Citations

PURPOSE STELLAR (ClinicalTrials.gov identifier: NCT02796261 ) was a phase III, randomized, open-label trial of eflornithine + lomustine versus lomustine monotherapy in patients with recurrent grade 3 astrocytoma. METHODS At trial initiation, eligibility criteria included: age ≥18 years, anaplastic astrocytoma (2016 WHO CNS Tumor classification [WHO CNS4]), first recurrence ≥6 months after radiation and temozolomide (TMZ), Karnofsky performance status ≥70, and no imaging findings consistent with grade 4 glioblastoma. Random assignment (1:1) was stratified by isocitrate dehydrogenase ( IDH ) mutation, age, resection extent, and geography. Patients received eflornithine (2.8 g/m 2 orally, every 8 hours [2 weeks on, 1 week off]) + lomustine (90 mg/m 2 orally, once every 6 weeks), or lomustine monotherapy (110 mg/m 2 once every 6 weeks). The primary end point was overall survival (OS). RESULTS Among 343 patients randomly assigned across 74 sites in eight countries, there was no difference in survival between eflornithine + lomustine and lomustine monotherapy (median OS 23.4 v 20.3 months, hazard ratio [HR], 0.94). Following changes in classification and grading in the 2021 WHO CNS5, a subset analysis of patients with IDH- mutant, grade 3 astrocytoma (n = 196), defined in 2024, before unblinding, showed clinically meaningful improvements in median OS with eflornithine + lomustine versus lomustine monotherapy (34.9 v 23.5 months, HR, 0.64) and median progression-free survival (PFS, 15.8 v 7.2 months, HR, 0.57). No differences were observed among patients with CNS grade 4 disease. Grade ≥3 treatment-emergent adverse events of relevance were related to reversible myelosuppression (eflornithine + lomustine 42% v lomustine monotherapy 29% of patients) and hearing impairment (24% v 0%). No new safety signals were identified. CONCLUSION Clinically meaningful improvements were observed; eflornithine + lomustine doubled PFS and improved OS in patients with recurrent IDH -mutant, grade 3 astrocytoma, but not grade 4 tumors, after prior radiotherapy and TMZ, consistent with its cytostatic mechanism of action.

Abstract Study Objectives Respiratory events during sleep induce immediate cardiac alterations, including increased RR intervals during events and decreased RR intervals after events. However, the extent to which related desaturations and arousals modulate these responses remains underexplored. We hypothesized that desaturations and arousals are the main contributors to respiratory event-related cardiac response, with greatest cardiac alterations expected when both are present. Methods We analyzed RR, QT, and heart rate-corrected QT (QTc) intervals before, during, and after 4310 respiratory events from 129 obstructive sleep apnea patients. Mixed-effect statistical models were utilized to assess the influence of the presence and severity of desaturations and arousals on the cardiac electrical response to respiratory events. Results There were no significant differences between pre- and post-respiratory event RR and QTc intervals in the absence of desaturation or arousal. Arousal (RR estimate = −23.9 ms; QTc estimate = 5.7 ms) or simultaneous desaturation and arousal (RR estimate = −32.8 ms; QTc estimate = 8.4 ms) modulated significantly (p < .05) mean RR and QTc intervals after respiratory events. Desaturation alone affected only RR intervals (estimate = −9.3 ms, p<.05). Greater desaturation depth (RR estimate = −0.09 ms; QTc estimate = 0.56 ms) and longer arousal duration (RR estimate = −3.52 ms; QTc estimate = 0.84 ms) were significant (p < .05) predictors of RR and QTc magnitude alterations after respiratory events. Conclusions Not all respiratory events have the same effects on cardiac electrophysiology; they are associated with acute alterations after events if they cause desaturations and/or arousal, with longer arousal and deeper desaturations increasing the magnitude of cardiac responses. Statement of Significance This study provides a detailed analysis of the temporal dynamics of cardiac response to respiratory events in obstructive sleep apnea patients, with a focus on the potential modulators of this response. Our observations present that not all respiratory events have the same effects on cardiac electrophysiology; they are associated with significant cardiac response if they cause desaturations and/or arousals, with longer arousal and deeper desaturations increasing the magnitude of cardiac response. Our results present evidence of possible modulators of post-event cardiac function, providing a deeper understanding of obstructive sleep apnea’s impact on health as potential underlying mechanisms leading to adverse cardiovascular events.

ABSTRACT Background Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis highly associated with systemic comorbidities. Accurate diagnosis and treatment remain challenging due to its rarity and clinical mimickers. Objectives To evaluate demographic, clinical features and treatment outcomes in patients referred with suspected PG at a tertiary wound care centre. Methods A prospective observational study was conducted of patients referred for suspected PG between April 2021 and June 2023. Demographic, clinical and laboratory data, including biopsies and tissue cultures, were collected. Patients were categorised as having PG vs alternative diagnoses based on diagnostic criteria from Su, Maverakis and the PARACELSUS score. Results Of 60 patients (female, 51.7%; mean [SD] age 52.9 [14.0] years), 44 (73.3%) met at least one published diagnostic criterion for PG. The most common comorbidity was IBD (63.6%), followed by inflammatory arthritis (25.0%) and monoclonal gammopathy of undetermined significance (MGUS) (4.5%). Systemic corticosteroids were used by 40.9% of patients before referral, but steroid‐sparing agents and biologics were the primary treatments after consultation. Biologics and steroid‐sparing agents were associated with significant improvement in disease activity using the PGA score (average score decreased from 2.3 to 1.5, p < 0.005), with 40.9% achieving complete remission. Elevated serum inflammatory markers and faecal calprotectin were observed in PG patients but absent in non‐PG cases. Conclusions These prospective data support previously published rates of association between PG and systemic comorbidities. Steroid‐sparing anti‐neutrophilic and targeted therapies are effective steroid‐sparing strategies in managing PG. Small sample size and referral bias may limit generalisability.

Goals: Describe the establishment and expansion of a global gastrointestinal (GI) partnership and its impact on the advancement of GI care in Rwanda. Background: GI disease disproportionately affects low- and middle-income countries. In Rwanda, governmental and nonprofit efforts have made significant progress in expanding access to health care in the wake of the 1994 genocide; however, specialized care remains largely unrecognized or inaccessible. In response, the Rwanda Ministry of Health established a partnership with an international gastroenterology NGO to address this critical need. Study: We present summative data generated by this partnership. To inform future global GI programs, we provide lessons learned and details about Rwanda’s successful establishment of an in-country, self-sustainable, and locally governed gastroenterology training program. Results: From 2017 to 2023, the partnership expanded the number of clinical sites receiving care from 4 to 11. Total procedural volume increased from 244 to 1069. Most common presenting upper GI symptoms included dyspepsia, reflux, and emesis, while most common lower GI symptoms included hematochezia and constipation. Since 2017, this partnership has increased the number of faculty volunteering in Rwanda (and Rwandan clinicians studying in US academic medical centers), expanded its geographical reach, assisted in the creation of a GI fellowship, and enabled Rwanda to become an East African hub for medical education. Conclusions: Lessons learned across ethical, financial, leadership, cultural, and medical domains from the successful establishment and expansion of an international GI partnership in Rwanda provides invaluable insights to guide development of future models of health care in emerging economies.

Purpose: Despite the 2022 American Heart Association/American College of Cardiology guidelines recommending cardiac rehabilitation (CR) after aortic dissection repair, both patient participation in CR and the associated clinical outcomes remain poorly understood. Methods: Adults (≥18 years of age) discharged alive following thoracic aortic dissection surgery across the Mayo Clinic Enterprise (January 2012 to November 2022), with follow-up until May 2024, were included (IRB #24-001141). Data were presented using summary statistics and logistic regression modeling. Results: A total of 186 patients were referred; 37% were female, and the median age was 64 (51, 73) years. Dissections were classified as type A (43%), type B (18%), or a combination, and 55% had residual dissection. Over half (53%) did not start CR, with older age (aOR = 0.97: 95% CI, 0.94 - 0.99; P = .003), family history of aortic dissections and/or aneurysms (aOR = 0.17: 95% CI, 0.04 - 0.54; P = .005), and tobacco use (aOR = 0.35: 95% CI, 0.13 - 0.91; P = .037) being associated with lower odds of enrollment. Of the 87 who enrolled, 34 did so at a Mayo Clinic facility. There were no complications, with no difference in adverse outcomes. Among those with evaluations at graduation from CR (n = 21), quality of life (Dartmouth index 16 [14, 19] vs 25 [22, 30]; P = .002) and 6-minute walk distance (488 [375, 531] vs 302 [235, 398] m; P = .001) improved. Conclusions: Following thoracic aortic dissection repair, CR significantly improved quality of life and functional capacity without adverse events. Further work is needed to improve enrollment and establish data-driven safety margins for exercise.

Objective Mycophenolate mofetil (MMF) can stabilize or improve lung function in systemic sclerosis–related interstitial lung disease (SSc‐ILD). We hypothesized that combining MMF with pirfenidone (PFD) would produce a significantly more rapid and/or greater improvement in lung function. Methods A randomized (1:1), double‐blind, placebo (PLA)‐controlled phase 2 trial was conducted in SSc‐ILD in which patients received PFD or PLA (801 mg three times daily) along with MMF (1,500 mg twice daily) for 18 months. The primary outcome was change in percent predicted forced vital capacity (FVC‐%). Linear mixed‐effects models assessed treatment differences in a modified intention‐to‐treat population. Results Only fifty‐one of 150 intended subjects (34%) were randomized (MMF+PLA, n = 24; MMF+PFD, n = 27). The FVC‐% improved from baseline to 18 months by 2.24 ± 1.35 (least‐squares mean [LSM] ± SEM) in the MMF+PLA group and 2.09 ± 1.28 in the MMF+PFD group (LSM treatment difference −0.14; P = 0.93). Median time to achieve a ≥3% improvement in FVC‐% was numerically faster in the MMF+PFD versus MMF+PLA group (12.3 vs 17.8 months, respectively), but the difference was not significant ( P = 0.33). For secondary outcomes, only the change over 18 months in the Patient‐Reported Outcomes Measurement Information System 29‐item physical function score, favoring MMF+PFD, reached statistical significance ( P = 0.04). Although other related patient‐reported outcomes (PROs) numerically favored the MMF+PFD group, as did quantitative high‐resolution computed tomography measures of ILD, the differences between groups did not reach statistical significance. Early withdrawals from study medication and adverse events of special interest were numerically greater with MMF+PFD (n = 8 vs 2 and n = 20 vs 7, respectively). Conclusion In this underpowered study, there was no statistically significant treatment difference in overall change in FVC‐% between groups. MMF+PFD was not as well tolerated as MMF+PLA.

Objective We examined the weight management practices of successful high school wrestlers to contribute meaningful data to the conversations that weight-certifying clinicians and athletic trainers have with athletes at the start of the wrestling season. Understanding how elite athletes navigate weight management can inform safer and more individualized guidance during preseason assessments. Specifically, we sought to determine the proportion of state-qualifying wrestlers who competed at or above their certified minimum weight class. We also quantified the magnitude of weight change from certification to state competition and analyzed seasonal trends in both body weight and body fat percentage over a 20-year period. Design Longitudinal retrospective review. Setting Four Minnesota high schools. Patients or Other Participants State-qualifying wrestlers from 2003 to 2023. Independent Variable State-qualifying weight class. Main Outcome Measure(s) Dependent variables are certification weight, measured body fat percent, and calculated minimum weight class. Results Only 48 wrestlers (52.7%; CI = 42.5%, 63.0%) competed at state in their minimum weight class, while the other 43 competed 1 to 2 weight classes above. Thirty-six wrestlers (39.6%) gained weight over the season. Conclusions Nearly half the successful wrestlers competed in weight classes above their minimum weight, while 5% lost 9% to 18% of their body mass over the wrestling season. This suggests factors other than maximizing individual athletic potential, such as team needs to fill a weight class, influence weight management decisions. Over the 20-year span of the study, trends toward lower measured body fat percentage and lower weight fluctuations suggest influences from sports specialization and year-round training and less emphasis on extreme leanness for competitive advantage. Athletes, in consultation with their coaches and clinicians, should select a competition weight class where they can adequately fuel, train, and recover. This may not be their minimum certified weight class.

Abstract Description PBC is an archetypal autoimmune disease where the dominant autoantigen is mitochondrial PDC-E2. Hitherto, PBC treatment has been neither specific nor directed toward restoration of tolerance. CNP-104, a tolerogenic nanoparticle encapsulating PDC-E2, is hypothesized to restore tolerance to pathogenic T cells. We conducted a Phase 2a First-in-Human randomized controlled trial of CNP-104 in PBC patients unresponsive/intolerant to ursodeoxycholic acid. The 42 enrolled subjects were randomized 2:1 to receive two doses of CNP-104 or placebo (PBO) one week apart and were followed for 120 days to assess safety and treatment durability. CNP-104 was safe and well-tolerated. Compared to PBO, the CNP-104 group had a reduced percentage of antigen-specific Th17 T cells and increased antigen-specific tolerogenic CD8+ T cell counts (TIGIT, GARP). ALP, ALT, and total bilirubin were similar between groups. Clinically relevant effects on albumin levels, liver stiffness, and the rate of change in 5-year UK-PBC risk for liver outcomes were improved in the CNP-104 group compared to PBO. This trial is limited by small size and data variability. Induction of antigen-specific T cell tolerance, shown by reduced Th17 cells and increased TIGIT and GARP cells correlates with improved liver stiffness, albumin, and UK-PBC. These findings suggest the CNP-104 tolerogenic mechanism of action translates to clinical benefits. These data support future studies with this unique therapeutic platform to treat PBC. Topic Categories Therapeutic Approaches to Autoimmunity (THER)

Abstract Twohey, E, Dobbs, WC, Malone, CM, Fields, JB, Jones, MT, and Jagim, AR. The use of a consumer-grade bioelectrical impedance analysis device for weight certification in collegiate wrestling: Implications for minimal wrestling weight determination. J Strength Cond Res 39(12): 1321–1326, 2025—Wrestlers are required to complete a preseason weight certification assessment, which includes a weigh-in, a hydration test, and a body fat percentage (BF%) measurement. This information is then used to establish their minimal wrestling weight (MWW) and minimal weight class. Skinfold (SKF) is the primary method used for determining body fat for collegiate wrestling, yet impedance devices are being considered for use in the future. The purpose of this study was to examine differences in body fat and the resulting MWW values derived from SKF and a consumer-grade multifrequency bioelectrical impedance analysis (MFBIA) device. Thirty-one collegiate male wrestlers produced a urine sample for urine specific gravity assessment to ensure adequate hydration status. Subjects then completed a weigh-in, followed by 2 body composition assessments using a (a) MFBIA device and (b) skinfold calipers to determine body density and BF%. No significant differences were observed for estimates of BF% (SKF: 13.4 ± 2.8% vs. MFBIA: 14.0 ± 3.3%; p = 0.198) or computed MWW values (SKF: 69.8 ± 8.7 kg vs. MFBIA: 69.4 ± 9.7 kg; p = 0.348) between devices. When determining the minimal weight class for each device, there were discrepancies in 11 of the 31 wrestlers (35%). Although the current MFBIA device can provide an acceptable estimate of BF% and similar resulting MWW value at the group level, the methods cannot be used interchangeably.