Late-onset noninfectious pulmonary complications (LONIPCs), most of which occur between 3 months and 2 years following allogeneic hematopoietic stem cell transplantation (HSCT), have a significant ...effect on patient outcomes and are highly associated with mortalities and morbidities. LONIPCs can involve all anatomic lung regions: bronchi, parenchyma, vessels, and pleura; this diversity can lead to various clinical entities. Bronchiolitis obliterans syndrome is the most frequent LONIPC. Most LONIPCs are associated with graft-versus-host disease. Evaluation of prophylactic strategies for LONIPCs is necessary to improve outcomes in high-risk allogeneic HSCT recipients.
: Progress in allogeneic hematopoietic stem cell transplantation (HSCT) procedures has been associated with improved survival in HSCT recipients. However, they have also brought to light ...organ-specific complications, especially pulmonary complications. In this setting, pulmonary complications are consistently associated with poor outcomes, and improved management of these complications is required.
: We review the multiple infectious and noninfectious lung complications that occur both early and late after allogeneic HSCT. This includes the description of these complications, risk factors, diagnostic approach and outcome. A literature search was performed using PubMed-indexed journals.
: Multiple lung complications after allogeneic HSCT can be diagnosed concomitantly and require a multidisciplinary approach. A specific clinical evaluation including a precise analysis of a lung CT scan is necessary. Management of these lung complications, especially the noninfectious ones, is impaired by the lack of prospective, randomized control trials, suggesting preventive strategies should be developed.
although they are major consumers of medications, there is little evidence-based data to guide prescribing and deprescribing of medications for very old adults (80+ years).
to discover the ...perceptions of very old adults, caregivers and health professionals in order to further examine the clinical and ethical issues raised by prescribing and deprescribing in very old age.
individual interviews were conducted with very old adults (n = 10) and caregivers (n = 6), whereas group interviews were conducted with health professionals (n = 11). The themes covered included perceptions of medication use, polypharmacy, deprescribing and patient-health professional relationships. Thematic analysis was used to identify areas of convergence and divergence.
very old adults are satisfied with the medications they are taking, do not see the need to reduce their medication use and consider their doctor as the expert who should make the decisions regarding treatment. The perceptions of caregivers are similar to those of older adults, whereas health professionals believe that very old adults take a lot of inappropriate medications and list multiple barriers to deprescribing. All participants describe a normalisation of medication use with ageing.
there is a dichotomy between the perception of the very old adults/caregivers and that of health professionals regarding the safety of medication in very old age. A cultural change regarding medication use seems essential to optimise therapy and support deprescribing in clinical practice since the potential issues raised by researchers do not resonate with the main stakeholders.
The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia ...treated with the tyrosine kinase inhibitor dasatinib.
This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (≤20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%.
Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.
This study aimed to describe the long-term outcomes of pulmonary arterial hypertension (PAH) induced by dasatinib.21 incident, right heart catheterisation-confirmed cases of dasatinib-induced PAH ...were identified from the French Pulmonary Hypertension Registry. Clinical and haemodynamic variables were compared from baseline to last follow-up (median (range) 24 (1-81) months).Median age was 52 years and 15 patients were female (71%). 19 patients received dasatinib for chronic myelogenous leukaemia for a median (range) duration of 42 (8-74) months before PAH diagnosis. No bone morphogenic protein receptor-2 (
) mutations were found in the 10 patients tested. Dasatinib was uniformly discontinued and 11 patients received PAH medications. Four patients died during follow-up. New York Heart Association functional class improved from 76% in class III/IV to 90% in class I/II (p<0.01). Median (range) 6-min walk distance improved from 306 (0-660) to 430 (165-635) m (p<0.01). Median (range) mean pulmonary arterial pressure improved from 45 (30-70) to 26 (17-50) mmHg (p<0.01) and pulmonary vascular resistance from 6.1 (3.2-27.3) to 2.6 (1.2-5.9) Wood units (p<0.01). Patients treated with PAH medications had worse baseline haemodynamics but similar long-term outcomes to untreated patients. PAH persisted in 37% of patients.Dasatinib-induced PAH frequently improves after discontinuation but persisted in over one-third of patients, therefore systematic follow-up is essential.
Interstitial lung diseases (ILDs) can be caused by mutations in the
and
genes, which encode the surfactant protein (SP) complex SP-A. Only 11
or
mutations have so far been reported worldwide, of ...which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic
or
mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives.
The consequences of the 11
or
mutations were analysed both
, by studying the production and secretion of the corresponding mutated proteins and
, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented.
For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28
mutation carriers, the mean age at ILD onset was 45 years (range 0.6-65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic.
This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic
or
mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.
Chromosomal translocations involving KMT2A gene are one of the most common genetic alterations found in pediatric acute myeloid leukemias (AML) although the molecular mechanisms that initiate the ...disease remain incompletely defined. To elucidate these initiating events we have used a human model system of AML driven by the KMT2A-MLLT3 (KM3) fusion. More specifically, we investigated changes in DNA methylation, histone modifications, and chromatin accessibility at each stage of our model system and correlated these with expression changes. We observe the development of a profound hypomethylation phenotype in the early stages of leukemic transformation after KM3 addition along with loss of expression of stem cell associated genes along with skewed expression in other genes such as S100A8/9 implicated in leukemogenesis. In addition, early increases in the expression of the lysine demethylase KDM4B was functionally linked to these expression changes as well as other key transcription factors. Remarkably, our ATAC-seq data showed that there were relatively few leukemiaspecific changes and the vast majority corresponded to open chromatin regions and transcription factor clusters previously observed in other cell types. Integration of the gene expression and epigenetic changes revealed the adenylate cyclase gene ADCY9 as an essential gene in KM3-AML, and suggest the potential for autocrine signalling through the chemokine receptor CCR1 and CCL23 ligand. Together, our results suggest that KM3 induces subtle changes in the epigenome while co-opting the normal transcriptional machinery to drive leukemogenesis.
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