ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation.

Short telomere syndromes manifest as familial idiopathic pulmonary fibrosis; they are the most common premature aging disorders. We used genome-wide linkage to identify heterozygous loss of function of ZCCHC8, a zinc-knuckle containing protein, as a cause of autosomal dominant pulmonary fibrosis. ZCCHC8 associated with TR and was required for telomerase function. In ZCCHC8 knockout cells and in mutation carriers, genomically extended telomerase RNA (TR) accumulated at the expense of mature TR, consistent with a role for ZCCHC8 in mediating TR 3' end targeting to the nuclear RNA exosome. We generated Zcchc8-null mice and found that heterozygotes, similar to human mutation carriers, had TR insufficiency but an otherwise preserved transcriptome. In contrast, Zcchc8-/- mice developed progressive and fatal neurodevelopmental pathology with features of a ciliopathy. The Zcchc8-/- brain transcriptome was highly dysregulated, showing accumulation and 3' end misprocessing of other low-abundance RNAs, including those encoding cilia components as well as the intronless replication-dependent histones. Our data identify a novel cause of human short telomere syndromes-familial pulmonary fibrosis and uncover nuclear exosome targeting as an essential 3' end maturation mechanism that vertebrate TR shares with replication-dependent histones.

Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma.

BACKGROUND: In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear. METHODS: We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed. RESULTS: Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group. CONCLUSIONS: The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).

Nivolumab and brentuximab vedotin with or without bendamustine for R/R Hodgkin lymphoma in children, adolescents, and young adults.

Children, adolescents, and young adults (CAYA) with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) without complete metabolic response (CMR) before autologous hematopoietic cell transplantation (auto-HCT) have poor survival outcomes. CheckMate 744, a phase 2 study for CAYA (aged 5-30 years) with R/R cHL, evaluated a risk-stratified, response-adapted approach with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response. Risk stratification was primarily based on time to relapse, prior treatment, and presence of B symptoms. We present the primary analysis of the standard-risk cohort. Data from the low-risk cohort are reported separately. Patients received 4 induction cycles with nivolumab plus BV; those without CMR (Deauville score >3, Lugano 2014) received BV plus bendamustine intensification. Patients with CMR after induction or intensification proceeded to consolidation (high-dose chemotherapy/auto-HCT per protocol). Primary end point was CMR any time before consolidation. Forty-four patients were treated. Median age was 16 years. At a minimum follow-up of 15.6 months, 43 patients received 4 induction cycles (1 discontinued), 11 of whom received intensification; 32 proceeded to consolidation. CMR rate was 59% after induction with nivolumab plus BV and 94% any time before consolidation (nivolumab plus BV ± BV plus bendamustine). One-year progression-free survival rate was 91%. During induction, 18% of patients experienced grade 3/4 treatment-related adverse events. This risk-stratified, response-adapted salvage strategy had high CMR rates with limited toxicities in CAYA with R/R cHL. Most patients did not require additional chemotherapy (bendamustine intensification). Additional follow-up is needed to confirm durability of disease control. This trial was registered at www.clinicaltrials.gov as #NCT02927769.

A mutation-independent approach for muscular dystrophy via upregulation of a modifier gene.

Neuromuscular disorders are often caused by heterogeneous mutations in large, structurally complex genes. Targeting compensatory modifier genes could be beneficial to improve disease phenotypes. Here we report a mutation-independent strategy to upregulate the expression of a disease-modifying gene associated with congenital muscular dystrophy type 1A (MDC1A) using the CRISPR activation system in mice. MDC1A is caused by mutations in LAMA2 that lead to nonfunctional laminin-α2, which compromises the stability of muscle fibres and the myelination of peripheral nerves. Transgenic overexpression of Lama1, which encodes a structurally similar protein called laminin-α1, ameliorates muscle wasting and paralysis in mouse models of MDC1A, demonstrating its importance as a compensatory modifier of the disease1. However, postnatal upregulation of Lama1 is hampered by its large size, which exceeds the packaging capacity of vehicles that are clinically relevant for gene therapy. We modulate expression of Lama1 in the dy2j/dy2j mouse model of MDC1A using an adeno-associated virus (AAV9) carrying a catalytically inactive Cas9 (dCas9), VP64 transactivators and single-guide RNAs that target the Lama1 promoter. When pre-symptomatic mice were treated, Lama1 was upregulated in skeletal muscles and peripheral nerves, which prevented muscle fibrosis and paralysis. However, for many disorders it is important to investigate the therapeutic window and reversibility of symptoms. In muscular dystrophies, it has been hypothesized that fibrotic changes in skeletal muscle are irreversible. However, we show that dystrophic features and disease progression were improved and reversed when the treatment was initiated in symptomatic dy2j/dy2j mice with apparent hindlimb paralysis and muscle fibrosis. Collectively, our data demonstrate the feasibility and therapeutic benefit of CRISPR-dCas9-mediated upregulation of Lama1, which may enable mutation-independent treatment for all patients with MDC1A. This approach has a broad applicability to a variety of disease-modifying genes and could serve as a therapeutic strategy for many inherited and acquired diseases.

Sleep extension and cardiometabolic health: what it is, possible mechanisms and real-world applications.

Short sleep duration is associated with heightened cardiometabolic disease risk and has reached epidemic proportions among children, adolescents and adults. Potential mechanisms underlying this association are complex and multifaceted, including disturbances in circadian timing, food intake and appetitive hormones, brain regions linked to control of hedonic eating, physical activity, an altered microbiome and impaired insulin sensitivity. Sleep extension, or increasing total sleep duration, is an emerging and ecologically relevant intervention with significant potential to advance our understanding of the mechanisms underlying the association between short sleep duration and the risk of cardiometabolic disease. If effective, sleep extension interventions have potential to improve cardiometabolic health across the lifespan. Existing data show that sleep extension is feasible and might have potential cardiometabolic health benefits, although there are limitations that the field must overcome. Notably, most existing studies are short term (2-8 weeks), use different sleep extension strategies, analyse a wide array of cardiometabolic health outcomes in different populations and, frequently, lack adequate statistical power, thus limiting robust scientific conclusions. Overcoming these limitations will require fully powered, randomized studies conducted in people with habitual short sleep duration and existing cardiometabolic risk factors. Additionally, randomized controlled trials comparing different sleep extension strategies are essential to determine the most effective interventions. Ongoing and future research should focus on elucidating the potential cardiometabolic health benefits of sleep extension. Such studies have high potential to generate crucial knowledge with potential to improve health and quality of life for those struggling with short sleep duration.

Study Design and Protocol of the Multisite Pregnancy 24/7 Cohort Study.

Hypertensive disorders of pregnancy and other adverse pregnancy outcomes (APOs) are associated with an increased risk of future maternal cardiovascular disease. Physical activity during pregnancy reduces the risk of these APOs, yet few meet physical activity guidelines during pregnancy. Little is known about the role of sedentary behavior or sleep in APOs, a critical gap in knowledge given these behaviors comprise the majority of a 24-hour day. To address this knowledge gap, the Pregnancy 24/7 cohort study (2020-2025) uses 2 devices for 24-hour activity assessment in each trimester of pregnancy to examine associations of sedentary behavior, sleep, and the 24-hour activity cycle (composition of sedentary behavior, physical activity, and sleep) with hypertensive disorders and other APOs. Participants (n = 500) are recruited from the University of Iowa, University of Pittsburgh, and West Virginia University in early pregnancy and followed through delivery. The activPAL3 micro and Actiwatch Spectrum Plus are worn in each trimester for 7 days of 24-hour wear to assess the 24-hour activity cycle. APOs are abstracted from medical charts. This study will provide critical data to fuel future research examining how modifying the 24-hour activity cycle in pregnancy can improve maternal health.

Sarcospan increases laminin-binding capacity of α-dystroglycan to ameliorate DMD independent of Galgt2.

In Duchenne muscular dystrophy (DMD), mutations in dystrophin result in a loss of the dystrophin-glycoprotein complex (DGC) at the myofiber membrane, which functions to connect the extracellular matrix with the intracellular actin cytoskeleton. The dystroglycan subcomplex interacts with dystrophin and spans the sarcolemma where its extensive carbohydrates (matriglycan and CT2 glycan) directly interact with the extracellular matrix. In the current manuscript, we show that sarcospan overexpression enhances the laminin-binding capacity of dystroglycan in DMD muscle by increasing matriglycan glycosylation of α-dystroglycan. Furthermore, we find that this modification is not affected by loss of Galgt2, a glycotransferase, which catalyzes the CT2 glycan. Our findings reveal that the matriglycan carbohydrates, and not the CT2 glycan, are necessary for sarcospan-mediated amelioration of DMD. Overexpression of Galgt2 in the DMD mdx murine model prevents muscle pathology by increasing CT2 modified α-dystroglycan. Galgt2 also increases expression of utrophin, which compensates for the loss of dystrophin in DMD muscle. We found that combined loss of Galgt2 and dystrophin reduced utrophin expression; however, it did not interfere with sarcospan rescue of disease. These data reveal a partial dependence of sarcospan on Galgt2 for utrophin upregulation. In addition, sarcospan alters the cross-talk between the adhesion complexes by decreasing the association of integrin ß1D with dystroglycan complexes. In conclusion, sarcospan functions to re-wire the cell to matrix connections by strengthening the cellular adhesion and signaling, which, in turn, increases the resilience of the myofiber membrane.

Genome-wide study identifies novel genes associated with bone toxicities in children with acute lymphoblastic leukaemia.

Bone toxicities are common among paediatric patients treated for acute lymphoblastic leukaemia (ALL) with potentially major negative impact on patients' quality of life. To identify the underlying genetic contributors, we conducted a genome-wide association study (GWAS) and a transcriptome-wide association study (TWAS) in 260 patients of European-descent from the DFCI 05-001 ALL trial, with validation in 101 patients of European-descent from the DFCI 11-001 ALL trial. We identified a significant association between rs844882 on chromosome 20 and bone toxicities in the DFCI 05-001 trial (p = 1.7 × 10-8). In DFCI 11-001 trial, we observed a consistent trend of this variant with fracture. The variant was an eQTL for two nearby genes, CD93 and THBD. In TWAS, genetically predicted ACAD9 expression was associated with an increased risk of bone toxicities, which was confirmed by meta-analysis of the two cohorts (meta-p = 2.4 × 10-6). In addition, a polygenic risk score of heel quantitative ultrasound speed of sound was associated with fracture risk in both cohorts (meta-p = 2.3 × 10-3). Our findings highlight the genetic influence on treatment-related bone toxicities in this patient population. The genes we identified in our study provide new biological insights into the development of bone adverse events related to ALL treatment.

Hypusination Maintains Intestinal Homeostasis and Prevents Colitis and Carcinogenesis by Enhancing Aldehyde Detoxification.

BACKGROUND & AIMS: The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis. METHODS: We used human colon tissue messenger RNA samples and publicly available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis. RESULTS: We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS messenger RNA and DHPS protein and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show down-regulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis. CONCLUSIONS: Hypusination in intestinal epithelial cells has a key role in the prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have a therapeutic impact.

Resistance exercise lowers blood pressure and improves vascular endothelial function in individuals with elevated blood pressure or stage-1 hypertension.

Lifestyle modifications are the first-line treatment recommendation for elevated blood pressure (BP) or stage-1 hypertension (E/S1H) and include resistance exercise training (RET). The purpose of the current study was to examine the effect of a 9-wk RET intervention in line with the current exercise guidelines for individuals with E/S1H on resting peripheral and central BP, vascular endothelial function, central arterial stiffness, autonomic function, and inflammation in middle-aged and older adults (MA/O) with untreated E/S1H. Twenty-six MA/O adults (54 ± 6 yr; 16 females/10 males) with E/S1H engaged in either 9 wk of 3 days/wk RET (n = 13) or a nonexercise control (Con; n = 13). Pre- and postintervention measures included peripheral and central systolic (SBP and cSBP) and diastolic BP (DBP and cDBP), flow-mediated dilation (FMD), carotid-femoral pulse wave velocity (cfPWV), cardiovagal baroreflex sensitivity (BRS), cardiac output (CO), total peripheral resistance (TPR), heart rate variability (HRV), and C-reactive protein (CRP). RET caused significant reductions in SBP {mean change ± 95% CI = [-7.9 (-12.1, -3.6) mmHg; P < 0.001]}, cSBP [6.8 (-10.8, -2.7) mmHg; P < 0.001)], DBP [4.8 (-10.3, -1.2) mmHg; P < 0.001], and cDBP [-5.1 (-8.9, -1.3) mmHg; P < 0.001]; increases in FMD [+2.37 (0.61, 4.14)%; P = 0.004] and CO [+1.21 (0.26, 2.15) L/min; P = 0.006]; and a reduction in TPR [-398 (-778, -19) mmHg·s/L; P = 0.028]. RET had no effect on cfPWV, BRS, HRV, or CRP relative to Con (P ≥ 0.20). These data suggest that RET reduces BP in MA/O adults with E/S1H alongside increased peripheral vascular function and decreased TPR without affecting cardiovagal function or central arterial stiffness.NEW & NOTEWORTHY This is among the first studies to investigate the effects of chronic resistance exercise training on blood pressure (BP) and putative BP regulating mechanisms in middle-aged and older adults with untreated elevated BP or stage-1 hypertension in a randomized, nonexercise-controlled trial. Nine weeks of resistance exercise training elicits 4- to 8-mmHg improvements in systolic and diastolic BP alongside improvements in vascular endothelial function and total peripheral resistance without influencing central arterial stiffness or cardiovagal function.

A Clinical Tool to Relate Youth Risk Factors to Adult Cardiovascular Events and Type 2 Diabetes: The International Childhood Cardiovascular Cohort Consortium.

OBJECTIVE: To translate data relating childhood cardiovascular (CV) risk factors and adult CV disease and type 2 diabetes mellitus (T2DM) to clinically actionable values. STUDY DESIGN: This was a prospective observational study (n = 38 589) in the International Childhood Cardiovascular Cohort Consortium. Children at age 3 through 19 years were enrolled in the 1970s and 1980s and followed for more than 30 years. Five childhood CV risk factors (smoking, body mass index [BMI], systolic blood pressure, triglycerides, and total cholesterol) were related to adult CV events. Secondary analyses in a subset included low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, glucose, and insulin level. Age- and sex-specific z scores were calculated for each risk factor, and a combined-risk z score was calculated by averaging z scores for the 5 key CV risk factors. Risk factor z scores were back-transformed to natural units for clinical interpretation, with hazard ratios for adult CV events presented in color-coded tables (green: no increased risk; orange: 1.4 to <2.0-fold increased risk; red: at least doubling of risk). Risk levels for development of adult T2DM on the basis of BMI, glucose, and insulin were similarly calculated and presented. RESULTS: Increased risk for CV events was observed at levels lower than currently defined abnormal clinical thresholds except for TC. Doubling of risk was observed at high normal levels just below the clinical cut point for abnormality. Risk for adult T2DM began at levels of BMI and glucose currently considered normal. CONCLUSIONS: On the basis of data showing significant relationships between childhood CV risk factors and adult CV events and T2DM, this study shows that risk in childhood begins below levels currently considered normal.

Demographics, Practice Analysis, and Geographic Distribution of Neuro-Ophthalmologists in the United States in 2023.

PURPOSE: To assess the demographic characteristics and geographic distribution of neuro-ophthalmologists practicing in the United States. DESIGN: A cross-sectional study. PARTICIPANTS: Neuro-ophthalmologists across the United States. METHODS: In this cross-sectional study, public databases from the American Academy of Ophthalmology, North American Neuro-ophthalmology Society, American Neurological Association, and American Academy of Neurology were used to identify neuro-ophthalmologists in the United States as of April 2023. Providers' office locations were geocoded using ArcGIS pro, version 2.9 (Esri). Data on age, sex, and residency and fellowship training were collected. Analysis was performed using SPSS 28.0 (IBM Corp.). MAIN OUTCOME MEASURES: Neuro-ophthalmologists' demographics, and information about their medical education, postgraduate education, residency training, fellowship training, years in practice, practice environment, and geographic distribution of neuro-ophthalmologists across the United States. RESULTS: A total of 635 neuro-ophthalmologists (436 male, 68.7%) were identified. The majority (599, 94.3%) graduated from an allopathic medical school. Most of the 85 physicians who held a secondary graduate degree had a PhD (54, 63.5%). Although approximately three-quarters (429, 67.6%) completed their residency in ophthalmology, 159 (25%) had residency positions in neurology and 47 (7.4%) had residency positions in both. Approximately one-third (191, 30.0%) were trained in more than 1 fellowship, including oculoplastics (78, 12.3%) or pediatric ophthalmology (53, 8.3%). The average post-fellowship years of experience was 23.7±13.7 years, with 134 (21.1%) in their early career (< 10 years), 120 (18.9%) in their mid-careers (10-19 years), and 381 (60.0%) in their late careers (> 20 years). Male neuro-ophthalmologists had 10.5±1.1 more years of experience than female neuro-ophthalmologists (P < 0.001). Three states (Maine, South Dakota, Wyoming) and 2897 counties (93.2%) had no neuro-ophthalmologists. Counties without a neuro-ophthalmologist had lower median income (P < 0.001), lower access to a vehicle (P = 0.024), and lower rates of health insurance (P = 0.012). CONCLUSIONS: Practicing neuro-ophthalmologists are mostly male and often are trained in more than 1 subspecialty. More than half of the practicing neuro-ophthalmologists are in their late careers, which may further exacerbate the existing geographic and socioeconomic disparities in access to neuro-ophthalmology. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Fentanyl dysregulates neuroinflammation and disrupts blood-brain barrier integrity in HIV-1 Tat transgenic mice.

Opioid overdose deaths have dramatically increased by 781% from 1999 to 2021. In the setting of HIV, opioid drug abuse exacerbates neurotoxic effects of HIV in the brain, as opioids enhance viral replication, promote neuronal dysfunction and injury, and dysregulate an already compromised inflammatory response. Despite the rise in fentanyl abuse and the close association between opioid abuse and HIV infection, the interactive comorbidity between fentanyl abuse and HIV has yet to be examined in vivo. The HIV-1 Tat-transgenic mouse model was used to understand the interactive effects between fentanyl and HIV. Tat is an essential protein produced during HIV that drives the transcription of new virions and exerts neurotoxic effects within the brain. The Tat-transgenic mouse model uses a glial fibrillary acidic protein (GFAP)-driven tetracycline promoter which limits Tat production to the brain and this model is well used for examining mechanisms related to neuroHIV. After 7 days of fentanyl exposure, brains were harvested. Tight junction proteins, the vascular cell adhesion molecule, and platelet-derived growth factor receptor-ß were measured to examine the integrity of the blood brain barrier. The immune response was assessed using a mouse-specific multiplex chemokine assay. For the first time in vivo, we demonstrate that fentanyl by itself can severely disrupt the blood-brain barrier and dysregulate the immune response. In addition, we reveal associations between inflammatory markers and tight junction proteins at the blood-brain barrier.

A gene expression-based model predicts outcome in children with intermediate-risk classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools are needed to tailor therapy. Here, we used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, to determine molecular correlates of treatment failure, and to develop an outcome model prognostic for pediatric cHL. A total of 246 formalin-fixed, paraffin-embedded tissue biopsies from patients enrolled in the Children's Oncology Group trial AHOD0031 were used for GEP and compared with adult cHL data. Eosinophil, B-cell, and mast cell signatures were enriched in children, whereas macrophage and stromal signatures were more prominent in adults. Concordantly, a previously published model for overall survival prediction in adult cHL did not validate in pediatric cHL. Therefore, we developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). In an independent validation cohort, we observed a significant difference in weighted 5-year EFS between high-risk and low-risk groups (75.2% vs 90.3%; log-rank P = .0138) independent of interim response, stage, fever, and albumin. We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Targeted radiotherapy for early-stage, low-risk pediatric Hodgkin lymphoma slow early responders: a COG AHOD0431 analysis.

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.

Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Transfers and anesthesia-related postoperative outcomes after 3361 same-day cancer surgeries at a freestanding surgery center: An observational retrospective study.

BACKGROUND AND OBJECTIVES: Expanding outpatient surgery to the increasing number of procedures and patient populations warrants continuous evaluation of postoperative outcomes to ensure the best care and safety. We describe adverse postoperative outcomes and transfer rates related to anesthesia in a large sample of patients who underwent same-day cancer surgery at a freestanding ambulatory surgery center. METHODS: Between January 2017 and June 2021, 3361 cancer surgeries, including breast and plastic, head and neck, gynecology, and urology, were performed. The surgeries were indicated for diagnosis, staging, and/or treatment. We report the incidence of transfers and adverse postoperative outcomes related to anesthesia. RESULTS: Breast and plastic surgeries were the most common (1771, 53%), followed by urology (1052, 31%), gynecology (410, 12%), and head and neck surgeries (128, 4%). Based on patients' first procedure, comorbidity levels were highest for urology (75% American Society of Anesthesiologists physical status score 3, 1.7% score 4) and lowest for breast surgeries (31% score 3, 0.2% score 4). Most gynecology surgeries used general anesthesia (97.6%), whereas breast surgeries used the least (38%). A total of seven patients (0.2%; 95% CI: 0.08%-0.4%) were immediately transferred to an outside hospital; four due to anesthesia-related reasons. Only 7 (0.2%) patients needed additional postoperative care related to anesthesia-related adverse events, specifically cardiac events (4), difficult intubations (2), desaturation (1), and agitation, nausea, and headache (1). CONCLUSIONS: The incidence of anesthesia-related adverse postoperative outcomes is low in cancer patients undergoing outpatient surgeries at our freestanding ambulatory surgery center. This suggests that carefully selected cancer patients, including patients with metastatic cancer, can undergo anesthesia for same-day surgery, making cancer care accessible locally and reducing stress associated with travel for treatment. More research investigating complication rates related to surgery and to cancer disease trajectory are needed to establish a complete evaluation of safety for outpatient cancer surgery.

Social Vulnerability and Mental Health Among People with HIV and Substance Use: The Role of Race.

Poor mental health significantly impacts people with HIV (PWH) and those who drink alcohol. Limited data exist on the combined effects of social determinants of health (social vulnerability) on mental health in PWH with unhealthy substance use. We investigated the relationship between social vulnerability and poor mental health in PWH and whether this relationship differed by race/ethnicity. We conducted a cross-sectional analysis using data from the Boston ARCH Cohort among PWH with current or past unhealthy substance use. We created a 23-item social vulnerability index (SVI) using a deficit accumulation approach comprised of social determinants of health indicators. We estimated whether higher SVI score is associated with anxiety and depressive symptoms using logistic regression analysis. Among 251 participants with a mean age of 52 (SD = 10) years, 67.3% were male, 52% Black, 21% Hispanic, 19% White, and 73% unemployed. The SVI had a mean of 9.30 (SD = 3.4) with a 1.5-18 range. Nearly two in five persons reported past month heavy alcohol use and 35% illicit drug use. The prevalence of anxiety and depressive symptoms was 34.4% and 54.2% respectively. Higher SVI score was associated with anxiety symptoms (adjusted odds ratio [aOR] = 2.01, 95% confidence interval [CI] 1.46, 2.76, p ≤ 0.001), and depressive symptoms (aOR = 2.42, 95% CI 1.74, 3.36, p ≤ 0.001). Race/ethnicity did not moderate the relationship between SVI and each mental health outcome. SVI was significantly associated with poor mental health across racial/ethnicity groups in this cohort. Interventions that address social vulnerability may improve well-being and quality of life for PWH.

Supplemental Nutrition Assistance Program participation gaps within a pediatric leukemia clinical trial cohort.

Poverty-exposed children with cancer are more likely to experience adverse outcomes. Supplemental Nutrition Assistance Program (SNAP) benefits improve food insecurity and child health outcomes, and could be used to mitigate disparities. We conducted a secondary analysis of parent-reported data collected in a frontline pediatric leukemia trial (NCT03020030) to assess SNAP eligibility (proxied by other means-tested program participation) and participation. At diagnosis, 105/287 families (37%) were SNAP-eligible, of whom 53 (50%) were SNAP participants. At 6 months, 104/257 families (41%) were SNAP-eligible, and 59 (57%) were SNAP participants. Interventions to increase benefits participation during childhood cancer treatment represent an immediate opportunity to reduce disparities.

Self-medication of pain and discomfort with alcohol and other substances by people with HIV infection and substance use disorder: preliminary findings from a secondary analysis.

There is a limited literature regarding factors associated with self-medication of pain and discomfort using alcohol, non-prescription substances or overuse of prescription medications among people living with Human Immunodeficiency Virus (HIV). This cross-sectional analysis used data from the Boston ARCH Cohort among participants with HIV infection and a history of alcohol or other substance use. Among 248 participants, 37% were female, 50% Black, 25% Latinx; 36% reported fair to poor health and 89% had CD4 cell counts >200/mm3. Half reported self-medication and of those, 8.8% reported doing so only with alcohol, 48.8% only with other substances and 42.4% with both alcohol and other substances. Those reporting self-medication were significantly (p < .05) younger (mean 47 vs 50 years), less employed (11% vs 21%), and less likely to have HIV viral suppression (60% vs. 80%). Depression, anxiety, and HIV symptoms were associated with significantly greater odds of self-medicating, as were substance dependence, recent injection substance use, heavy alcohol use, cocaine use, opioid use, sedative use, and cannabis use. Self-medication, highly prevalent and associated with worse mental health symptoms, greater substance use, and lesser HIV disease control, should be explored by HIV clinicians caring for people who use substances.