Citations

Introduction: Hypertension in midlife, but not late life, is a robust predictor of subsequent dementia. However, the fraction of dementia attributable to hypertension might vary depending on the age of the population considered, and the age through which dementia onset occurs. Here, we investigated associations of hypertension assessed at various ages with incident dementia by age 80 or 90, then estimated population attributable fractions (PAF) for dementia from hypertension categories at each of these age groups. Hypothesis: Given hypertension prevalence increases with age but its relative risk for dementia tends to decrease, we had no prior expectation of the age at which the PAF’s would be highest. We hypothesized, however, that PAFs for incident dementia would be higher when hypertension is measured in midlife age groups versus late-life age groups. Methods: We leveraged 32 years of follow-up data from the Atherosclerosis Risk in Communities study (ARIC), a prospective, community-based cohort that enrolled participants aged 45-64 years from four US communities (Washington County, MD; Forsyth County, NC; Jackson, MS; and selected suburbs of Minneapolis, MI) at ARIC visit 1 (1987-1989). Participants were followed through 2018-2019. We used Cox proportional hazards models to estimate hazard ratios, then quantified PAFs, of dementia by age 80 and 90 from hypertension assessed at ages of 45-54 (ARIC visit 1), 55-64 (ARIC visits 1 and 4), 65-74 (ARIC visits 4 and 5), and 75-84 (ARIC visit 5). Results: Hypertension was assessed among 7,572 participants aged 45-54; 12,033 aged 55-64; and 6,561 aged 65-74. By age 80 the number identified as having incident dementia was 711, 910, and 372, respectively. Relative to normotension, hypertension in each age category was associated with hazard ratios (HRs) greater than 1.0 for dementia from hypertension by age 80. The PAF for dementia by age 80 from hypertension measured at age 45-54 was 15.3% (95% CI = 6.9, 22.3%), 19.1% (95% CI = 9.9, 26.9%) at ages 55-64, and 19.9% (95% CI = -4.4, 38.5%) at ages 65-74. By age 90, the number of incident dementia cases were 958; 2,302; and 1,327, respectively; and, among the 2,086 participants aged 75-84, 400 incident dementia cases. HRs were slightly smaller than those by age 80, while hypertension assessed in the 75-84 age group was not significant. The PAFs for dementia by age 90 from hypertension at age 45-54 was 13.8% (95% CI = 6.6, 20.0%), 12.9% (95% CI = 7.0, 18.2%) at ages 55-64, 10.9% (95% CI = 0.02, 21.0%) at ages 65-74, and non-significant at ages 75-84. Conclusions: Public health interventions targeting hypertension in midlife through early late-life might reduce a sizeable proportion of dementia cases.

Background: Heart failure (HF) is associated with metabolic alterations, including ketogenesis. However, determinants of ketogenesis and risk of mortality in HF is not defined. Total ketone bodies (KB) include β-hydroxybutyrate, acetoacetate, and acetone and can be measured in plasma by nuclear magnetic resonance (NMR). The aim of this study is to determine the relationship between KB and clinical characteristics in a community HF cohort and to assess the association between KB and all-cause mortality. Methods: A population-based cohort of 1,389 HF patients was prospectively enrolled between 2003 and 2012. Plasma KB was measured by LP4 NMR LipoProfile ® assay/test on the Vantera® NMR analyzer platform. A conditional inference tree method (ctree R Package) was used to determine optimal KB group cut points. Associations between clinical characteristics and KB were measured with Wilcoxon rank sum test and Pearson’s Chi-squared test. Kaplan-Meier method estimated survival. Cox regression analyses were used to estimate associations between KB concentrations and mortality. Results: Among the 1,382 HF patients with KB measurements, the median age was 78 years (IQR 68-84) and 52% were men. Median KB was 180 μM (IQR 134-308). Patients were divided into two groups with lower KB (≤471.5 μM) and higher KB (>471.5 μM). Patients with higher KB (N=210) had lower BMI, higher BNP, and were more likely to be in the New York Heart Association class III-IV; however, these patients were less likely to have hyperlipidemia, coronary disease, or diabetes mellitus (P < 0.05). Age, sex, creatinine, ejection fraction, or Meta-Analysis Global Group in Chronic HF (MAGGIC) score did not differ by KB group. Higher KB was associated with worse survival (figure). After adjustment for the MAGGIC score, higher KB was associated with increased risk of mortality (HR 1.3; 95% CI, 1.08-1.48). Conclusions: In this community HF cohort, higher KB was associated with increased mortality, independent of the MAGGIC score.

AbstractObjectiveImprove data‐driven research to inform clinical decision‐making with pediatric epilepsy surgery patients by expanding the Pediatric Epilepsy Research Consortium Epilepsy Surgery (PERC‐Surgery) Workgroup to include neuropsychological data. This article reports on the process and initial success of this effort and characterizes the cognitive functioning of the largest multi‐site pediatric epilepsy surgery cohort in the United States.MethodsPediatric neuropsychologists from 18 institutions completed surveys regarding neuropsychological practice and the impact of involvement in the collaborative. Neuropsychological data were entered through an online database. Descriptive analyses examined the survey responses and cognitive functioning of the cohort. Statistical analyses examined which patients were evaluated and if composite scores differed by domain, demographics, measures used, or epilepsy characteristics.ResultsPositive impact of participation was evident by attendance, survey responses, and the neuropsychological data entry of 534 presurgical epilepsy patients. This cohort, ages 6 months to 21 years, were majority White and non‐Hispanic, and more likely to have private insurance. Mean intelligence quotient (IQ) scores were below to low average, with weaknesses in working memory and processing speed. Full‐scale IQ (FSIQ) was lowest for patients with younger age at seizure onset, daily seizures, and magnetic resonance imaging (MRI) abnormalities.SignificanceWe established a collaborative network and fundamental infrastructure to address questions outlined by the Epilepsy Research Benchmarks. There is a wide range in the age and IQ of patients considered for pediatric epilepsy surgery, yet it appears that social determinants of health impact access to care. Consistent with other national cohorts, this US cohort has a downward shift in IQ associated with seizure severity.

AbstractBackgroundOver the past decade, advances in sepsis identification and management have resulted in decreased sepsis mortality. This increase in survivorship has highlighted a new clinical obstacle: chronic critical illness (CCI), for which there are no effective treatment options. Up to half of sepsis survivors suffer from CCI, which can include multi‐organ dysfunction, chronic inflammation, muscle wasting, physical and mental disabilities, and enhanced frailty. These symptoms prevent survivors from returning to regular day‐to‐day activities and are directly associated with poor quality of life.MethodsMice were subjected to cecal ligation and puncture (CLP) with daily chronic stress (DCS) as an in vivo model to study sepsis late‐effects/sequelae on skeletal muscle components. Longitudinal monitoring was performed via magnetic resonance imaging, skeletal muscle and/or muscle stem cell (MuSCs) assays (e.g., post‐necropsy wet muscle weights, minimum Feret diameter measurements, in vitro MuSC proliferation and differentiation, number of regenerating myofibres and numbers of Pax7‐positive nuclei per myofibre), post‐sepsis whole muscle metabolomics and MuSC isolation and high‐content transcriptional profiling.ResultsWe report several findings supporting the hypothesis that MuSCs/muscle regeneration are critically involved in post‐sepsis muscle recovery. First, we show that genetic ablation of muscle stem cells (MuSCs) impairs post‐sepsis muscle recovery (maintenance of 5–8% average lean mass loss compared with controls). Second, we observe impaired MuSCs expansion capacity and morphological defects at 26 days post‐sepsis compared with control MuSCs (P < 0.001). Third, when subjected to an experimental muscle injury, sepsis‐recovered mice exhibited evidence of impaired muscle regeneration compared with non‐septic mice receiving the same muscle injury (CLP/DCS injured mean minimum Feret is 92.1% of control injured, P < 0.01). Fourth, we performed a longitudinal RNA sequencing study on MuSCs isolated from post‐sepsis mice and found clear transcriptional differences in all post‐sepsis samples compared with controls. At Day 28, CLP/DCS mice satellite cells have multiple altered metabolic pathways, such as oxidative phosphorylation, mitochondrial dysfunction, sirtuin signalling and oestrogen receptor signalling, compared with controls (P < 0.001).ConclusionsOur data show that MuSCs and muscle regeneration are required for effective post‐sepsis muscle recovery and that sepsis triggers morphological, functional, and transcriptional changes in MuSCs. Moving forward, we strive to leverage a more complete understanding of post‐sepsis MuSC/regenerative defects to identify and test novel therapies that promote muscle recovery and improve quality of life in sepsis survivors.

Background: The fillet flap is a reliable flap for reconstruction of large deformities following oncologic resection. It provides healthy, nonradiated tissue for coverage with the secondary benefit of preserving other potential donor sites for reconstruction. Methods: A retrospective review of the medical records of eight patients who underwent fillet flap reconstruction from 2013 to 2021 at Mayo Clinic, Arizona, were analyzed. Results: Eight patients who underwent four hemipelvectomies, three forequarter amputations, and one below the knee amputation were identified. Patients’ ages ranged between 24 and 66 years. All indications for oncologic ablation were curative. Defect sizes ranged from 16 × 20 to 30 × 60 cm. Four pedicled flaps and four free fillet flaps were performed. Indication for free fillet flap was tumor invasion of local vascular structures. There was no flap loss in the pedicled group (follow-up ranged from 1 to 9 years), and one of four free fillet flaps had a successful long-term outcome (follow-up 36 months). Conclusions: Successful free fillet flap reconstruction in the setting of oncologic resection is a difficult task to achieve. Changes to the management of case 3F allowed for a successful transfer. Immediate elevation and anastomosis of the flap before oncologic resection, large caliber recipient vessels and isolation from the zone of injury, protection of the anastomosis, and delay in flap inset all contributed to flap survival. It is our belief that applying these general considerations in large oncologic resections with free fillet flap transfer may aid in successful flap transfer and improve its survival odds.

Abstract Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab (Cemi) is a PD-1 inhibitor approved for the treatment of NSCLC, cutaneous basal, and squamous cell cancer. Here, we report current efficacy rates of Cemi in combination with paclitaxel followed by AC. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included paclitaxel 80 mg/m2 IV weekly x 12 and Cemi 350 mg IV given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MRI imaging; and imaging response (at 3 weeks, 12 weeks and prior to surgery) were used along with accumulating pCR data to continuously update and estimate pCR rates for trial arms. Analysis was modified intent to treat. Patients who switched to non-protocol therapy count as non-pCR. The goal is to identify (graduate) regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within responsive signatures. Cemi was eligible to graduate in 3 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemi being superior to the dynamic control. Results: 60 HER2- patients (28 HR+ and 32 HR-) received Cemi arm treatment. The control group included 357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemi graduated in HR-/HER2- signature. Estimated pCR rates (as of June 2022) are summarized in the table. Immune-related endocrine disorders include: hypothyroid (14.5%), adrenal insufficiency (10%), hyperthyroid (4.8%),) and thyroiditis (3.2%). Only one grade 3 adrenal insufficiency was observed. All immune related AE’s were manageable. Additional biomarker analyses are ongoing and will be presented at the meeting. Response predictive subtypes (Immune+ vs Immune-) and additional predictive biomarkers were assessed. Associations with pCR will be presented at SABCS. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Anti-PD-1 therapy with Cemi resulted in a higher predicted pCR rate in HR-/HER2- 55 rate% disease compared to control at 29%. Immune-mediated AE’s were observed. This data is consistent with previously published data using check point inhibitors in early-stage HR-/HER2- breast cancer. Estimated pCR rates Citation Format: Erica Stringer-Reasor, Rebecca A. Shatsky, Jo Chien, Anne Wallace, Judy C. Boughey, Kathy S. Albain, Hyo S. Han, Rita Nanda, Claudine Isaacs, Kevin Kalinsky, Zahi Mitri, Amy S. Clark, Christos Vaklavas, Alexandra Thomas, Meghna S. Trivedi, Janice Lu, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van ’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. PD11-01 Evaluation of the PD-1 Inhibitor Cemiplimab in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-01.

Abstract PURPOSE: Treatment options for patients (pts) with HER2+ BCBM remain limited. We previously reported that neratinib monotherapy is associated with a volumetric central nervous system objective response rate (CNS ORR) of 8%, whereas the combination of neratinib and capecitabine resulted in a volumetric CNS ORR of 49% (in lapatinib-naïve pts). Preclinical data suggest that neratinib may overcome resistance to trastuzumab-emtansine (T-DM1) and that the combination has potential CNS efficacy. Here, we report results of neratinib plus T-DM1 in pts with HER2+ BCBM. PATIENTS AND METHODS: In this prospective, multicenter, phase II study, pts with measurable HER2+ BCBM received neratinib 160 mg orally once daily plus T-DM1 3.6 mg/kg IV every 21 days in three parallel-enrolling cohorts. Cohort 4A enrolled pts with previously untreated brain metastases. Cohort 4B enrolled pts with BCBM progressing after prior local CNS-directed therapy without prior exposure to T-DM1. Cohort 4C enrolled pts with BCBM progressing after prior local CNS-directed therapy who had previous exposure to T-DM1. Diarrhea prophylaxis with colestipol and loperamide was required during cycle 1. Cohorts 4A and 4B were single-stage with a planned enrollment of 20 patients; cohort 4C had a two-stage design, with a requirement for at least 1 of the first 9 pts to achieve a response in order to enroll a total of 24 patients. The primary endpoint was Response Assessment in Neuro-Oncology-Brain Metastases (RANO BM) in each cohort separately. Correlative studies included patient-reported outcomes (PROs) for gastrointestinal toxicity. RESULTS: We enrolled 6, 17, and 21 patients to cohorts 4A, 4B, and 4C, during 11/07/2018 – 11/01/2021. Enrollment was stopped prematurely due to slow accrual. Across Cohorts 4A-4C, the median number of prior lines of chemotherapy prior to enrollment was 2 (range 1-10); 25% received prior lapatinib and no patients received prior tucatinib. In cohorts 4B and 4C (prior CNS-treated cohorts), 33% had prior CNS surgery and &gt;94% had prior CNS radiation. Among evaluable patients, CNS ORR in cohorts 4A (n=6), 4B (n=16), and 4C (n=21) was 50.0% (95% CI 18.8- 81.2%), 25.0% (95% CI 8.3-52.6%), and 38.1% (95% CI 19.0-61.3%), respectively. Median (range) number of cycles completed for 4A, 4B, and 4C was 4.5 (1-15), 4 (range 0-49+), and 6 (0-23); three patients on Cohort 4B remain on protocol therapy (cycles 14, 45, and 49). The overall survival at 12-months for cohorts 4A, 4B, and 4C was 83.3% (95% CI, 58.3-100%), 86.2% (95% CI 70-100%), and 83.3% (95% CI 67.6-100%). Diarrhea was the most common grade 3 toxicity (19.0–33.3% across cohorts); one grade 4 liver function event occurred in cohort 4B. Updated efficacy results will be reported at the meeting; PRO analyses are ongoing. CONCLUSION: Intracranial activity was observed for the combination of neratinib plus T-DM1 across all three enrolled cohorts, including those with prior T-DM1 exposure, suggesting synergistic effects of this treatment combination. Our data provide additional evidence for consideration of neratinib-based combinations in pts with HER2+ BCBM. Citation Format: Rachel Freedman, Siyang Ren, Nabihah Tayob, Rebecca Gelman, Karen L. Smith, Raechel Davis, Alyssa Pereslete, Victoria Attaya, Christine Cotter, Wendy Y. Chen, Cesar Augusto Santa-Maria, Catherine Van Poznak, Beverly Moy, Adam M. Brufsky, Michelle Melisko, Ciara C. O’Sullivan, Nadia Ashai, Yasmeen Rauf, Julie Nangia, Dario Trapani, Jennifer Savoie, Robyn Burns, Antonio C. Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy U. Lin. Translational Breast Cancer Research Consortium Trial 022: Neratinib and Trastuzumab-Emtansine for HER2+ Breast Cancer Brain Metastases (BCBM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-03.

Abstract Background Pulmonary embolism (PE) in the pediatric population is uncommon, and due to a silent presentation often unrecognized entity that remains one of the most challenging medical conditions in the emergency department (ED). Risk factors for PE in children include nephrotic syndrome, immobility, obesity, congenital heart disease, and malignancy. In patients with PE, thromboembolism has been reported to occur at unusual venous sites including the veins within the central nervous system and abdomen. Although penile pain is a rare presenting symptom in the ED, in patients with hypercoagulability, it can herald a life threating event such as PE prompting further evaluation. Case presentation A 15-year-old male with a history of B-cell acute lymphoblastic leukemia who presented to the ED with an 18-hour history of penile pain. In the ED, the patient was in acute distress and rated his pain as 9/10. Initial vital signs were within normal limits, except mild tachypnea. On physical examination, his penile shaft was erythematous, indurated, and tender to palpation. He received fentanyl and morphine for pain. A complete blood cell count revealed pancytopenia with a platelet count of 73 x 109/L (139–320 x 109/L). A work-up for sexually transmitted diseases, urolithiasis, urinary tract infection, deep venous thrombosis (DVT), and priapism was negative. Approximately two hours after morphine administration, his saturations started dropping to mid-70’s. A computed tomography pulmonary angiogram (CTPA) revealed bilateral segmental acute pulmonary embolism involving multiple segmental right and left lower lobe pulmonary arteries. Penile pain and hypoxia have resolved with heparin. Conclusions PE is easily missed diagnosis among children who present to the ED and can be potentially fatal. A high index of suspicion is required in asymptomatic and oligo-symptomatic children with prothrombotic risk factors who develop thromboembolism-related symptoms at unusual sites as well as hypoxia in the ED setting.