Haematological parameters associated with postpartum haemorrhage after vaginal delivery: Results from a French cohort study.

BACKGROUND: Immediate postpartum haemorrhage (PPH) is a major, feared and often unpredictable issue. Besides many clinical risk factors, some biological parameters could also be predictive of PPH. OBJECTIVE: To study simple and easily accessible haematological parameters as potential risk factors for PPH after vaginal delivery. METHODS: All women who had a vaginal delivery between April 1, 2013 and May 29, 2015 in the maternity ward of Brest University Hospital (France) were included, after oral informed consent obtained. Clinical data were collected by obstetricians or midwives during antenatal care visits, labour and delivery, and recorded by trained research assistants. Haematological variables, including immature platelet fraction, were measured from a blood sample systematically collected at the entrance in the delivery room. PPH, measured with a graduated collector bag, was defined as blood loss of at least 500 ml. RESULTS: 2742 women were included. PPH occurred in 141 (5%) women. Seven clinical factors were independently associated with PPH: pre-eclampsia (OR 5.85, 95%CI 2.02, 16.90), multiple pregnancy (OR 3.28, 95%CI 1.21, 8.91), assisted reproduction (OR 2.75, 95%CI 1.45, 5.20), antepartum bleeding (OR 2.15, 95%CI 1.24,3.73), post-term delivery (OR 1.93, 95%CI 1.17, 3.17), obesity (OR 2.95, 95%CI 1.76, 4.93) and episiotomy (OR 2.51, 95%CI 1.63, 3.74). Three haematological factors were additionally identified as independent risk factors for PPH: platelets < 150 Giga/L (OR 2.98, 95%CI 1.63, 5.46), fibrinogen < 4.5 g/l (OR 1.86, 95%CI 1.21, 2.87) and APTT ratio ≥ 1.1 (OR 2.16, 95%CI 1.31, 3.57). Immature platelet fraction was not associated with PPH. CONCLUSION: Besides classical clinical risk factors, this study identifies simple haematological parameters as risk factors for PPH.

Results of a Prospective Study of High-Dose or Conventional Anthracycline-Cyclophosphamide Regimen Plus Radiotherapy for Localized Adult Non-Hodgkin's Primary Bone Lymphoma.

Background. Primary bone lymphoma (PBL) is a rare entity that has only been reviewed in one prospective and small retrospective studies, from which it is difficult to establish treatment guidelines. We prospectively evaluated high-dose or conventional anthracycline-cyclophosphamide dose and radiotherapy for PBL. Patients and Methods. The GOELAMS prospective multicenter study (1986-1998) enrolled adults with localized high-grade PBL according to age and performance status (PS). Patients <60 years received a high-dose CHOP regimen (VCAP) and those ≥60 years a conventional anthracycline-cyclophosphamide regimen (VCEP-bleomycin); all received intrathecal chemotherapy and local radiotherapy. Results. Among the 26 patients included (VCAP: 19; VCEP-bleomycin: 7), 39% had poor PS ≥2. With a median follow-up of 8 years, overall survival, event-free survival, and relapse-free survival were 64%, 62%, and 65%, respectively, with no significant difference between treatment groups. Poor PS was significantly associated with shorter OS and EFS. Conclusions. Our results confirm the efficacy of our age-based therapeutic strategy. High-doses anthracycline-cyclophosphamide did not improve the outcome. VCEP-bleomycin is effective and well tolerated for old patients. The intensification must be considered for patients with PS ≥2, a poor prognostic factor.

Eczematous dermatosis and thrombocytosis induced by efalizumab: two new side effects.

Efalizumab was authorized to be put on the market in France starting July 21, 2005. Its efficacy and tolerance profile in plaque psoriasis at a dose of 1 mg kg(-1) weekly in a subcutaneous injection have been studied in phase III trials. At the current moment, more than 3,500 patients have been included in clinical trials. Flu-like symptoms (fever, chills, headaches, nausea, vomiting, myalgia) are the most frequent adverse events. On the skin, a localized papular rash or the aggravation of the psoriasis in an edematous or even pustular form are the two most regularly observed complications. At the biological level, hyperlymphocytosis and a temporary increase in alkaline phosphatases without clinical consequences are the most frequent anomalies. We report 2 adverse events under efalizumab that to our knowledge have never been described: a case of an eczematous rash and a case of thrombocytosis.

Contribution of fluorescence in situ hybridization analyses to the characterization of masked and complex Philadelphia chromosome translocations in chronic myelocytic leukemia.

Bone marrow samples from 112 patients with chronic myelocytic leukemia were investigated using cytogenetic methods. Fluorescent in situ hybridization (FISH) with whole-chromosome paints and BCR-ABL probes was used to confirm and/or complete the banding findings when a variant or a masked Philadelphia chromosome (Ph) translocation was found. Eight variant Ph translocations were identified. Three-way Ph translocations were found in seven patients. Chromosome 4 was involved in two of these cases and chromosomes 3, 11, 14, 17, and 16 in one case each; in the patient with chromosome 16 involvement, a ring of the translocated chromosome 9 was identified, that is r(9)t(9;16;22). The eighth patient had a five-way Ph translocation: t(2;9;16;22;22). The BCR-ABL fusion gene was detected on the Ph chromosome in all eight cases; two cases presented also a deletion of the 5' ABL region on the derivative chromosome 9. In the five-way translocation, the 3' DNA sequence of the ABL oncogene was fused with the 5' DNA sequence of the BCR gene on the Ph chromosome and the 5' end of ABL was inserted into the other chromosome 22. A masked Ph chromosome was identified in one of the 112 patients; it involved the insertion of the 3' ABL into BCR on an apparently normal chromosome 22, resulting in the BCR-ABL fusion gene. In conclusion, FISH analyses allowed not only a more accurate characterization of complex Ph translocations with subtle abnormalities and the identification of cryptic rearrangements, but also the recognition of deletion of the 5' ABL region, which could carry with it a poor prognosis.

Long-term outcome with pentostatin treatment in hairy cell leukemia patients. A French retrospective study of 238 patients.

With the introduction of new drugs such as alpha-interferon (IFN) and purine analogs, the management of hairy cell leukemia (HCL) patients has changed. However, deoxycoformycin (DCF) produced higher complete remission rates than IFN. The current study was undertaken to provide long-term data on duration of overall survival (OS) and disease-free survival (DFS) and incidence of subsequent malignancies. We retrospectively analyzed the data of patients treated with DCF (4 mg/m2/day, every 2 weeks) from 39 French centers. In 84 of 238 included patients, DCF was the first-line therapy. Pretreatment variables influencing the achievement of complete remission, DFS, and OS were identified by multivariate analysis. Two hundred and thirty-eight patients received a median of nine cycles (range, 1-19 cycles). A complete remission was obtained in 182 of 230 evaluable patients (79%) and a partial response was obtained in 38 patients, for an overall response rate of 95.6%. In the multivariate analysis hemoglobin level less than 100 g/l and leukocytes less than 2 x 10(9)/l were parameters adversely influencing complete remission achievement. With a median follow-up of 63.5 months (range, 0.39-138.4 months), disease recurrence was observed in 34 of 220 responding patients (15%). The estimated 5-years and 10-years DFS was 88.1% and 68.8%, respectively. Hemoglobin level less than 100 g/l and leukocytes less than 2 x 10(9)/l were the pre-treatment variables associated with a shorter DFS. The estimated 5-year and 10-year OS were 89.4% and 88.7%, respectively. Hemoglobin level less than 100 g/l, leukocytes less than 2 x 10(9)/l, and adenopathy were significant factors of reduced survival. Hematologic toxicity was the main side-effect, followed by infection and emesis. During the period of follow-up, 18 patients developed second cancer, but the standardized incidence ratio was 0.95. Pentostatin is a highly effective regimen for hairy cell leukemia that produces durable complete responses. Toxicity of DCF is acceptable. Subsequent malignancies do not appear to be increased with pentostatin treatment.

Front-line high-dose therapy with autologous stem cell transplantation for high risk Hodgkin's disease: comparison with combined-modality therapy.

This retrospective study compares high-dose therapy (HDT) with autologous stem cell transplantation and combined-modality treatment (CT) as a first-line therapy for Hodgkin's disease (HD) for patients with both a clinical stage (CS) IV and/or a mediastinal mass > or =0.45 of the thoracic diameter (MM > or =0.45) at diagnosis, and an incomplete response after the first-line chemotherapy. Data on 42 grafted patients (GP) in Nantes Hospital, France and on 108 combined-modality treated patients (CTP) from two protocols of the GOELAMS group, France (POF 81 and H90) was analyzed. Both groups were comparable except for pulmonary disease in excess in the grafted group (P = 0.01). Among GP, 95% were in complete response at the end of first-line treatment and 77% among CTP. Median follow-up was 53 months (range, 7 to 128 months) for GP and 88 months (range, 25 to 181 months) for CTP. The 5-year freedom from progression (FFP) and event-free survival (EFS) rates were better for GP (87% vs 55% for FFP: P = 0.0004 and 81% vs 51% for EFS: P = 0.0004) whereas the overall survival (OS) rates did not differ significantly (85% for GP vs 71% for CTP: P = 0.06). Similar results were obtained for the groups with a response > or =50% after initial chemotherapy: 91% vs 65% for FFP, P = 0.01; 87% vs 61% for EFS, P = 0.02; and 92% vs 77% for OS, P = 0.2; and for the groups with a response <50%: 80% vs 22% for FFP, P = 0.0003; 72% vs 13% for EFS, P = 0.0001; and 76% vs 46% for OS, P = 0.04. This study shows a better control of the disease with HDT.

[Coronary thrombosis on patient with the factor V Leiden mutation]. / Thrombose coronarienne sur facteur V Leiden.

We report a documented observation of coronary thrombosis occurring in a 25-year-old patient with no risk factor, presenting a hereditary thrombophilia (facteur V Leiden) diagnosed a few months earlier in a context of venous thrombosis. This patient had a spread out anterior myocardial infarction with cardiac arrest due to a ventricular fibrillation; although he was quickly rescued by the mobile intensive Care Unit, the patient died 48 hours later, after cerebral anoxia. The mutation called factor V Leiden is a widely spread hereditary family thrombophilia (5 to 6% of the population) and is characterized by a resistance to activated C protein provoking a hypercoagulable state. The unexpected arterial thrombosis, very rare in that case, can be extremely serious and raises the question of a preventive medication such as antiplatelet agent or low-molecular-weight heparin as soon as the genetic abnormally has been proved to be symptomatic.

Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon alpha-2b for the treatment of chronic myelogenous leukemia patients in chronic phase.

Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.

CD5-induced apoptosis of B cells in some patients with chronic lymphocytic leukemia.

Although B chronic lymphocytic leukemia (B-CLL) is characterized by prolonged survival of CD5(+) B cells in vivo, these cells apoptose spontaneously in vitro. The effect of CD5 ligation on apoptosis was studied in 27 newly diagnosed patients with B-CLL, in relation to the expression of surface IgM (sIgM), CD79b, CD38, CD72 and CD19. B cells from 15 patients (group I) were resistant to anti-CD5-induced apoptosis, whereas apoptosis above spontaneous levels was seen in the remaining 12 studied (group II). Group II was then subdivided on the basis of differences in the time required to reach maximum apoptosis: whilst B cells from seven patients underwent apoptosis by 18 h, those from the remaining five needed 36 h to apoptose. The expression of sIgM, CD5, CD79b and CD38 was higher in group II than group I, suggesting that signaling for apoptosis might operate via CD79, and that CD38 expression was required. As shown by flow cytometry and confirmed by Western blotting, apoptosis was associated with a decrease in the ratios of Bcl-2/Bax and Bcl(XL)/Bax, due to an increase in the level of Bax, but no change in that of Bcl-2. This heterogeneous apoptotic response to CD5 ligation offers an explanation for the incomplete success of anti-CD5 monoclonal therapy, and might help identify patients who would respond to such treatment.

The use of recombinant factor VIIa (NovoSeven) in a patient with a factor XI deficiency and a circulating anticoagulant.

A 75-year-old female known to have a chronic myelomonocytic leukaemia and an acquired FXI deficiency (FXI level, 5%) related to a FXI inhibitor (38 Bethesda units) was admitted to the hospital for acute pneumonia associated with a bulky pleural effusion. A therapeutic puncture was found to be essential for the patient. But, such a procedure is a haemostatic challenge which requires adequate preparation. A first treatment composed of intravenous immunoglobulins and immunosuppressive therapy failed to eradicate the inhibitor and to restore a normal FXI level. In this context, steroids or FXI concentrates were not recommended. Thus, small doses of recombinant activated factor VII were used to achieve haemostasis. The procedure was successful, the tolerance was good and no adverse events occurred.

A case of chronic myelomonocytic leukaemia and factor XI deficiency with a circulating anticoagulant.

Inhibitors against factor XI (FXI) have been frequently described in patients who acquired inhibitors (due to auto-immune disorders, malignancies or infections), but less often in those with a congenital deficiency of this factor, who had received plasma infusions. The present report concerns one such inhibitor found in the plasma of a patient with chronic myelomonocytic leukaemia and infected by B19 parvovirus, who was neither a heterozygote nor a homozygote for FXI deficiency, and who had no bleeding tendency despite a very low FXI level. Taking this case into account, we discuss and present the clinical and biological features of acquired FXI deficiency caused by an inhibitor.

Value of autologous stem cell transplantation with purged bone marrow as first-line therapy for follicular lymphoma with high tumor burden: a GOELAMS phase II study.

This prospective phase II study was undertaken to evaluate the efficacy and toxicity of early intensive therapy followed by purged autologous bone marrow transplantation (ABMT) in patients with follicular lymphoma with high tumor burden. All patients received the VCAP regimen (vindesine, cyclophosphamide, doxorubicin and prednisone) as conventional chemotherapy and DHAP as second-line therapy. Twenty-nine consecutive patients were included in the study. Twenty-seven patients were grafted, seven in first complete remission (CR) and 20 in first partial remission (PR). Preparative therapy consisted of cyclophosphamide and total body irradiation (TBI) in all the patients. With a median follow-up of 6 years, the actuarial overall survival is 64% and the actuarial event-free survival is 55%. Two treatment-related early deaths were observed. Eleven patients were informative for serial PCR analysis of minimal residual disease after ABMT: two relapsed, four remained disease-free with PCR positivity and five were disease-free with PCR negativity. These encouraging results lay the basis of future prospective randomized trials comparing autologous stem cell transplantation as front-line treatment with conventional chemotherapy for patients with bad prognostic factors.

Granulocyte colony-stimulating factor after intensive consolidation chemotherapy in acute myeloid leukemia: results of a randomized trial of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques.

PURPOSE: Ten years after the first clinical studies, the clinical impact of myeloid growth factors in acute myeloid leukemia is still unclear. One of the objectives of the Groupe Ouest-Est Leucémies Aigues Myeloblastiques (GOELAM) 2 trial was to evaluate the benefit of granulocyte colony-stimulating factor (GCSF) given only after the two courses of intensive consolidation chemotherapy (ICC) used to maintain complete remission (CR). PATIENTS AND METHODS: One hundred ninety-four patients who were in CR after induction treatment were randomly assigned to receive G-CSF (100 patients) or no G-CSF (94 patients) after two courses of ICC (ICC 1, high-dose cytarabine plus mitoxantrone; ICC 2, amsacrine plus etoposide). G-CSF (filgrastim) was administered from the day after chemotherapy until granulocyte recovery at a daily dose of 5 microg/kg. RESULTS: In the G-CSF group, the median duration of neutropenia (< 0.5 x 10(9)/L) was dramatically reduced, both after ICC 1 (12 v 19 days, P <.001) and after ICC 2 (20 v 28 days, P <.001). The median duration of hospitalization was also significantly shorter in the G-CSF group (24 v 27 days after ICC 1, P <.001; 29 v 34 days after ICC 2, P <. 001). The median duration of intravenous antibiotics was significantly reduced after ICC 1 and ICC 2, and the median duration of antifungal therapy was significantly reduced after ICC 1. However, the incidence of microbiologically documented infections, the toxic death rate, the 2-year disease-free survival, and the 2-year overall survival were not affected by G-CSF administration. Moreover, the median interval between ICC1 and ICC2 was reduced by only 2 days, and the number of patients undergoing ICC2 was not increased in the G-CSF arm. CONCLUSION: G-CSF should be administered routinely after ICC to reduce the duration of neutropenia and hospitalization. However, G-CSF did not seem to significantly increase the feasibility of this two-course program or modify overall outcome.

Identification of new type 2B von Willebrand disease mutations: Arg543Gln, Arg545Pro and Arg578Leu.

We report the identification in five patients (three families) affected with type 2B von Willebrand disease (VWD) of three heterozygous nucleotide substitutions at the codon for arginine 543, 545 and 578 of the mature von Willebrand factor (VWF) subunit resulting in a glutamine, proline and leucine substitution, respectively. These mutations are located in the A1 loop where prevalent type 2B mutations (Arg543Trp, Arg545Cys and Arg578Gln) have been already identified at the same positions. By in vitro mutagenesis of full-length cDNA of VWF and transient expression in Cos-7 cells, we have shown that the six corresponding mutated recombinant VWFs (Gln543, Trp543, Cys545, Pro545, Leu578 and Gln578 rVWF) exhibited quantitatively normal expression and normal multimeric pattern but increased ristocetin- and botrocetin-induced binding to platelets as compared with that for wild-type rVWF. The two mutations at position 545 induced the greatest reactivity for GPIb of corresponding rVWFs as compared to the two mutations at positions 543 and 578.