Daily practice management of myelodysplastic syndromes in France: data from 907 patients in a one-week cross-sectional study by the Groupe Francophone des My��lodysplasies

Background

There is little published information on the everyday clinical management of myelodysplastic syndromes in real world practice.

Design and Methods

We conducted a cross-sectional study of all patients with myelodysplastic syndromes attending 74 French centers in a 1-week period for inpatient admission, day-hospital care or outpatient visits.

Results

Nine hundred and seven patients were included; 67.3% had lower-risk myelodysplastic syndromes (International Prognostic Scoring System: low or intermediate-1). Karyotype had been analyzed in 82.5% of the cases and was more often of intermediate or poor risk in patients under 65 years old compared with those who were older. Red blood cell transfusions accounted for as many as 31.4% of the admissions. Endogenous erythropoietin level was less than 500 IU/L in 88% of the patients tested. Erythroid stimulating agents had been or were being used in 36.8% of the lower risk patients, iron chelation in 31% of lower risk patients requiring red blood cell transfusions and lenalidomide in 41% of lower risk patients with del 5q. High-dose chemotherapy, hypomethylating agents, low dose cytarabine and allogeneic stem cell transplantation had been or were being used in 14.8%, 31.1%, 8.8% and 5.1%, respectively, of higher-risk patients.

Conclusions

Karyotype is now assessed in most patients with myelodysplastic syndromes, and patients under 65 years old may have more aggressive disease. Apart from erythroid-stimulating agents and, in higher-risk myelodysplastic syndromes, hypomethylating agents, specific treatments are used in a minority of patients with myelodysplastic syndromes and red blood cell transfusions still represent the major reason for hospital admission.     

ABO incompatibility and non myeloablative allogeneic stem cell transplantation]

ABO incompatibility is not a barrier for allogeneic hematopoietic stem cell transplantation but is associated with specific complications. Major ABO incompatibility is associated with delayed erythroid engraftment, increased transfusion requirement and cases of pure red cell aplasia. Minor ABO incompatibility may be responsible for acute haemolytic reactions in the first months following transplantation. The widely used non myeloablative conditioning regimens might modify the management of ABO incompatibility. They could favour pure red cell aplasia development in the setting of major ABO mismatch since they are associated with a prolonged persistence of host anti-donor isohemagglutinins after allogeneic hematopoietic stem cell transplantation. In the setting of minor ABO incompatibility, the use of peripheral blood stem cells and the nature of graft-versus-host disease prophylaxis regimen may have an impact on the incidence of haemolytic reactions. In that review, the clinical and therapeutic aspects of ABO incompatibility are studied, especially regarding the impact of the conditioning regimen intensity.     

Predictive factors of septic shock and mortality in neutropenic patients

Neutropenia is a major risk factor for developing a serious infection. Bacteremia still causes significant mortality among neutropenic patients with cancer. The purpose of this study was to identify risk factors for septic shock and for mortality in neutropenic patients with leukemia and bacteremia. Consecutive samples from 20 patients with acute myeloid leukemia and bacteremia were studied during a 1 year period (January–December 2003). All patients received empirical antibiotic therapies for febrile episodes using ceftazidime plus amikacin. About 110 neutropenic febrile episodes were noted: clinically documented 14.54%, microbiologically documented 16.36% and fever of unknown origin 69.09%. Gram-negative organism caused eight febrile episodes: Pseudomonas (5), Klebsiella (3). Gram-positive organism caused 10 episodes: Staphylococcus (6), Streptococci (2), Enterococci (2). Pulmonary infection accounted for 25% of clinically documented infections. About 14 of the 110 febrile episodes were associated with septic shock causing mortality in 7 patients. In a univariate analysis variables associated with septic shock were: pulmonary infection (OR = 17, p = 0.001), serum bicarbonate < 17 mmol/l (OR = 68, p < 0.001) and serum lactate >3 mmol/l (OR = 62, p < 0.001). Variables associated with mortality were: pulmonary infection (OR = 83, p < 0.001) and serum bicarbonate < 17 mmol/l (OR = 61, p < 0.001).

In a multivariate analysis two variables were associated with septic shock: pulmonary infection (OR = 5, p = 0.043) and serum lactate >3 mmol/l (OR = 10, p = 0.003). An elevated serum lactate (>3 mmol/l) and low serum bicarbonate (< 17 mmol/l) at the onset of bacteremia are useful biomarkers in predicting septic shock and mortality in neutropenic patients.     

Ultrasound assessment of the diaphragm during the first days of mechanical ventilation compared to spontaneous respiration: a comparative study.

Introduction : In critically ill patients, the diaphragm is subject to several aggressions mainly those induced by mechanical ventilation (MV). Currently, diaphragmatic ultrasound has become the most useful bedside for the clinician to evaluate diaphragm contractility. Aim: To examine the effects of MV on the diaphragm contractility during the first days of ventilation. M ethods: Two groups of subjects were studied: a study group (n=30) of adults receiving MV versus a control group (n=30) of volunteers on spontaneous ventilation (SV). Using an ultrasound device, we compared the diaphragmatic thickening fraction (DTF). Secondly, we analysed the relationship between DTF and weaning. Results: comparatively to SV group,patients of MV group have a higher end expiratory diameter (EED) (2.09 ± 0.6 vs. 1.76 ± 0.32 mm, p=0.01) and a lower DTF (39.9 ± 12.5% ​​ vs. 49.0 ± 20.5%, p=0.043). Fourteen among the 30 ventilated patients successfully weaned. No significant correlation was shown between DTF and weaning duration (Rho= - 0.464, p=0.09). A DTF value > 33% was near to be significantly associated with weaning success (OR=2; 95% CI= [1.07-3.7], p=0.05) with a sensitivity at 85.7%. Conclusions: diaphragmatic contractility was altered from the first days of MV. A DTF value >32,7% was associated to the weaning success and that may be useful to predict successful weaning with sensitivity at 85.7%.     

Do inhaled corticosteroids increase the risk of Pneumocystis pneumonia in people with lung cancer?

Pneumocystis pneumonia(PCP) is a life-threatening infection in immunocompromised patients. It is relatively uncommon in patients with lung cancer. We report a case of PCP in a 59-year-old man with a past medical history of chronic obstructive pulmonary disease treated with formoterol and a moderate daily dose of inhaled budesonide. He had also advanced stage non-small lung cancer treated with concurrent chemo-radiation with a cisplatin-etoposide containing regimen. The diagnosis of PCP was suspected based on the context of rapidly increasing dyspnea, lymphopenia and the imaging findings. Polymerase chain reaction testing on an induced sputum specimen was positive for Pneumocystis jirovecii. The patient was treated with oral trimethoprim-sulfamethoxazole and systemic corticotherapy and had showed clinical and radiological improvement. Six months after the PCP diagnosis, he developed a malignant pleural effusion and expired on hospice care. Through this case, we remind the importance of screening for PCP in lung cancer patients under chemotherapeutic regimens and with increasing dyspnea. In addition, we alert to the fact that long-term inhaled corticosteroids may be a risk factor for PCP in patients with lung cancer. Despite intensive treatment, the mortality of PCP remains high, hence the importance of chemoprophylaxis should be considered.     

Posterior cerebral encephalopathy

Posterior reversible encephalopathy (PRE) is a recent syndrome characterized by headache, vomiting, seizures, visual loss, altered mental status with or without motor or sensitive deficit. Neuroimaging demonstrates symmetrical posterior cortical and subcortical lesions. The aetiology remains uncertain but vascular hypotheses is the most retained. We report a case of a 21 year old man with posterior cerebral encephalopathy, the toxic hypo these remains the most probable.     

A genome wide SNP genotyping study in the Tunisian population: specific reporting on a subset of common breast cancer risk loci

Background

Breast cancer is the most common cancer in women worldwide. Around 50% of breast cancer familial risk has been so far explained by known susceptibility alleles with variable levels of risk and prevalence. The vast majority of these breast cancer associated variations reported to date are from populations of European ancestry. In spite of its heterogeneity and genetic wealth, North-African populations have not been studied by the HapMap and the 1000Genomes projects. Thus, very little is known about the genetic architecture of these populations.

Methods

This study aimed to investigate a subset of common breast cancer loci in the general Tunisian population and to compare their genetic composition to those of other ethnic groups. We undertook a genome-wide haplotype study by genotyping 135 Tunisian subjects using the Affymetrix 6.0-Array. We compared Tunisian allele frequencies and linkage disequilibrium patterns to those of HapMap populations and we performed a comprehensive assessment of the functional effects of several selected variants.

Results

Haplotype analyses showed that at risk haplotypes on 2p24, 4q21, 6q25, 9q31, 10q26, 11p15, 11q13 and 14q32 loci are considerably frequent in the Tunisian population (>?20%). Allele frequency comparison showed that the frequency of rs13329835 is significantly different between Tunisian and all other HapMap populations. LD-blocks and Principle Component Analysis revealed that the genetic characteristics of breast cancer variants in the Tunisian, and so probably the North-African populations, are more similar to those of Europeans than Africans.Using eQTl analysis, we characterized rs9911630 as the most strongly expression-associated SNP that seems to affect the expression levels of BRCA1 and two long non coding RNAs (NBR2 and LINC008854). Additional in-silico analysis also suggested a potential functional significance of this variant.

Conclusions

We illustrated the utility of combining haplotype analysis in diverse ethnic groups with functional analysis to explore breast cancer genetic architecture in Tunisia. Results presented in this study provide the first report on a large number of common breast cancer genetic polymorphisms in the Tunisian population which may establish a baseline database to guide future association studies in North Africa.

     

The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism

Manipulation of metabolic pathways in hematological cancers has therapeutic potential. Here, we determined the molecular mechanism of action of the metabolic modulator dichloroacetate (DCA) in leukemic cells. We found that DCA induces the AMP-activated protein kinase (AMPK)/p53 pathway with increased efficacy in tumors expressing wild type (wt p53). Clinically relevant, low concentrations of doxorubicin synergize in vitro and in vivo with DCA to further enhance p53 activation and to block tumor progression. Leukemia cell lines and primary leukemic cells containing mutant p53 are resistant to the above-described combination approach. However, DCA synergized with the Hsp90 inhibitor 17-AAG to specifically eliminate these cells. Our studies strongly indicate that depending on the p53 status, different combination therapies would provide better treatment with decreased side effects in hematological cancers.