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Several phase I trials and pilot studies using Monoclonal Antibody (MoAb) have been performed in B-cell neoplasms, but this approach has not until now been extensively tested in myeloid leukemias. Recently, we evaluated the use of anti-Granulocyte-Macrophage Colony-Stimulating Factor MoAb (Anti-GM-CSF MoAb) in acute myeloid leukemia (AML). Eight patients fulfilled inclusion criteria and received a single course of Anti-GM-CSF MoAb infusion during 5 to 15 days. Anti-GM-CSF MoAb was well tolerated and was detectable in pharmacokinetics studies. Using Human Anti-Rat Antibodies (HARA), we also observed an immunological response to the MoAb. Despite sufficient levels detected in the serum and biological activity of Anti-GM-CSF MoAb in vivo, no anti-leukemic effect was noted, except for one patient who had a decrease of 50% in the marrow blast cell mass. These observations indicate that leukemic proliferation in vivo involves a complex network spanning many mechanisms, and inhibition of leukemia is not effective if only one of these key targets is attacked. The development of these new approaches may be more effective in the future.

Objective: To describe the outcome of an unselected large series of patients with lymphoblastic lymphoma (LBL) treated in a single institution., Patients and Methods: Sixty-two patients were treated between 1980 and 1992. Induction chemotherapy (CT) to achieve complete response (CR) was: French Multicenter Acute Lymphoblastic Leukemia (ALL) protocols (38), non-Hodgkin's Lymphoma (NHL) protocols (20). Thirty patients underwent transplant after achieving CR (allogeneic 12; autologous 18)., Results: Forty-six patients (74%) achieved CR and 16 (26%) failed to respond. The patients who received an ALL induction had an 89% CR rate, while the CR rate was 52% in patients who received a NHL-like regimen. With a median follow-up of 93 months (range 36-187), the actuarial overall survival (OS) rate for all patients is 49% at five years and 41% at 10 years, and the actuarial event-free survival (EFS) rate is 45% and 37%. OS and EFS in the grafted population are, respectively, 60% and 56% at five years. Our results also show a trend toward a longer OS in allografted group., Conclusions: ALL induction therapy is more effective than the NHL-like regimen for augmenting the CR rate. Autologous or allogeneic transplantation should be considered as consolidation therapy in high-risk group patients.

The study presented is a clinical and economic comparison of bone marrow (BM) and blood cells (BC) allogeneic transplantation. We performed a case-control study to compare 17 patients receiving allogeneic BC transplant in a pilot study to an historical group of 17 patients allografted with BM. We evaluated the clinical outcomes and the direct medical costs of transplantation from conditioning regimen until day 100 by detailed observation of patients' medical records. Patients in the BC group received a median of 8 x 10(6)/kg CD34+ cells (1.58-29.1) and 266 x 10(6)/kg CD3+ cells (128-469). All patients had neutrophil engraftment with a median of 14 days in the BC group vs 19 days in the BM group (P < 0.05). The Kaplan-Meier estimation of the median number of days to a platelet count of > 25 x 10(9)/l, independent of platelet transfusion, was significantly shorter in the BC group (15 (9-74)) compared with the BM group (25 (15-45)). Acute graft-versus-host disease (AGVHD) of grade > or = 2 was not significantly different between the two groups. Patients treated with BC presented a US$16,134 decrease in the cost of the first 100 days (29%, P = 0.006). Our comparison suggested that platelet reconstitution and total costs were in favor of the BC group.

Clinical data and animal models afford evidence for anti-leukemia immunity in humans, but the interactions critical for blast cell recognition are unresolved. Expression of B7 molecules by antigen-presenting cells (APC) provides co-stimulatory signals to T lymphocytes via CD28 and CTLA-4 which prevent the induction of alloantigen-specific tolerance. Conversely, expression of CD40 ligand by stimulated T cells activates APC via CD40. In human hematological B cell malignancies (follicular lymphoma and chronic lymphocytic leukemia), the defect in alloantigen presentation of tumoral cells can be repaired by up-regulation of B7 and other co-stimulatory molecules via CD40. We studied the role of B7 molecules in alloimmune recognition and the various ways to improve the antitumoral response on peripheral blood leukemic cells from 20 patients with a diagnosis of primary acute myeloid leukemia (AML). We focused on myelo/monocytic M4/M5 French-American-British classification subtypes which are considered as the neoplastic counterpart of normal monocytes, a prototypic APC. In one-way mixed lymphocyte reaction of CD4+ T cells against leukemic cells, differences in B7-1, B7-2 or CD40 expression by AML cells did not induce specific cytokine secretion; interleukin (IL)-2 and interferon (IFN)-gamma were detected but not IL-4, corresponding to a Th1 pattern. Blockade experiments showed that proliferation and IFN-gamma secretion only partially depended on B7 molecules, which in contrast had a pivotal role in IL-2 synthesis. In contrast with murine models which suggest a pivotal role for CD80/B7-1 in the immune response against AML, our data support a greater role for CD86/B7-2, in line with the baseline expression of CD86/B7-2 and lack of CD80/B7-1 on most M4/M5 AML cells. AML cell stimulation via CD40: (1) significantly improved IL-2 secretion but not proliferation of responding T lymphocytes, (2) increased CD54/ICAM-1 expression in three quarters of cases, (3) failed in most cases to induce CD40-specific CD80/B7-1 up-regulation, and (4) had a weak effect on CD86/B7-2 expression. These data contrast with the very efficient up-regulation of both B7 co-stimulatory molecule expression and tumoral cell alloimmune recognition following CD40 stimulation in B cell malignancy models. The role of the defective B7 molecule up-regulation by the CD40 pathway in inefficient tumor immunogenicity of primary AML cells has to be further investigated, in particular using transfection experiments of CD80/B7-1-deficient AML cell lines. From our in vitro data we conclude that B7 molecules play an important role in the alloimmune surveillance of AML as suggested by the high B7 molecule dependency of IL-2 secretion. Nonetheless, the contribution of B7 molecules to alloimmune T cell proliferation against primary AML cells in human and the way to improve it--regulation via CD40 in particular--differ from B cell malignancies and murine models, suggesting the requirement for specific strategies in the development of antitumor immunity.

Interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) have shown synergistic immunomodulatory and anti-tumor effects in preclinical studies. The present study was designed to assess the effects of the combination of these cytokines after autologous bone marrow transplantation (ABMT). Ten patients received rIFN-gamma alone and 13 patients the combination of rIFN-gamma + rIL-2. Patients received transplants because of lymphoma (10 patients), acute leukemia (3 patients) or solid tumors (10 patients). Immunotherapy was started at a median of 67 days after ABMT. All patients received either 5 x 10(6) (8 pts) or 10 x 10(6) IU/m2 (16 pts) rIFN-gamma by subcutaneous injection 3 times weekly for 14 weeks. rIL-2 therapy consisted of 5 cycles of continuous intravenous infusion of 12 x 10(6) IU/m2/day starting 1 week after administration of rIFN-gamma. In the rIFN-gamma group, toxicity was mild and some biological changes were seen (NK/LAK activation, increase of phagocytosis and of NBT reduction). The combination of rIFN-gamma with rIL-2 did not increase the usual rIL-2 toxicity. NK/LAK cytotoxicity was strongly activated after the first cycle of rIL-2 and was maintained until the end of therapy. Granulocyte chemotaxis was defective after cycle 1 but recovered thereafter. We conclude that the administration of rIFN-gamma + rIL-2 is feasible after ABMT. Our data suggest that the combination may have prolonged the immunologic activation provided by rIL-2 and some improvement of the deleterious effects of rIL-2 on granulocyte functions was achieved. Controlled studies are warranted to assess the impact of this strategy on biological response and patient outcome.

Purpose: To demonstrate the feasibility and efficacy of six ambulatory high-dose sequential chemotherapy courses that include three intensified cycles supported by stem-cell infusion in high-risk and high-intermediate-risk untreated non-Hodgkin's lymphoma (NHL) patients., Patients and Methods: A pilot nonrandomized study included 20 untreated patients aged less than 60 years with aggressive histologically identified NHL and two or three adverse-prognosis criteria (International Index). Patients received an ambulatory regimen with high-dose chemotherapy supported by granulocyte colony-stimulating factor (G-CSF) and repeated peripheral-blood stem-cell (PBSC) infusion. The median age was 39 years (range, 20 to 59), with 13 men and seven women. Chemotherapy consisted of one cycle every 21 days for a total of six cycles. The first three cycles (A1, A2, and A3) consisted of cyclophosphamide (Cy) 3,000 mg/m2, doxorubicin (Doxo) 75 mg/m2, and vincristine 2 mg (plus corticosteroids). The last three cycles (B4, B5, and B6) consisted of the same drug combination plus etoposide 300 mg/m2 and cisplatin 100 mg/m2. For an expected duration of 18 weeks, the projected dose-intensity was 25 mg/m2/wk for Doxo and 1,000 mg/m2/wk for Cy. G-CSF 300 micrograms was administered from day 6 following each cycle until neutrophil reconstitution. Two aphereses were performed at approximately day 13 after each A cycle, and PBSCs were injected at day 4 of each B cycle. Radiotherapy on tumor masses > or = 5 cm was scheduled after completion of the last cycle., Results: The median duration of grade 4 neutropenia was 1 day (range, 0 to 7) for each A cycle and 4 days (range, 1 to 10) for each B cycle (P = .02). The median duration of grade 4 thrombopenia was 0 days (range, 0 to 8) for each A cycle and 6 days (range, 1 to 21) for each B cycle (P < .001). Hospitalization for febrile neutropenia was required for 18% and 44% of patients during cycles A and B, respectively (P < .01). Only three patients did not complete the protocol: one due to emergency surgery after cycle B4, one who died after cycle B5 from interstitial pneumonia, and one with delayed hematologic reconstitution after cycle B4. Chemotherapy delivery was optimal (median actual relative dose-intensity, 97%; range, 66 to 100). The median total dose administered over 18 weeks was 18,000 mg Cy (range, 12,000 to 18,000), 450 mg Doxo (range, 300 to 450), 900 mg etoposide (range, 300 to 900), and 300 mg cisplatin (range, 100 to 300). Evaluation of response after six courses showed 13 complete remissions ([CRs] 65%), four partial remissions (PRs), two nonresponses (NRs), and one toxic death. With a median follow-up period of 25 months (range, 16 to 43), 15 patients are alive, with 12 in continuous first CR; five patients relapsed (four of four PRs and one of 13 CRs). Two-year survival and failure-free survival (FFS) rates are 73% and 56%, respectively. The disease-free survival (DFS) rate for the CRs is 86%., Conclusion: PBSC support contributes to the feasibility of first-line, very-high-dose, ambulatory chemotherapy delivery in poor-risk NHL and is associated with a high rate of remission and FFS.

Pericentric inversion of chromosome 16, translocation (16;16) and del(16q), resulting in a chimerical fusion of CBFbeta and MYH11 genes, are typically seen in the M4Eo French-American-British (FAB) classification subset of acute myelogenous leukemia (AML). In this study, we analyzed 70 cases of acute non-lymphoblastic leukemia, mainly of the M4 or M5 type. We report the very unusual presence of the t(16;16) and CBFbeta/MYH11 fusion transcript in an M7 patient. Ten M4Eo and four non-M4Eo patients presented an inv(16), t(16;16) or CBFbeta/MYH11 fusion transcript. In most cases, the common 'A-type' CBFbeta/MYH11 fusion transcript was detected. In addition to the eight different breakpoints and the three alternative splicing variants already described, evidence of a new CBFbeta/MYH11 fusion transcript was found which involves a 785-bp deletion of MYH11. Moreover, two patients had an unusual transcript, to our knowledge only observed once. Only one patient had abnormal eosinophilic differentiation without chromosome 16 cytogenetic abnormalities or detectable CBFbeta/MYH11 fusion. Conversely, only one patient presented CBFbeta/MYH11 fusion without abnormal eosinophilic differentiation. Altogether, our data suggest a correlation between the CBFbeta/MYH11 fusion transcript and characteristic abnormal eosinophilic differentiation, whatever the FAB subtype or the percentage of abnormal eosinophils

Objectives: Describe and analyze the processes which lead to patient compliance or non-compliance in HIV treatment trials and to develop a model for strategies aimed at improving compliance and facilitating inclusion (adherence) of these patients., Method: First, 12 members of the health care teams at two day care clinics (Internal medicine unit, Sainte-Marguerite Hospital, Marseille and Hematology unit, Cimiez Hospital, Nice) were interviewed. In addition, 40 patients involved in the Delta trial (known compliance in 22, non compliance in 7, trial refusal in 7 and eligibility in 5 who were not invited to participate) responded in semi-directive discussions., Results: The physicians found that the responses were a priori in agreement with patient compliance for those who had participated. Physicians tended to introduce "unofficial" criteria to select patients on the basis of "psychosociological" patterns. Patient agreement to begin the trial or to refuse inclusion and their compliance to medical prescriptions depended in part on their personal opinion concerning AIDS treatment. Patients who presevered in following medical prescriptions in the long-term trial adapted their lifestyle to the new care system (participation in the trial) and discussed their "adaptation" with the physician. The importance of the patient-physician relationship is of prime importance in the behavior of compliant patients., Conclusion: A communication strategy, reinforcing patient adherence at inclusion and favoring compliance during the trial should be part of the "basic rules" for controlled regulation of compliance in clinical trials.

Objective: To describe the impact of HIV diagnosis on contraception, incidence of pregnancy and live-births among HIV-infected women in France., Design: Follow-up of women included in a French cohort of HIV-infected adults (SEROCO)., Methods: In 17 hospital-based units and one private practitioners' network in the Paris area and south-east region of France, 412 HIV-infected women (volunteers) were enrolled from 1988 to 1993, shortly after HIV diagnosis (median, 3 months), and followed for a median of 3 years. The main outcome measures were incidence and outcome of pregnancy, proportions of women sexually active and methods of contraception., Results: The incidence of pregnancy decreased significantly from 20.4 per 100 person-years in the year preceding HIV diagnosis to 7.9 per 100 person-years after HIV diagnosis (P < 0.001), whereas the proportion of pregnancies voluntarily interrupted doubled (63 versus 29%). The proportion of women who were sexually inactive increased from 5% before HIV diagnosis to 20% thereafter. During followup, 80% of sexually active women were using contraceptive methods., Conclusions: The study supports an association between the discovery of HIV infection and a decrease in the proportion of women who are sexually active, a decrease in the incidence of pregnancy in general and live-births in particular, and an increase in the proportion of pregnancies voluntarily interrupted. Nevertheless, 24% of the women became pregnant and around 20% of sexually active women were not using any contraception. The high rate of voluntary abortion may indicate that many of these pregnancies were unplanned and could have been prevented.

Background: AIDS-related sclerosing cholangitis occurs in patients with advanced immunodeficiency, but ductal pancreatic alterations have not been evaluated in large series., Methods: Twenty-nine consecutive patients with a mean age of 33 years underwent ERCP for biliary work-up. Complete pancreatography was obtained in 28 patients. Serum levels of amylase were increased in 17 patients prior to ERCP. The mean duration of HIV infection was 6.1 years (range 3 to 10 years)., Results: Fifteen patients (53.6%) had pancreatographic changes classified according to the Cambridge classification (stage 1, 4 cases; stage 2, 7 cases; stage 3, 4 cases). Dilatations, irregularities, short stenoses of the main pancreatic duct, and irregularities of side branches were the most frequent abnormalities. Fourteen of these 15 patients (93.3%) had cholangitis and a CD4 cell count of less than 60 per cubic millimeter. Risk factors for pancreatic damage were similar in patients with and without pancreatographic changes. Opportunistic infection occurred in 14 of 15 patients with pancreatographic changes (candida, cytomegalovirus, cryptosporidia, microsporidia, and mycobacteria)., Conclusion: Abnormal pancreatographies were found in about half of the HIV-infected patients who underwent ERCP. The pancreatographic features were suggestive of chronic pancreatitis and were closely related to the presence of AIDS-related sclerosing cholangitis.

In 204 adult patients with de novo acute myeloid leukemia (AML), we prospectively compared allogeneic bone marrow transplantation (alloBMT), autologous stem cell transplantation (ASCT) and chemotherapy (Chemo). 162 patients (79.4%) achieved a complete remission (CR). Of the 135 patients who were still in CR after consolidation, 96 patients were less than 46 years of age: 36 patients had an HLA-identical sibling donor and were allocated for alloBMT (group I); they were compared to the 60 other patients who did not have an HLA-identical sibling donor and were treated with either ASCT or chemotherapy (group II). The 3-year disease-free survival was higher for group I patients (66.5 +/- 16%) than for the 60 group II patients (42.4 +/- 13%) (P < 0.05). The actuarial risk of relapse at 3 years was significantly lower for group I patients (24 +/- 15%) than for the other 60 group II patients (56 +/- 13%; P < 0.009). By multivariate analysis, the disease-free survival and risk of relapse were influenced by the initial WBC count (P < 0.02 and P < 0.006), the number of chemotherapy courses for CR (P < 0.001 and P < 0.01) and the type of post-induction treatment (alloBMT vs no alloBMT; P < 0.1 and P < 0.02). The 99 patients who did not fulfill the inclusion criteria for alloBMT were given intensive chemotherapy including high-dose aracytine. When they were still in CR (n = 77), these patients were then randomized for either ASCT (n = 39) or Chemo (n = 38). We were unable to detect any statistical difference between ASCT and Chemo for either disease-free survival, risk of relapse or survival. These results indicate that alloBMT seems to produce results which are at least superior to those of other therapeutic modalities. The results of either ASCT or Chemo look similar.

High-dose chemotherapy (HDC) supported by autologous transplantation of blood stem cells (BSC) is used increasingly for patients with poor-risk malignancies. We report our experience with 93 consecutive patients who were mobilized with recombinant human granulocyte colony-stimulating factor (rhG-CSF) alone. They received a fixed dose of G-CSF for 5 or 6 days, and BSC were collected by leukapheresis. Aphereses were evaluated for MNC, CD34+ cells, and CFU-GM counts and cryopreserved. All patients received a conditioning regimen without TBI. Engraftment was assessed as the first of 2 consecutive days on which patients achieved 0.5 and 1 x 10(9)/L neutrophils and an unsupported platelet count of 25 x 10(9)/L. Multivariate analysis was performed to study patients and graft characteristics that could influence reconstitution. The G-CSF priming regimen was well tolerated and allowed collection of BSC for all patients, 66% of them achieving >3 x 10(6)/kg CD34+ cells, and 86% achieving >10 x 10(4) CFU-GM/kg. The numbers of collected CD34 and CFU-GM cells were highly correlated. The number of courses of chemotherapy prior to collection, a diagnosis of breast cancer, the use of rhG-CSF posttransplant, and the numbers of CFU-GM and CD34+ cells reinfused were correlated with hematologic recovery. In a multivariate analysis, however, the number of CD34+ cells was the only factor independently influencing both granulocyte and platelet recovery. Patients who received at least 3 x 10(6)/kg CD34+ cells achieved granulocyte reconstitution on day 11 after reinfusion (range 8-15) and an unsupported platelet count of 25 x 10(9)/l on day 14 (range 12-180), significantly earlier than patients who received fewer cells (p < 0.001). In addition, G-CSF administration postreinfusion independently enhanced granulocyte reconstitution but not platelet recovery. In conclusion, CD34+ cell number appears to be the only factor predicting both granulocyte and platelet reconstitution. Based on this study, the collection of a minimal number of 3 x 10(6)/kg CD34+ cells appears desirable.

In this pilot study; we assessed the immunosuppressive and the antileukemic potential of a combination of busulfan and melphalan prior to allogeneic BMT in 25 adult patients with refractory or relapsed hematological malignancies. Twelve patients were transplanted for acute myeloid leukemia (relapse: five patients; primary refractory: four patients; second remission: two patients), two patients for primary refractory acute lymphoblastic leukemia, nine patients for chronic myelogenous leukemia (accelerated phase: six patients; blastic phase: three patients) and two patients for primary refractory lymphoma. All received an unmanipulated marrow from HLA-identical siblings. All patients but one engrafted (median time to ANC > or = 0.5 x 10(9)/l = 17 days, to platelets > or = 50 x 10(9)/l = 29 days). Full chimerism was documented in the seven evaluable patients. The probability for developing acute GVHD was 58%. Complete remission was obtained in 17/18 measurable patients. With a 42 month median follow-up, eight patients are alive in unmaintained remission. The 4-year probabilities for relapse, survival, and DFS are respectively: 42%, 35%, and 31%. These results show that the combination of busulfan and melphalan ensures an effective immunosuppression allowing long-term engraftment. This regimen can provide long-term disease-free survival in patients with high-risk disease and thus represents an interesting alternative to the CY and/or TBI-containing regimens.

Paroxysmal nocturnal haemoglobinuria (PNH) is defined as a somatic mutation of a clonal population of stem cells. Consequently, when aplastic anaemia (AA) occurs in patients with a history of PNH, allogeneic bone marrow transplantation is considered as the only effective treatment. The impact of immunosuppressive therapy has not been reported in this situation. We present observations of three PNH patients who developed AA and were effectively treated with cyclosporin A (CSA). Because of lack of improvement with other treatments, CSA alone was given at a dose of 5-10mg/kg/d. Complete response (CR) was obtained in two patients after 6 and 24 months respectively. A partial response (PR) was observed in the third patient after 12 months. Transient elevated LDH and haemosiderinuria persisted in all cases. DAF and MIRL deficiency were still documented in the two patients in CR. Two patients (one CR, one PR) ceased CSA therapy after 12 months and relapsed within 3-6 months. CSA was reinitiated and led to platelet recovery in one patient after 6 months. The persistence of the abnormal PNH clone is coherent with the hypothesis that CSA does not act directly on the PNH clone but probably acts through regulation of the inhibitory effects of immunocompetent cells on haemopoiesis. These observations suggest that patients suffering from severe AA complicated PNH should not be excluded from immunosuppressive therapy.

A prospective randomized study was conducted comparing the efficacy and toxicity of two anthracyclines for the treatment of patients with acute myeloid leukemia (AML) between 55 and 75 years. A total of 220 patients were randomized to receive as induction chemotherapy cytosine arabinoside (Ara-C: 100 mg/m2/day; continuous infusion for 7 days) combined with either daunorubicin (DNR: 50 mg/m2/day, i.v. bolus for 3 days) (n=108) or idarubicin (IDA: 8 mg/m2/day, i.v. bolus for 5 days) (n=112). The complete remission (CR) rate was similar (P=0.296) after IDA (76/112; 68%) and DNR (66/108; 61%) (P=0.3). For patients aged 55-65, the CR rate was significantly higher after IDA (39/47; 83%) than after DNR (29/50; 58%) (P=0.007). Persistent leukemia was more frequent after DNR (26/108) than after IDA (13/112; P=0.015). Hematological and extra-hematological toxicities were similar. The CR patients were given a consolidation course of chemotherapy with Ara-C: 50 mg/m2/12 h, subcutaneously for 5 days, combined with either DNR:30 mg m2/day, i.v. bolus for 3 days or IDA:8 mg/m2/day i.v. bolus for 3 days according to the initial randomization, and then received a continuous maintenance treatment for 2 years. The survival and disease-free survival (DFS) were similar in both groups; there was no difference in the risk of relapse. However, there was a trend for a longer event-free survival (EFS) in the IDA group than for the DNR patients (P=0.07). Our results seem to indicate that IDA is probably more efficient than DNR for AML patients between 55 and 75 years, and confirm the data published in other studies comparing prospectively IDA and DNR in adults.

Human immunodeficiency virus (HIV) infection as seen in Europe and the United States has predominantly been contracted through male homosexual sex or intravenous drug abuse. In infected subjects, the brain is frequently affected both clinically and neuropathologically. The aim of this multicenter study has been to evaluate the value of single-voxel proton magnetic resonance spectroscopy (MRS) in the assessment of the neurological complications of acquired immunodeficiency syndrome (AIDS). MRS (voxel size = 8 ml, TR/TE = 1600/135 msec) was performed in 137 HIV-1-seropositive patients and 64 healthy controls without risk factors at three clinical MR sites operating at 1.5 T. The first result of this multicenter trial is that good reproducibility of results among participating sites was found. This demonstrates the reliability and robustness of MRS in the study of in vivo brain metabolism. In HIV patients, there was no significant correlation between metabolite ratios of brain detected by MRS and CDC grouping of patients or CD4 count. In contrast, the variations of brain metabolite ratios (NA/Cr, NA/Cho, and Cho/Cr) were related to the occurrence of encephalopathy, brain atrophy, or diffuse white matter lesions. There was no significant difference in brain metabolites between male homosexual AIDS patients and male intravenous drug user AIDS patients, whatever their neurological status (neurosymptomatic or neuroasymptomatic). Thus, the mode of transmission of HIV infection does not appear to affect the cerebral changes observed in the proton spectra from AIDS patients. Because of its ease of implementation and high information content, single-voxel proton MRS is likely to play a significant role in the evaluation of HIV-related encephalopathies.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a stem cell, involving myeloid, erythroid, megacaryocyte, lymphoid B-cells and "natural killer" cells. The hallmark of CML is the Philadelphia (Ph) chromosome which is a shortened chromosome 22 (22q-) resulting from a reciprocal translocation involving chromosome 9 and chromosome 22, designed t (9;22) (q34;q11). This translocation juxtaposes parts of two genes; ABL on chromosome 9 and BCR (breakpoint cluster region) on chromosome 22. Transcription of the BCR/ABL fusion gene results in an hybrid mRNA that is translated into a 210 kDa or 190 kDa protein, depending on the location of the breakpoint in the bcr region. This protein plays a key role in CML: its tyrosine-kinase activity, that differs from the normal ABL product, may be involved in leukemic cell growth. Nonetheless, the loss of the negative cell growth regulation by c-ABL, or BCR/ABL fusion protein interaction with other cellular genes (such as RAS or c-MYC) could also be involved in CML pathophysiology. A better understanding of the molecular mecanisms of CML could lead to specific treatment, such as tyrosine-kinase inhibitors, synthetic oligodeoxynucleotides, or site-specific DNA-binding proteins designed against BCR/ABL oncogenic fusion sequence.

We report the case of a patient having Philadelphia-negative, bcr-abl-positive chronic myeloid leukemia. In situ hybridization showed the presence of the bcr-abl fusion on the chromosome 9 long arm in all mitoses observed. Stability of the disease was very difficult to obtain because of serious adverse effects to interferon and chemotherapy, mainly grade IV neutropenia, and a blast crisis occurred 12 months after diagnosis. Only three other patients with such presentation (Philadelphia negative, bcr-abl positive with bcr-abl fusion on the chromosome 9 long arm) have been reported, with a poor therapeutic response and outcome in two of them. Translocation of BCR to chromosome 9 may therefore have a worse prognosis than translocation of ABL to chromosome 22 in Philadelphia-negative chronic myeloid leukemia.

m-BCR chronic myeloid leukaemia (CML) is a rare entity. We report a patient presenting with Philadelphia (Ph)-positive, m-BCR-positive acute lymphoblastic leukaemia (ALL) who achieved complete remission after induction chemotherapy, but showed a majority of Ph-positive mitoses during this remission. A diagnosis of m-BCR CML was established and the patient was given interferon alpha therapy. This is the first m-BCR CML presenting as ab initio ALL. This report emphasizes the importance of karyotyping Ph-positive ALL during remission so as not to misdiagnose CML patients who can benefit from Interferon therapy.

The Philadelphia chromosome (Ph) is the cytogenetic hallmark of chronic myeloid leukaemia (CML) and is used to confirm the diagnosis of CML based on clinical and morphological criteria. We investigated 14 patients with features of CML but without detectable Ph chromosome. In seven patients, referred to as BCR+, M-bcr/abl rearrangement was detected by polymerase chain reaction (PCR). The seven remaining patients did not have M-bcr/abl rearrangement and are described as BCR-. BCR- patients were younger, had lower white blood cell counts (WBC) and lower basophilia. Four BCR- and four BCR+ patients underwent blastic transformation (BT). Response to therapy was fairly similar in both populations. According to French-American-British (FAB) Cooperative Leukaemia Group guidelines, all BCR- patients were classified as having classic form CML or 'chronic granulocytic leukaemia' (CGL) when based only on morphological data. This study further confirms the existence of true CML cases without Ph chromosome or M-bcr/abl rearrangement and shows that this entity differs only slightly from classic form Ph+ CML. The Ph-BCR- subgroup raises two problems. First, the differential diagnosis with atypical CML or CMML, based on morphological data, and secondly, the therapeutic follow-up in the absence of a specific marker. In contrast, the residual disease of Ph-BCR- patients can be monitored by PCR. More advanced molecular and biochemical techniques will be required to understand which molecular mechanisms underlie Ph-BCR- CML, resulting in phenotypes sometimes indistinguishable from Ph+ CML.

A survey was carried out in May-June 1992, in the city of Marseille (South-Eastern France), to analyze attitudes towards ethical issues associated with the care of HIV-infected patients in a random sample of general practitioners (GPs) (telephone interviews; answer rate = 78.6%; n = 313). A total of 70.6% were consulted by HIV carriers and 48.9% regularly took care of these patients over the past year. Multi-dimensional analysis showed that support for HIV mandatory screening was related to lack of knowledge and experience with HIV infection, high perception of risks associated with HIV care, and the individual characteristics of GPs, such as religious beliefs and intolerance to uncertain situations. GPs with experience of regular care of HIV carriers had the same opinions than the rest of the sample about 'creation of specialized hospitals for AIDS patients' and similar attitudes toward HIV testing 'without patients' consent' or breaching of confidentiality of HIV diagnosis. Debates on ethical issues among GPs cannot be reduced to a simplistic division of a 'liberal group' highly involved in prevention and HIV care and a 'conservative' majority more or less inclined to stigmatize HIV-infected patients. Ambiguous messages on these issues from health authorities and professional ethical bodies may have very negative impacts on the attitudes of primary care physicians regarding the acceptability of HIV-infected patients.

Clinical and pathological characteristics as well as outcome of 45 Hodgkin's disease (HD) cases collected by the French registry of HIV-associated tumors between January 1987 and December 1989 (all clinically staged according to the Ann Arbor system) were analyzed and compared with those of a cohort of 407 patients with clinical stages (CS) IA to IVB enrolled between September 1981 and August 1988 in a multicentric clinical trial. The route of HIV infection, initial CD4 cell count at the time of HD diagnosis and CDC class of HIV infection were studied as well as the progression to AIDS onset were recorded. HIV-HD is characterized by a predominance of advanced CS (75%), B symptoms (80%) and mixed cellularity histology (49%), as well as by early bone marrow involvement (24%); a specific feature is the rare occurrence of mediastinal involvement (13% in HIV-HD versus 71% in primary HD). With standard therapies, 79% of the patients achieved a complete remission, but hematological and infectious complications were very frequent. The proportion of intravenous drug abusers (IVDA) in HIV-HD (38%) is higher than in French HIV-infected population as a whole (20.8%). Median CD4 cell count was 306/microliters at the time of HD diagnosis, while only 5 cases (11%) were preceded by an AIDS manifestation; progression to AIDS rate was 94% at 2 years. Overall 2-year survival was 41%, with 71% for patients with an initial CD4 cell count over 300/microliters and 0% for those with CD4 cell count lower than 300/microliters (p < 0.01); opportunistic infections were the most frequent cause of death. HIV-HD seems to occur preferentially in.(ABSTRACT TRUNCATED AT 250 WORDS)

The object of this study supported by the French Agency for AIDs Research (ANRS) was to assess knowledge and attitudes of pregnant women towards HIV infection and testing, and to compare them according to the outcome of the pregnancy (elective abortion vs delivery). Between March 22 and April 26, 1992, all women ending their pregnancy and attending one of the 72 medical centres located in South-Eastern France were asked to complete an anonymous questionnaire (n = 4303). 3,854 (89.6%) responded: 2,825 women at delivery (WD) and 764 who chose an elective abortion (WA). 61.7% of WD and 24.1% of WA declared having been tested for HIV during pregnancy (p < 0.001). Among women who reported not having been HIV tested, very few did so because they refused the test (1.7% among WD and 1.4% among WA-NS). Prior HIV testing was less frequent among WA than among WD (45.8% vs 58.8%--p < 0.001). 2.8% of women tested during prenatal care and 20% in the context of abortion did not know the result of their test (p < 0.001). Knowledge about HIV transmission declared by WD did not differ significantly from that declared by WA. However, risky behaviours were more frequent among WA than among WD (38.9% vs 17.7%--p < 0.001). This research shows that French screening HIV policy in the context of pregnancy remains mainly motivated by foetal concerns. Although women who abort voluntarily report risky behaviours more frequently, the opportunity of information and counselling towards them is relatively neglected in comparison with women who deliver.

Objectives: To estimate HIV seroprevalence in the two main remand and short-stay prisons of south-eastern France and to gather linked anonymous risk-factor information., Setting: Baumettes prison, Marseille, France between 16 November and 21 December 1992., Participants: Using a self-administered questionnaire about HIV testing and risk factors for HIV infection, 295 male and 137 female inmates were interviewed. The response rate was 96% (100 and 90% for men and women, respectively). At the same time, 279 of a total of 432 (65%) inmates were serologically tested for HIV; 153 (35%) declined to provide a blood sample., Design: Anonymous cross-sectional and surveillance survey., Results: Twenty per cent of participants (84 our of 432) were intravenous drug (heroin) users (IVDU), 51% of whom reported needle-sharing prior to incarceration; 23% reported more than two sexual partners during the last year, and 13% sexual intercourse with an IVDU during the last 5 years. HIV status was available for 356 inmates (82%; 65% from blood samples and 17% from the questionnaire); 39 were HIV-infected (10.9%; 95% confidence interval, 7.7-14.2). The inmates not tested for HIV reported proportionally less risky behaviours than non-HIV-infected inmates. HIV seroprevalence was significantly higher among recidivist inmates (19.9 versus 4.4%; P < 0.0001). The rate of HIV infection was particularly high among IVDU (34 out of 84; 40%). More female non-IVDU were HIV-infected than male non-IVDU (4.1 versus 0.6%; P = 0.04)., Conclusions: This study demonstrates the high prevalence of HIV infection in south-eastern French prisons, especially among IVDU. The rates may be related to the high prevalence of risky drug practices and to delays in the development of HIV prevention programmes for IVDU in France. The higher seroprevalence rate among recidivist inmates might be the result of risk behaviours during imprisonment. Another hypothesis is that recidivist inmates are at greater risk of HIV infection because of higher levels of drug use.

We have examined 9 healthy volunteers and 63 HIV-patients (16 asymptomatic patients and 47 patients with clinical AIDS-dementia complex, ADC) by magnetic resonance spectroscopy (MRS) and imaging (MRI) on a Siemens Magnetom SP63 (1.5 T). Proton MRS of the brain was performed at 63 MHz using the PRESS sequence (echo time = 135 ms, TR = 1.6 s). Four main results have been found: (1) HIV-related encephalopathy induces significant modifications of brain metabolism analyzed by MRS and the most sensitive metabolic parameter is the N-acetyl-aspartate/Choline ratio, (2) the correlation between MRS and MRI is good in 75% of patients, (3) in 4 of the 16 neuro-asymptomatic patients (i.e. 25%) a metabolic encephalopathy was found while MRI was still normal, and (4) MR spectra describe 3 different pathological metabolic patterns in the brain of HIV patients. Two patterns might correspond to the two entities of HIV-induced lesions i.e. HIV encephalitis and HIV-related progressive leukoencephalopathy.

Objective: To assess whether postprandial dietary thermogenesis contributes to weight loss during HIV infection., Methods: The thermogenic response to a test meal (15 kcal/kg) was evaluated with indirect calorimetry in 16 HIV-infected patients in a stable condition and compared with a control group. Patients were compared according to AIDS (n = 8) or non-AIDS (n = 8) status and to body weight loss (WL; n = 9) or no loss (NL; n = 7). Indirect calorimetry was performed after fasting 6 h and during 5 h after the test meal., Results: Maximum value of energy expenditure was reached later in the WL group than in the control and NL group (200 versus 30 min, respectively). Energy expenditure returned to the initial value 300 min after the test meal (last measurement) in the control group but remained elevated in the patient group. Energy expenditure after food intake was more elevated in HIV-infected patients than in controls, especially in patients with detectable clinical change in their nutritional status (0.96 versus 0.72 kcal/kg body weight)., Conclusion: Both kinetics and quantitative aspect of dietary thermogenesis are modified during HIV infection and the different variations are dependent on the extent of body weight loss.

Objective: To determine circulating viral load in HIV-2-infected individuals., Methods: Viral load was determined in 40 HIV-2-infected adults using standardized quantitative cell and qualitative plasma viraemia assays. We also tested for proviral HIV-2 DNA using single and nested polymerase chain reaction (PCR) in fresh lymphocytes from 27 subjects. The results were compared, on the basis of the CD4+ lymphocyte count, with our published data for HIV-1 infection., Results: HIV-2 was isolated from peripheral blood mononuclear cells (PBMC) from 19 individuals and plasma from four patients. The rate of cell and plasma viraemia positivity correlated with the CD4+ cell count and HIV-2 virus load increased as the CD4+ cell count fell. The cellular HIV-2 load in the patients with a CD4+ count < 200 x 10(6)/l was similar to reported values for HIV-1, but the HIV-2 isolation rate from the plasma of these individuals was significantly lower than for HIV-1. When the CD4+ count was between 200 and 500 x 10(6)/l, the rate of HIV-2 isolation from plasma and the cellular virus load were both significantly lower than for HIV-1. When the CD4+ count was > 500 x 10(6)/l, HIV-1 and HIV-2 were undetectable in plasma and HIV-1 was isolated from PBMC in significantly more cases than HIV-2. By single PCR, amplification were positive in 14 out of 27 subjects and there was a correlation between positivity and CD4+ cell count. By nested PCR, only four of the 27 subjects, all with a high CD4+ count, remained negative., Conclusions: Differences in viral load between individuals infected with HIV-2 and those infected with HIV-1 could partly account for reported differences in the pathogenicity of the two viruses.

Background: The first cases of Hodgkin's disease (HD) associated with HIV infection were reported in 1984. Since then, short series of seropositive patients suffering from HD have been published. In order to identify the characteristics, treatment response and outcome of HIV-associated Hodgkin's disease (HIV-HD), the data of HIV-HD patients recorded between 1987 and 1989 were analysed and compared with those of primary HD patient and with those of HIV-associated non-Hodgkin's lymphoma (HIV-NHL), registered during the same period., Patients and Methods: The 45 cases of HD collected by the French registry of HIV-associated tumors between January 1987 and December 1989 were included in this study. All patients were clinically staged according to the Ann Arbor system. To compare HIV-HD characteristics with those of primary HD, we used a cohort of 407 patients with clinical stages (CS) IA to IVB, who were enrolled between September 1981 and August 1988 in a multicentric clinical trial. To identify the relationship between HIV-HD and the course of HIV infection we studied, when available, the routes of infection, initial CD4 cell count at the moment of HD diagnostic as well as the CDC class of HIV infection and compared these data with the same parameters observed in 142 HIV-NHL enrolled in the registry during the same period., Results: HIV-HD is characterized by an increase in mixed-cellularity histology (49%), with a predominance of advanced stages (75%) and B symptoms (80%). A unique observation is made regarding mediastinal involvement, present in only 13% of HIV-HD (71% in primary HD). The HIV-HD/HIV-NHL ratio was significantly higher in intravenous drug abusers than in male homosexuals. Median CD4 cell count was 306/microliters at HIV-HD diagnosis, and only 11% of the cases were preceded by an AIDS manifestation. With standard therapy, 79% of the patients achieved complete remission, but hematological and infectious complications were very frequent. The progression to AIDS rate was 94% at two years and opportunistic infections were the most frequent cause of death. Overall two-year survival was 41% with 71% for patients with initial CD 4 cell counts higher than 300/microliter and 0% for those with CD4 cell counts lower than 300/microliter (P < 0.01)., Conclusion: HIV-HD has a particular clinico-pathological profile when compared to primary HD, with a predominance of mixed-cellularity type, a high frequency of advanced stages and a high proportion of patients without mediastinal involvement. Moreover, HIV-HD seems to occur preferentially in the group of subjects infected by needle sharing. Standard HD therapy seems to be efficient but excessively toxic.

Twelve HIV-positive patients who either underwent or seroconverted after bone marrow transplantation (BMT) at the University of Marseille between 1981 and 1985 were reviewed in order to observe their rates of development of AIDS. Two patients were HIV positive prior to transplantation, while ten seroconverted after transplantation. Six patients underwent autologous BMT and six underwent allogeneic BMT; all of their respective donors were seronegative. Eleven patients developed AIDS (92%), with a mean AIDS-free time (AFT) of 1 year 8 months after BMT. Seven of those subjects died, with a mean survival over a 5-year follow-up period of 2.14 years after BMT. Five autologous recipients had a mean AFT of 2 years 3 months, with the sixth patient being AIDS free. The mean AFT for the allogeneic recipients was 1 year 2 months (p = NS), all of whom developed AIDS. These data suggest that the development of AIDS was rapid from the time when our patients seroconverted. However, this was not initially accompanied by poor survival. In summary, BMT may be indicated for HIV-positive patients who required myeloablation, despite an enhanced development of AIDS.