Asciminib is a novel inhibitor of ABL1 and ABL2 gene fusions in ALL but requires the ABL SH3 domain for efficacy.

High-risk Ph-like ALL includes genomic rearrangement of the ABL1 and ABL2 genes (collectively ABL-rearranged, ABLr), and novel treatments are required. For the first time, we demonstrate asciminib efficacy in ABLr ALL, but only when the ABL SH3 domain is present.

Adolescents' implicit and explicit attitudes toward their peers with genetic conditions.

INTRODUCTION: Previous research has demonstrated that children lacking knowledge about genetic disorders may have harmful attitudes toward people with disabilities, but disability awareness can successfully modify these attitudes. We explored adolescents' implicit and explicit attitudes toward peers with genetic conditions to determine whether improved genetics/genomics literacy can mitigate the impact of ableism in this population. METHODS: English-speaking adolescents (10-18 years) from British Columbia were invited to complete a Disability Attitudes Implicit Association Test (DA-IAT) and participate in a semi-structured focus group centering on a fictionalized vignette about an adolescent with Down syndrome. We used pragmatism as an analytical paradigm. Descriptive and inferential statistics were used to analyze DA-IAT and sociodemographic data; phronetic iterative analysis with constant comparison as a coding strategy for transcripts; and interpretive description to develop a conceptual model. RESULTS: Twenty-two adolescents completed the DA-IAT and participated in one of four focus groups. Participants had a statistically significant implicit preference for non-disabled people (D-score = 0.72, SD = 0.44; t = 7.18, p < .00001). They demonstrated greater diversity in their explicit attitudes during the focus groups. Although participants articulated a positive attitude toward improved genetics education, results demonstrate their belief that social and personal interactions with disabled peers would be essential to address negative perceptions. CONCLUSIONS: This study lays important groundwork to understand, explain, and influence the negative attitudes of adolescents toward individuals with disabilities. Findings will be used to inform the design of interventions that address biased perceptions of people with genetic disorders, with the goal of reducing prejudices and improving social interactions.

Two-year safety outcomes of iPS cell-derived mesenchymal stromal cells in acute steroid-resistant graft-versus-host disease.

The first completed clinical trial of induced pluripotent stem cell (iPS cell)-derived cells was conducted in 15 participants with steroid-resistant acute graft-versus-host disease. After intravenous infusion of mesenchymal stromal cells (CYP-001 derived from a clone of human iPS cells), we reported the safety, tolerability and efficacy within the primary evaluation period at day 100. We now report results at the 2-year follow-up: 9 of 15 (60%) participants survived, which compares favorably with previously reported outcomes in studies of steroid-resistant acute graft-versus-host disease. Causes of death were complications commonly observed in recipients of allogeneic hematopoietic stem cell transplantation, and not considered by the investigators to be related to CYP-001 treatment. There were no serious adverse events, tumors or other safety concerns related to CYP-001. In conclusion, systemic delivery of iPS cell-derived cells was safe and well tolerated over 2 years of follow-up, with sustained outcomes up to 2 years after the first infusion. ClinicalTrials.gov registration: NCT02923375 .

Elements of successful NIH grant applications.

Is there a formula for a competitive NIH grant application? The Serenity Prayer may provide one: "Grant me the serenity to accept the things I cannot change, the ability to change the things I can, and the wisdom to know the difference." But how to tell the difference? In this Perspective, we provide an inclusive roadmap-elements of NIH funding. Collectively, we have over 30 y of peer review experience as NIH Scientific Review Officers in addition to over 30 y of program experience as NIH Program Officers. This article distills our NIH experience. We use Euclid's 13-book landmark, The Elements, as our template to humbly share what we learned. We have three specific aims: inform, guide, and motivate prospective applicants. We also address ways that support diversity and inclusion among applicants and young investigators in biomedical research. The elements we describe come from a wide range of sources. Some themes will be general. Some will be specific. All will be candid. The ultimate goal is a competitive application, serenity, and hopefully both.

How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

Kidney replacement therapy: trends in incidence, treatment, and outcomes of myocardial infarction and stroke in a nationwide Scottish study.

BACKGROUND AND AIMS: Patients with kidney failure have a higher risk of cardiovascular disease compared with the general population. Whilst temporal trends of myocardial infarction and stroke are declining in the general population, these have not been evaluated in patients with kidney failure. This study aimed to describe national trends in the incidence, treatment, and outcomes of myocardial infarction and stroke in patients with kidney failure (i.e. on dialysis or with a kidney transplant) over a 20-year period, stratified by age and sex. METHODS: In this retrospective national data linkage study, all patients with kidney failure in Scotland (UK) receiving kidney replacement therapy between January 1996 and December 2016 were linked to national hospitalization, prescribing, and death records. The primary outcomes were the incidence of myocardial infarction and stroke, and subsequent cardiovascular death. Generalized additive models were constructed to estimate age-standardized, sex-stratified incidence rates and trends in cardiovascular and all-cause death. RESULTS: Amongst 16 050 patients with kidney failure [52 (SD 15) years; 41.5% women], there were 1992 [66 (SD 12) years; 34.8% women] and 996 [65 (SD 13) years; 45.1% women] incident myocardial infarctions and strokes, respectively, between January 1996 and December 2016. During this period, the age-standardized incidence of myocardial infarction per 100 000 decreased in men {from 4376 [95% confidence interval (CI) 3998-4785] to 1835 (95% CI 1692-1988)} and women [from 3268 (95% CI 2982-3593) to 1369 (95% CI 1257-1491)]. Similarly, the age-standardized incidence of stroke per 100 000 also decreased in men [from 1978 (95% CI 1795-2175) to 799 (95% CI 729-875)] and women [from 2234 (95% CI 2031-2468) to 903 (95% CI 824-990)]. Compared with the general population, the incidence of myocardial infarction was four- to eight-fold higher in patients with kidney failure, whilst for stroke it was two- to four-fold higher. The use of evidence-based cardioprotective treatment increased over the study period, and the predicted probability of cardiovascular death within 1 year of myocardial infarction for a 66-year-old patient with kidney failure (mean age of the cohort) fell in men (76.6% to 38.6%) and women (76.8% to 38.8%), and also decreased in both sexes following stroke (men, from 63.5% to 41.4%; women, from 67.6% to 45.8%). CONCLUSIONS: The incidence of myocardial infarction and stroke has halved in patients with kidney failure over the past 20 years but remains significantly higher than in the general population. Despite improvements in treatment and outcomes, the prognosis of these patients following myocardial infarction and stroke remains poor.

IDH-mutant myeloid neoplasms are associated with seronegative rheumatoid arthritis and innate immune activation.

ABSTRACT: High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA.

Special Issue "Advances in Molecular Pathogenesis and Targeted Therapies for Myeloid Neoplasms".

Myeloid neoplasms (MNs) constitute a diverse group of haematological malignancies that includes myelodysplastic neoplasms (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndrome, and acute myeloid leukaemia (AML) [...].

Population pharmacokinetics of posaconazole in allogeneic haematopoietic stem cell transplant patients.

BACKGROUND: Invasive fungal disease (IFD) in the early post-allogeneic HSCT (alloHCT) period is associated with increased likelihood of catastrophic outcomes. The utility of oral modified release (MR) posaconazole tablets is limited by reduced drug absorption from gastrointestinal toxicity induced by cytotoxic chemotherapy, necessitating a switch to the IV posaconazole formulation. OBJECTIVES: To describe the population pharmacokinetics of posaconazole for oral MR and IV formulations in alloHCT patients and determine dosing regimens likely to achieve therapeutic exposures. METHODS: We performed a prospective observational pharmacokinetic study in adult patients in the early post-alloHCT period requiring a change in posaconazole formulation (oral to IV). Samples were analysed using a validated LC-MS/MS method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. RESULTS: Twenty patients aged between 21 and 70 years were included in the study. A two-compartment model, incorporating mucositis/diarrhoea to modify the bioavailability for oral administration best described the data. To achieve ≥90% PTA, simulations showed that higher than currently recommended doses of oral MR posaconazole were required for prophylaxis Cmin targets (≥0.5 and ≥0.7 mg/L), while increased doses of both formulations were required for IFD treatment PK/PD targets, with patients experiencing oral mucositis/diarrhoea unlikely to achieve these. CONCLUSIONS: Increased doses of posaconazole should be considered for both prophylaxis and treatment of IFD to increase the proportion of alloHCT patients achieving therapeutic exposures, particularly the oral formulation in patients with mucositis and/or diarrhoea. Posaconazole therapeutic drug monitoring should be considered for all formulations in this setting.

The prevalence of gastroesophageal reflux disease and laryngopharyngeal reflux in patients with dysphagia after radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: The prevalence of gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) in post-irradiated patients with nasopharyngeal carcinoma (NPC) is unknown. MATERIALS AND METHODS: In a cross-sectional study, 31 NPC and 12 control patients completed questionnaires for GERD/LPR before esophageal manometry and 24-h pH monitoring. The DeMeester score and reflux finding score (RFS) were used to define GERD and LPR, respectively. Risk factors were identified. RESULTS: 51.6% of NPC and 8.3% of control patients, and 77.4% of NPC and 33% of control patients, were GERD-positive and LPR-positive, respectively. The GERD/LPR questionnaire failed to identify either condition in patients with NPC. No parameter differences in esophageal manometry or pneumonia incidence were noted between GERD/LPR-positive and GERD/LPR-negative patients. Post radiotherapy duration, high BMI, lack of chemotherapy, and dysphagia were positive risk factors for GERD/LPR. CONCLUSIONS: A high prevalence of GERD/LPR in patients with post-irradiated NPC exists, but reflux symptoms are inadequate for diagnosis.

A Safety and Feasibility Trial of Ultrasound-Guided Radiofrequency Ablation of Parotid Warthin's Tumor.

OBJECTIVE: To determine if ultrasound-guided (USG) radiofrequency ablation (RFA) of Parotid Warthin's tumor under local anesthesia is a safe and effective procedure. STUDY DESIGN: Safety and feasibility study. SETTING: Tertiary academic medical center. METHODS: This is an IDEAL phase 2a trial in a tertiary referral center. Twenty patients with Parotid Warthin's tumor were recruited. RFA was done between September and December 2021 for all 20 patients using a CoATherm AK-F200 machine with a disposable, 18G × 7 mm radiofrequency electrode. Results and follow-up statistics were compared with a historic sample of patients with parotid Warthin's tumor who underwent parotidectomy between 2019 and 2021 in the same center. RESULTS: Nineteen patients were included in the analysis as 1 patient dropped out after 4 weeks of follow-up. The mean age for the RFA group was 67 years old with most of them being male smokers. At a median of 45 weeks (44-47 weeks) postprocedure there was a 7.48 mL (68.4%) volume reduction compared to baseline. Three patients had transient facial nerve (FN) paresis, 1 recovered within hours, and the other 2 by 12 weeks follow-up. Three patients had great auricular nerve numbness; 1 patient had infected hematoma treated in an out-patient manner. Compared to a historic cohort of parotidectomy patients for Warthin's tumor, there was no significant difference in FN paresis and other minor complications between the 2 treatment modalities. CONCLUSION: The current analysis suggests that USG RFA of Warthin's Tumor is a safe alternative to parotidectomy with shorter operative time and length of stay.

Impulse Oscillometry Versus Spirometry to Detect Bronchiolitis Obliterans Syndrome in Bilateral Lung Transplant Recipients: A Prospective Diagnostic Study.

BACKGROUND: Chronic lung allograft dysfunction (CLAD), and especially bronchiolitis obliterans syndrome (BOS), remain dominant causes of morbidity and mortality after lung transplantation. Interest is growing in the forced oscillation technique, of which impulse oscillometry (IOS) is a form, as a tool to improve our understanding of these disorders. However, data remain limited and no longitudinal studies have been published, meaning there is no information regarding any capacity IOS may have for the early detection of CLAD. METHODS: We conducted a prospective longitudinal study enrolling a consecutive sample of adult bilateral lung transplant recipients with healthy lung allografts or CLAD and performed ongoing paired IOS and spirometry tests on a clinically determined basis. We assessed for correlations between IOS and spirometry and examined any predictive value either modality may hold for the early detection of BOS. RESULTS: We enrolled 91 patients and conducted testing for 43 mo, collecting 558 analyzable paired IOS and spirometry tests, with a median of 9 tests per subject (interquartile range, 5-12) and a median testing interval of 92 d (interquartile range, 62-161). Statistically significant moderate-to-strong correlations were demonstrated between all IOS parameters and spirometry, except resistance at 20 Hz, which is a proximal airway measure. No predictive value for the early detection of BOS was found for IOS or spirometry. CONCLUSIONS: This study presents the first longitudinal data from IOS after lung transplantation and adds considerably to the growing literature, showing unequivocal correlations with spirometry but failing to demonstrate a predictive value for BOS.

Granulocyte Colony-Stimulating Factor (Neupogen®; Filgrastim) Accelerates Neutrophil Recovery in a Rodent Model of Sulfur Mustard-Induced Hematologic Toxicity.

OBJECTIVE: Evidence of myelosuppression has been negatively correlated with patient outcomes following cases of high dose sulfur mustard (SM) exposure. These hematologic complications can negatively impact overall immune function and increase the risk of infection and life-threatening septicemia. Currently, there are no approved medical treatments for the myelosuppressive effects of SM exposure. METHODS: Leveraging a recently developed rodent model of SM-induced hematologic toxicity, post-exposure efficacy testing of the granulocyte colony-stimulating factor drug Neupogen® was performed in rats intravenously challenged with SM. Before efficacy testing, pharmacokinetic/pharmacodynamic analyses were performed in naïve rats to identify the apparent human equivalent dose of Neupogen® for efficacy evaluation. RESULTS: When administered 1 d after SM-exposure, daily subcutaneous Neupogen® treatment did not prevent the delayed onset of hematologic toxicity but significantly accelerated recovery from neutropenia. Compared with SM controls, Neupogen®-treated animals recovered body weight faster, resolved toxic clinical signs more rapidly, and did not display transient febrility at time points generally concurrent with marked pancytopenia. CONCLUSIONS: Collectively, this work corroborates the results of a previous pilot large animal study, validates the utility of a rodent screening model, and provides further evidence for the potential clinical utility of Neupogen® as an adjunct treatment following SM exposure.

Autologous Faecal Microbiota Transplantation to Improve Outcomes of Haematopoietic Stem Cell Transplantation: Results of a Single-Centre Feasibility Study.

Haematopoietic stem cell transplantation (HSCT) is a curative approach for blood cancers, yet its efficacy is undermined by a range of acute and chronic complications. In light of mounting evidence to suggest that these complications are linked to a dysbiotic gut microbiome, we aimed to evaluate the feasibility of faecal microbiota transplantation (FMT) delivered during the acute phase after HSCT. Of note, this trial opted for FMT prepared using the individual's own stool (autologous FMT) to mitigate the risks of disease transmission from a donor stool. Adults (>18 years) with multiple myeloma were recruited from a single centre. The stool was collected prior to starting first line therapy. Patients who progressed to HSCT were offered FMT via 3 × retention enemas before day +5 (HSCT = day 0). The feasibility was determined by the recruitment rate, number and volume of enemas administered, and the retention time. Longitudinally collected stool samples were also collected to explore the influence of auto-FMT using 16S rRNA gene sequencing. n = 4 (2F:2M) participants received auto-FMT in 12 months. Participants received an average of 2.25 (1-3) enemas 43.67 (25-50) mL total, retained for an average of 60.78 (10-145) min. No adverse events (AEs) attributed to the FMT were identified. Although the minimum requirements were met for the volume and retention of auto-FMT, the recruitment was significantly impacted by the logistical challenges of the pretherapy stool collection. This ultimately undermined the feasibility of this trial and suggests that third party (donor) FMT should be prioritised.

ANZTCT consensus position statement on ruxolitinib in steroid-refractory acute and chronic graft-versus-host disease.

This position paper provides an overview of the assessment and management of both acute and chronic graft-versus-host disease (GvHD). There is a focus on the use of ruxolitinib, a selective inhibitor of Janus kinase (JAK)1 and JAK2, for the treatment of corticosteroid-refractory and corticosteroid-dependent GvHD.

Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures: Overlapping science in radiation and sulfur mustard injuries to lung and skin.

PURPOSE: To summarize presentations and discussions from the 2022 trans-agency workshop titled "Overlapping science in radiation and sulfur mustard (SM) exposures of skin and lung: Consideration of models, mechanisms, organ systems, and medical countermeasures." METHODS: Summary on topics includes: (1) an overview of the radiation and chemical countermeasure development programs and missions; (2) regulatory and industry perspectives for drugs and devices; 3) pathophysiology of skin and lung following radiation or SM exposure; 4) mechanisms of action/targets, biomarkers of injury; and 5) animal models that simulate anticipated clinical responses. RESULTS: There are striking similarities between injuries caused by radiation and SM exposures. Primary outcomes from both types of exposure include acute injuries, while late complications comprise chronic inflammation, oxidative stress, and vascular dysfunction, which can culminate in fibrosis in both skin and lung organ systems. This workshop brought together academic and industrial researchers, medical practitioners, US Government program officials, and regulators to discuss lung-, and skin- specific animal models and biomarkers, novel pathways of injury and recovery, and paths to licensure for products to address radiation or SM injuries. CONCLUSIONS: Regular communications between the radiological and chemical injury research communities can enhance the state-of-the-science, provide a unique perspective on novel therapeutic strategies, and improve overall US Government emergency preparedness.

Reproducible Bioinformatics Analysis Workflows for Detecting IGH Gene Fusions in B-Cell Acute Lymphoblastic Leukaemia Patients.

B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by diverse genomic alterations, the most frequent being gene fusions detected via transcriptomic analysis (mRNA-seq). Due to its hypervariable nature, gene fusions involving the Immunoglobulin Heavy Chain (IGH) locus can be difficult to detect with standard gene fusion calling algorithms and significant computational resources and analysis times are required. We aimed to optimize a gene fusion calling workflow to achieve best-case sensitivity for IGH gene fusion detection. Using Nextflow, we developed a simplified workflow containing the algorithms FusionCatcher, Arriba, and STAR-Fusion. We analysed samples from 35 patients harbouring IGH fusions (IGH::CRLF2 n = 17, IGH::DUX4 n = 15, IGH::EPOR n = 3) and assessed the detection rates for each caller, before optimizing the parameters to enhance sensitivity for IGH fusions. Initial results showed that FusionCatcher and Arriba outperformed STAR-Fusion (85-89% vs. 29% of IGH fusions reported). We found that extensive filtering in STAR-Fusion hindered IGH reporting. By adjusting specific filtering steps (e.g., read support, fusion fragments per million total reads), we achieved a 94% reporting rate for IGH fusions with STAR-Fusion. This analysis highlights the importance of filtering optimization for IGH gene fusion events, offering alternative workflows for difficult-to-detect high-risk B-ALL subtypes.

Adverse outcomes for chronic myeloid leukemia patients with splenomegaly and low in vivo kinase inhibition on imatinib.

Variability in the molecular response to frontline tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia may be partially driven by differences in the level of kinase inhibition induced. We measured in vivo BCR::ABL1 kinase inhibition (IVKI) in circulating mononuclear cells after 7 days of therapy. In 173 patients on imatinib 600 mg/day, 23% had low IVKI (<11% reduction in kinase activity from baseline); this was associated with higher rates of early molecular response (EMR) failure; lower rates of major molecular response (MMR), and MR4.5 by 36 months, compared to high IVKI patients. Low IVKI was more common (39%) in patients with large spleens (≥10 cm by palpation). Notably 55% of patients with large spleens and low IVKI experienced EMR failure whereas the EMR failure rate in patients with large spleens and high IVKI was only 12% (p = 0.014). Furthermore, patients with large spleen and low IVKI had a higher incidence of blast crisis, inferior MMR, MR4.5, and event-free survival compared to patients with large spleen and high IVKI and remaining patients. In nilotinib-treated patients (n = 73), only 4% had low IVKI. The combination of low IVKI and large spleen is associated with markedly inferior outcomes and interventions in this setting warrant further studies.

A Personalized Risk Model for Azacitidine Outcome in Myelodysplastic Syndrome and Other Myeloid Neoplasms Identified by Machine Learning Model Utilizing Real-World Data.

Azacitidine is an approved therapy for higher-risk myelodysplastic syndrome (MDS). However, only 30-40% patients respond to azacitidine, and the responses may take up to six cycles to become evident. Delayed responses and the myelosuppressive effects of azacitidine make it challenging to predict which patients will benefit. This is further compounded by a lack of uniform prognostic tools to identify patients at risk of early treatment failure. Hence, we performed a retrospective analysis of 273 consecutive azacytidine-treated patients. The median overall survival was 16.25 months with only 9% alive at 5 years. By using pre-treatment variables incorporated into a random forest machine learning model, we successfully identified those patients unlikely to benefit from azacytidine upfront (7.99 vs. 22.8 months, p < 0.0001). This model also identified those who required significantly more hospitalizations and transfusion support. Notably, it accurately predicted survival outcomes, outperforming the existing prognostic scoring system. By integrating somatic mutations, we further refined the model and identified three distinct risk groups with significant differences in survival (5.6 vs. 10.5 vs. 43.5 months, p < 0.0001). These real-world findings emphasize the urgent need for personalized prediction tools tailored to hypomethylating agents, reducing unnecessary complications and resource utilization in MDS treatment.