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SummaryBackgroundRacial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival.AimTo evaluate the impact of HCV treatment on such disparities.MethodsIn a retrospective cohort study, we analysed 6069 patients with HCV‐related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia.ResultsThe mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%–15%, 20% vs. 10%–17% and 10% vs. 5%–7%, respectively; all p < 0.0001). Treatment rate with direct‐acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients (p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10‐year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients (p < 0.0001). There were no statistically significant differences among those with SVR (p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non‐U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001).ConclusionDAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection.

Abstract Study Objectives Rapid eye movement sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g. Parkinson’s disease (PD), Lewy body dementia, and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD)—henceforth “neurotrauma” (NT)—increase the odds of RBD by ~2.5-fold and are associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD. Methods Participants ≥18 years with overnight polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal Synucleinopathy Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory, and autonomic function, were completed. This cross-sectional analysis compared cases (n = 24; RBD + NT) to controls (n = 96; RBD), matched for age (~60 years), sex (15% female), and years of education (~15 years). Results RBD + NT reported earlier RBD symptom onset (37.5 ± 11.9 vs. 52.2 ± 15.1 years of age) and a more severe RBD phenotype. Similarly, RBD + NT reported more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to RBD. No differences in olfaction or color vision were observed. Conclusions This cross-sectional, matched case:control study shows individuals with RBD + NT have significantly worse neurological measures related to common features of an overt synucleinopathy. Confirmatory longitudinal studies are ongoing; however, these results suggest RBD + NT may be associated with more advanced neurological symptoms related to an evolving neurodegenerative process.

ImportancePostoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence.ObjectiveTo evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins.Design, Setting, and ParticipantsThe American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (&amp;gt;1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023.Main Outcomes and MeasuresMain outcomes were risk factors for local recurrence.ResultsA total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group.Conclusions and RelevanceIn this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

Background: Baseline concussion testing can be helpful to perform when providing concussion care for young athletes. To appropriately interpret these data, it is important to understand how certain factors may affect concussion testing. Purpose: To examine the relationship of sociodemographic and health variables with baseline concussion testing in young athletes. Study Design: Cross-sectional study; Level of evidence, 3. Methods: High school and middle school athletes competing in sports or positions at high risk for concussion (football, soccer, ice hockey, wrestling, lacrosse, and pitchers/catchers in baseball/softball) during the 2020-2021 or 2021-2022 academic years completed annual baseline concussion testing and were included in the study. Baseline data included self-reported demographic and medical information, a graded symptom checklist, the Standardized Assessment of Concussion, and the King-Devick test. A validated measure, HOUSES (HOUsing-based index of SocioEconomic Status), was used to determine participants’ socioeconomic status (SES) by linking personal address information to publicly available property data. Multivariable linear regression models were fit to analyze the relationship of concussion baseline testing to sociodemographic and health variables. Results: Among the eligible 2747 athletes (mean age, 15.4 ± 1.5 years; 73.6% male), the mean Standardized Assessment of Concussion score was 26.7 ± 2.0 and the mean best King-Devick test time was 50.3 ± 10.1 seconds. Higher baseline symptom severity scores were related to lower SES ( P = .002). A lower (ie, poorer) mean Standardized Assessment of Concussion score was significantly associated with the following in the multivariable model: male sex ( P < .001), younger age ( P < .001), Black/African American race ( P = .029), Hispanic ethnicity ( P = .016), previous diagnosis of learning disorder or attention-deficit hyperactivity disorder ( P < .001), and lower SES ( P = .003). A higher (ie, poorer) mean King-Devick test time was related to younger age, previous diagnosis of a learning disorder or attention-deficit hyperactivity disorder, and lower SES (all P < .001). Conclusion: Baseline concussion testing was found to be associated with certain sociodemographic variables and underlying health conditions in high school and middle school athletes.

Abstract Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

BACKGROUND: Recent World Health Organization (WHO) classifications (5 th edition), International Consensus Classification (ICC) recognized TP53-mutated ( TP53mut) myeloid neoplasms (MNs) as a distinct subcategory, acknowledging their uniformly poor outcomes. However, there are critical differences between the two guidelines in how TP53 allelic status is assigned. Both WHO-5 and ICC acknowledged the poor outcome of multi-hit TP53mut but excluded single-hit TP53mut. These changes are driven by a pivotal study demonstrating favourable outcome of single-hit TP53mut, however this study predominantly included de novo myelodysplastic syndromes (MDS) cases (Bernard et al. Nat Med 2020). In contrast, we previously reported poor outcome of TP53mut therapy-related myeloid neoplasm (t-MN) irrespective of the allelic status of TP53 (Hiwase et al Blood 2022andShah et al BCJ 2023). Finally, the ICC removed the subcategory of “therapy-related,” substituting it with diagnostic qualifiers instead. The WHO has grouped t-MN with secondary MN and renamed it as “myeloid neoplasm post cytotoxic therapy,” with the assertion that only multi-hit T P53mut MDS occurring post-cytotoxic therapy have poor outcome compared with single-hit. METHODS: We analyzed one of the largest international cohorts of TP53mut MN (n=544) with full characterization of TP53mut allele status utilizing uniform ICC criteria and similar large numbers of de novo and t-MN cases managed at Mayo Clinic Enterprise (USA) and South Australian MDS Registry, Adelaide (Australia) with clinical, integrated genomic profiling, and long-term follow-up. RESULTS: In our cohort of TP53mut MN (n=544), 475 (87.3%) MN had TP53mut variant allele frequency (VAF) of ≥10% and thus satisfied ICC criteria for TP53mut MN. Majority of TP53mut t-MN presented with MDS (bone marrow (BM) blasts 0-9%) compared de novo MN (62% vs. 48%; P=0.0012). While acute myeloid leukemia (AML) (BM blasts ≥20%) were more prevalent in TP53mutde novo MN compared to t-MN (38% vs. 24%; P= 0.001) and there was no difference in frequency of MDS/AML (BM blasts 10-19%) between the two cohorts (14% vs. 14%; P=0.8) ( Figure 1A). Majority of TP53mut were observed in the DNA-binding domain in t-MN and de novo MN (95% vs. 96.2%; P=0.48). However, mutations in Tetramer Domain were more frequent in t-MN (4.3% vs. 0.3%; P=0.002), whereas those in the TAD2 domain were more frequent in de novo TP53mut MN (2.4 vs. 0%; P =0.006). Integrating the mutation, conventional G-banding cytogenetic, copy number variation (CNV), FISH, and SNP array analysis, TP53mut MDS (BM blast 0-9%; n=260) were classified as multi-hit (n=179, 68.9%) or multi-equivalent (n=35, 13.5%) and single-hit (n=46, 17.7%) (Arber et al. Blood 2022). Striking enrichment of multi-hit/multi-hit equivalent was observed in TP53mut t-MDS compared to de novo MDS (91% vs. 72%; P&lt;0.0001). While single-hit TP53mut were prevalent in de novo MDS compared to t-MDS (28% vs. 9%; P&lt;0.0001). Importantly, median overall survival (OS) of single-hit was significantly longer than multi-hit de novo MDS (25.4 vs. 7.2 months; P=0.0002). In contrast to this we did not observe OS difference between single-hit and multi-hit TP53mut t-MDS (11.6 vs. 10.9 months; P =0.73) ( Figure 1B). CONCLUSION: Our study based on a large international cohort of T53mut MN provides compelling evidence that in contrast to de novo MDS, single hit TP53mut t-MDS is associated with poor outcome. Our data supports the consideration of single hit t-MDS as a multi-hit equivalent.

Background ABBV-383 is an off-the-shelf, fully human B-cell maturation antigen (BMCA) X CD3 bispecific antibody with bivalent BCMA domain and low CD3 affinity that targets both BCMA-expressing multiple myeloma (MM) cells and CD3-expressing T cells. ABBV-383 has shown promising activity in an ongoing phase 1 study in patients (pts) with relapsed/refractory (RR) MM ( Voorhees et al. ASH 2022; Weisel et al. EHA 2023). Here, we report the safety and efficacy results from the ABBV-383 IV Q3W at 20 mg, 40 mg and 60 mg dose levels. Methods The phase 1 dose escalation (ESC) and expansion (EXP) study (NCT03933735) of ABBV-383 enrolled pts with RRMM with ≥3 prior lines of therapy (LOT), including a PI, IMiD, and an anti-CD38 mAb with no prior BCMA exposure. After exploring 14 dose levels in dose ESC, 3 dose levels were further explored in dose EXP including ABBV-383 Q3W IV 20 mg, 40 mg, and 60 mg, until disease progression/unacceptable toxicity. The primary objectives were to determine safety/tolerability, PK/PD, and RP2D. The secondary objective was to evaluate clinical activity. Responses were investigator assessed per IMWG 2016 criteria and adverse events (AEs) by CTCAE v5.0. Results As of 17May2023, 220 pts were treated with ABBV-383, 73 pts in the dose ESC and 147 in the dose EXP with 32 pts at 20 mg, 55 pts at 40 mg, and 61 pts at 60 mg Q3W. Median duration of follow up was 7.1 (0.8-36.9), 12.2 (1.3-34.4) and 24.2 (0.6-33.4) months (mo) in the 20 mg, 40 mg and 60 mg dose levels with 25%, 36% and 21% pts continuing treatment (tx), respectively. Median age for all pts was 68 yrs (range, 35-92 yrs), Median prior LOT was 5 (range, 3-23), and 80% were triple-class refractory. Baseline characteristics are summarized in Table 1 by dose level. Treatment-emergent (TE) AEs were reported in 97% (78% ≥G3) of pts at 20 mg, 100% (84% ≥G3) of pts at 40 mg, and 100% (82% ≥G3) of pts at 60 mg. CRS, the most common TEAE, occurred in 50% (34% G1/13% G2/3% G3) of pts at 20 mg, 71%(45% G1/25% G2/0% ≥G3) of pts at 40 mg, and 70%(51% G1/18% G2/2% G3) of pts at 60mg. At the 3 dose levels, CRS occurring after the first dose had median time to onset of 1 day (range, 1-2) and median duration was 2 days (range, 1-10). ICANS occurred in 3% (3% G1/0% ≥G2) of pts at 20 mg, 5% (2 % G1/4% G2/0% ≥G3) of pts at 40 mg, and 5% (3% G2/2% G3) of pts at 60 mg. No G4/5 CRS or ICANS occurred. Infections occurred in 56% (25% ≥G3) of pts at 20 mg, 71% (26% ≥G3) of pts at 40 mg, and 57% (34% ≥G3) of pts at 60 mg; most frequently (≥10%) reported were upper respiratory tract infections (15%, G3/4 1%), pneumonia (14%, G3/4 12%), urinary tract infections (12%, G3/4 3%), and COVID-19 (11%, G3/4 1%). At 20 mg, 40 mg, and 60 mg, the incidence of neutropenia was 41% (25% ≥G3), 42% (31% ≥G3), and 43% (34% ≥G3); anemia 50% (25% ≥G3), 55% (31% ≥G3), and 38% (13% ≥G3); thrombocytopenia 44% (28% ≥G3), 36% (16% ≥G3) and 26% (13% ≥G3), respectively. The tx discontinuation due to AEs was 6%, 11%, 10% in 20 mg, 40 mg and 60 mg, respectively, with no single PT reported in &gt;2 pts. Clinical responses are shown in Figure 1. The median time to ≥VGPR was 0.7mo (0.7-5.8) at 20 mg, 1.0mo (0.7-10.4) at 40 mg, and 1.4 mo (0.7-7.8) at 60 mg. The median DOR was 9.7 mo (3.5-not reached (NR)) at 20 mg, and NR at 40 mg and 60 mg. The Kaplan-Meier (KM) estimates for DOR at 12 mo was 42% at 20 mg, 70% at 40 mg, 66% at 60 mg. The mPFS was 3.8 mo (2.4-7.9) at 20mg, 13.7mo (5.0-NR) at 40 mg, and 11.2 mo (4.8-NR) at 60 mg. The KM estimates for PFS at 12 mo was 19% at 20 mg, 51% at 40 mg, 49% at 60 mg. The median OS was 21.6 mo (7.9-NR) at 20 mg, and NR at 40 mg and 60 mg. ABBV-383 at 20 mg, 40 mg, and 60 mg led to rapid and transient production of key proinflammatory cytokines (IL-6, IL8, IFN-γ, and TNF-α), and reduction of soluble BCMA levels over time that were associated with disease response. ABBV-383 also promoted T-cell activation and proliferation with upregulation of CD69 and KI67 markers on peripheral CD4 and CD8 T cells in evaluable pts. Conclusions ABBV-383 showed a manageable safety profile at dosages of 20 mg, 40 mg, and 60 mg IV Q3W, with low incidence of TEAEs leading to discontinuation. Also, extended Q3W dosing interval with no step-up dosing schedule of ABBV-383 may provide enhanced convenience. However, 20 mg yielded numerically lower responses when compared to 40 mg and 60 mg. At 40 mg and 60 mg, ABBV-383 monotherapy yielded deep and durable responses with mPFS of 13.7 mo and 11.2 mo, and 12-month DOR of 70% and 66% (mDOR NR in pts with ≥CR), respectively. These results in heavily pretreated RRMM pts support further clinical evaluation.