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We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.

AbstractIntroductionTo address the need for remote assessments of cognitive decline and dementia, we developed and administered electronic versions of the Clinical Dementia Rating (CDR®) and the Financial Capacity Instrument‐Short Form (FCI‐SF) (F‐CAP®), called the eCDR and eFCI, respectively.MethodsThe CDR and FCI‐SF were adapted for remote, unsupervised, online use based on item response analysis of the standard instruments. Participants completed the eCDR and eFCI first in clinic, and then at home within 2 weeks.ResultsOf the 243 enrolled participants, 179 (73%) cognitively unimpaired (CU), 50 (21%) with mild cognitive impairment (MCI) or dementia, and 14 (6%) with an unknown diagnosis, 84% and 85% of them successfully completed the eCDR and eFCI, respectively, at home.DiscussionThese results show initial feasibility in developing and administering online instruments to remotely assess and monitor cognitive decline along the CU to MCI/very mild dementia continuum. Validation is an important next step.

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S–specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19–vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.

The acute effects of various respiratory viral infections have been well studied, with extensive characterization of the clinical presentation as well as viral pathogenesis and host responses. However, over the course of the recent COVID-19 pandemic, the incidence and prevalence of chronic sequelae after acute viral infections have become increasingly appreciated as a serious health concern. Post-acute sequelae of COVID-19, alternatively described as “long COVID-19,” are characterized by symptoms that persist for longer than 28 days after recovery from acute illness. Although there exists substantial heterogeneity in the nature of the observed sequelae, this phenomenon has also been observed in the context of other respiratory viral infections including influenza virus, respiratory syncytial virus, rhinovirus, severe acute respiratory syndrome coronavirus, and Middle Eastern respiratory syndrome coronavirus. In this Review, we discuss the various sequelae observed following important human respiratory viral pathogens and our current understanding of the immunological mechanisms underlying the failure of restoration of homeostasis in the lung.

BackgroundWeight gain after a breast cancer diagnosis is common and is associated with inferior outcomes. Young survivors may be especially susceptible to weight changes given the impact of treatment on menopausal status.MethodsThe authors identified women who were diagnosed with stage 0 to III breast cancer at age 40 years or younger between 2006 and 2016 from a multicenter prospective cohort. Self‐reported weight was collected at diagnosis and at 1 year and 3 years postdiagnosis. Tumor and treatment data were obtained from medical records and patient surveys. Multinomial logistic regression was used to identify the factors associated with weight gain (≥5%) or weight loss (≥5%) versus stable weight at 1 year and 3 years postdiagnosis.ResultsThe cohort included 956 women with a median age of 37 years at diagnosis. Mean weight significantly increased over time from 66.54 ± 14.85 kg at baseline to 67.33 ± 15.53 and 67.77 ± 14.65 kg at 1 year and 3 years, respectively (p ≤ .001 for both comparisons). The proportion of women experiencing ≥5% weight gain increased from 24.8% at 1 year to 33.9% at 3 years. At 1 year, less self‐perceived financial comfort, Black race, and stage III disease were significantly associated with weight gain; at 3 years, only less self‐perceived financial comfort remained significant. Baseline overweight or obesity was significantly associated with weight loss at both time points. Chemotherapy, endocrine therapy, and treatment‐related menopause were not associated with weight change.ConclusionsOne third of young breast cancer survivors experienced clinically significant weight gain 3 years after diagnosis; however, treatment‐related associations were not observed. Age‐appropriate lifestyle interventions, including the reduction of financial barriers, are needed to prevent weight gain in this high‐risk population.

Abstract Children’s Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). “Rapid early responders” (RERs) had a negative PET1 (PET1−); “slow early responders” (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as “within the PET1+ site” or “initially involved but outside the PET1+ site.” Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003.

Abstract Purpose: Regulatory T-cells (Treg) are essential to Tregs homeostasis and modulate the antitumor immune response in patients with lymphoma. However, the biology and prognostic impact of Tregs in splenic marginal zone lymphoma (SMZL) have not been studied. Experimental Design: Biopsy specimens from 24 patients with SMZL and 12 reactive spleens (rSP) from individuals without lymphoma were analyzed by using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), CyTOF (mass cytometry) analysis, and flow cytometry to explore the phenotype, transcriptomic profile, and clinical significance of intratumoral Tregs and their subsets. The biological characteristics and cell signaling pathways of intratumoral Treg subsets were confirmed by in vitro functional assays. Results: We found that Tregs are more abundant in SMZL patients' spleens than rSP, and Tregs from patients with SMZL and rSP can be separated into CD161+Treg and CD26+Treg subsets. CD161+Tregs are increased in SMZL but have dysregulated immune function. We found that CD161+Treg and CD26+Tregs have unique gene expression and phenotypic profiles and are differentially correlated with patient outcomes. Specifically, increased CD161+Tregs are significantly associated with a favorable prognosis in patients with SMZL, whereas CD26+Tregs are associated with a poor prognosis. Furthermore, activation of the IL2/STAT5 pathway contributes to the induction of CD26+Tregs and can be reversed by STAT5 inhibition. Conclusions: IL2/STAT5-mediated expansion of CD26+Tregs contributes to a poor clinical outcome in SMZL and may represent a therapeutic opportunity in this disease.

10607 Background: Young women with breast cancer who carry germline genetic pathogenic variants predisposing to breast and other cancers, including BRCA1 or BRCA2, may face unique challenges when making fertility decisions. Limited data exist on differences in fertility preferences, concerns, and preservation strategies between carriers and non-carriers. Methods: Participants in the Young Women’s Breast Cancer Study, a prospective cohort of women diagnosed with breast cancer at ≤ 40 yrs, who completed a baseline survey with a modified Fertility Issues Survey were included in this analysis. Genetic variant status was determined by medical record review complemented by survey self-report. We excluded carriers whose test date was after baseline survey completion or unknown. Fisher exact and Wilcoxon signed-rank tests were used to compare categorical and continuous variables, respectively, between carriers and non-carriers. Results: Of 1052 eligible women, 118 (11%) tested positive for a pathogenic variant (59% BRCA1, 32% BRCA2, 4% TP53, and 5% other unique pathogenic mutations) and 934 (89%) tested negative or were not tested. Carriers’ median age was 36 yrs (range 23-40) vs 37 (range 17-40, p = 0.01) in non-carriers. Similar proportions (p = 0.67) of carriers (38%, [45/118]) and non-carriers (37%, [343/934]) desired more biologic children before diagnosis. Desire declined after diagnosis similarly in both groups (carriers, 25% [29/118] vs non-carriers, 26% [242/934], p = 0.46). Among these women (n = 271), concern about passing on cancer risk to offspring was common and, although numerically higher among carriers, this difference was not statistically significant (carriers, 55% [16/29] vs non-carriers, 40% [96/242], p = 0.12). In contrast, among those not interested in or unsure about future fertility (n = 738), concern about cancer risk heritability was infrequently reported as affecting fertility decisions (carriers, 11% [9/83] vs non-carriers, 9% [56/655], p = 0.54). The same proportions (p = 0.89) of carriers (36% [43/118]) and non-carriers (36% [339/934]) were somewhat or very concerned about becoming infertile after cancer treatment, and fertility preservation strategy utilization was similar between groups (carriers, 11% [13/118] vs non-carriers, 12% [111/934], p = 0.21). Conclusions: Young women with breast cancer who carry germline pathogenic variants are similarly concerned about future fertility and as likely to pursue fertility preservation as non-carriers. Concern about cancer risk heritability was common among both carriers and non-carriers desiring future fertility, suggesting a gap between perceived and actual risk. Genetic counseling should be included in fertility discussions for all young women with breast cancer, with tailored, risk-mitigating recommendations for those who carry genetic variants.

7504 Background: The anti-CD30 antibody drug conjugate, Brentuximab vedotin (Bv) is approved for adults with advanced stage HL but its use has not been established in children or adolescents. We compared the efficacy and safety of Bv with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide (Bv-AVE-PC) to the standard pediatric dose intensive regimen ABVE-PC, inclusive of bleomycin. Methods: This multicenter randomized, open-label phase 3 study enrolled patients 2-21 years (yrs) with previously untreated HL, stages IIB + bulk, IIIB, IVA, IVB. Patients were randomized to 5 cycles of either ABVE-PC or Bv-AVE-PC given every 21 days with granulocyte colony-stimulating factor support. Centrally reviewed PET-CT after 2 cycles (PET2) identified slow responding lesions (SRL) defined as Deauville score > 3. Involved site radiotherapy (ISRT) was given to bulky mediastinal adenopathy and SRL. The primary objective was 3-year EFS; events include relapse/progression, second malignant neoplasm (SMN) or death. Final data cutoff was 31 December 2021. Results: 600 participants were enrolled across 151 institutions from March 2015 to August 2019; 587 were eligible. Median age was 15.6 yrs (range 3.4-21). Patient and disease characteristics were balanced across study arms. Histology was nodular sclerosing in 76.5%. Stage distribution: 20.6% IIB-bulk; 19.3% IIIB; 28.5% IVA; 31.7% IVB. At a median follow-up of 42.1 mos (0.1-80.9), 3-year EFS (95%CI) by intent-to-treat analyses was 82.5% (77.4, 86.5) with ABVE-PC and 92.1% (88.4, 94.7) with Bv-AVE-PC (HR 0.41 (0.25, 0.67), p = 0.0002). Median time to 1st event was 9.4 months for both arms but the range differs by arm (3.6-57.8 ABVE-PC; 1.3, 25.8 Bv-AVE-PC). Relapse rate was 17% following ABVE-PC and 7% with Bv-AVE-PC. One SMN is noted in each arm: thyroid cancer at 57.8 mos and acute myeloid leukemia at 20.3 mos. 3-year overall survival (95%CI) was 98.5% (96.0, 99.4) for ABVE-PC and 99.3% (97.3, 99.8) for Bv-AVE-PC (p = 0.38). PET2 SRL rates were comparable (ABVE-PC 19% vs. Bv-AVE-PC 18%, p = 0.8). As-treated ISRT receipt did not differ (ABVE-PC 55.7% vs. Bv-AVE-PC 52.7%, p = 0.69). No difference in grade 3/4 adverse events was observed; myelosuppression, reflected in a 32% incidence of > grade 3 febrile neutropenia, did not differ by arm (p = 0.67). Only 19% of patients experienced > grade 2 neuropathy by the Balis pediatric neuropathy scale, with no difference between arms (p = 0.86). Conclusions: Brentuximab vedotin with AVE-PC in a dose intensive regimen has superior efficacy to ABVE-PC for pediatric patients with high-risk HL. A 59% risk reduction in EFS was achieved with no increase in toxicity and with fewer patients receiving ISRT compared to prior pediatric trials for high-risk HL. Clinical trial information: 02166463.