Citations

Abstract Mutations in chromatin regulator ASXL1 are frequently identified in myeloid malignancies, in particular ∼40% of patients with chronic myelomonocytic leukemia (CMML). ASXL1 mutations are associated with poor prognosis in CMML and significantly co-occur with NRAS mutations. Here, we show that concurrent ASXL1 and NRAS mutations defined a population of CMML patients who had shorter leukemia-free survival than those with ASXL1 mutation only. Corroborating this human data, Asxl1−/− accelerated CMML progression and promoted CMML transformation to acute myeloid leukemia (AML) in NrasG12D/+ mice. NrasG12D/+;Asxl1−/− (NA) leukemia cells displayed hyperactivation of MEK/ERK signaling, increased global levels of H3K27ac, upregulation of Flt3. Moreover, we find that NA-AML cells overexpressed all the major inhibitory immune checkpoint ligands: programmed death-ligand 1 (PD-L1)/PD-L2, CD155, and CD80/CD86. Among them, overexpression of PD-L1 and CD86 correlated with upregulation of AP-1 transcription factors (TFs) in NA-AML cells. An AP-1 inhibitor or short hairpin RNAs against AP-1 TF Jun decreased PD-L1 and CD86 expression in NA-AML cells. Once NA-AML cells were transplanted into syngeneic recipients, NA-derived T cells were not detectable. Host-derived wild-type T cells overexpressed programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) receptors, leading to a predominant exhausted T-cell phenotype. Combined inhibition of MEK and BET resulted in downregulation of Flt3 and AP-1 expression, partial restoration of the immune microenvironment, enhancement of CD8 T-cell cytotoxicity, and prolonged survival in NA-AML mice. Our study suggests that combined targeted therapy and immunotherapy may be beneficial for treating secondary AML with concurrent ASXL1 and NRAS mutations.

AbstractIntroductionLiver transplant anesthesiology is an evolving and expanding subspecialty, and programs have, in the past, exhibited significant variations of practice at transplant centers across the United States. In order to explore current practice patterns, the Quality & Standards Committee from the Society for the Advancement of Transplant Anesthesia (SATA) undertook a survey of liver transplant anesthesiology program directors.MethodsProgram directors were invited to participate in an online questionnaire. A total of 110 program directors were identified from the 2018 Scientific Registry of Transplant Recipients (SRTR) database. Replies were received from 65 programs (response rate of 59%).ResultsOur results indicate an increase in transplant anesthesia fellowship training and advanced training in transesophageal echocardiography (TEE). We also find that the use of intraoperative TEE and viscoelastic testing is more common. However, there has been a reduction in the use of veno‐venous bypass, routine placement of pulmonary artery catheters and the intraoperative use of anti‐fibrinolytics when compared to prior surveys.ConclusionThe results show considerable heterogeneity in practice patterns across the country that continues to evolve. However, there appears to be a movement towards the adoption of specific structural and clinical practices.

AbstractHuman antimicrobial consumption largely occurs in the ambulatory setting, with inappropriate or unnecessary antimicrobial prescribing well documented in the literature. In 2020, The Joint Commission implemented a regulatory standard requiring the development and implementation of antimicrobial stewardship programs (ASP) in those institutions surveyed under the ambulatory accreditation standard. While experience with inpatient antimicrobial stewardship has continued to increase, ambulatory ASPs are programmatically distinct and can present unique challenges with regards to operationalizing regulatory components. Herein, we lay a framework for addressing the task of developing an ambulatory ASP for a large health system by reviewing the regulatory requirements, examining relevant recent publications, and describing our institutional experience.

Abstract Eosinophilic esophagitis (EoE), gastritis (EG), and/or duodenitis (EoD) are associated with accumulation and activation of eosinophils and mast cells in the esophagus, stomach, and/or duodenum, respectively. Lirentelimab (AK002), an antibody against siglec-8, depletes eosinophils and inhibits mast cells. We performed an open-label extension (OLE) study of subjects who completed ENIGMA (a randomized, double-blind, placebo-controlled phase 2 study of lirentelimab in adults with symptomatic, biopsy-confirmed EG and/or EoD, with or without EoE) to evaluate long-term responses. Methods Subjects who received 4 monthly infusions of lirentelimab or placebo during ENIGMA (n = 59) were eligible for the OLE; they received monthly, escalating doses of lirentelimab (0.3 or 1 mg/kg escalating to 3 mg/kg). Symptoms were assessed weekly using an electronic daily patient-reported outcome questionnaire and total symptom scores (TSS) were calculated. Patients underwent upper endoscopy with biopsy at screening and at the end of ENIGMA (day 99, week 16, blinded); in the OLE, endoscopies were performed on day 323 (30 weeks after the first dose in the OLE). Histopathology was assessed by a single pathologist. Results Fifty-eight subjects entered the OLE; 45 completed ≥52 weeks lirentelimab (including exposure during ENIGMA) and 29 completed 70 weeks. Mean TSS improved through week 70 (Figure 1). Subjects receiving 70 weeks lirentelimab (ENIGMA+OLE) had further improvements in TSS from baseline (mean reductions: 68% at weeks 29–30, 70% at weeks 51–52, 75% at weeks 69–70). Symptom scores (abdominal pain, nausea, vomiting, early satiety, appetite loss, abdominal cramping, bloating, diarrhea) decreased significantly from baseline. Treatment response was not associated with concomitant EoE. The most common adverse event was mild to moderate infusion-related reactions, usually with the first infusion. Conclusion In the OLE of the ENIGMA study, patients with EG and or EoD (with or without concomitant EoE) who received lirentelimab had sustained tissue eosinophil depletion and significant long-term symptom improvement. Symptoms continued to improve with duration of treatment. Lirentelimab appears to be a promising targeted treatment for EG and/or EoD.

Abstract Although the prevalence of eosinophilic gastrointestinal disorders (EGIDs) is increasing, there is evidence that eosinophilic gastritis and/or duodenitis (EG/EoD) are underdiagnosed. Patients with EG/EoD often present with chronic, non-specific gastrointestinal (GI) symptoms, similar to patients with functional GI disorders. We hypothesized that systematic evaluation, including multiple esophageal, gastric and duodenal biopsies, of patients with chronic GI symptoms might reveal a high rate of gastroduodenal eosinophila, with or without eosinophilic esophagitis (EoE). Methods We performed a prospective multi-center study of patients with non-specific GI symptoms for ≥6 months, from 20 sites. Patients completed a questionnaire assessing abdominal pain, abdominal cramping, early satiety, bloating, nausea, vomiting, diarrhea, and loss of appetite. Those with daily average symptom severity scores ≥3/10 for any single symptom underwent esophagogastroduodenoscopy (EGD) with collection of 4 esophageal (EoE), 8 gastric, and 4 duodenal biopsies, analyzed by central pathologists. Histologic criteria for EoE was ≥15eos/hpf in ≥1 esophageal site and for EG/EoD was peak eosinophil counts ≥30/hpf in ≥5 gastric hpfs and/or 3 duodenal hpfs—criteria used in randomized trials. Results Of 556 patients screened, 405 (73%) met symptom criteria and underwent EGD; 181 patients (45%, mean age 45, 73% female) who underwent EGD met the histologic criteria for EG/EoD, and of these, 7% also had EoE diagnosed. Overall 2% met histologic criteria for EoE alone. Of patients who met the histologic criteria for EG/EoD, 93% were previously diagnosed with gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), or functional dyspepsia (FD) (Figure 1). The average duration of GI symptoms in the screened population as well as those that met histologic criteria for EG/EoD was 11 years. Conclusion Forty-five percent of patients with moderate-to-severe GI symptoms who underwent EGD met histologic criteria for EG/EoD. Over 90% of these patients had previously been diagnosed with GERD, IBS, and/or FD, and had minimal overlap with EoE. EGD with systematic gastroduodenal biopsies, and intentional evaluation for tissue eosinophilia, should be performed in patients with chronic GI symptoms. Accurate diagnosis of EG/EoD is required for appropriate, targeted treatment and improved outcomes of patients with moderate-to-severe GI symptoms.

Wolframin-1–positive neurons in the entorhinal cortex of mouse brain propagate tau to the hippocampal CA1 region resulting in memory impairment.