Epidemiology,clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.     

The complex karyotype and chronic lymphocytic leukemia: prognostic value and diagnostic recommendations

Chromosomal abnormalities are frequently observed in patients with chronic lymphocytic leukemia (CLL) and have prognostic value. Deletions of the short arm of chromosome 17 (and/or mutations TP53) predict resistance to chemoimmunotherapy and shorter progression-free survival after targeted therapies. Although the complex karyotype (CK) is strongly predictive of a poor prognosis in hematologic malignancies such acute myeloid leukemia or myelodysplastic syndrome, its value in CLL is subject to debate. Here, we review the literature on the CK in CLL and examine its prognostic value with different treatments. We also propose a standardized method for defining a CK in all types of hematopoietic neoplasm.     

Staying awake – a genetic region that hinders α2 adrenergic receptor agonist‐induced sleep

How external stimuli prevent the onset of sleep has been little studied. This is usually considered to be a non‐specific type of phenomenon. However, the hypnotic drug dexmedetomidine, an agonist at α₂ adrenergic receptors, has unusual properties that make it useful for investigating this question. Dexmedetomidine is considered to produce an ‘arousable’ sleep‐like state, so that patients or animals given dexmedetomidine become alert following modest stimulation. We hypothesized that it might be more difficult to make mice unconscious with dexmedetomidine if there was a sufficient external stimulus. Employing a motorized rotating cylinder, which provided a continuous and controlled arousal stimulus, we quantitatively measured the ability of such a stimulus to prevent dexmedetomidine loss of righting reflex in two inbred strains of mice (C57BL/6 and 129X1). We found that whereas the C57BL/6 strain required a strong stimulus to prevent dexmedetomidine‐induced hypnosis, the 129X1 strain stayed awake even with minimal stimuli. Remarkably, this could be calibrated as a simple threshold trait, i.e. a binary ‘yes–no’ response, which after crossing the two mouse strains behaved as a dominant‐like trait. We carried out a genome‐wide linkage analysis on the F₂ progeny to determine if the ability of a stimulus to prevent dexmedetomidine hypnosis could be mapped to one or more chromosomal regions. We identified a locus on chromosome 4 with an associated Logarithm of Odds score exceeding the pre‐established threshold level. These results show that complex traits, such as the ability of a stimulus to reverse drug‐induced hypnosis, may have precise genetic determinants.     

Endoscopic Internal Drainage with Enteral Nutrition (EDEN) for Treatment of Leaks Following Sleeve Gastrectomy

Background

Endoscopic treatment of gastric leaks (GL) following sleeve gastrectomy (SG) involves different techniques; however, standard management is not yet established. We report our experience about endoscopic internal drainage of leaks using pigtail stents coupled with enteral nutrition (EDEN) for 4 to 6 weeks until healing is achieved.

Methods

In 21 pts (18 F, 41 years), one or two plastic pigtail stents were delivered across the leak 25.6 days (4–98) post-surgery. In all patients, nasojejunal tube was inserted. Check endoscopy was done at 4 to 6 weeks with either restenting if persistent leak, or removal if no extravasation of contrast in peritoneal cavity, or closure with an Over-the-Scope Clip® (OTSC®) if contrast opacifying the crossing stent without concomitant peritoneal extravasation.

Results

Twenty-one out of 21 (100 %) patients underwent check endoscopy at average of 30.15 days (26–45) from stenting. In 7/21 (33.3 %) patients leak sealed, 2/7 needed OTSC®. Second check endoscopy, 26.7 days (25–42) later, showed sealed leak in 10 out 14; 6/10 had OTSC®. Four required restenting. One patient, 28 days later, needed OTSC®. One healed at 135 days and another 180 days after four and seven changes, respectively. One patient is currently under treatment. In 20/21 (95.2 %), GL have healed with EID treatment of 55.5 days (26–?180); all are asymptomatic on a normal diet at average follow-up of 150.3 days (20–276).

Conclusions

EDEN is a promising therapeutic approach for treating leaks following SG. Multiple endoscopic sessions may be required.     

Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome

Epigenetic information is available from contemporary organisms, but is difficult to track back in evolutionary time. Here, we show that genome-wide epigenetic information can be gathered directly from next-generation sequence reads of DNA isolated from ancient remains. Using the genome sequence data generated from hair shafts of a 4000-yr-old Paleo-Eskimo belonging to the Saqqaq culture, we generate the first ancient nucleosome map coupled with a genome-wide survey of cytosine methylation levels. The validity of both nucleosome map and methylation levels were confirmed by the recovery of the expected signals at promoter regions, exon/intron boundaries, and CTCF sites. The top-scoring nucleosome calls revealed distinct DNA positioning biases, attesting to nucleotide-level accuracy. The ancient methylation levels exhibited high conservation over time, clustering closely with modern hair tissues. Using ancient methylation information, we estimated the age at death of the Saqqaq individual and illustrate how epigenetic information can be used to infer ancient gene expression. Similar epigenetic signatures were found in other fossil material, such as 110,000- to 130,000-yr-old bones, supporting the contention that ancient epigenomic information can be reconstructed from a deep past. Our findings lay the foundation for extracting epigenomic information from ancient samples, allowing shifts in epialleles to be tracked through evolutionary time, as well as providing an original window into modern epigenomics.Ancient DNA research started in the mid-1980s with the successful cloning and sequencing of a short mitochondrial DNA fragment from the quagga zebra, a species that became extinct in the early 20th century (Higuchi et al. 1984). Soon after, the invention of PCR unlocked access to this fragmented and degraded DNA material (Pääbo 1989), making it possible to amplify short gene markers of interest and compare their sequence to that from extant organisms. This illuminated a range of topics ranging from the reconstruction of the evolutionary origins of several now-extinct iconic mammals (Orlando et al. 2003; Krause et al. 2006), the evaluation of the possible role played by major past climatic changes in driving mega-fauna extinctions (Shapiro et al. 2004; Campos et al. 2010; Lorenzen et al. 2011), to the identification of the pathogens responsible for massive historical outbreaks (Taubenberger et al. 1997).However, before the advent of next-generation sequencing (NGS) platforms, the amount of ancient sequence information one had access to was limited to several tens of thousands of nucleotides at best (Noonan et al. 2005, 2006), and until very recently, sequencing whole ancient mitochondrial genomes was considered a major achievement (Cooper et al. 2001; Krause et al. 2006). Parallel sequencing of millions to billions of short DNA fragments has revolutionized ancient DNA research, and today a series of ancient genomes has been reconstructed from humans (Rasmussen et al. 2010, 2011; Keller et al. 2012; Raghavan et al. 2013), archaic hominins (Green et al. 2010; Reich et al. 2010; Meyer et al. 2012), the woolly mammoth (Miller et al. 2008), and several microbial pathogens (Bos et al. 2011; Martin et al. 2013; Schuenemann et al. 2013; Yoshida et al. 2013). Those mainly date back to recent historical periods or the Late Pleistocene, but most recently, the characterization of a 560,000- to 780,000-yr-old horse draft genome revealed that genomic information could be retrieved over much longer evolutionary time scales, probably up until the last million years (Orlando et al. 2013).Ancient genomes have provided important new insights into human evolution and dispersals (Rasmussen et al. 2010, 2011; Keller et al. 2012; Raghavan et al. 2013), revealing an admixture between contemporary human ancestors and archaic hominins (Green et al. 2010; Reich et al. 2010; Meyer et al. 2012) and multiple early human expansions into both Asia and North America (Rasmussen et al. 2010, 2011). The information gained from these samples has largely been limited to nucleotide polymorphisms. Unlike mutations, epigenetic modifications do not alter the underlying DNA sequence, but can be inherited across cell divisions and from parents to offspring and can control gene expression by reshaping cytosine methylation landscapes, nucleosome organization, and histone modification patterns. The range of biological processes that depend on some level of epigenetic regulation is diverse and includes imprinting (Bird 2002), transposition (Hollister and Gaut 2009), cell differentiation (Meissner et al. 2008), and cancer (Teschendorff et al. 2011). In this study, we use the Saqqaq genome that was retrieved from an ∼4000-yr-old tuft of hair of a Paleo-Eskimo from Greenland and sequenced to an average depth of 20× (Rasmussen et al. 2010). We demonstrate that NGS data can be used in the absence of bisulfite or further experimental treatment to directly infer genome-wide nucleosome organization and regional methylation levels, thereby providing the first survey of an ancient epigenome.     

Emergency air evacuation of patients with acute respiratory failure due to SARS-CoV-2 from Mayotte to Reunion Island

In February 2021, an explosion of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia overwhelmed the only hospital in Mayotte. To report a case series of patients with acute respiratory failure (ARF) due to SARS-CoV-2 who were evacuated by air from Mayotte to Reunion Island.This retrospective observational study evaluated all consecutive patients with ARF due to SARS-CoV-2 who were evacuated by air from Mayotte Hospital to the intensive care unit (ICU) of Félix Guyon University Hospital in Reunion Island between February 2, and March 5, 2021.A total of 43 patients with SARS-CoV-2 pneumonia were evacuated by air, for a total flight time of 2 hours and a total travel time of 6 hours. Of these, 38 patients (88.4%) with a median age of 55 (46–65) years presented with ARF and were hospitalized in our ICU. Fifteen patients were screened for the SARS-CoV-2 501Y.V2 variant, all of whom tested positive. Thirteen patients (34.2%) developed an episode of severe hypoxemia during air transport, and the median paO₂/FiO₂ ratio was lower on ICU admission (140 [102–192] mmHg) than on departure (165 [150–200], P = .022). Factors associated with severe hypoxemia during air transport was lack of treatment with curare (P = .012) and lack of invasive mechanical ventilation (P = .003). Nine patients (23.7%) received veno-venous extracorporeal membrane oxygenation support in our ICU. Seven deaths (18.4%) occurred in hospital.Emergency air evacuation of patients with ARF due to SARS-CoV-2 was associated with severe hypoxemia but remained feasible. In cases of ARF due to SARS-CoV-2 requiring emergency air evacuation, sedated patients receiving invasive mechanical ventilation and curare should be prioritized over nonintubated patients. It is noteworthy that patients with SARS-CoV-2 pneumonia related to the 501Y.V2 variant were very severe despite their young age.     

Sex and gender differences in Alzheimer’s disease: current challenges and implications for clinical practice

Alzheimer’s disease (AD) is characterized by high heterogeneity in disease manifestation, progression and risk factors. High phenotypic variability is currently regarded as one of the largest hurdles in early diagnosis and in the design of clinical trials; there is therefore great interest in identifying factors driving variability that can be used for patient stratification. In addition to genetic and lifestyle factors, the individual’s sex and gender are emerging as crucial drivers of phenotypic variability. Evidence exists on sex and gender differences in the rate of cognitive deterioration and brain atrophy, and in the effect of risk factors as well as in the patterns of diagnostic biomarkers. Such evidence might be of high relevance and requires attention in clinical practice and clinical trials. However, sex and gender differences are currently seldom appreciated; importantly, consideration of sex and gender differences is not currently a focus in the design and analysis of clinical trials for AD. The objective of this position paper is (i) to provide an overview of known sex and gender differences that might have implications for clinical practice, (ii) to identify the most important knowledge gaps in the field (with a special regard to clinical trials) and (iii) to provide conclusions for future studies. This scientific statement is endorsed by the European Academy of Neurology.     

Impaired virus-specific T cell responses in patients with myeloproliferative neoplasms treated with ruxolitinib

Ruxolitinib is effective in myeloproliferative neoplasms (MPN) but can cause reactivation of silent infections. We aimed at evaluating viral load and T-cell responses to human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) in a cohort of 25 MPN patients treated with ruxolitinib. EBV-DNA and HCMV-DNA were quantified monthly using real-time polimerase chain reaction (PCR) on peripheral blood samples, and T-cell subsets were analyzed by flowcytometry. HCMV and EBV-directed T-cell responses were evaluated using the IFN-γ ELISPOT assay. Most patients had CD4+ and/or CD8+ T-cells below the normal range; these reductions were related to the duration of ruxolitinib treatment. In fact, reduced T-lymphocytes' subsets were found in 93% of patients treated for ≥5 years and in 45% of those treated for <5 years (P = .021). The former also had lower median numbers of CD4+ and CD8+ cells. Subclinical reactivation of EBV and HCMV occurred in 76% and 8% of patients. We observed a trend to an inverse relationship between EBV and CMV-specific CD4+ and CD8+ T-cell responses and viral load, and a trend to an inverse correlation with ruxolitinib dose. Therefore, our data suggest that the ruxolitinib treatment may interfere with immunosurveillance against EBV and HCMV.