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Background The American Society of Clinical Oncology (ASCO) launched the Diversity in Oncology initiative in 2017 to address the need for increased minority representation in the hematology-oncology workforce. A recent series of reports, titled “State of the Oncology Workforce in America,” published in JCO Oncology Practice in 2021 and 2022, focused on this issue. Notably, these reports did not include any data regarding the representation of Asian minorities in the field. Therefore, our objective was to assess the proportion of Asian professionals within the hematology-oncology workforce, encompassing both practitioners and trainees. Methods We conducted a comprehensive search for publicly available data regarding Asian representation among US hematology-oncology practitioners and trainees in both adult and pediatric fields. Our primary data sources included the 2020 US Census, the Association of American Medical Colleges, the Accreditation Council for Graduate Medical Education, and various professional societies. We defined practitioners to include hematologist-oncologists, gynecologic oncologists, radiation oncologists, surgical oncologists, hematopathologists, hematology-oncology nurse practitioners, hematology-oncology physician assistants, and nurses specializing in hematology-oncology. Trainees encompassed fellows and residents. Additionally, we gathered comparable data on the US population, medical students, adult internal medicine residents, gynecology residents, pediatric residents, pathology residents, surgery residents, nurses, nurse practitioners, and physician assistants. To provide a comprehensive overview of the hematology-oncology workforce, we utilized data from 2020 to 2022, and whenever possible, we collected longitudinal data on trainees over the years. Results As of 2020, Asians represented 6.2% of the US population. Among hematology-oncology physician practitioners, the percentage of Asian individuals ranges from 14.7% to 32.1%, including 32.1% of adult hematologist-oncologists, 20.4% of pediatric hematologist-oncologists, 25.9% of radiation oncologists, 14.7% of gynecologic oncologists, and 7.0% of hematology-oncology physician assistants. In the realm of physician trainees, Asian representation is between 17.9% and 35.3%, with 35.3% of adult hematology-oncology fellows, 20.0% of pediatric hematology-oncology fellows, 26.4% of radiation oncology residents, and 17.9% of gynecologic oncology fellows. Additionally, the proportion of Asian residents from which hematology-oncology fellows are drawn ranges from 14.9% to 35.9%. Specifically, 35.9% of internal medicine residents, 22.0% of pediatric residents, 14.9% of gynecology residents, 26.6% of pathology residents, and 19.2% of surgical residents are Asian. Furthermore, 26.7% of medical students identify as Asian. Notably, the proportions of Asian hematology-oncology trainees and medical students have remained relatively stable from 2005 to 2022. Data on hematopathologists, surgical oncologists, and non-physician practitioners are limited, although Asian representation among hematology-oncology physician assistants is 7.0% and among nurses is 7.2%. Conclusions Asians comprise a large segment of the hematology-oncology workforce in the US. While only 1 in 20 people in the US are Asians, between 1 in 3 and 1 in 5 hematology-oncology physician practitioners and trainees, are Asians. Data are limited for non-physician practitioners. Asian minority representation should be highlighted and considered as an example of success in diversity in hematology-oncology workforce. This framework should be embraced moving forward to continue advancing minority representation throughout the field of hematology-oncology.

Introduction MYD88 L265P mutations (MUT) are found in 90% of patients with Waldenstrom macroglobulinemia (WM) and lead to the activation of pro-survival signaling. Limited literature has demonstrated that patients with MYD88 wild-type (WT) WM have poorer responses to conventional therapies and a higher likelihood of histological transformation. Increasingly the role of non-coding genomics in lymphomagenesis has demonstrated importance and currently, the epigenetic landscape of MYD88 WT WM remains underexplored. This study utilized a multi-omics approach to assess DNA methylation in MYD88 WT WM compared to MYD88 MUT patients and controls. Methods Bone marrow samples were prospectively collected from 20 subjects [3 MYD88 WT/CXCR4 WT WM, 12 MYD88 MUT WM and 5 normal controls] and positive selection for CD19+ and/or CD138+ B cells was performed. The analysis focused on the comparison between MYD88 WT WM to normal controls and MYD88-WT to MUT WM. Genome-wide DNA methylation analysis was performed, and CpG methylation ratios were segmented into 200-bp regions. Differentially methylated regions (DMRs) were determined using a Q-value <0.05 and absolute methylation difference ≥10%. Next, RNA-seq data was interrogated and differentially expressed genes (log2fold change>0.5 or <-0.5, false discovery rate<0.05) with corresponding promoter hypo- or hypermethylation were assessed. Ingenuity Pathway Analysis was used to determine potentially epigenetically regulated pathways using a corrected p<0.05. Results Comparing MYD88 WT WM samples to controls, a statistically greater number of hypermethylated DMRs were observed across genomic regions (hyper- vs hypomethylated): promoter (29129 vs 6300), 3'untranslated region (UTR) (2068 vs 1551), 5'UTR (10169 vs 735), intron (30344 vs 24511), exon (2224 vs 6855), CpG island (30372 vs 1240) and CpG shore (14477 vs 5872) (all p<0.001). Next, mRNA analysis demonstrated that 214 genes were differentially up-/downregulated with concordant promoter hypo-/hypermethylation. On the assessment of promoter-methylation-based pathways, multiple pathways involved in cell signaling, proliferation, gene regulation, cytokine and immune signaling and metabolism were found to be deregulated. Most pathways were found to be negatively enriched in MYD88 WT patients compared to controls including several members of interleukin (IL) signaling (IL-2, IL-3, IL,7) and regulators of cell proliferation and signaling including mTOR, PI3K/AKT, and p53. Positive enrichment of the PTEN, FGFR3 and ERK/MAPK pathways were observed. Underlying multiple pathways was promoter hypermethylation with corresponding mRNA downregulation of AKT3 and PIK3CA. Furthermore, promoter hypomethylation with transcript upregulation of PTEN was observed. Next, in comparison of MYD88 WT to MUT samples, a statistically greater number of hypermethylated DMRs were observed across genomic regions (hyper- vs hypomethylated): promoter (24829 vs 2544), 3'UTR (3534 vs 378), 5'UTR (6111 vs 605), intron (52292 vs 5360), exon (21066 vs 2187), CpG island (18334 vs 1551) and CpG shore (16351 vs 1957) (all p<0.001). Assessing mRNA expression, 354 genes were up-/downregulated with concordant promoter hypo-/hypermethylation. Pathway analysis revealed positive enrichment of the mitotic G1 phase to G1/S transition pathway with upregulation of the CDK4, LYN, and PSMA6 transcripts in MYD88 WT compared to MUT samples. Further, negative enrichment of cell signaling regulators including the RHO GTPase family, IL pathways (IL-4, IL-8, IL-13, IL-17) and integrin signaling were found in MYD88 WT compared to MUT samples. Underlying multiple pathways were downregulation with promoter hypermethylation of BCL2, an important regulator of apoptosis. Conclusion Genome-wide methylation analysis of MYD88 WT WM revealed a unique DNA methylation profile, with potential epigenetic alteration of key oncogenic transcripts and pathways. The negative enrichment of cell signaling and cytokine/inflammatory pathways in MYD88 WT samples compared to controls and MYD88 MUT WM suggests an epigenetic mechanism for immune evasion and potentially underlies the reduced response to conventional WM-directed therapies. Overall, this study reveals that MYD88 WT WM is epigenetically distinct from MYD88 MUT WM and regulators such as methylation may underlie the unique clinical and phenotypic properties observed.

Introduction: Over 80,000 new cases of Non-Hodgkin's Lymphoma (NHL) are diagnosed annually, but modifiable risk factors are largely unknown. Circadian disruption has been identified as a risk factor for several cancers, including breast and prostate cancer, and affects immune cells such as Natural Killer (NK) cells and T-helper cells. Disruptions in circadian rhythms can lead to aberrant immune cell trafficking and proliferation. Despite this biological connection, evidence linking circadian disruptions to NHL remains inconclusive. Only single Mendelian Randomization (MR) study (PMID: 32895918) has explored the causal relationship between sleep traits and overall NHL risk, without examining NHL subtypes. Studies have shown distinct risk factor profiles among NHL subtypes. Therefore, this study aims to investigate the causal relationship between sleep traits and NHL subtypes in European populations using MR. Methods: We conducted a two-sample MR analyses using genome-wide association studies (GWAS) summary data on sleep traits and NHL subtypes. The GWAS summary statistics on sleep traits were obtained from publicly available UKBiobank datasets. The sleep traits analyzed included chronotype (N=449,734), insomnia (N=237,627), sleep duration (N=446,118), daytime sleepiness (N=452,071), short sleep (N=411,934), and long sleep (N=339,926). Only independent, genome-wide significant SNPs (p < 5×10-8) were considered as valid instruments. The NHL subtype-specific summary statistics came from the InterLymph including follicular lymphoma (FL: N=6,508 cases / 64,183 controls), mantle cell lymphoma (MCL: N=1,169 cases / 61,603 controls), and Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL: N=1,697 cases / 59,333 controls). Our primary analysis used the random-effects inverse-variance weighted (IVW) method. In addition, we employed MR-Egger to adjust for directional pleiotropy. Heterogeneity in the MR results was evaluated with Cochran's Q statistic. Results: The IVW method did not identify any statistically significant causal association between sleep traits and the risk of NHL subtypes (FL,MCL,WM/LPL), but did yield several intriguing associations. Chronotype (early rising) showed a tendency towards a marginally an increased NHL risk across subtypes [Odds ratio (OR) range: 1.07 - 2.56]. Conversely, a decreased risk was noted for long sleep (≥ 9 hours vs. 7-8 hours) [OR range: 0.19 - 0.62], insomnia [OR range: 0.72 - 0.88], and short sleep (excludes MCL) [OR range: 0.12 - 0.72]. Confidence limit for long sleep was wide due to small number of variants (N=8). The MR-Egger regression analysis did not provide evidence of significant directional horizontal pleiotropy. The F-statistics for all sleep traits were greater than 10 indicating absences of weak instrument bias. Conclusions: Our study found no statistically significant associations between sleep traits and three NHL subtypes (FL, MCL, WM/LPL) in European populations. However, we observed potential influences of chronotype, long and short sleep, and insomnia on NHL risk. These findings align with and extend previous MR study by providing subtype-specific insights. Future directions include expanding our analysis to additional NHL subtypes, generating polygenic risk scores, and conducting stratified analyses using the InterLymph population. These efforts aim to further elucidate the complex relationship between sleep characteristics and NHL risk across diverse subtypes and populations.

Background: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN), further categorized as MD (WBC < 13 x 109/L) and MP (≥ 13 x 109/L) subtypes with an inherent risk for AML transformation (Am J Hematol 2024; 99: 1142). Hypomethylating agents (HMA), decitabine (DAC) and azacitidine, are the only FDA approved agents for the management of CMML, with complete remission rates of <20%, and a recent prospective study showing no event free survival benefit of DAC over hydroxyurea in MP-CMML (J Clin Oncol 2023; 41: 1888). TET2 mutations (TET2MT) occur in approximately 60% of CMML cases. TET2 converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), resulting in DNA demethylation (Nat Rev Gen 2017; 18: 517). IV ascorbic acid (AA) at pharmacologic concentrations demonstrates anti-cancer activity via H2O2-induced oxidative stress and DNA demethylation mediated by TET-activation. AA, a cofactor of TET2, binds to its catalytic domain, restores, and enhances TET1/2/3 activity. Given the synergistic impact of IV AA and HMA on DNA methylation, we designed a phase II clinical trial testing the safety and efficacy of standard dose decitabine and high dose IV AA in HMA-naïve CMML patients. Methods: LS1781 (NCT03418038) is an investigator-initiated, prospective, single-arm, single-institution, phase II trial assessing the safety and preliminary efficacy of high-dose IV AA in combination with DAC for patients with TET2MT CMML. DAC 20 mg/m2 Days 1-5 of each 28-day cycle is given as standard of care. With each cycle, IV AA (1g/kg, maximum 100g) is given 3 times on Days 1, 3, 5 via central line within 2 hours after DAC. Patients are encouraged to take oral AA 1000 mg once daily on non-treatment days. The primary endpoint is overall response rate determined by IWG MDS/MPN 2015 criteria after 4 cycles of therapy. Secondary endpoints include safety and side effects. Exploratory endpoints include the impact of AA on TET2MT variant allele fraction, plasma cytokine levels, DNA methylation and hydroxymethylation (as measured by Infinium MethylationEPIC array), and hematopoietic progenitor colony forming assay assessment (colony counts and impact on differentiation). Inclusion criteria include patients ≥ 18 years with TET2MT CMML, ≤1 cycle of HMA or ESA (hydroxyurea allowed), platelets ≥ 20,000/m3, ANC ≥ 500/mm3, and Cockcroft-Gault creatinine clearance ≥ 60 mL/min/m2. Twenty-three patients will be enrolled at Mayo Clinic Rochester and the Mayo Clinic Health System, based on power calculations to demonstrate enhanced complete response and overall response rates, in comparison to those seen historically with decitabine alone. Dose modifications have been established and will be considered based on adverse events. Treatment will be discontinued for disease progression or in the event of ≥ Grade 3 adverse events that do not resolve promptly. After completion of up to 12 cycles, patients with stable disease or better may continue single agent DAC with or without oral AA. Enrollment to the trial began in February 2024, with 2 patients enrolled at the time of abstract submission.

Abstract Objectives Protein-truncating variants in the TTN gene are a well-established cause of dilated cardiomyopathy (DCM). We report a novel case of DCM caused by a mobile element insertion (MEI) in TTN, through which we highlight the key features of MEIs in next-generation sequencing data. Because of the rarity of MEIs, the next-generation sequencing data features associated with these events may be mistaken as noise, potentially leading to missed diagnoses. Methods Next-generation sequencing gene panel testing for DCM was performed on a 17-year-old male patient presenting with severe left ventricular dilatation and systolic dysfunction. Manta was used for structural variant detection, followed by manual review of NGS data for potential structural variants. Results Manta detected a potential insertion in TTN. Manual review identified hallmark features consistent with a LINE-1 MEI. This finding was orthogonally confirmed by long-range polymerase chain reaction and gel electrophoresis, which indicated an insertion of approximately 4 to 5 kilobase pairs. The insertion disrupted the reading frame of TTN within an A-band exon, resulting in protein truncation that was classified as likely pathogenic. Conclusions This case expands the mutational spectrum of TTN protein-truncating variants. It also underscores the importance of recognizing rarer types of pathogenic variants (eg, MEIs) to produce accurate genetic diagnostics.

AbstractGastroenteropancreatic neuroendocrine tumours (GEP‐NETs), which may be hormone secreting (e.g., gastrinomas and insulinomas) or non‐secreting (also known as non‐functioning NETs) are associated with severe morbidity and have a median overall survival of 75–124 months. Studies have highlighted the importance of epigenetic mechanisms in GEP‐NETs pathogenesis, with the most frequently mutated genes being the epigenetic regulators, MEN1, DAXX, and ATRX. However, the consequences of these aberrant epigenetic mechanisms are poorly understood. The calcium sensing receptor (CASR), a G protein coupled‐receptor, is epigenetically silenced in cancers, and therefore we examined its role in GEP‐NET subtypes. Using RNA‐Scope and quantitative PCR analyses in two independent tumour cohorts from Europe (n = 18 patients) and the USA (n = 46 patients) we showed that CASR mRNA is almost completely absent in gastrinomas, insulinomas and non‐functioning pancreatic NETs. Furthermore, immunohistochemical staining confirmed a significant reduction in CaSR protein expression in all GEP‐NET subtypes, compared to normal islets. DNA methylationEPIC and ATAC‐seq analyses in the pancreatic NET cell line QGP‐1 showed the CaSR promoter was both hypermethylated and in a region of closed chromatin. Furthermore, transfection of wild type CaSR into QGP‐1 cells decreased cell viability, in keeping with the CaSR having a role in cellular proliferation. In summary, our study reveals that CaSR expression is decreased in GEP‐NETs and that this reduced expression is likely due to DNA methylation and chromatin changes. Moreover, we demonstrate that transfection of the CaSR into a PNET cell line reduces cell viability, thereby indicating that the CaSR acts as a tumour suppressor in this tumour type.

Abstract GBM AGILE(NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies against a common control. Paxalisib, a PI3K/mTOR inhibitor, is the 3rd arm in the trial to conclude evaluation. METHODS Paxalisib was open to patients with newly diagnosed unmethylated (NDU) and recurrent (RD) glioblastoma, with three possible signatures: NDU, RD, and All(NDU+RD). Arm enrollment occurred Dec2020 through May2022. Control patients were enrolled from study initiation (July2019) and were treated with temozolomide(NDU) or lomustine(RD). GBM AGILE investigational arms have 1 or 2 stages, with adaptive randomization in stage 1 and fixed randomization if arms continue to stage 2. Efficacy is based on OS hazard ratio(HR) of Arm/Control. Efficacy goal is final Bayesian probability ≥ 98% for HR<1.00 in combined Stages. An Arm continues to Stage 2 if Bayesian predictive power (PP) ≥ 0.8. An Arm stops accruing in Stage 1 if it reaches maximal sample size(N) or does not meet a minimum efficacy threshold (PP<0.25 for all signatures when N>50). Clinical cut-off is 12 months after accrual stops. The maximum N for paxalisib was approximately 150(Stage 1) and 50(Stage 2). RESULTS After paxalisib reached >150 patients in Stage 1, accrual stopped [Paxalisib/control N 54/75(NDU), 100/188(RD)]. Neither PP thresholds for moving to Stage 2 nor stopping for minimum efficacy were met. Following an unplanned public disclosure that the arm did not continue to stage 2, clinical cut-off for final analysis (planned May2023) was updated to public disclosure date (August2022). At final analysis mean HRs were 0.89(NDU), 1.25(RD), 1.05(All), probabilities of HR<1.00 of 0.72(NDU), 0.076(RD), 0.398(All). Model estimated median OS paxalisib/control (months) were 14.77/13.84(NDU) and 8.58/10.06(RD). CONCLUSION Paxalisib did not show survival benefit over cumulative control in final primary analysis; additional secondary analyses are being considered. GBM AGILE continues to rapidly and efficiently assess therapies in ND and RD glioblastoma.

AbstractBackground and purposeLower left atrial (LA) function is associated with higher dementia risk and may be mechanistically linked through vascular brain injury, an established correlate for higher dementia risk. Using data from the Atherosclerosis Risk in Communities study, we assessed the cross‐sectional association between LA function and brain magnetic resonance imaging (MRI) markers of vascular brain injury.MethodsWe included 1488 participants who were free of prevalent dementia, stroke, or atrial fibrillation and who underwent a two‐dimensional echocardiogram and brain MRI in 2011–2013 (mean [± standard deviation] age 76 [± 5] years, 60% female, 27% Black). LA function measures (reservoir, conduit, contractile strain) were assessed in quartiles. Brain MRI measures included cerebral microbleeds, brain infarcts, and white matter hyperintensity (WMH) volume. Logistic regression was used for dichotomous outcomes. Linear regression was used for WMH volume.ResultsOverall, 343 (23%) and 344 participants (23%) had ≥1 cerebral microbleed or brain infarct. After multivariable adjustments, the lowest LA reservoir and conduit strain quartiles (vs. highest quartile) were associated with higher odds of the presence of ≥1 cerebral microbleed (odds ratios [95% confidence intervals] 1.78 [1.42–2.22] and 1.52 [1.22–1.90]). Compared to the highest quartile, participants in the lowest LA conduit strain quartile had 1.51 (95% confidence interval 1.22–1.88) times higher odds of having ≥1 brain infarct. Lower LA contractile strain was associated with lower odds of brain infarcts. No association with WMH volume was noted.ConclusionsWe found that LA reservoir and conduit strain were associated with cerebral microbleeds and brain infarcts. Lower LA function may be linked to dementia risk via vascular brain injury. Prospective studies are needed to confirm these findings.

Background A multidisciplinary approach improves guideline‐directed medical therapy in systolic heart failure (HF), but its efficacy in patients with HF due to cardiac sarcoidosis is unreported. Methods and Results In a retrospective cohort study, we reviewed 848 patients from our institutional cardiac sarcoidosis clinics, identifying those with a cardiac sarcoidosis diagnosis, HF (left ventricular ejection fraction <50%) at index evaluation, and echocardiograms within 90 days and 11 to 36 months. Patients were stratified by participation in a pharmacist‐led medication therapy management (MTM) program for guideline‐directed medical therapy optimization (MTM versus non‐MTM [NMTM]) without randomization. Demographics, left ventricular ejection fraction, guideline‐directed medical therapy (quantified by Kansas City Medical Optimization score), and immunosuppressive therapy were assessed. Primary outcomes included changes in Kansas City Medical Optimization score, left ventricular ejection fraction, and cardiovascular event–free survival (unplanned HF hospitalization, left ventricular assist device /heart transplant, or death). The final cohort included 111 patients (median age, 57 years; 34% women; 64% New York Heart Association class I–II); 43 (39%) were MTM and 68 (61%) were NMTM. Mean Kansas City Medical Optimization score was similar at index evaluation (MTM, 23.2; NMTM, 29.6; P =0.83). At follow‐up (median, 16 months), the Kansas City Medical Optimization score increased significantly in both groups (MTM, 23.2 to 74.8; P <0.001; NMTM, 29.6 to 58.7; P <0.001) but was higher in MTM ( P =0.001). Mean left ventricular ejection fraction trended toward higher values in MTM (44.4% versus 40.0%, P =0.05). The primary clinical outcome occurred in 1 MTM (2.3%) and 16 NMTM (23.5%) patients, with higher risk in NMTM (hazard ratio, 11.97 [95% CI, 1.58–90.54]; P =0.002). Conclusions In this retrospective cohort study, a pharmacist‐led MTM program was associated with favorable guideline‐directed medical therapy optimization and lower risk of adverse cardiovascular outcomes in patients with cardiac sarcoidosis with HF.

BACKGROUND Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of IFN-γ, a cytokine implicated in the pathogenesis of LP. METHODS In this phase II trial, 12 patients with cutaneous LP received 2 mg daily baricitinib for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and posttreatment samples. RESULTS An early and sustained clinical response was seen, with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8 + , and CXCL13 + cytotoxic T cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis. CONCLUSION This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP. TRIAL REGISTRATION NCT05188521 FUNDING Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.