumor will be discussed.

[Adult T-cell leukemia and non-malignant adenopathies associated with HTLV I virus. Apropos of 17 patients born in the Caribbean region and Africa]. / Leucémies à cellules T de l'adulte et adénopathies non malignes associées au virus HTLV I. A propos de 17 malades originaires des Caraïbes et d'Afrique.

Adult T-cell leukaemia is the first blood disease caused by a retrovirus: HTLV-1. The authors report the first French series of 15 patients, of whom 9 came from the classical endemic areas--the Antilles and outer Caribbean Islands--and 6 from Africa where the serological prevalence of HTLV-1 is high but few cases of adult T-cell leukaemia have been reported. Emphasis is laid on the importance of immunodeficiency (refractory strongyloidiasis, Pneumocystis carinii pneumonia, polyclonal B lymphoproliferative syndrome) and of other pathologies associated with the retrovirus (polyarthritis, lymphocytic interstitial pneumonia). The authors also describe the presence of adenopathy in healthy carriers: either adenitis suggestive of retroviral infection, or Castelman's disease adenopathy. These clinical presentations are similar to those described in lymphadenopathy syndromes due to the human immunodeficiency viruses. Aggressive lymphomas require chemotherapy, but sooner or later resistance develops, and the prognosis is very poor. The indications for allogeneic bone marrow transplantation are still to be determined. The diagnosis of adult T-cell leukaemia must be considered in all patients with blood disease coming from the endemic areas.

[Autoimmune thrombopenic purpura. Clinical practices during diagnosis. A French survey and recommendations. French College of Hemotologists Evaluation Commission]. / Purpura thrombopénique auto-immun. Pratiques cliniques lors du diagnostic. Enquête française et recommandations.

THE SURVEY: To better ascertain diagnostic and treatment strategies used by physicians for idiopathic thrombocytopenic purpura, a questionnaire was addressed to 298 French hematologists and pediatricians. One hundred and ten responses were analyzed. DIAGNOSTIC APPROACH: Thrombocytopenia was determined on capillary blood samples by 50% of the physicians and platelet-associated antibody by 44%. Bone marrow aspirates were obtained more frequently in adults (85%) than in children (47%) and immune disorders were more often investigated in 95% of adults and in 68% of children. THERAPEUTICS: Treatment threshold was lower in children (20.10(9)/l) than in adults (50.10(9)/l). Corticoidsteroids was the treatment of choice in adults (98%) and children received either IV immunoglobulins (61%) and/or corticosteroids (63%); higher doses were used in children (> or = 2 mg/kg versus 1 mg/kg) for shorter periods (> or = 2 weeks versus > 3 weeks). Treatment failure was evaluated earlier in children (< 10 days) than in adults (> 20 days). RECOMMENDATIONS: 1. Diagnosis. Based on repeatedly low platelet counts and verification that only platelets are involved. Clinical examination is normal excepting rare cases of severe hemorrhage. Search for antiplatelet antibodies is non-contributive 2. Treatment Short-term corticosteroids, both in children and adults. Intravenous gammaglobulins should be limited to cases with signs of severe hemorrhage. 3. Consult the complete guidelines for each individual clinical situation.

[Primary non-Hodgkin lymphoma of the nasal fossae and sinuses. Apropos of 8 cases]. / Les lymphomes non hodgkiniens primitifs des fosses nasales et des sinus. A propos de 8 cas.

The authors report their experience about 8 cases of nasal lymphomas diagnosed and treated between 1987 and 1993. Behind ordinary symptoms, a very bad forecast lymphoma may be hidden. Histological diagnosis is sometimes difficult and needs voluminous fresh fragments. During the evolution of this affection, local temporary nasal and paranasal remissions are often noted after chimiotherapy and/or radiotherapy, but rapidly appear visceras secondary localisations, suggesting an underestimation of the nasal and paranasal sinuses localisations among the treated non-Hodgkin's lymphomas population.

Prognostic factors and evolution of acquired aplastic anemia in childhood. A prospective analysis of 48 androgen-treated cases.

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.

Epidemiology of aplastic anemia in France: a prospective multicentric study. The French Cooperative Group for Epidemiological Study of Aplastic Anemia.

Incidence rates of aplastic anemia (AA) are rare among defined populations. Since June, 1984, a cooperative group, including 83 University medical centers throughout metropolitan France, prospectively recorded new cases of AA and followed them up. Inclusion criteria were: at least two depressed blood cell lineages (hemoglobin less than or equal to 10 g/100 mL and reticulocytes less than or equal to 50 x 10(9)/L, granulocytes less than or equal to 1.5 x 10(9)/L, platelets less than or equal to 100 x 10(9)/L) and a bone marrow biopsy compatible with the disease. Between May, 1984, and April, 1987, 292 cases were recorded. After exclusion of constitutional disease, 27 patients did not satisfy the inclusion criteria with relation to either bone marrow or blood evaluations and seven patients were initially misdiagnosed (shown in the follow-up), leaving 250 confirmed AA cases in the register. The annual incidence in France appeared to be about 1.5 per million inhabitants. The sex ratio of AA cases was similar to that of the population. In men, two peaks of incidence were observed: one between 15 and 30 years and one after 60 years. In women, the only peak was observed after 60 years. An excess of cases was observed in small towns but not in rural areas. About two of every three cases had severe AA, with a possible excess in younger cases. Based on a minimum follow-up of 1 year for 238 patients, the fatality rate was estimated at 17% at 3 months after diagnosis and at 34% at 1 year. Among 243 suspected etiologies reported by the physicians, 74% were declared idiopathic, 13% presumably associated to drug toxicity, and 5% related to hepatitis. AA appears to be a rare and severe disease in metropolitan France, often of unknown origin, a fact that emphasizes the necessity of controlled etiologic studies.

[Familial IgG kappa myeloma in a mother and her daughter. Review of the literature]. / Myélome familial IgG kappa chez une mére et sa fille. Revue de la littérature.

The case of a multiple myeloma secreting IgG kappa in both mother and daughter is reported and discussed in the light of previous reports of familial myeloma and myeloma occurring in spouses. In March 1981, the 60-year-old daughter complained of fatigue leading to the discovery of anemia. The diagnosis of myeloma was based on the association of a monoclonal IgG kappa (57.5 g/l) with low serum levels of IgM and IgA and of an increase (38%) in bone marrow plasma cells. She was treated by chemotherapy and by radiotherapy on bone lesions which appeared during the course of treatment. She died in June 1983. In October 1984, the 84-year-old mother was also found to have anemia. The diagnosis of myeloma was based on the association of a monoclonal IgG kappa (24.5 g/l) with low serum levels of IgM and IgA, 0.6 g/l of Bence-Jones protein in urine, an increase (12%) of atypical plasma cells, and of multiple lytic lesions on X-ray. Familial myeloma has been exceptionally reported. We have found only one case in mother and daughter where the myeloma protein was respectively IgA and IgG. The light chain isotype was not determined. Cases of myeloma occurring in spouses have equally been rarely reported in the medical literature. Genetic transmission of chromosomal determinants for myeloma or a type of response to environmental factors have been suspected as well as environmental determinants for myeloma. Genetically abnormal regulation of immunoglobulin synthesis is another possibility.

Drug use and aplastic anaemia: the French experience. French Cooperative Group for the Epidemiological Study of Aplastic Anaemia.

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.