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Objectives While extracorporeal shockwave therapy (ESWT) may be an efficacious adjunctive treatment option for musculoskeletal injuries, current research is limited by significant heterogeneity within treatment protocols. This study aims to establish international expert consensus recommendations on ESWT terminology, parameters, procedural considerations, contraindications and side effects in the application of ESWT to sports injuries. Methods A systematic literature search was performed on the use of ESWT for musculoskeletal and sports medicine injuries to identify potential panellists, followed by the development of a steering committee-led questionnaire. A three-stage, modified Delphi questionnaire was provided to a panel of 41 international clinical and research experts across 13 countries. Panellists had the opportunity to suggest edits to existing statements or recommend additional statements in Round 1. Consensus was defined as≥75% agreement. Results All 41 panellists completed Rounds 1, 2 and 3. Consensus was reached on 69/118 statements (58.5%), including recommendations on terminology and fundamental concepts, indications for use, procedural aspects for tendinopathy and bone pathologies, treatment correlations with imaging, periprocedural and postprocedural considerations, absolute and relative contraindications and potential side effects. Of the 49 statements that did not reach consensus, 17/49 (34.7%) were related to procedural aspects of bone pathology. Conclusion This international panel presents recommendations on ESWT terminology, indications and treatment considerations to guide ESWT use and decision-making by sports medicine clinicians. While our panel supported the use of ESWT in the treatment of bone pathologies, certain procedural aspects of ESWT specific to these injuries did not reach consensus and require further investigation.

ABSTRACT EPHA2 is a receptor tyrosine kinase highly expressed in many cancers. By analyzing cancer patient databases for mutations in the EPHA2 coding sequence, we found that cholangiocarcinoma (a hepatobiliary cancer with dismal prognosis) exhibits a uniquely high incidence of EPHA2 mutations. To deUine the functional signiUicance of these mutations, we generated representative EPHA2 mutants and monitored major receptor autophosphorylation sites as indicative of kinase activity-dependent signal transduction (known as forward signaling). We found that missense mutations in the ligand-binding domain abrogate ligand binding and ligand-induced EPHA2 tyrosine phosphorylation, while most missense mutations in the kinase domain abrogate kinase activity. We detected less pronounced effects of missense mutations in other domains, which vary depending on the phosphosite, suggesting that these EPHA2 mutations might differentially affect (or bias) different downstream signaling pathways. Other EPHA2 mutations introduce early stop codons and encode receptor truncated forms lacking all or part of the kinase domain. We also found that an EPHA2 secreted truncated form, a transmembrane truncated form, and a full-length kinase inactive mutant can inhibit tyrosine phosphorylation of co-expressed EPHA2 wild-type. Taken together, these data suggest that mutations interfering with EPHA2 forward signaling facilitate cholangiocarcinoma development. We indeed obtained evidence that an EPHA2 kinase inactive mutant, but not EPHA2 wild-type, can induce proliferative masses consistent with well differentiated cholangiocarcinoma in a validated mouse model of cholangiocarcinogenesis. Taken together, our Uindings suggest that EPHA2 is a driver gene in cholangiocarcinoma and that its forward signaling has tumor suppressor activity.

Abstract Objective Dravet syndrome is a developmental and epileptic encephalopathy characterized by drug‐resistance, lifelong seizures, and significant comorbidities including intellectual and motor impairment. Receiving a diagnosis of Dravet syndrome is challenging for parents/caregivers, and little research has focused on how the diagnosis should be given. A Delphi consensus process was undertaken to determine key aspects for healthcare professionals (HCPs) to consider when communicating a Dravet syndrome diagnosis to parents/caregivers. Methods Following a literature search and steering committee review, 34 statements relating to the first diagnosis consultation were independent‐ and anonymously voted on (from 1, totally inappropriate, to 9, totally appropriate) by an international group of expert child neurologists, neuropsychiatrists, nurses, and patient advisory group (PAG) representatives. The statements were divided into five chapters: (i) communication during the first diagnosis consultation, (ii) information to be delivered during the first diagnosis consultation, (iii) points to be reiterated at the end of the first diagnosis consultation, (iv) information to be delivered at subsequent consultations, and (v) communication around genetic testing. Statements receiving ≥ 75% of the votes with a score of ≥7 and/or with a median score of ≥8 were considered consensual. Results The statements were evaluated by 44 HCPs and PAG representatives in the first round of voting; 29 statements obtained strong consensus, 3 received good consensus, and 2 did not reach consensus. The committee reformulated and resubmitted 4 statements for evaluation (42/44 voters): 3 obtained strong consensus and 1 remained not consensual. The final consensual recommendations include guidance on consultation setting, key disease aspects to convey, how to discuss genetic testing results, disease evolution, and the risk of SUDEP, among other topics. Significance It is hoped that this international Delphi consensus will facilitate a better‐structured initial diagnosis consultation and offer further support for parents/caregivers at this challenging time of learning about Dravet syndrome. Plain Language Summary Diagnosis of Dravet syndrome, a rare and severe form of childhood‐onset epilepsy, is often challenging to give to parents. This international study developed guidance and recommendations to help healthcare professionals better structure and personalize this disclosure. By following this advice, doctors can provide more tailored support to families, improving their understanding and management of the condition.

OBJECTIVE Spinal cord cavernous malformations (SCCMs) are rare vascular malformations with a capricious prognosis. Given the eloquent nature of the spinal cord, considerable surgical morbidity may be encountered. Therefore, conservative management has emerged as a valid alternative, especially for incidental lesions diagnosed on ubiquitous imaging. The aim of this systematic review and meta-analysis was to evaluate the safety and efficacy of surgical versus conservative management of SCCMs. METHODS Following PRISMA guidelines, this study included articles published in full-text form comparing the outcomes following conservative and surgical management of SCCMs. Collected variables included the total number of patients, spine level, resection, myelotomy, follow-up duration, bleeding, motor weakness, pain, bladder and/or bowel dysfunction, and neurological improvement or deterioration after discharge. The primary outcome of interest was long-term functional outcome. RESULTS Eleven articles comprising 515 patients were included, of whom 343 (66.6%) underwent resection and 172 (33.4%) were managed conservatively. Patients who underwent surgery were more likely to have preoperative motor deficits, hemorrhagic episodes, and bladder and/or bowel dysfunction, indicating increased disease severity. Resection was associated with significantly improved long-term functional outcomes (OR 3.27, 95% CI 1.72–6.24) compared with conservative management. There was no significant difference between the two groups regarding odds of long-term clinical deterioration (OR 1.03, 95% CI 0.35–3.03). However, the risk of hemorrhagic episodes during follow-up was higher in the conservative group (17.3%) compared with the surgical group (1.69%). The odds of hemorrhage during follow-up were lower in the surgical group, although not statistically significant (OR 0.24, 95% CI 0.05–1.05). CONCLUSIONS This study highlights that while surgical management of SCCMs is associated with better long-term functional outcomes and reduced risk of recurrent hemorrhage, treatment decisions must be carefully tailored to the individual patient, particularly given the potential risks associated with surgery. Conservative management, although less invasive, carries a nonnegligible risk of hemorrhage during follow-up, warranting close monitoring. These findings parallel management strategies used for brainstem cavernomas, for which surgery is reserved for cases with low surgical risk and worsening neurological symptoms. However, the limitations of current data, including selection bias and heterogeneity in reporting, emphasize the need for a multi-institutional registry to better define the natural history of SCCMs and inform future management strategies.

Introduction: Four randomized clinical trials have not demonstrated the superiority of anticoagulation over antiplatelet therapy in the prevention of recurrent embolic stroke of undetermined source (ESUS). In this multicenter observational cohort study, we evaluated long-term outcomes associated with various antithrombotic strategies according to potential embolic sources. Methods: A multicenter retrospective observational cohort of consecutive adult patients with ESUS was queried (n=27 sites). Comparisons were made between patients treated with single or combination antiplatelet therapy versus anticoagulation (direct oral anticoagulant, vitamin K antagonist, low molecular weight heparin) with or without antiplatelet therapy initiated within 7 days of stroke. The primary composite outcome of recurrent stroke, major bleeding, or death was assessed using unadjusted and adjusted Cox proportional hazards regression, with clustering by site. Causal inference was assessed using inverse probability of treatment weighted regression adjustment (IPTWRA), accounting for propensity for antiplatelet treatment, with effect estimates summarized as the average treatment effect (ATE) over time (in days). Adjusted models accounted for age, stroke severity, vascular risk factors, and major categories of potential embolic sources. Results: Of the 2201 included patients (n=218 treated with anticoagulation) followed over a median of 564 days (interquartile range [IQR] 154-1124), the median age was 65y (IQR 54-74) and 49.8% were female. Patients treated with anticoagulation were older with more frequent previous stroke, concomitant left ventricular dysfunction, and more severe deficits. Over 4541 person-years of follow-up, the annualized incidence rate of the primary outcome was 14.6% (95% confidence interval [CI], 13.6%-15.8%). Compared to anticoagulation, antiplatelet(s) use was not associated with a lower risk of the primary outcome in the adjusted Cox model (HR 0.91, 95% CI, 0.64-1.29) or in the IPTWRA model (average treatment effect 0.14, 95% CI, -1376.6 to 1376.9). Major bleeding events trended toward significance in the adjusted Cox model (HR 0.51, 95% CI 0.25-1.04) but were no different with IPTWRA (ATE 58.9, 95% CI, -125.4 to 243.2). Conclusions: These results validate the observations of randomized trials indicating a lack of benefit of anticoagulation over antiplatelet therapy in ESUS. A more detailed analysis of heterogeneity of treatment effect is under way.

142 Background: Fruquintinib (F) is a highly selective, oral tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors (VEGFRs -1, -2, -3) that is approved by the US FDA and in the EU, UK, and Japan for previously treated metastatic colorectal cancer (mCRC), regardless of biomarker status. FRESCO-2 (NCT04322539) met its primary endpoint demonstrating significantly improved overall survival (OS) with F + best supportive care (BSC) vs placebo (P) + BSC. This subgroup analysis assessed landmark survival of all FRESCO-2 patients (pts), and baseline (BL) characteristics and safety data of pts treated with F who had OS ≥10 months (mos) compared with the intent-to-treat (ITT) population (pop). Methods: Pts were randomized 2:1 to receive F 5 mg or matching P, by mouth, once daily, 3 weeks on, 1 week off, + BSC. Pts had received prior chemotherapy, anti-VEGF therapy and, if RAS wild type, anti-EGFR therapy; and had prior exposure to trifluridine/tipiracil (TAS-102) and/or regorafenib. The hazard ratio (HR) between the two treatment arms was calculated from a stratified Cox proportional hazard model with treatment group as the only covariate in the model. Results: In the ITT pop, OS was improved with F vs P (HR 0.66); OS rates (95% confidence intervals [CIs]) at 6 and 9 mos were 60.4% (55.9–64.9) vs 41.5% (35.0–48.0) and 41.1% (36.4–45.8) vs 28.2% (22.1–34.3), respectively. Progression-free survival (PFS) rates (95% CIs) at 6 and 9 mos were 23.8% (19.7–28.0) vs 1.1% (0–2.6) and 11.3% (8.1–14.6) vs 0.5% (0–1.6), respectively. Of 461 pts who received F, 113 (24.5%) had OS ≥10 mos (range 10.0–18.9) with a median duration of F treatment of 6.3 mos (range 0.7–19.1). Among pts receiving F, a higher proportion (≥10% difference) of pts with OS ≥10 mos had no liver metastases (mets) and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 at BL compared with the ITT pop (Table). In pts with OS ≥10 mos, 61.9% experienced a grade ≥3 treatment-emergent adverse event compared with 62.7% in the ITT pop. Conclusions: Longer-term OS and PFS rates at 6 and 9 mos were higher with F vs P in the FRESCO-2 ITT pop. The data show a higher proportion of pts with OS ≥10 mos had an absence of liver mets and ECOG PS 0 at BL than the ITT pop. The safety profile of F in pts with OS ≥10 mos was consistent with the ITT pop. Clinical trial information: NCT04322539 . BL characteristics of pts treated with F with OS ≥10 mos vs ITT pop. BL characteristic Pts with OS ≥10 mos (n=113) ITT pop(n=461) ECOG PS (0 / 1), % 54.0 / 46.0 42.5 / 57.5 Median time since 1 st CRC diagnosis, mos 52.0 47.2 Primary tumor location at 1 st diagnosis (colon / rectum / both), % 51.3 / 35.4 / 13.3 60.5 / 31.0 / 8.5 Primary site at 1 st diagnosis (colon left / colon right), % 42.5 / 15.9 41.6 / 21.0 Liver mets, % 58.4 73.5 Median duration of mCRC, mos 42.7 37.9 Prior lines of therapy for mCRC (≤3 / >3), % 26.5 / 73.5 27.1 / 72.9 Prior TAS-102, % 46.9 52.1 Prior regorafenib, % 12.4 8.7

Importance Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

Abstract Background Long-term use of corticosteroids (CS) is a concern for patients with Crohn’s disease (CD), as prolonged use is associated with increased mortality and adverse outcomes. Upadacitinib (UPA), an oral, selective, reversible Janus kinase inhibitor, is approved for the treatment of moderate-to-severe CD and demonstrated CS-sparing efficacy, with a consistent safety profile through maintenance week (wk) 52.1-4 Here, we evaluated the long-term efficacy of UPA in achieving CS-free clinical and endoscopic outcomes in patients enrolled in the ongoing U-ENDURE long-term extension (LTE) study. Methods Patients who completed the U-ENDURE 52-wk maintenance study were eligible for the subsequent LTE study wherein they continued their previously assigned treatment (once daily UPA 15 mg [UPA15] or UPA 30 mg [UPA30]). Efficacy was assessed from LTE wk 0-wk48, among patients with 2 year (yr) (100 wk) of total maintenance therapy, within the overall population and in patients with baseline CS use (induction wk 0). CS-free endpoints (without CS use for ≥90 days before evaluation), included clinical remission (per stool frequency/abdominal pain score [SF/APS] and CD Activity Index [CDAI]), endoscopic response, and endoscopic remission, were evaluated using both as-observed and nonresponder imputation (NRI) methods, with NRI analysis presented in text. Safety was not evaluated here but was reported previously.3 Results Among patients with 2 yr of total maintenance therapy, 35.7% (87/244) received CS at baseline, with 13.1% (32/244) receiving CS at any time during the LTE study regardless of baseline CS use. Among patients taking baseline CS and those who received CS at any time during the LTE study (n=20), the median (range) time of CS use was 127.5 (2-1589) days. CS-free clinical remission was achieved at LTE wk 0 and wk 48 per SF/APS (overall population: UPA15, 71.7%, 58.9%; UPA30, 81.8%, 57.7%; patients with baseline CS use: UPA15, 71.8%, 53.8%; UPA30, 79.2%, 54.2%, NRI, Fig.1A-B) and CDAI criteria (overall population: UPA15, 74.8%, 60.7%; UPA30, 83.9%, 65.0%; patients with baseline CS use: UPA15, 74.4%, 56.4%; UPA30, 81.3%, 58.3%, NRI, Fig.1C-D). At LTE wk 48, a high fraction of UPA-treated patients achieved CS-free endoscopic response (overall population: UPA15, 48.6%; UPA30, 55.5%; patients with baseline CS use: UPA15, 38.5%; UPA30, 60.4%, NRI) and CS-free endoscopic remission (overall population: UPA15, 33.6%; UPA30, 46.0%; patients with baseline CS use: UPA15, 28.2%; UPA30, 54.2%, NRI, Fig.2). Conclusion Patients with moderate-to-severe CD who received long-term UPA maintenance treatment sustained high rates of CS-free clinical and endoscopic outcomes, suggesting that UPA may serve as an effective long-term CS-sparing therapy. References 1.RINVOQ [package insert], extended-release tablets, FDA Prescribing Information. AbbVie Inc; 2022. Accessed 1 June 2022.2. 2.RINVOQ [package insert], prolonged-release tablets. EMA Summary of Product Characteristics. AbbVie; 2022. Accessed 1 June 2022. 3.Loftus EV and Panes J et al. N Engl J Med 2023;388:1966-1980. J 4.M C Dubinsky, et al. JCC, 17; (Supp_1); 2023: i104–i106.

Abstract Background Tumor necrosis factor-like ligand 1A (TL1A) is upregulated in inflammatory bowel disease and believed to promote inflammation and intestinal fibrosis. RO7790121, an anti-TL1A antibody, showed promising results in the phase IIa TUSCANY trial.1 Here we report post-hoc analyses of patient-reported outcomes from the TUSCANY-2 trial. Methods This phase IIb, multicenter, randomized, double-blind, treat-through, dose-ranging study evaluated RO7790121 in patients (pts) aged 18–75 years with moderately to severely active ulcerative colitis (UC) (total Mayo score [MS] ≥6, endoscopic subscore ≥2). Pts were randomized to receive subcutaneous (SC) RO7790121 50mg, 150mg, 450mg or matched placebo (PBO) monthly during the 12-week induction period, and SC RO7790121 50mg, 150mg or 450mg monthly during the 40-week treat-through maintenance period. To assess efficacy of RO7790121 in supporting pts achieving early symptomatic improvement, rectal bleeding (RB), stool frequency (SF) and partial modified MS (RB+SF) were evaluated at baseline and Weeks 2, 4, 8, 12 and 14. The exploratory endpoint of symptomatic remission, defined as a RB subscore of 0 and a SF subscore of 0 or 1, was assessed throughout induction. Safety was assessed throughout the study. Results Overall, 245 pts received ≥1 dose of RO7790121 or PBO. At Week 2, pts receiving RO7790121 were more likely to report a RB subscore of 0 (34% RO7790121; 20% PBO) and less likely to report a RB subscore of 2 or 3 (25% RO7790121; 40% PBO) (Figure). Improvements in SF increased from Week 2 and throughout induction, with ~60% of pts receiving RO7790121 reporting a SF subscore of 0 or 1 at Weeks 12 and 14, vs ~40% for PBO. Greater rates of symptomatic remission were observed in pts receiving RO7790121 vs PBO throughout induction and from Week 2 (17.5% RO7790121; 8.9% PBO) (Table). Treatment-emergent adverse events (TEAEs) were reported during induction in 117/245 pts, the most common (reported in ≥5% of pts in any treatment group) were nausea, urinary tract infection and UC (highest in the 50mg arm), anemia (highest in the placebo arm) and fatigue, headache and pyrexia (highest in the 450mg arm). Serious TEAEs were reported in ten pts during induction (PBO=4; 50mg=3; 450mg=3); two were treatment related (PBO=1; 450mg=1). There were six treatment discontinuations due to TEAEs and a generally similar safety profile was observed during the maintenance period. Conclusion Greater and earlier improvements in RB and SF were observed in pts receiving RO7790121 vs PBO. These results indicate early symptom relief and a favorable safety profile for pts treated with RO7790121, supporting its further clinical development. RO7790121 is currently being evaluated in phase III studies (NCT06589986 and NCT06588855). References 1.Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A antibody PF-06480605 safety and efficacy for ulcerative colitis: A phase 2a single-arm study. Clin GastroenterolHepatol. 2021;19(11):2324-2332.e6. http://doi.org/10.1016/j.cgh.2021.06.011