Pascale Fabbro-Peray

Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia. The pilot randomised controlled NOH-PE trial.

Administration of heparin in the secondary prevention of placental vascular complications is still experimental. In women with a previous severe pre-eclampsia, we investigated the effectiveness of enoxaparin, a low-molecular-weight heparin, in preventing these complications. Between January 2000 and January 2010, 224 women from the NOHA First cohort, with previous severe pre-eclampsia but no foetal loss during their first pregnancy and negative for antiphospholipid antibodies, were randomised to either a prophylactic daily dose of enoxaparin starting from the positive pregnancy test (n=112), or no enoxaparin (n=112). The primary outcome was a composite of at least one of the following: pre-eclampsia, abruptio placentae, birthweight ≤ 5th percentile, or foetal loss after 20 weeks. Enoxaparin was associated with a lower frequency of primary outcome: 8.9% (n=10/112) vs. 25 % (28/112), p=0.004, hazard ratio = 0.32, 95% confidence interval (0.16-0.66), p=0.002. Enoxaparin was safe, with no obvious side-effect, no thrombocytopenia nor major bleeding event excess. This pilot study shows that enoxaparin given early during the second pregnancy decreases the occurrence of placental vascular complications in women with a previous severe pre-eclampsia during their first pregnancy.

Enoxaparin for the secondary prevention of placental vascular complications in women with abruptio placentae: The pilot randomised controlled NOH-AP trial

Administration of heparin in the secondary prevention of placental vascular complications is still experimental. In women with a previous placental abruption, we investigated the effectiveness of enoxaparin, a low-molecular-weight heparin, in preventing these complications. Between January 2000 and January 2009, 160 women from the NOHA First cohort, with previous abruptio placentae but no foetal loss during their first pregnancy and negative for antiphospholipid antibodies, were randomised to either a prophylactic daily dose of enoxaparin starting from the positive pregnancy test (n=80), or no enoxaparin (n=80). The primary outcome was a composite of at least one of the following: abruptio placentae, preeclampsia, birthweight < 5th percentile, or foetal loss after 20 weeks. Enoxaparin was associated with a lower frequency of primary outcome: 12.5% (n=10/80) vs. 31.3 % (25/80), p=0.004, adjusted hazard ratio = 0.37, 95% confidence interval (0.18-0.77), p=0.011. Enoxaparin was safe, with no obvious side-effect, no thrombocytopenia nor major bleeding event excess. This pilot study shows that enoxaparin given early during the second pregnancy decreases the occurrence of placental vascular complications in women with a previous placental abruption during their first pregnancy.

Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study.

The incidence of thrombosis in the purely obstetric form of antiphospholipid syndrome is uncertain. We performed a 10-year observational study of 1592 nonthrombotic women who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of thrombotic events among women positive for antiphospholipid Abs (n = 517), women carrying the F5 6025 or F2 rs1799963 polymorphism (n = 279), and women with negative thrombophilia screening results (n = 796). The annual rates of deep vein thrombosis (1.46%; range, 1.15%-1.82%), pulmonary embolism (0.43%; range, 0.26%-0.66%), superficial vein thrombosis (0.44%; range, 0.28%-0.68%), and cerebrovascular events (0.32%; range, 0.18%-0.53%) were significantly higher in aPLAbs women than in the other groups despite low-dose aspirin primary prophylaxis. Women carrying 1 of the 2 polymorphisms did not experience more thrombotic events than women who screened negative for thrombophilia. Lupus anticoagulant was a risk factor for unprovoked proximal and distal deep and superficial vein thrombosis and women in the upper quartile of lupus anticoagulant activity had the highest risk. Despite data suggesting that aPLAbs may induce pregnancy loss through nonthrombotic mechanisms, women with purely obstetric antiphospholipid syndrome are at risk for thrombotic complications.

Variable compliance with clinical practice guidelines identified in a 1-day audit at 66 French adult intensive care units.

Objective:Clinical guidelines should provide a framework for managing patients hospitalized in intensive care units. Little is known about guideline compliance in real-life practice. To evaluate compliance rates for a large bundle of intensive care unit practice guidelines and determine factors associated with noncompliance to these guidelines. Design, Setting, and Patients:A bundle of 13 clinical guidelines was elaborated by a group of senior physicians. Four external consultants validated the process. Then, a 1-day audit was performed at 66 participating adult intensive care units in 39 institutions by a group of 64 junior investigators supervised by senior intensivists. At the bedside, investigators collected data from 625 patients hospitalized in those units. Interventions and Measurements:The eligibility and compliance rates were determined for each clinical recommendation. The rate of full compliance to each eligible clinical guideline was calculated. Mortality data were requested 28 days after the completion of the audit. Main Results:The eligibility rate ranged from 11% (sepsis bundle) to 80% (identified closest relative). The median compliance rate was 75% (60–100), ranging from 24% (sedation monitoring) to 96% (identified closest relative and bacteriological sampling before initiating antibiotics). Our results showed that only 24% (20–27) of patients in our cohort received fully compliant care. The 28-day survival probability was .77 (.73–.80). Conclusions:At the bedside, clinical guidelines are fully applied in 24% of patients. Our study underlines the need to both improve the process of implementation and become cognizant of excessive proliferation of clinical guidelines.

Comparative incidence of pregnancy outcomes in thrombophilia-positive women from the NOH-APS observational study

The incidence of pregnancy outcomes in women with constitutive thrombophilia is uncertain. We observed women with no history of thrombotic events (nonthrombotic), who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of complications during a new pregnancy attempt among women carrying the F5 rs6025 or F2 rs1799963 polymorphism (n = 279; low-molecular-weight heparin [LMWH] treatment during pregnancy only in case of prior fetal death), and women with negative thrombophilia screening results as control women (n = 796; no treatment). Among women with prior recurrent abortions, thrombophilic women were at increased risk for fetal death. Among women with prior fetal death, thrombophilic women experienced less fetal death recurrences, less preterm births and preeclampsia, and more live births as they were treated with LMWH. In nonthrombotic F5 rs6025 or F2 rs1799963 heterozygous women with prior pregnancy loss, fetal loss may indicate a clinical subgroup in which future therapeutic randomized controlled trials testing the effect of LMWH prophylaxis are required in priority.

Diagnostic value and prognostic significance of plasmatic proteasome level in patients with melanoma

Abstract:u2002 Plasmatic proteasome (p‐proteasome) also called circulating proteasome has recently been described as a tumor marker. We investigated the diagnostic and prognostic accuracies of p‐proteasome levels in a melanoma population classified according to the American Joint Committee on Cancer staging system. Using an ELISA test, we measured p‐proteasome levels in 90 patients and 40 controls between March 2003 and March 2008. The subunit composition of p‐proteasomes was determined in metastatic melanoma by proteomic analysis. The mean p‐proteasome levels were correlated with stages (Pu2003<u20030.0001; rSu2003=u20030.664). They were significantly higher in patients with stage IV and stage III with lymph node metastasis (9187u2003±u20031294 and 5091u2003±u2003454u2003ng/ml, respectively) compared to controls (2535u2003±u2003187u2003ng/ml; Pu2003<u20030.001), to stage I/II (2864u2003±u2003166u2003ng/ml; Pu2003<u20030.001) and to stage III after curative lymphadenectomy (2859u2003±u2003271u2003ng/ml; Pu2003<u20030.001). The diagnostic accuracy of p‐proteasome was evaluated by receiver operating characteristic analysis. With a cut‐off of 4300u2003ng/ml, diagnostic specificity and sensitivity of p‐proteasome for regional or visceral metastases were respectively 96.3% and 72.2%. In univariate analysis, high p‐proteasome levels (>4300u2003ng/ml) were significantly correlated with an increased risk of progression [hazard ratio (HR)u2003=u20037.34; 95% CI 3.54–15.21, Pu2003<u20030.0001] and a risk of death (HRu2003=u20035.92; 95% CI 2.84–12.33, Pu2003<u20030.0001). In multivariate analysis, high p‐proteasome levels were correlated with a poorer clinical outcome in the subgroup analysis limited to patients with disease stages I, II and III. Proteomic analysis confirmed the presence of all proteasome and immunoproteasome subunits. Taken together, these results indicate that p‐proteasomes are a new marker for metastatic dissemination in patients with melanoma.

Clinical use of p-proteasome in discriminating metastatic melanoma patients: Comparative study with LDH, MIA and S100B protein

Plasmatic proteasome (p‐proteasome) has recently been described as a new marker for metastatic melanoma. The objective of this study was to compare the diagnostic and prognostic values of p‐proteasome with three other melanoma serological markers: S100B protein, melanoma inhibitory activity protein (MIA) and lactate dehydrogenase (LDH) in the plasma of 121 stage I–IV melanoma patients. Laboratory analyses were performed by standardized ELISA (p‐proteasome, MIA), immunoluminometric assay (S100B) and colorimetry (LDH). We found that all markers were relevant for discriminating metastatic from nonmetastatic patients but p‐proteasome displayed the highest diagnostic accuracy. P‐proteasome and S100B were the most sensitive (58.1%) and p‐proteasome and MIA the most specific (98.7 and 100%) in detecting metastatic disease. P‐proteasome and S100B had the highest area under receiver operating characteristics curve, 0.811 (95% CI: 0.725–0.897) and 0.822 (95% CI: 0.738–0.906), respectively. These two markers were the best in detecting patients with lymph node metastases. S100B, MIA and LDH diagnostic accuracy was increased when these markers were combined with p‐proteasome. As shown with univariate analysis, shorter progression‐free and overall survival rates were significantly associated with elevated plasma levels of each markers. The multivariate Cox regression analysis identified p‐proteasome as the only independent predictor of a poorer progression‐free survival (p = 0.030). In conclusion, this comparative study established that p‐proteasome quantification in combination with other melanoma biomarkers is an attractive approach for the biological follow‐up of melanoma patients.

The A6936G polymorphism of the endothelial protein C receptor gene is associated with the risk of unexplained foetal loss in Mediterranean European couples

The endothelial protein C receptor (EPCR) is expressed by trophoblast cells. Mid-gestation pregnancy loss is described in animals with a haemochorial placenta lacking EPCR. The A6936G allele of the EPCR gene (PROCR) may be associated with lower EPCR densities on trophoblasts, but data are lacking for its effect on the risk of pregnancy loss in humans. A 1:2 case-control study on unexplained pregnancy loss was nested in the NOHA First cohort: 3,218 case couples and 6,436 control couples were studied for PROCR A6936G, coagulation factor V gene (F5) G1691A and coagulation factor II gene (F2) G20210A polymorphisms. Ethnicity and time of pregnancy loss defined through biometry-based gestational ages (embryonic loss < 10(th) week > or = foetal loss) were analysed. The PROCR A6936G allele, in mothers and fathers, was associated only with foetal loss in both Europeans and non-Europeans. Increasing probability levels of carrying a homozygous child were increasingly associated with the risk of foetal demise. The F5 G1691A and F2 G20210A alleles, only in mothers, were only and independently associated with foetal loss in Europeans. In our population, the PROCR A6936G allele describes women, but also men and thus couples, at risk for first unexplained foetal loss. This risk is independent of the foetal loss risk conferred to our local Mediterranean European women by the F5 G1691A and F2 G20210A alleles. Data confirm that the relationship between thrombophilias and pregnancy loss varies according to ethnicity and loss type.

R49: Valeurs diagnostique, pronostique et caractérisation structurale des protéasomes plasmatiques dans le mélanome

Introduction Les proteasomes plasmatiques (p-proteasomes) ou proteasomes circulants sont consideres comme des nouveaux marqueurs seriques tumoraux. Objectif Determiner les valeurs diagnostiques et pronostiques des p-proteasomes dans une population de patients atteints de melanome classee selon la classification AJCC. Methodologie Les taux de p-proteasomes etaient quantifies chez 90 patients et 40 temoins entre mars 2003 et mars 2008 avec un test ELISA. La composition des p-proteasomes etait determinee par analyse proteomique chez des patients atteints de melanome metastatique (nxa0=xa03). Resultats Les concentrations moyennes de p-proteasomes etaient correlees aux stades cliniques. Elles etaient significativement plus elevees chez les patients stade IV et stade III avec atteinte ganglionnaire (9 187 ± 1 294 et 5 091 ± 454 ng/mL, respectivement) comparativement aux temoins (2 535 ± 187xa0ng/mL, p 4 300xa0ng/mL) etaient significativement correles a un risque accru de progression (HR = 7,34, IC 95 % 3,54 a 15,21).