[The use of administrative health databases in infectious disease epidemiology and public health]. / Apport des bases médico-administratives en épidémiologie et santé publique des maladies infectieuses.

BACKGROUND: The public health burden resulting from infectious diseases requires efforts in surveillance and evaluation of health care. The use of administrative health databases (AHD) and in particular the French national health insurance database (SNIIRAM) is an opportunity to improve knowledge in this field. The SNIIRAM data network (REDSIAM) workshop dedicated to infectious diseases conducted a narrative literature review of studies using French AHD. From the results, benefits and limits of these new tools in the field of infectious diseases are presented. METHODS: Publications identified by the members of the workgroup were collected using an analytical framework that documented the pathology of interest, the aim of the study, the goal of the developed algorithm, the kind of data, the study period, and the presence of an evaluation or a discussion of the performance of the performed algorithm. RESULTS: Fifty-five articles were identified. A majority focused on the field of vaccination coverage and joint infections. Excluding vaccine coverage field, the aim of 28 studies was epidemiological surveillance. Twenty-six studies used hospital databases exclusively, 18 used ambulatory databases exclusively and 4 used both. Validation or discussion of the performed algorithm was present in 18 studies. CONCLUSIONS: The literature review confirmed the interest of the French AHD in the infectious diseases field. The AHD are additional tools of the existing surveillance systems and their use will probably be more frequent in the coming years given their advantage and reliability. However, incoming users need to be assisted. Thus, the workgroup will contribute to a reasonable use of AHD and support future developments.

Limited impact of prognostic factors in patients with recurrent glioblastoma multiforme treated with a bevacizumab-based regimen.

Bevacizumab has demonstrated activity in patients with recurrent glioblastoma. However, the impact of prognostic factors associated with recurrent glioblastoma treated with cytotoxic agents has not been determined in patients treated with bevacizumab. To analyze the prognostic factors and clinical benefits of bevacizumab and irinotecan treatment in patients with recurrent glioblastoma. This monocentric study retrospectively analyzed all patients with recurrent glioblastoma who were treated with at least one cycle of bevacizumab and irinotecan at our institution from April 2007 to May 2010. Multivariate analysis was used to analyze prognostic factors for overall survival (OS) from the initiation of bevacizumab administration. Among the 100 patients that were identified (M/F: 65/35), the median age was 57.9 years (range: 18-76). Karnofsky Performance Status (KPS) was <70 in 44 patients and ≥ 70 in 56 patients; 83 % of the patients were on steroids. The median tumor area was 2012 mm². The median progression free survival was 3.9 months (CI 95 %: 3.4-4.3). The median OS was 6.5 months (CI 95 %: 5.6-7.4). Multivariate analysis revealed that OS was affected by KPS (p = 0.024), but not by gender, age, steroid treatment, number of previous lines of treatment, tumor size, or time from initial diagnosis. KPS was improved in 30 patients, including 14/44 patients with an initial KPS <70. The median duration of maintained functional independence (KPS ≥ 70) was 3.75 months (CI 95 %: 2.9-4.6). The median OS from initial diagnosis was 18.9 months (CI 95 %: 17.5-20.3). In patients with recurrent glioblastoma treated with bevacizumab, KPS was revealed as the only factor to impact OS. The clinical benefits associated with this regimen appear valuable. A positive impact of bevacizumab administration on OS of patients with glioblastoma multiforme is suggested.

[How to handle unexpected biological abnormalities observed in the pre-donation workup for hematopoietic stem cell transplantation: an SFGM-TC report on pre-transplant cytomegalovirus, Epstein-Barr virus, Toxoplasma gondii, or syphilis IgM positive serology test]. / Conduite à tenir devant une anomalie biologique découverte lors du bilan pré-don cellules souches hématopoïétiques: sérologie IgM positive pour le cytomégalovirus, le virus d'Epstein-Barr, la toxoplasmose, ou la syphilis.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of pre-transplant donor's cytomegalovirus, Epstein-Barr virus, Toxoplasma gondii, or syphilis IgM positive serology test.

[How to handle unexpected biological abnormalities observed in the pre-donation workup for hematopoietic stem cell transplantation: an SFGM-TC report on pre-transplant positive pregnancy test and monoclonal gammapathy]. / Conduite à tenir devant un problème du donneur de cellules souches hématopoïétiques: test de grossesse positif et gammapathie monoclonale.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of common issues related to the donor: pre-transplant pregnancy and monoclonal gammopathy.

[Metabolic testing rates after initiation of antipsychotic treatment in persons initially treated by conventional mood-stabilizers]. / Surveillance métabolique biologique après initiation d'un traitement antipsychotique chez des personnes traitées par lithium ou anticonvulsivants.

OBJECTIVES: To assess the rate of metabolic testing after initiation of second-generation antipsychotics (SGA) prescription in persons initially treated by conventional mood-stabilizers (lithium or anticonvulsants, as a proxy of bipolar disorder diagnosis) and to compare the rates of metabolic testing in these persons with those in persons with initiation of first-generation antipsychotics (FGA) prescription or with no antipsychotic prescription. METHOD: Data were anonymously extracted from the 2004 to 2006 French national health database of the Régime Social des Travailleurs Indépendants (RSI). Patients aged 18 years and over were included in the cohort if they fulfilled the following criteria over a three-month inclusion period: refunding of lithium or anticonvulsant over the 3 months without discontinuation (as a proxy of bipolar disorder diagnosis), no concomitant refunding over the 3months of antipsychotic, and no concomitant refunding over the 3 months of an anti-diabetic drug (as a marker of diabetes) or a lipid-lowering drug (as a marker of hyperlipidemia). Metabolic testing was assessed using information collected in the RSI database on the reimbursement of glucose-specific serum tests (glycaemia) and lipid-specific serum tests (total cholesterol). Serum glucose and lipid testings were assessed at baseline and at 12-week follow-up for the first episode of antipsychotic dispensing. Multivariate analyses were performed to compare the rate of metabolic testing in users of SGA to those of users of FGA and to those of non-users of antipsychotics. RESULTS: Three thousand one hundred and seventy patients were included. Of the 490 (15.4%) persons with a first episode of antipsychotic dispensing after the index date, 138 (4.3%) were dispensed only FGA over the first episode and 352 (11.1%) SGA (including 37 patients with both SGA and FGA dispensing). Metabolic testing at baseline and at 12-week follow-up was performed for 14% of persons with initiation of FGA and 12% with initiation of SGA. Almost no patient had both baseline and follow-up testing. Testing rates were lower for lipid testing than for glucose testing. Compared to persons with no antipsychotic, persons with SGA were significantly more likely to have metabolic testing at baseline and at follow-up, independently from other characteristics (adjusted OR=0.24, 95% CI 0.16 to 0.36). No difference was found between persons with SGA and those with FGA (adjusted OR=1.12, 95%CI 0.62 to 2.0). Regarding the other characteristics associated with likelihood of metabolic testing (irrespective of the treatment group), women were more likely than men to have metabolic testing at baseline but not at follow-up. Elderly persons and persons with low occupational status were more likely to have metabolic testing at follow-up. CONCLUSION: From a public health point of view, such findings indicate that the metabolic risks associated with SGA use in real-life conditions are widely underestimated. Regarding the temporal trends of antipsychotic prescription, with the dramatic rise of SGA use observed in most countries, it is a public health priority to improve metabolic monitoring in SGA users, irrespective of the underlying diagnosis. Since it is more complex to modify pre-existing inadequate practices than to initiate correct ones in new prescribers, great attention should be paid to the need for delivering strong messages regarding the metabolic risks associated with SGA prescription during the initial training of physicians.

Therapeutic drug monitoring of posaconazole in allogeneic hematopoietic stem cell transplantation patients who develop gastrointestinal graft-versus-host disease.

Posaconazole (PCZ) is the latest triazole antifungal agent that has been approved for prophylaxis of invasive aspergillosis in high-risk immunocompromised patients, such as allogeneic hematopoietic stem cell transplantation patients, who develop graft-versus-host disease (GVHD). PCZ has high interindividual variability with regard to its plasma drug trough concentrations (C(min)). Moreover, the concentration-efficiency relationship remains to be better characterized in prophylaxis. To determine the variability factors in plasma drug concentrations, the PCZ C(min) and clinical parameters (localization of GVHD, presence of diarrhea, and diagnosis of invasive aspergillosis) were collected retrospectively in 29 consecutive allogeneic hematopoietic stem cell transplantation patients who developed GVHD and were receiving prophylactic PCZ (200 mg, 3 times/day, for ≥7 days). Blood samples were analyzed at steady state to determine the PCZ C(min) by liquid chromatography-tandem mass spectrometry. The average PCZ C(min) was 1.28 ± 0.82 mg/liter (mean ± standard deviation; n = 292 dosages), with an intraindividual variability of 49% and an interindividual variability of 64%. Twenty percent of C(min)s were below 0.7 mg/liter, which is considered the threshold of efficacy by the Food and Drug Administration. The patients who had gastrointestinal (GI) GVHD experienced a 24% reduction in the posaconazole C(min), compared with those with other localizations of GVHD. This decrease reached 33% when patients presented with diarrhea due to GI GVHD or an infectious etiology. PCZ C(min)s were 26% lower when invasive aspergillosis was declared. These data demonstrate that GI disturbances affect drug concentrations. Thus, therapeutic monitoring of PCZ can be used to detect low drug concentrations, possibly resulting in a lack of efficacy of invasive aspergillosis prophylaxis.

Influence of hay and animal feed exposure on respiratory status: a longitudinal study.

Our aim was to study respiratory symptoms and lung function decline in farmers, with particular attention to the influence of handling hay, straw and animal feed. From a cohort recruited in 1993-1994, 219 (82.6%) dairy farmers, 130 (62.5%) nondairy agricultural workers and 99 (66.4%) controls were re-evaluated in 2006. They answered medical and occupational questionnaires, underwent spirometric tests at both evaluations and pulse oximetry in 2006. Dairy and nondairy agricultural workers showed an increased risk for usual morning phlegm (adjusted OR 4.27 (95% CI 1.41-12.95) and 3.59 (95% CI 1.16-11.10), respectively). Animal feed handling was associated with increased risks of wheezing (p = 0.01) and usual morning phlegm (p = 0.04); hay or straw handling was associated with increased risk of wheezing (p = 0.008). Adjusting for smoking, age, height, sex and altitude, dairy farmers had greater declines in forced expiratory volume in 1 s (FEV(1))/forced vital capacity ratio (p = 0.01) than controls. An increased decline in FEV(1) for all agricultural workers was associated with animal feed handling, both measured as a categorical (currently versus never handling; p = 0.05) or quantitative value (years of exposure during the survey period; p = 0.03). Hay, straw or animal feed handling represents a risk factor of bronchial symptoms and, for animal feed only, of accelerated decline in expiratory flows.

Impact of duration of antidepressant treatment on the risk of occurrence of a new sequence of antidepressant treatment.

INTRODUCTION: Despite the recommendation that antidepressant treatment should be continued for several months to reduce the risk of relapse/recurrence of depression, early discontinuation is frequent in naturalistic conditions. The study was aimed at exploring the impact of early discontinuation of antidepressant treatment on the risk of antidepressant re-initiation. METHODS: A follow-up study of persons (n=35,053) starting antidepressant treatment was performed using a representative sample of the French Social Security Insurance national database. RESULTS: The risk of re-initiation of antidepressant treatment was higher if the duration of the index episode of antidepressant treatment was ≥ 6 months [hazard ratio (HR)=2.35; 95% CI 2.25-2.45) or 2-5 months (HR=1.65; 95% CI 1.59-1.71) compared to ≤ 1 month. The other characteristics independently associated with re-initiation of treatment were older age, female gender, low income, serious chronic illness, index prescription by a specialist and co-prescription of other psychotropic drugs. CONCLUSIONS: The lower risk of re-initiation of antidepressant treatment in persons with shorter-than-recommended duration of antidepressant treatment might be explained by overprescription of antidepressants in persons with sub-threshold symptoms.

The vaginal microbiota and its association with human papillomavirus, Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium infections: a systematic review and meta-analysis.

BACKGROUND: The vaginal microbiota may modulate susceptibility to human papillomavirus (HPV), Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium infections. Persistent infection with a carcinogenic HPV is a prerequisite for cervical cancer, and C. trachomatis, N. gonorrheae and M. genitalium genital infections are all associated with pelvic inflammatory disease and subsequent infertility issues. OBJECTIVES: To evaluate the association between these infections and the vaginal microbiota. DATA SOURCES: The search was conducted on Medline and the Web of Science for articles published between 2000 and 2016. STUDY ELIGIBILITY CRITERIA: Inclusion criteria included a measure of association for vaginal microbiota and one of the considered STIs, female population, cohort, cross-sectional and interventional designs, and the use of PCR methods for pathogen detection. METHODS: The vaginal microbiota was dichotomized into high-Lactobacillus vaginal microbiota (HL-VMB) and low-Lactobacillus vaginal microbiota (LL-VMB), using either Nugent score, Amsel's criteria, presence of clue cells or gene sequencing. A random effects model assuming heterogeneity among the studies was used for each STI considered. RESULTS: The search yielded 1054 articles, of which 39 met the inclusion criteria. Measures of association with LL-VMB ranged from 0.6 (95% CI 0.3-1.2) to 2.8 (95% CI 0.3-28.0), 0.7 (95% CI 0.4-1.2) to 5.2 (95% CI 1.9-14.8), 0.8 (95% CI 0.5-1.4) to 3.8 (95% CI 0.4-36.2) and 0.4 (95% CI 0.1-1.5) to 6.1 (95% CI 2.0-18.5) for HPV, C. trachomatis, N. gonorrhoeae and M. genitalium infections, respectively. CONCLUSIONS: Although no clear trend for N. gonorrhoeae and M. genitalium infections could be detected, our results support a protective role of HL-VMB for HPV and C. trachomatis. Overall, these findings advocate for the use of high-resolution characterization methods for the vaginal microbiota and the need for longitudinal studies to lay the foundation for its integration in prevention and treatment strategies.

[Bevacizumab/irinotecan. An active treatment for recurrent high grade gliomas: preliminary results of an ANOCEF Multicenter Study]. / Bevacizumab/irinotecan. Un nouveau traitement actif dans les gliomes de haut grade récidivants: résultats préliminaires d'une étude multicentrique de l'Anocef.

RATIONALE: Second-line chemotherapy is disappointing in recurrent high-grade gliomas. Dramatic responses in recurrent high-grade gliomas have been reported in a recent monocentric trial with a novel association combining bevacizumab (anti-VEGF monoclonal antibody agent) and irinitecan. OBJECTIVE: To report the experience of the ANOCEF group (French speaking neuro-oncology association) using the bevacizumab-irinotecan combination in recurrent high-grade gliomas. METHODS: Eight centers were involved in this retrospective multicenter study. Bevacizumab-irinotecan was delivered as previously described in a compassional setting to non-selected patients suffering from a high-grade glioma (WHO grade III and IV). Response rate at two months of the onset of the treatment was analyzed using the Macdonald criteria. The toxicity profile of the treatment was also investigated. RESULTS: From 2006 to 2007, 77 patients were treated (median age: 52 years; median Karnofsky score: 70) for a recurrent high-grade glioma (49 grade IV, 28 grade III). At two months, the response rates were objective response=36% (54% in grade III and 27% in grade IV); stable disease=39%; progressive disease=13%; patients not evaluable because of a rapid fatal clinical deterioration=12%. Improvement was noted in 49% of patients. Among the main toxicities, we noted; intratumoral hemorrage (n=5 with spontaneous regression in three) and thromboembolic complications including venous thrombophlebitis (n=4), pulmonary embolism (n=2), myocardial infarction (n=1), grade III-IV hematotoxicity (n=2), reversible leukoencephalopathy (n=1). CONCLUSION: This retrospective multicenter study adds further arguments in favor of the promising results of this new combination and its potential rapidity of action in recurrent high-grade gliomas. Antiangiogenic agents expose the patients to a well-known risk of thromboembolic and hemorragic complications, necessitating careful follow-up and patient selection in light of the cardiovascular contraindications.

Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition.

Considerable experimental and epidemiological evidence suggests that elevated endogenous sex steroids - notably androgens and oestrogens - promote breast tumour development. In spite of this evidence, postmenopausal androgen replacement therapy with dehydroepiandrosterone (DHEA) or testosterone has been advocated for the prevention of osteoporosis and improved sexual well-being. We have conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. Levels of DHEA sulphate (DHEAS), (Delta4-androstenedione), testosterone, oestrone, oestradiol and sex-hormone binding globulin (SHBG) were measured in prediagnostic serum samples of 677 postmenopausal women who subsequently developed breast cancer and 1309 matched control subjects. Levels of free testosterone and free oestradiol were calculated from absolute concentrations of testosterone, oestradiol and SHBG. Logistic regression models were used to estimate relative risks of breast cancer by quintiles of hormone concentrations. For all sex steroids -the androgens as well as the oestrogens - elevated serum levels were positively associated with breast cancer risk, while SHBG levels were inversely related to risk. For the androgens, relative risk estimates (95% confidence intervals) between the top and bottom quintiles of the exposure distribution were: DHEAS 1.69 (1.23-2.33), androstenedione 1.94 (1.40-2.69), testosterone 1.85 (1.33-2.57) and free testosterone 2.50 (1.76-3.55). For the oestrogens, relative risk estimates were: oestrone 2.07 (1.42-3.02), oestradiol 2.28 (1.61-3.23) and free oestradiol (odds ratios 2.13 (1.52-2.98)). Adjustments for body mass index or other potential confounding factors did not substantially alter any of these relative risk estimates. Our results have shown that, among postmenopausal women, not only elevated serum oestrogens but also serum androgens are associated with increased breast cancer risk. Since DHEAS and androstenedione are largely of adrenal origin in postmenopausal women, our results indicated that elevated adrenal androgen synthesis is a risk factor for breast cancer. The results from this study caution against the use of DHEA(S), or other androgens, for postmenopausal androgen replacement therapy.

Autologous or allogeneic stem cell transplantation as post-remission therapy in refractory or relapsed acute myeloid leukemia after highly intensive chemotherapy.

Post-remission options were compared in a population of 262 relapsing and refractory acute myeloid leukemia patients achieving complete remission (CR) after the same re-induction according to etoposide - mitoxantrone - cytarabine (EMA) trials. The selection of post-remission therapy depended on trial recommendations, age, performance status, and availability of an HLA-identical sibling. One hundred and thirty patients received chemotherapy consolidation courses, 50 received autologous stem cell transplantation (SCT), and 43 underwent allogeneic bone marrow transplantation (BMT), while 39 did not receive any additional therapy. The preliminary analysis identified 3 favorable prognostic factors correlated with event-free survival (EFS): M3 subtype, previous CR duration > 1 year, and transplantation. Three year EFS was 68 vs. 23% with autologous SCT and allogeneic BMT in M3 patients and, respectively, 41 vs. 20% in non-M3 patients. Three year probabilities of treatment-related mortality were 11 and 47%, respectively. A statistical model was conceived with adjustment on prognostic factors and post-remission option. In the multivariate analysis, autologous SCT appeared significantly better than allogeneic BMT (P < 0.01) or chemotherapy (P = 0.001), while allogeneic BMT was not statistically different than chemotherapy. This indicates a high treatment-related toxicity with allogeneic BMT in patients re-induced by highly intensive chemotherapy, and therefore a tendency for a better outcome with autologous SCT as post-remission treatment in those patients.

Molecular analysis of cyclin-dependent kinase inhibitors in human leukemias.

Recurrent anomalies of the short arm of chromosome 9, including interstitial deletions and translocations, have often been described. Recently two cyclin-dependent kinase inhibitors, known as P16 (INK4A/MTS1) and P15 (INK4B/MTS2), which map to 9p21, have been found deleted in a wide range of tumors and particularly in leukemic cells. We report here Southern blot analyses of cyclin-dependent kinase inhibitors (P16, P15, P21, and P27) status in primary tumoral cells of 121 patients with acute lymphoblastic leukemias, 85 patients with acute myeloid leukemias and 42 patients with B-chronic lymphocytic leukemias. P16 inactivation was found in 25 of 38 T-ALLs and in 28 of 83 B-lineage ALLs. In eight cases (three T-ALLs and five B-lineage ALLs), one or both alleles of P16 locus were rearranged. In these cases, breakpoints occurred within the two major breakpoints cluster regions previously described in T-ALLs. Homozygous P16 deletions were observed in two of 85 AMLs but in none of the 42 B-CLL cases tested. Our results suggest that P16 inactivation are the most frequent event observed in ALL (44%), are quite rare in AML (<2%) and seem to be absent in CLL. Search for P27 and P21 deletion was negative in B/T-lineage ALLs and monoallelic deletions of P27 were found in four AML cases (5%).

Late autologous transplantation in chronic myelogenous leukemia with peripheral blood progenitor cells mobilized by G-CSF and interferon-alpha.

In chronic myelogenous leukemia (CML), autologous stem cell transplantation could be a promising new approach for patients with no cytogenetic response after interferon alpha (IFN-alpha) therapy. We report data on 28 CML patients autotransplanted in chronic phase with peripheral blood progenitor cells mobilized with G-CSF (5 microg/kg/day x 5 days) given subcutaneously while continuing IFN-alpha therapy. At mobilization, 23 patients (82%) were in complete hematological remission (CHR), 16 (57%) achieved a minor cytogenetic response (mcr). We obtained, after stimulation, a median of 37.4 x 10(9)/l (6.9-108) white blood cells, 7.2 x 10(8)/kg (2.2-16.6) mononuclear cells, 39 x 10(4)/kg (4.8-403.5) CFU-GM and 4.2 x 10(6)/kg (0-58.6) CD34+ cells. Six patients received GM-CSF after transplantation. All patients engrafted, with no significant influence stemming from the Sokal index score and pretransplantation IFN-alpha therapy duration. The first cytogenetic evaluation after transplantation showed 11 (39%) major cytogenetic response (Mcr), and nine (32%) mcr with no significant correlation between these responses, the Sokal index score, and pretransplantation IFN-alpha therapy duration, although there was a significant impact from GM-CSF administration (P=0.01). After transplantation, 26 patients received IFN-alpha alone or associated with hydroxyurea. The median follow-up was 12 months after transplantation and 57 months after diagnosis. At the time of follow-up, nine patients were in CHR, six remained stable in chronic phase, three presented an mcr and one remained in Mcr. At the last follow-up, 22 patients were alive. We conclude that the results of this strategy are encouraging in poor IFN-alpha responders but that other prospective studies that try to maintain the cytogenetic responses obtained immediately after transplantation are needed.

Transplantation with selected autologous peripheral blood CD34+Thy1+ hematopoietic stem cells (HSCs) in multiple myeloma: impact of HSC dose on engraftment, safety, and immune reconstitution.

OBJECTIVE: The aims of our study performed in myeloma were to evaluate the performance and the safety of Systemix's high-speed clinical cell sorter, to assess the safety and efficacy of deescalating cell dose cohorts of CD34+Thyl+ hematopoietic stem cells (HSCs) as autologous grafts by determining engraftment, and to assess the residual tumor cell contamination using polymerase chain reaction (PCR) amplification assays of patient-specific complementarity determining region III (CDR III) analysis for residual myeloma cells. MATERIALS AND METHODS: The clinical trial was performed in 31 multiple myeloma patients, using purified human CD34+Thyl+ HSCs mobilized from peripheral blood with cyclosphosphamide and granulocyte-macrophage colony-stimulating factor to support a single transplant after high-dose melphalan 140 mg/m2 alone (cohort 1) and with total body irradiation (TBI) (cohorts 2-5) after an HSC transplant cell dose de-escalation/escalation design. RESULTS: Twenty-three patients were transplanted. Engraftment data in the melphalan + TBI cohorts confirmed that HSC doses above the threshold dose of 0.8 x 10(6) CD34+Thy1+ HSCs/ kg provided prompt engraftment (absolute neutrophil count >0.5 x 10(9)/L day 10; platelet count >50 x 10(9)/L day 13). A higher rate of infections was observed in the early and late follow-up phases than usually reported after CD34+ selected or unselected autologous transplantation, which did not correlate with the CD34+Thy1+ HSC dose infused. Successful PCR for CDR III could only be performed in five patients on initial apheresis product and final CD34+Thy1+ HSC product and showed a median tumor log reduction >3.12. CONCLUSIONS: CD34+Thy1+ HSCs are markedly depleted or free of detectable tumor cells in multiple myeloma and are capable of producing fast and durable hematopoietic reconstitution at cell doses >0.8 x 10(6) CD34+Thy1+ HSCs/kg. The delayed immune reconstitution observed is not different from that described in unselected autologous bone marrow and peripheral blood mononucleated cells transplants in multiple myeloma and may be corrected by addition of T cells either to the graft or to the patient in the posttransplant phase.

Expression of beta1-integrins and pseudo-immunoglobulins on acute promyelocytic leukemia cells and its modifications during in vitro differentiation.

Adhesion molecules are involved in cell-cell interactions and therefore probably play a role in the differentiation and egress of cells from the bone marrow, which might be potentially important in the biology of acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) is known to induce in vitro and in vivo differentiation of APL cells and to favor their release from the bone marrow into the blood at initiation of therapy. In order to determine whether these effects might be mediated in part by modifications of beta1-integrin and pseudoimmunoglobulin expression on APL cells, the expression of these adhesion molecules on bone marrow (BM) blast cells from 24 APL patients was assayed at diagnosis by an indirect immunofluorescence method. CD49b, CD49d, CD49e, CD49f, CD54, CD58, and CD56 were expressed respectively on 18%+/-20% (0-66%), 40%+/-31% (0-96%), 48%+/-32% (0-97%), 29%+29% (1-94%), 51%+/-30% (5-98%), 37%+/-24% (1-85%) and 32%+/-31% (0-97%) of APL cells, with respectively 39%, 71%, 79%, 50%, 70%, 70%, and 53% positive cases (> or = 20% positive cells). Despite a wide variability between individual samples, the expression of beta1-integrins and that of pseudo-immunoglobulins tended to be higher in APL in comparison with that of a cohort of 63 patients with other AML subtypes with significant differences for CD54 expression (51%+/-30% vs 28%+/-27%, P=0.006) and CD56 expression (37%+/-24% vs 17%+/-19%, P=0.0003). An in vitro differentiation assay was performed in nine cases. Cells were harvested after 4-7 days of culture and studied for the expression of adhesion molecules. Granulocytic differentiation was marked by persistence of CD15 expression. Antigen expression was decreased after culture with ATRA for all beta1-integrins (except CD49b and CD49f) and pseudoimmunoglobulins (except CD54) tested. However, changes were statistically significant only for CD56 (P=0.04), CD49d (P=0.02) and CD49e (P=0.01). The modifications in the expression of the beta1-integrins and pseudo immunoglobulins were not specific to ATRA-induced differentiation, but commonly observed with differentiation. Furthermore, the modifications in the adhesive properties of APL cells to extracellular matrix proteins, observed on adhesion assays, were not statistically significant after ATRA-induced differentiation. Overall, the level of expression of beta1-integrins and pseudo-immunoglobulins was higher in APL than in other AML subtypes, and appeared modified with induced differentiation. This was not specific of ATRA, but might be involved in the general differentiation phenomenon. The modulation of adhesion molecules does not seem a sufficient requisite for the development of the retinoic acid syndrome, but could nevertheless be part of the increase in leukocyte counts observed during the first days of ATRA therapy.

Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Société Française de Greffe de Moelle (SFGM).

To assess the place of allogeneic hematopoietic stem cell transplantation (HSCT) in the advanced stage of acute myeloid leukemia (AML), we retrospectively analyzed 379 consecutive patients who underwent allogeneic HSCT for advanced AML. The median follow-up of the entire cohort was 7.5 years. Sixty-nine patients (18%) were transplanted with primary resistant disease. Three hundred and ten (82%) were relapsed patients, 94 (30%) of whom were in untreated relapse, 67 (22%) in refractory relapse and 149 (48%) in 2nd or 3rd complete remission at time of transplantation. The 5-year probabilities of overall survival (OS), disease-free survival (DFS), and transplant-related mortality (TRM) were 22 +/- 4%, 20 +/- 4%, 45 +/- 6%, respectively. In multivariate analysis, we demonstrated the favorable impact on OS, DFS and TRM of two factors over which we have no control (age <15 years, complete remission achievement) and three factors over which we have some control (female donor, acute and chronic graft-versus-host disease). The results of this study suggest that the graft-versus-leukemia effect is important in advanced AML and that new HSCT modalities are needed for some patients with this indication.

Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87.

The French protocol LALA 87 was designed to compare three different postinduction strategies in adult acute lymphocytic leukemia (ALL): chemotherapy, autologous transplantation, and allogeneic transplantation. This trial demonstrated a significant superiority of allogeneic bone marrow transplantation (BMT) in high-risk ALL patients. Similarly, there was a trend in favor of autologous BMT over chemotherapy in those same patients. Allogeneic BMT was not superior to autologous BMT or chemotherapy in less aggressive leukemia (standard-risk ALL). Further improvements are warranted in the treatment of adult ALL. The authors' current ongoing study is stratifying patients to allocate them to regimens with risk-adapted treatment intensity.