Citations

Background and Objectives: This survey study aimed to (1) identify patient/family research priorities in pediatric-onset multiple sclerosis (POMS), and (2) delineate optimized methods for research study/clinical trials design, engagement, and implementation. Methods: Participants were as follows: (1) parents of a child (<18 years) with POMS enrolled in a national registry, (2) adolescents (13–17 years) with POMS in the registry, and (3) adults (18–40 years) with POMS receiving care at a registry affiliated clinic. Of 293 eligible participants, 192 completed surveys. Results: Experiences with health care and medications were generally positive but there remain areas of priority improvement. Incentives to participate in clinical trials included medications previously tested and in pill form, bloodwork/study visits required ⩾ every 3 months, cognitive testing ⩽1 hour, compensation for travel and time, ability to continue current multiple sclerosis (MS) medication, option to take study medication if on placebo, and individualized study feedback. Priorities for clinical research were (1) psychosocial impact, (2) cognitive/academic impact, (3) environmental risk, and (4) nutrition. Conclusions: Results highlighted the importance of a holistic approach to study design and a focus on the impact of disease on daily life to best engage patients and families in POMS clinical trials and research.

84 Background: Local therapies potentially offer a curative approach for patients with oligometastatic colorectal cancer (CRC). The effectiveness of systemic chemotherapy following definitive local treatment in this setting is not well-defined. Tumor-informed circulating tumor DNA (ctDNA) might guide management strategies after curative-intent local treatment. Methods: This is a single institution retrospective study of patients with CRC who underwent curative-intent local therapy to an isolated site of metastatic disease and had post-intervention tumor-informed ctDNA (Signatera) testing. The study was approved by the institutional review board. Clinical characteristics, including ctDNA results, were collected and evaluated. Kaplan-Meier method and log-rank test were used to calculate and compare disease-free survival (DFS). Factors associated with DFS were analyzed using multivariate Cox proportional hazards model. Results: 45 patients were included with median age of 59 years, 62% being male, 91% white, and 53% with stage IV disease at diagnosis. 37% of the patients had RAS mutations, no patient had BRAF mutation, and 2.2% patient had mismatch repair deficient disease. Isolated liver metastases were present in 80% of patients, lung metastases in 11% and other sites in 9%. 44 patients received chemotherapy prior to definitive treatment, with a median treatment duration of 16 weeks. ctDNA tests were done prior to local therapy in 23 patients, with 14 cases (61%) testing positive. Definitive treatment included resection (58%), ablation (13%), radiotherapy (4%), and multimodality (25%). Post-definitive treatment chemotherapy was administered to 24 (53%) patients. ctDNA positivity following definitive therapy was observed in 10 patients (22%), which was associated with a poorer prognosis, with a median DFS of 5.3 months compared to 21.3 months for the ctDNA-negative group (p<0.001). These findings were confirmed on multivariate analysis. In patients who had negative ctDNA after definitive local treatment, median DFS was 14.9 months for those who received post-intervention chemotherapy versus 21.3 months for those without post-intervention chemotherapy (p=0.835). Conclusions: Patients with negative ctDNA results following definitive local therapy for isolated metastatic CRC have better prognosis. Post-intervention chemotherapy in this group of patients was not associated with improved DFS. ctDNA guided omission of post-intervention chemotherapy following curative-intent local treatment of oligometastatic CRC warrants further study. [Table: see text]

Abstract Aim Women with gestational diabetes mellitus (GDM) display adverse lifetime cardiometabolic health. We examined whether early metformin in GDM could impact cardiometabolic risk factors postpartum. Methods EMERGE, a double-blind, placebo-controlled trial, randomized pregnancies 1:1 to placebo or metformin at GDM diagnosis and followed participants from randomization until 12 ± 4 weeks postpartum. In total, 478 pregnancies were available for postpartum maternal assessment, 237 and 241 assigned to metformin and placebo respectively. Weight (kg), body mass index (BMI) (kg/m2), waist circumference (cm), and blood pressure (mmHg) were measured, infant feeding method documented, and blood specimens drawn for a 75-gram oral glucose tolerance test, fasting insulin, C-peptide, and lipid analysis. Results Despite similar weight and BMI at trial randomization, participants receiving metformin had significantly lower weight (79.5 ± 15.9 vs 82.6 ± 16.9 kg; P = .04) and BMI (29.3 [5.6] vs 30.5 [5.4]; P = .018) at the postpartum visit. However, no difference in weight change from randomization to 12 weeks postpartum was observed between metformin and placebo groups. Overall, 29% (n = 139) of the cohort met criteria for prediabetes or diabetes, with no positive impact with metformin. There were also no differences in measurements of insulin resistance, blood pressure, or lipids between groups. Conclusion Early metformin use in GDM did not impact important cardiometabolic parameters in the early postpartum period despite significant benefits in weight gain and insulin use in pregnancy.

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan–Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar’s test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

Background Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Methods and Results We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM‐HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity–Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β‐2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein–outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), or high‐sensitivity cardiac troponin. Conclusions Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON‐HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. Registration URL: https://www.clinicaltrials.gov ; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

TPS8123 Background: A minority of patients with unresectable stage III non-small cell lung cancer (NSCLC) may be cured by chemoradiotherapy (CRT). Adjuvant checkpoint inhibition through PD-L1 blockade after CRT improved survival compared to placebo in the PACIFIC trial (median progression-free survival (mPFS) 16.9 vs 5.6 months (mo), median overall survival (mOS) 47.5 vs 29.1 mo), but overall survival at 5 years remains below 50% (Spigel D, et al J Clin Oncol 2022, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9015199/ . Only patients completing CRT without progression and with good performance status were eligible for this approach. Neoadjuvant checkpoint inhibition would allow more patients the opportunity to benefit from immunotherapy and may attenuate tumor-related immunosuppression via depletion of regulatory T cells and clonal expansion of effector T cells, thereby improving tumor immunogenicity. Neoadjuvant atezolizumab had favorable outcomes compared to historic PACIFIC data in the phase II single arm trial, AFT-16 (mPFS 30 mo and mOS not reached). Whether combination immunotherapy therapy before CRT will improve outcomes in this setting is the question posed in the AFT-57 trial. Methods: This phase II randomized Alliance Foundation Trials study (AFT-57) will evaluate safety and efficacy of atezolizumab with or without the anti-TIGIT monoclonal antibody, tiragolumab, before and after definitive CRT with concurrent atezolizumab. The primary endpoint is PFS in the two experimental arms with a goal to select the most promising regimen for further study. AFT-57 will randomly assign 158 patients with stage III NSCLC (AJCC v8), Eastern Cooperative Oncology Group performance status 0-1, no active autoimmune disease and no underlying organ dysfunction to 2 cycles of neoadjuvant atezolizumab (1200 mg intravenously [IV] every 21 days) with or without tiragolumab (600 mg IV). Non-progressing patients will receive carboplatin and paclitaxel weekly with atezolizumab 1200 mg IV every 21 days concurrent with 60 Gray involved field thoracic radiation in 30 daily fractions (Monday - Friday) followed by atezolizumab with or without tiragolumab on the same schedule as the neoadjuvant doses, with a plan to complete one year of therapy. A pilot cohort of 20 patients for whom tiragolumab will be combined with atezolizumab during chemoradiotherapy is planned toward the end of accrual. Correlative science includes tissue and blood-based immune-related biomarkers at baseline and during therapy. This trial utilizes the Alliance Participant Engagement Portal, a patient-facing site designed to provide information and resources to Alliance clinical trial participants. The trial was activated on 12/7/23 with the first patient screened 1/19/24. Clinical trial information: NCT05798663 .

This article addresses clinical challenges of photon-counting detector (PCD) CT in pediatric patients by outlining fundamental terminology, explaining technical aspects, and providing protocol guidance for the first commercially available PCD CT scanner.

Colorectal cancer (CRC) poses a significant global health challenge. Notably, the risk of CRC escalates with age, with the majority of cases occurring in those over the age of 65. Despite recent progress in tailoring treatments for early and advanced CRC, there is a lack of prospective data to guide the management of older patients, who are frequently underrepresented in clinical trials. This article reviews the contemporary landscape of managing older individuals with CRC, highlighting recent advancements and persisting challenges. The role of comprehensive geriatric assessment is explored. Opportunities for treatment escalation/de-escalation, with consideration of the older adult’s fitness level. are reviewed in the neoadjuvant, surgical, adjuvant, and metastatic settings of colon and rectal cancers. Immunotherapy is shown to be an effective treatment option in older adults who have CRC with microsatellite instability. Promising new technologies such as circulating tumor DNA and recent phase III trials adding later-line systemic therapy options are discussed. Clinical recommendations based on the data available are summarized. We conclude that deliberate efforts to include older individuals in future colorectal cancer trials are essential to better guide the management of these patients in this rapidly evolving field.

Abstract Rationale Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. Objectives To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. Methods Patients in the Bronchiectasis and NTM Research Registry with ⩾5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. Measurements and Main Results In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline FEV1 percent predicted, age, hospitalization within 2 years before baseline, body mass index, and sex (all P &lt; 0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar, regardless of NTM status, except that annual exacerbations were lower in patients with NTM (P &lt; 0.05). Conclusions Outcomes, including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate, were similar across 5 years in patients with bronchiectasis with or without NTM.