[Telomeropathies: A study of 15 cases]. / Téloméropathies de recrutement hématologique : étude de 15 cas.

INTRODUCTION: Telomeres are composed of a repeated sequence of double-stranded nucleotides TTAGGG and numerous proteins including the Shelterin complex. Their main role is to maintain the stability of the genome during cell replication through a mechanism of copying the repeted sequence by the telomerase complexe. All the diseases involving a deregulation of this complex are now grouped together under the term telomeropathies. They are difficult to diagnose and manage. Our objective was to describe the clinico-biological characteristics and treatments used, in patients affected by telomeropathies previously seen by an hematologist followed at the Lille University Hospital Center. METHODS: This is a retrospective, single-center study carried out within the department of internal medicine-clinical immunology, Reference center for rare autoimmune and systemic diseases at Lille University Hospital Center between 2005 and 2020 including all patients followed for telomeropathy. RESULTS: Probands and relatives were included. Fifteen patients were studied from 10 independant families. Sixty percent had an heterozygous TERC gene mutation. Sixty seven percent had haematological diseases including macrocytosis, anemia and/or thrombocytopenia, 20 % had a fibrotic hepatic disease, 27 % had a fibrotic pulmonary disease. Lymphocyte immunophenotyping showed a double negative T lymphocyte population with γδ TCR expression in 5 (33 %) patients. Forty-seven percent of the patients had not received any treatment. Twenty-seven percent were on androgen therapy. Twenty percent had received cyclosporine and 13 % anti-lymphocyte serum in the context of initial misdiagnosis. CONCLUSION: It is important to be aware of the complexity of telomeropathies, a differential diagnosis of immune aplastic anemia, in order to optimize management and avoid inappropriate treatments. Allografting of hematopoietic stem cells is the only potentially curative treatment. Our analysis found particularities in immunophenotyping lymphocyte not previously described to our knowledge, whose physiopathological imputability remains to be demonstrated.

Effects of azacitidine in 93 patients with IDH1/2 mutated acute myeloid leukemia/myelodysplastic syndromes: a French retrospective multicenter study.

Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) remains inconsistent in IDH1/2-mutated MNs and the potential of serum 2HG as a suitable marker of response to AZA is unknown. To address these questions, we retrospectively analyzed 93 MNs patients (78 AML, 11 MDS, 4 CMML) with IDH1/2 mutations treated with AZA. After a median of 5 cycles of AZA, overall response rate was 28% (including 15% complete remission) and median OS was 12.3 months (significantly shorter in AML compared to MDS/CMML patients). In multivariate analysis of AML patients, DNMT3A mutation was associated with shorter OS while IDH1/2 mutation subtypes had no independent impact. No difference was observed in serum 2HG levels upon AZA treatment between responding and refractory patients suggesting that serum 2HG cannot be used as a surrogate marker of AZA response.

[Endoscopic lung volume reduction for emphysema]. / Réduction de volume pulmonaire endoscopique dans l'emphysème.

Lung hyperinflation which is a hallmark of advanced emphysema plays a major role in the exertional dyspnoea experienced by patients. This has led to the development of surgical lung volume reduction which, though effective, is also associated with significant morbidity and mortality. The goal of endoscopic lung volume reduction which has developed over several years is to decrease hyperinflation without exposing patients to the risks of surgery. Several endoscopic techniques have been assessed by high quality controlled studies: airway by-pass, instillation of glue, insertion of coils or unidirectional valves, vapour ablation. The aim of this review is to present the results of these studies in terms of functional benefit and side effects. Based on these studies, an algorithm for the endoscopic management of advanced forms of emphysema is proposed.

Is Acute Myeloblastic Leukemia in Children Under 2 Years of Age a Specific Entity? A Report from the FRENCH ELAM02 Study Group.

The clinical and biological characteristics of children under 2 years (infants) with acute myeloid leukemia (AML) are different from those of older children. We aimed to describe the specific characteristics of this population and the potential factors that influence the prognosis. We analyzed data concerning 438 children with newly-diagnosed AML treated in the ELAM02 protocol between March 2005 and December 2011, of which 103 were under 2 years old at diagnosis. The evaluation criteria were overall survival (OS) and event-free survival (EFS) of infants vs older children. The clinical and biological features were secondary criteria. Infants presented more frequent extra-medullary presentation than older children. They had a significantly higher proportion of skin lesions and central nervous system involvement (15% vs 3%, p < 0.0001 and 26% vs 12%, p = 0.0005, respectively). The global incidence of KMT2A rearrangements was nearly 55% for infants vs 11% for older children (p < 0.0001). Median 5-year OS was 70.4% for infants vs 71.4% for older children (p = 0.83). Five-year EFS was 67% for infants vs 58% for older children (p = 0.27). Infants with AML represent a cohort of patients with specific clinical and biological features. These remarkable differences had no significant impact on their outcome in the ELAM02 protocol.

Impact of Wilms' tumor 1 expression on outcome of patients undergoing allogeneic stem cell transplantation for AML.

The monitoring of the minimal residual disease by Wilms' tumor 1 expression (MRDWT1) is a standardized test, which can be used in over 80% of patients with AML. To investigate the prognostic value of MRDWT1 in patients undergoing allogeneic stem cell transplantation (allo-SCT) for AML, MRDWT1 was monitored 3 months after transplantation in 139 patients. MRDWT1 positivity did not lead to any therapeutic intervention. Median follow-up was 39.3 (6.4-99.8) months. Patients with positive MRDWT1 at 3 months experienced more often post-transplant relapse (27/30, 90%) than those with negative MRDWT1 (16/109, 14.7%) (P<0.0001). Similarly, a shorter 3-year event-free survival (EFS) was observed in MRDWT1-positive patients (10% vs 72.3% in MRDWT1-negative patients, P<0.0001). The correlation between relapse and MRDWT1 was stronger in blood than in bone marrow samples. Multivariate analysis confirmed the detrimental role of 3-month positive MRDWT1 for relapse (hazard ratio (HR): 15.42; 95% confidence interval (CI): 7.53-31.59; P<0.0001) and EFS (HR: 10.71; 95% CI: 5.41-21.21; P<0.0001). Interestingly, 3-month chimerism was less predictive of relapse than positive MRDWT1. In conclusion, our results demonstrate the usefulness of peripheral blood MRDWT1 monitoring in identifying very high-risk patients, who could benefit from an early preemptive treatment, and those who do not need such an intervention.

[Bronchiolitis with airflow obstruction in adults]. / Bronchiolites avec trouble ventilatoire obstructif de l'adulte.

PURPOSE: The purpose of this paper is twofold: to describe the clinical and anatomical characteristics of bronchiolitis associated with airflow obstruction in adults; to present through a clinical approach, a classification of the main aetiologies or pathological frames associated with that entity. KEY POINTS: The constrictive bronchiolitis type is the most frequently encountered. On clinical grounds, cough, crackles, and a progressive dyspnea develop usually within a few weeks. Radiological signs of bronchiolar abnormalities are best visualized on high resolution expiratory CT scan. The decrease in maximal airflows and oxygen tension is of limited amplitude and poorly reversible with bronchodilators. Diagnosis is easily performed when a causative event, or the clinical context, can be delineated: inhalation of toxic fumes, diffuse bronchiectasis, rheumatoid arthritis, lung or bone marrow transplantation. Delayed formation of bronchiectasis in the central airways is common. The treatment is not standardized; corticosteroids are usually prescribed as a first line therapy; the benefit of the addition of, or substitution with immunosuppressive drugs has not been adequately evaluated, but is, on the mean, of limited amplitude. PERSPECTIVES: Recent advances in the identification of inhaled agents toxic for the distal airways help in establishing appropriate measures of prevention. When the aetiology of the bronchiolitis cannot be suspected, extensive search of a causative agent should be performed, including microbial and mineral analysis of bronchoalveolar products. Negative results should lead to perform a surgical lung biopsy. The study of chronic rejection processes in animal models of lung transplantation, the identification of inhibitory factors of bronchiolar fibrogenesis, and the efficacy of some anti-cytokines on inflammatory processes could result in new therapeutic approaches.

Protein expression under uracil privation in Lactobacillus sakei.

Lactobacillus sakei is a lactic acid bacterium belonging to the natural flora of fresh and vacuum-packed meat, and is used as the starter for manufacturing fermented sausages. This species is now being studied at the genetic level. We investigated uracil prototrophy of strain 23K in order to validate the proteomic approach to study metabolism regulations. Cells grown without uracil had lower growth rates than with uracil. Protein analysis by 2D gel electrophoresis showed that at least three polypeptides were specifically induced in the absence of uracil. Two of these polypeptides were identified as orotate phosphoribosyl transferase, catalyzing the fifth step of pyrimidine biosynthesis, and PyrR, the transcriptional regulator of the pyr operon, respectively.

[Corticosteroid therapy of non-asthmatic chronic obstructive bronchopneumopathies]. / Corticothérapie des bronchopneumopathies chroniques obstructives non asthmatiques.

BASIS OF TREATMENT: Chronic obstructive pulmonary disease (COPD) is a common condition. Medical, and particularly drug, therapy still provides insufficiently effective relief. Corticosteroid treatment relies on the effect of these drugs on the underlying inflammatory mechanisms. Their efficacy has been demonstrated in asthma which exhibits certain features common with COPD. INDICATIONS: Short-term corticosteroid regimens are generally well tolerated. Clinical data favor their use in certain cases of acute decompensation. Long-term systemic regimens are not warranted due to the risk of adverse effects and the difficulty in maintaining appropriate dosages. Inhaled corticosteroids are widely used although the efficacy remains controversial. IMPORTANT DRAWBACKS: Clear evidence of efficacy from large controlled trials is still lacking. The difficulty encountered in obtaining such evidence is an indication of the minimal impact of such treatment and raises the question of its clinical pertinence. Patients exhibiting features similar to those observed in asthma (atopy, eosinophilia, improvement with bronchodilatation, non-smokers...) should be able to benefit from corticosteroids. For others a therapeutic test would be advisable to identify responders who could benefit from a preventive effect on the progression of COPD or associated asthma. A test lasting a few weeks at sufficient dosage is needed for subjective and objective (respiratory function tests) assessment. This costly therapy would not be warranted in non-responders, particularly in light of the expected secondary effects. Current evidence does not point to corticosteroid therapy as the much needed fully effective treatment for COPD.