Citations

The CD40-CD40L co-stimulatory dyad has been identified as critical player in atherosclerosis. Our previous work has shown that CD40 and CD40L have cell divergent effects on atherosclerosis. Deficiency of the CD40-CD40L dendritic cell-T cell axis decreased atherosclerosis via reducing T helper 1 responses, whereas deficiency of macrophages CD40 reduced atherosclerosis by enhancing efferocytosis and reducing necrotic core content. CD40 is highly expressed on B cells and interacts with CD40L on T cells to induce antibody production and T follicular helper cell responses. We therefore hypothesize that deletion of CD40 will reduce atherosclerosis. We aim to unravel the role of B cell CD40 in atherosclerosis. CD40 expression on B cell subsets was determined on peripheral blood mononuclear cells of patients and correlated with severity of coronary artery disease (CAD). Atherosclerosis was analyzed in CD19 Cre CD40 flfl ApoE -/- mice that were fed an atherogenic diet for 14 weeks. Patients with CAD showed a decrease in CD40 on their putative B1 cells, which was associated with increased plaque burden and decreased plaque fibrosis as detected by coronary intravascular ultrasound. Depletion of CD40 on B cells in ApoE -/- mice resulted in a decreased germinal center formation and inadequate IgM production as expected. However, in line with our patient data, absence of B cell-CD40 increased atherosclerosis. This was caused by a reduction in B1 cells and consequently a reduction in atheroprotective anti-oxidation specific epitope (OSE) IgMs. Transfer of CD40-competent B1b cells in B cell-CD40-deficient mice restored anti-OSE IgM levels and prevented the increase in atherosclerosis. CD40-deficient B1b cells have an altered mTOR signaling pathway, impaired mitochondrial function, excessive uptake of lipids, increased cellular stress and accelerated cell death. Data indicate that CD40-deficiency promotes phosphorylation of RAPTOR and protein kinase B (AKT). We have identified a novel function of CD40 on B1b cells. B1b cell-CD40 exerts an anti-atherogenic role by regulating B1b cell metabolic homeostasis via mTOR pathway. Further mechanistic insights into how CD40 mounts adequate atheroprotective anti-OSE IgM production are currently being investigated.

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135

Restoration of elbow flexion is a priority in treating adult traumatic brachial plexus injuries. A tendon transfer is an ideal option for patients not candidates for reconstructive nerve surgery or free-functioning muscle transfer. For patients with a partial brachial plexus injury or a pan plexus injury with adequate recovered triceps function and loss of elbow flexion, a triceps-to-biceps tendon transfer is a nonmicrosurgical option to restore elbow flexion. The technique of triceps-to-biceps transfer in which the complete triceps tendon is transferred laterally, secured lateral to the radial tuberosity, and reinforced with suture to the biceps tendon is described.

Abstract Acute graft-versus-host disease (GVHD) grading systems that use only clinical symptoms at treatment initiation such as the Minnesota risk identify standard and high-risk categories but lack a low-risk category suitable to minimize immunosuppressive strategies. We developed a new grading system that includes a low-risk stratum based on clinical symptoms alone and determined whether the incorporation of biomarkers would improve the model’s prognostic accuracy. We randomly divided 1863 patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) who were treated for GVHD into training and validation cohorts. Patients in the training cohort were divided into 14 groups based on similarity of clinical symptoms and similar nonrelapse mortality (NRM); we used a classification and regression tree (CART) algorithm to create three Manhattan risk groups that produced a significantly higher area under the receiver operating characteristic curve (AUC) for 6-month NRM than the Minnesota risk classification (0.69 vs 0.64, P = .009) in the validation cohort. We integrated serum GVHD biomarker scores with Manhattan risk using patients with available serum samples and again used a CART algorithm to establish 3 MAGIC composite scores that significantly improved prediction of NRM compared to Manhattan risk (AUC, 0.76 vs 0.70, P = .010). Each increase in MAGIC composite score also corresponded to a significant decrease in day 28 treatment response (80% vs 63% vs 30%, P < .001). We conclude that the MAGIC composite score more accurately predicts response to therapy and long-term outcomes than systems based on clinical symptoms alone and may help guide clinical decisions and trial design.

3016 Background: PN in patients (pts) with NF1 can cause pain, disfigurement, impaired quality of life (QoL), and can undergo malignant transformation. ReNeu (NCT03962543), a multicenter, open-label, Phase 2b study, evaluated efficacy and safety of the highly selective, oral, investigational MEK1/2 inhibitor mirdametinib in adult (≥18 y) and pediatric (2-17 y) pts with inoperable NF1 PN causing significant morbidities. Methods: Mirdametinib was administered as a capsule or dispersible tablet (2 mg/m 2 BID, max 4 mg BID) without regard to food in 3 wk on/1 wk off 28-d cycles. The primary endpoint was confirmed objective response rate (ORR; percentage of pts with MRI-assessed ≥20% reduction of target PN volume by blinded independent central review [BICR] within the 24-cycle treatment phase). The minimum clinically relevant ORR (null) was defined as 23% for adults and 20% for pediatrics. Ptscould continue treatment in an optional long-term follow-up (LTFU) phase. Additional key endpoints were duration of response (DoR), time to response (TTR), change from baseline (BL) in target PN volume, pain severity (Numerical Rating Scale-11 [NRS-11]), pain interference (Pain Interference Index [PII]), health-related (HR) QoL (PedsQL), and safety. Results: All114 pts (58 adult, 56 pediatric) received mirdametinib. As of the 20 Sept 2023 data cutoff (DCO), BICR-confirmed ORR during the treatment phase was 41% (95% CI, 29-55; P<.001 vs null) in adults and 52% (95% CI, 38-65; P<.001 vs null) in pediatric pts. Two adult pts and 1 pediatric pt also had a confirmed response in the ongoing LTFU. Median (min, max) target PN volumetric best response from BL was -41% (-90, 13) and -42% (-91, 48) in adult and pediatric pts, respectively. As of the DCO, median treatment duration was 22 mo for each cohort and median DoR was not reached. Median (range) TTR was 7.8 (4-19) mo in adult pts and 7.9 (4-19) mo in pediatric pts. Adult and pediatric pts had statistically significant improvements from BL to cycle 13 in NRS-11, PII, and key PedsQL measures. Most frequent (≥35% pts) treatment-emergent adverse events (TEAEs) were dermatitis acneiform, diarrhea, nausea, and vomiting in adults and diarrhea, dermatitis acneiform, and vomiting in pediatric pts. 16% and 25% of adult and pediatric pts, respectively, had grade ≥3 treatment-related AEs, and 22% and 9%, respectively, discontinued due to TEAEs. Conclusions: In ReNeu, the largest multicenter NF1 PN trial reported to date, mirdametinib demonstrated a statistically significant ORR by BICR, with deep and durable PN volume reductions, significant improvements in pain severity, pain interference, and HRQoL, and a manageable safety profile in both adults and children. Together with a dispersible tablet formulation, these results underscore mirdametinib’s potential to become an important new treatment option for NF1 PN pts across all ages. Clinical trial information: NCT03962543 .

BACKGROUND AND OBJECTIVES: The palliative impact of spine surgery for metastatic disease is evolving with improvements in surgical technique and multidisciplinary cancer care. The goal of this study was to prospectively evaluate long-term clinical outcomes including health-related quality-of-life (HRQOL) measures, using spine cancer–specific patient-reported-outcome (PRO) measures, in patients with symptomatic spinal metastases who underwent surgical management. METHODS: The Epidemiology, Process, and Outcomes of Spine Oncology (EPOSO, ClinicalTrials.gov identifier: NCT01825161) trial is a prospective-observational cohort study that included 10 specialist centers in North America and Europe. Patients aged 18 to 75 years who underwent surgery for spinal metastases were included. Prospective assessments included both spine tumor–specific and generic PRO tools which were collected for a minimum of 2 years post-treatment or until death. RESULTS: Two hundred and eighty patients (51.8% female, mean age 57.9 years) were included. At presentation, the mean Charlson Comorbidity Index was 6.0, 35.7% had neurological deficits as defined by the American Spinal Cord Injury Association scores, 47.2% had high-grade epidural spinal cord compression (2-3), and 89.6% had impending or frank instability as measured by a Spinal Instability Neoplastic Score of ≥7. The most common primary tumor sites were breast (20.2%), lung (18.8%), kidney (16.2%), and prostate (6.5%). The median overall survival postsurgery was 501 days, and the 2-year progression-free-survival rate was 38.4%. Compared with baseline, significant and durable improvements in HRQOL were observed at the 6-week, 12-week, 26-week, 1-year, and 2-year follow-up assessments from a battery of PRO questionnaires including the spine cancer–specific, validated, Spine Oncology Study Group Outcomes Questionnaire v2.0, the Short Form 36 version 2, EuroQol-5 Dimension (3L), and pain numerical rating scale score. CONCLUSION: Multi-institutional, prospective-outcomes data confirm that surgical decompression and/or stabilization provides meaningful and durable improvements in multiple HRQOL domains, including spine-specific outcomes based on the Spine Oncology Study Group Outcomes Questionnaire v2.0, for patients with metastatic spine disease.

Introduction Subjectively experienced cognitive difficulties are common in youth with postural orthostatic tachycardia syndrome. The pathophysiological and psychological contributions of these cognitive impairments remain unclear. Method Participants were 96 adolescents and young adults diagnosed with postural orthostatic tachycardia syndrome and admitted to an intensive pain treatment program. Participants completed cognitive assessment and measures of postural orthostatic tachycardia syndrome symptoms, pain intensity, pain catastrophizing, anxiety, depression, and functional disability. Results Self-reported autonomic symptom intensity, but not severity of heart rate change, was associated with cognitive performance. Symptoms of depression were associated with decreases in most measures of cognitive functioning. Pain intensity, pain catastrophizing, and depression but not cognitive scores and physiological measures, were significant predictors of disability. Conclusion Depression appears to be a significant contributor to the cognitive difficulties in youth with postural orthostatic tachycardia syndrome. These findings highlight the importance of assessing and treating affective symptoms in this population along with medical and lifestyle approaches to treating postural orthostatic tachycardia syndrome symptoms.

Abstract Background: In patients with micro- and macrometastases in the sentinel lymph node (SLN) after neoadjuvant chemotherapy (NAC), additional positive nodes are found in &gt;60% of cases and axillary lymph node dissection (ALND) is currently considered standard of care. The likelihood of finding additional positive lymph nodes in patients with residual isolated tumor cells (ITCs) is unknown, and the benefit of ALND is unclear. As a consequence, surgical management of the axilla in these patients is not standardized. We sought to evaluate how often additional positive lymph nodes are found, to determine factors associated with ALND, and to compare oncological outcomes in patients treated with and without ALND after identification of residual ITCs in the SLN. Methods: Data were collected from 42 centers: 20 in the Oncoplastic Breast Consortium (OPBC) and EUBREAST networks, and 22 in North and South America. We included patients with cT1-4 N0-3 breast cancer at diagnosis who underwent NAC followed by axillary staging with either SLN biopsy (SLNB) or targeted axillary dissection (TAD) and were found to have residual ITCs [ypN0(i+)]. Single-tracer mapping was allowed for cN0 patients, while dual mapping or TAD was required for cN+ cases. Axillary treatment included completion ALND and/or nodal radiotherapy (RT). Competing risk analysis was performed to assess the cumulative incidence rates of any axillary recurrence (AR), locoregional recurrence (LRR), and any invasive (locoregional or distant) recurrence. Five-year cumulative incidence rates were compared between patients who underwent ALND and those who did not using the Gray’s test. Type I error rate was set to 0.05 (α). Results: We included 412 patients treated with NAC followed by surgery from 01/2009-05/2022. 146 (35.4%) had completion ALND and 266 (64.6%%) did not. Median patient age was 48 years. The majority (57%) of patients had clinical T2 tumors, and 68% had biopsy-proven N1 disease. Most were HR+/HER2- (41%) or HER2+ (39%). Most patients (80%) received anthracycline and taxane-based chemotherapy regimens. Nodal RT was administered to 83% of patients. The median number of SLNs with ITCs was 1. Patients treated with ALND were more likely to have ITCs detected on frozen section (61% v 6.7%, p&lt; 0.001), to have N2/3 disease at presentation (15.1% v 5.6%, p=0.001) and to have LVI (40% v 26%, p=0.004) (Table 1). There was no significant trend over time in the proportion of patients undergoing completion ALND during the study period (p=0.5). In the ALND group, additional positive nodes were found in 43/146 (29.5%) of cases, and consisted of macrometastases in 11/146 (7.5%), micrometastases in 9/146 (6.2%), and ITCs in 23/146 (15.8%). 5-year rates of any AR, LRR, and any invasive recurrence in the entire cohort were 2.7% (95% CI 1.2-5.4), 2.8% (95% CI 1.2-5.4) and 16% (95% CI 11-21), respectively. There was no statistical difference between patients who underwent ALND and those who did not in any of the 3 endpoints (2.2% v 3.1%, p=0.6), (2.6% v 3.0%, p=0.4) and (14% v 18%, p=0.12), respectively. Conclusion: The likelihood of finding additional positive lymph nodes in patients with ITCs after NAC is lower than in patients with residual micro- and macrometastases, and in the majority of cases, they contain ITCs. Nodal recurrence after omission of ALND is rare in this population. Overall, these results do not support routine ALND in patients with residual ITCs. Table 1. Clinicopathological Features of the Study Cohort, Stratified by Type of Axillary Surgery Frequency (row percent) reported for categorical variables, and median (IQR) reported for continuous variables. SLNB sentinel lymph node biopsy; TAD targeted axillary dissection; SLNs sentinel lymph nodes; LNs lymph nodes; pCR pathologic complete response; ACT anthracycline and taxane; AC anthracycline; H Herceptin, HP, Herceptin and Perjeta; TC taxol (or Taxotere) and carboplatinum; LVI lymphovascular invasion; BCS breast-conserving surgery. ^ Applied to HER2- tumors only (n=252). ^^ Applies to HER2+ tumors only (n=160). # LVI was present on core biopsy or final pathology. * Applies to BCS patients only (n=175). ** Applies to mastectomy patients only (n=237). Citation Format: Giacomo Montagna, Alison Laws, Massimo Ferrucci, Mary Mrdutt, Natália Polidorio, Varadan Sevilimedu, Tracy-Ann Moo, Andrea Barrio, Marissa K. Boyle, Flavia Vidal Cabero, Daniela Cocco, Fabio Corsi, Angelena Crown, Meghan R. Flanagan, Mehmet Ali Gulcelik, Callie Hlavin, Justyna Jelinska, Hasan Karanlik, Susan Kesmodel, Henry Kuerer, Sherko Küemmel, Cornelia Leo, Tehillah Menes, Melissa Pilewskie, Nina Pislar, Nicola Rocco, Jai Min Ryu, Leonardo Soares, Christoph Tausch, M. Umit Ugurlu, CICERO URBAN, Astrid Botty van de Bruele, Denise Vorburger, Fredrik Wärnberg, Anna Weiss, Austin Williams, Stephanie Wong, Steven G. Woodward, Susie X. Sun, Jennifer Q. Zhang, M. Firdos Ziauddin, Guldeniz Karadeniz Cakmak, Nuran Bese, Thorsten Kühn, Judy Boughey, Tari King, Nina Ditsch, Maggie Banys-Paluchowski, Monica Morrow, Walter Weber. Are nodal ITCs after neoadjuvant chemotherapy an indication for axillary dissection? The OPBC05/EUBREAST-14R/ICARO study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-02.