[Which anticoagulant or antiplatelet treatment for cancer patients with thrombocytopenia ?] / Quel anticoagulant ou antiagrégant chez le patient oncologique présentant une thrombocytopénie ?

Cancer patients have an increased thrombotic risk of arterial and venous thrombosis. Thrombocytopenia, particularly with anticoagulation, exposes the patient to an increased risk of bleeding but does not reduce the risk of recurrent thrombosis. When platelets are < 50 × 109/l, the strategy regarding anticoagulation must be reassessed. Based on the thrombotic and bleeding risks as well as the expected duration of thrombocytopenia, management options include full-dose treatment with platelet transfusion, reduced-dose anticoagulation or withholding antithrombotic therapy. Aspirin treatment appears to be a reasonable choice for thrombocytopenic (> 30 × 109/l) patients with acute coronary syndrome. This paper will review the guidelines on anticoagulation and antiplatelet therapy in thrombocytopenic cancer patients.

Les patients avec un cancer ont un risque thrombotique artériel et veineux accru. En cas de thrombocytopénie et traitement anticoagulant (ou antiagrégant), ils sont exposés à un risque hémorragique augmenté mais conservent un risque thrombotique élevé. L'évaluation de l'anticoagulation s'impose pour des thrombocytes < 50 × 109/l. En fonction des risques thrombotique et hémorragique et de la durée de la thrombocytopénie, les options sont la poursuite de l'anticoagulation, le recours aux transfusions plaquettaires, la réduction de la dose ou son interruption. Un traitement par aspirine en cas de syndrome coronarien aigu est raisonnable pour des thrombocytes > 30 × 109/l. Cet article propose une revue des recommandations concernant les traitements anticoagulants ou antiagrégants en cas de thrombocytopénie chez les patients oncologiques.

[Systemic mastocytosis and bone impact]. / Mastocytose systémique et impact osseux.

Systemic mastocytosis is a rare disease characterized by the uncontrolled clonal proliferation of abnormal mast cells in one or more extracutaneous organs. It is no longer considered a myeloproliferative neoplasia but a distinct subgroup following the review of the classification by WHO in 2016. The average age at diagnosis is 60 years regardless of gender. Bone involvement, in the broad sense, is very common and often asymptomatic. Osteoporosis or bone fragility concerns approximately 20 % of cases. The particularity of bone damage directly induced by mast cell proliferation is its heterogeneity, sometimes combining osteolysis and osteosclerosis simultaneously. This makes the interpretation of paraclinical values (bone density, biomarkers) complex and the therapeutic attitude becomes a real challenge.

La mastocytose systémique est une maladie rare se caractérisant par la prolifération clonale incontrôlée de mastocytes anormaux dans un ou plusieurs organes extracutanés. La classification par l'OMS a été révisée en 2016 et ne la considère plus comme une néoplasie myéloproliférative mais comme un sous-groupe disctint. L'âge moyen au diagnostic est de 60 ans sans distinction de sexe. L'atteinte osseuse, au sens large, est très fréquente et souvent asymptomatique. L'ostéoporose ou fragilité osseuse concerne environ 20 % des cas. La particularité de l'atteinte osseuse directement induite par la prolifération mastocytaire est son hétérogénéité, mêlant ostéolyse et ostéosclérose parfois simultanément. Cela rend l'interprétation des valeurs paracliniques (densité osseuse, biomarqueurs) complexe et l'attitude thérapeutique devient un vrai challenge.

Inferior Outcome of Addition of the Aminopeptidase Inhibitor Tosedostat to Standard Intensive Treatment for Elderly Patients with AML and High Risk MDS.

Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66-81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (n = 116), days 1-21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60-77%) vs 64% (55-73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (p = 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation was more common in the tosedostat arm as well. The results of the present study show that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients.

Improvement of relative survival in elderly patients with acute myeloid leukaemia emerging from population-based cancer registries in Switzerland between 2001 and 2013.

Acute Myeloid Leukaemia (AML) is a rare and heterogeneous haematological malignancy with increasing incidence in the elderly. We performed a population-based, observational analysis of AML cases reported to the Cantonal Cancer Registries in Switzerland. Data was aggregated by the National Institute for Epidemiology and Cancer Registration and stratified for the two time periods 2001-2007 and 2008-2013. Overall, 2351 new AML cases were registered with a stable age-standardised incidence rate (3.0 [95 CI: 2.8-3.2] per 100,000 person-years). This indicates that our observed raise of annual AML cases (+10.9%) is mainly related to demographic ageing and not to an increase of age-specific risks. The fraction of non-classifiable AML cases decreased over time (54.6% to 41.8%) but remained high in elderly patients (65-74yrs: 44%; 75-84yrs: 54.2%, 85+yrs: 59.1%), suggesting less accurate diagnostics and reporting with increasing age. 5yrs relative survival (RS) correlated with AML risk class (favorable: 61.7%-68.4%; adverse risk: 11.4%-21.9%) and age (<65yrs: 42.6-43.3%; 75-84yrs: 2.0-3.0%), but improved only modestly overall (19.2% to 23.3%). Interestingly, we identified a significant improvement of RS in patients aged 65-74yrs (5yrs: 5.2% to 13.5%; p<0.001). As surrogate for changes in management, we found an increase of allogeneic haematopoietic stem cell transplantations (1.4 to 7%) and clinical trial activities (25 to 29%) for elderly AML patients during the observation period. Our analysis indicates that recent progress made in management of elderly AML patients results in an improvement of survival on a population-based level in Switzerland and that therapeutic nihilism is not justifiable.

Short-term psychological impact on family members of intensive care unit patients.

OBJECTIVE: This study aimed to evaluate the short-term psychological impact on family members of intensive care unit (ICU) patients during their stay in the unit. METHODS: Thirty-two first-degree relatives of patients treated in the ICU of two general hospitals were investigated for symptoms of early posttraumatic stress reaction, anxiety, and depression. Patients' and relatives' sociodemographic data and information pertaining to the patients' ICU treatment were collected. Family members were assessed at intake and before discharge through the Center for Epidemiological Studies Depression Scale, the State-Trait Anxiety Inventory, and the Impact of Event Scale. RESULTS: High rates of anxiety, depressive (97%), and posttraumatic stress (81%) symptoms were recorded at the initial assessment. Although symptoms remitted significantly, 87% and 59% of the sample fulfilled the criteria for a depressive and posttraumatic stress reaction, respectively, at the second assessment. Women exhibited higher levels of distress and more persisting symptoms than men did. Trait anxiety was the most significant predictor (P<.001) of the severity of depressive symptoms and the single predictor of the development of posttraumatic stress reaction (P<.000); also, state anxiety was a predictor of the development of posttraumatic stress symptoms, especially of the female gender. CONCLUSIONS: Family members of ICU patients exhibit high levels of distress that persist throughout their relatives' hospitalization. Women and individuals with high trait anxiety are at increased risk for developing such reactions. Severe early anxiety responses predicted the development of posttraumatic stress symptoms. Early case identification and intervention may prevent the full development of posttraumatic stress disorder.

Successful treatment of refractory adult-onset Still's disease with infliximab. A prospective, non-comparative series of four patients.

In this prospective, non-comparative case series, four patients with severe and highly active adult-onset Still's disease (AOSD), refractory to high doses of corticosteroids (which had been combined with methotrexate in three of them) and methotrexate were treated with infliximab (initial dose 3-5 mg/kg, continuing at intervals depending on the patient's individual disease activity). Resolution of their symptoms, which was evident within few days after the first infusion, and a parallel rapid improvement of the acute inflammatory response indices were observed in all. Concomitant corticosteroid treatment was reduced after the first courses of treatment with infliximab, which was well tolerated, and complete disease remission was sustained during a 5-18-month follow-up period. Although further studies to confirm long-term efficacy and safety in larger numbers of patients are needed, we suggest that administration of infliximab with observation for objective improvement is the treatment of choice in cases of AOSD refractory to conventional treatment.

Clonotypic analysis of immunoglobulin heavy chain sequences in patients with Waldenström's macroglobulinemia: correlation with MYD88 L265P somatic mutation status, clinical features, and outcome.

We performed IGH clonotypic sequence analysis in WM in order to determine whether a preferential IGH gene rearrangement was observed and to assess IGHV mutational status in blood and/or bone marrow samples from 36 WM patients. In addition we investigated the presence of MYD88 L265P somatic mutation. After IGH VDJ locus amplification, monoclonal VDJ rearranged fragments were sequenced and analyzed. MYD88 L265P mutation was detected by AS-PCR. The most frequent family usage was IGHV3 (74%); IGHV3-23 and IGHV3-74 segments were used in 26% and 17%, respectively. Somatic hypermutation was seen in 91% of cases. MYD88 L265P mutation was found in 65,5% of patients and absent in the 3 unmutated. These findings did not correlate with clinical findings and outcome. Conclusion. IGH genes' repertoire differed in WM from those observed in other B-cell disorders with a recurrent IGHV3-23 and IGHV3-74 usage; monoclonal IGHV was mutated in most cases, and a high but not omnipresent prevalence of MYD88 L265P mutation was observed. In addition, the identification of 3 patients with unmutated IGHV gene segments, negative for the MYD88 L265P mutation, could support the hypothesis that an extra-germinal B-cell may represent the originating malignant cell in this minority of WM patients.

Prognostic significance of serum free light chains in chronic lymphocytic leukemia.

Background. Serum free light chains (sFLC), the most commonly detected paraprotein in CLL, were recently proposed as useful tools for the prognostication of CLL patients. Objective. To investigate the prognostic implication of sFLC and the summated FLC-kappa plus FLC-lambda in a CLL patients' series. Patients and Methods. We studied 143 CLL patients of which 18 were symptomatic and needed treatment, while 37 became symptomatic during follow-up. Seventy-two percent, 18%, and 10% were in Binet stage A, B and C, respectively. Median patients' followup was 32 months (range 4-228). Results. Increased involved (restricted) sFLC (iFLC) was found in 42% of patients, while the summated FLC-kappa plus FLC-lambda was above 60 mg/dL in 14%. Increased sFLC values as well as those of summated FLC above 60 were related to shorter time to treatment (P = 0.0005 and P = 0.000003, resp.) and overall survival (P = 0.05 and P = 0.003, resp.). They also correlated with ß 2-microglobulin (P = 0.009 and P = 0.03, resp.), serum albumin (P = 0.009 for summated sFLC), hemoglobin (P < 0.001), abnormal LDH (P = 0.037 and P = 0.001, resp.), Binet stage (P < 0.05) and with the presence of beta symptoms (P = 0.004 for summated sFLC). Conclusion. We confirmed the prognostic significance of sFLC in CLL regarding both time to treatment and survival and showed their relationship with other parameters.

Melatonin secretion after head injury: a pilot study.

PRIMARY OBJECTIVE: To investigate the circadian rhythm of serum melatonin in patients with traumatic brain injury (TBI) during Intensive Care Unit (ICU) stay and its relationship with core body temperature fluctuations and measures of severity of their condition. METHODS AND PROCEDURES: The pilot study was conducted in the ICU of a general hospital in Athens, Greece. Blood melatonin was determined in eight patients consecutively admitted at the ICU following severe head injury, eight times per day during the first and second day following admission. Core body temperature was recorded at hourly intervals. Patients were also assessed with the Glasgow Coma Score (GCS) and the APACHE II score. RESULTS: Melatonin concentrations were lower than the normally reported values. Mean night-time melatonin levels were higher than mean daytime levels both on the first and second days, although not statistically significant. Diurnal variation of melatonin was associated with the GCS. Thus, patients with low GCS (n = 4) did not exhibit a consistent diurnal variation of melatonin, whereas those with high GCS (n = 4) retained the normally expected fluctuations. CONCLUSIONS: ICU-treated TBI patients exhibit reduced melatonin levels and a circadian secretion profile which is related to the severity of the injury. Patients with more severe head trauma exhibit a clearly disrupted pattern of melatonin secretion, whereas those with less severe trauma preserve a relatively intact diurnal rhythm. Furthermore, the diurnal secretion pattern of melatonin appeared to be dissociated from the circadian rhythm of core body temperature. These preliminary findings may have implications for the management of TBI patients.

Serial determination of FLT3 mutations in myelodysplastic syndrome patients at diagnosis, follow up or acute myeloid leukaemia transformation: incidence and their prognostic significance.

The incidence of FLT3 mutations (internal tandem duplication and Asp835) was investigated in bone marrow samples from 97 patients with myelodysplastic syndrome [(MDS); excluding cases with refractory anaemia with excess blasts in transformation] at the time of diagnosis and several time points thereafter. Three patients had FLT3 mutations at presentation. Forty-two patients progressed to acute myeloid leukaemia (AML), including the three patients with FLT3 mutations at MDS diagnosis. Three additional patients acquired FLT3 mutations and progressed to AML in 1 month. FLT3 mutations seem to be a critical additional genetic event that transforms a minority of MDS patients to AML.