Citations

AbstractCorrectly diagnosing and classifying seizures and epilepsies is paramount to ensure the delivery of optimal care to patients with epilepsy. Focal seizures, defined as those that originate within networks limited to one hemisphere, are primarily subdivided into focal aware, focal impaired awareness, and focal to bilateral tonic–clonic seizures. Focal epilepsies account for most epilepsy cases both in children and adults. In children, focal epilepsies are typically subdivided in three groups: self‐limited focal epilepsy syndromes (e.g., self‐limited epilepsy with centrotemporal spikes), focal epilepsy of unknown cause but which do not meet criteria for a self‐limited focal epilepsy syndrome, and focal epilepsy of known cause (e.g., structural lesions—developmental or acquired). In adults, focal epilepsies are often acquired and may be caused by a structural lesion such as stroke, infection and traumatic brain injury, or brain tumors, vascular malformations, metabolic disorders, autoimmune, and/or genetic causes. In addition to seizure semiology, neuroimaging, neurophysiology, and neuropathology constitute the cornerstones of a diagnostic evaluation. Patients with focal epilepsy who become drug‐resistant should promptly undergo assessment in an epilepsy center. After excluding pseudo‐resistance, these patients should be considered for presurgical evaluation as a means to identify the location and extent of the epileptogenic zone and assess their candidacy for a surgical procedure. The goal of this seminar in epileptology is to summarize clinically relevant information concerning focal epilepsies. This contributes to the ILAE's mission to ensure that worldwide healthcare professionals, patients, and caregivers continue to have access to high‐quality educational resources concerning epilepsy.

Importance Physical abuse is a common but preventable cause of long-term childhood morbidity and mortality. Despite the strong association between abuse in an index child and abuse in contact children, there is no guidance outlining how to screen the latter, significantly more vulnerable group, for abusive injuries. Consequently, the radiological assessment of contact children is often omitted, or variably performed, allowing occult injuries to go undetected and increasing the risk of further abuse. Objective To report an evidence-based and consensus-derived set of best practices for the radiological screening of contact children in the context of suspected child physical abuse. Evidence Review This consensus statement is supported by a systematic review of the literature and the clinical opinion of an internationally recognized group of 26 experts. The modified Delphi consensus process comprised 3 meetings of the International Consensus Group on Contact Screening in Suspected Child Physical Abuse held between February and June 2021. Findings Contacts are defined as the asymptomatic siblings, cohabiting children, or children under the same care as an index child with suspected child physical abuse. All contact children should undergo a thorough physical examination and a history elicited prior to imaging. Contact children younger than 12 months should have neuroimaging, the preferred modality for which is magnetic resonance imaging, and skeletal survey. Contact children aged 12 to 24 months should undergo skeletal survey. No routine imaging is indicated in asymptomatic children older than 24 months. Follow-up skeletal survey with limited views should be performed if abnormal or equivocal at presentation. Contacts with positive findings should be investigated as an index child. Conclusions and Relevance This Special Communication reports consensus recommendations for the radiological screening of contact children in the context of suspected child physical abuse, establishing a recognized baseline for the stringent evaluation of these at-risk children and providing clinicians with a more resilient platform from which to advocate for them.

Background Lead performance is suboptimal in young patients and a main cause of device system failure. Our objective was to assess early and midterm outcomes after epicardial device implantation in a contemporary pediatric cohort. Methods A total of 116 consecutive pediatric patients underwent 137 epicardial device implantations from 2010 to 2019. Forty pacemakers and 97 implantable cardioverter defibrillators (ICDs) were implanted. Lead failure was defined as leads repaired, replaced, or abandoned due to fracture, dislodgement, or dysfunction. Freedom from device system failure was determined using Kaplan-Meier analysis. Results Mean age at implantation was 10 ± 5 years, 46 (34%) were younger than 8 years old, 41 (30%) had prior cardiac surgery, and 38 (28%) had prior devices. Main indications were acquired heart block (17/40 [43%]), sinus node dysfunction (14/40 [35%]), and congenital heart block (7/40 [18%]) for pacemakers, and hypertrophic cardiomyopathy (46/97 [47%]), long QT syndrome (31/97 [32%]), and ventricular arrhythmia (17/97 [18%]) for ICDs. There were no early deaths. Three-year freedom from device system failure was 80% (95% CI 73%, 88%) for all patients and 88% (95% CI 79%, 99%) for patients <8 years old. Device system failure causes included lead fracture (20/34 [59%]), lead dysfunction (5/34 [15%]), lead dislodgement (5/34 [15%]), infection (3/34 [9%]), and pericarditis (1/34 [3%]). Reintervention was required in 26/34 (76%) device system failures. Conclusions Epicardial device implantation is safe, shows acceptable midterm outcomes in children, and is an effective option in patients younger than 8 years old. Close device surveillance continues to be essential to detect lead failure early and ensure timely reintervention.

Abstract Introduction: Use of long-term endocrine therapy (ET) for ER+ breast cancer often leads to acquired ESR1 mutations (mutESR1), causing endocrine resistance, tumor progression, and poor prognosis. An unmet clinical need exists for treating ER+ mBC patients with mutESR1, particularly after progression on CDK4/6 inhibitors (CDK4/6i). ELAINE 2 is an open-label, phase 2, multicenter trial evaluating safety and efficacy of lasofoxifene (LAS [selective estrogen receptor modulator]) plus abemaciclib (Abema [CDK4/6i], provided by Eli Lilly) in patients with ER+/HER2- and mutESR1 mBC who progressed after prior ET. Preliminary data with LAS plus Abema showed median progression-free survival of 55.7 wks, objective response rate of 50%, and 24-wk clinical benefit (CB) rate of 69%, with an acceptable safety and tolerability profile. Here, we report ESR1 ctDNA mutant allele frequency (MAF) and correlations of ESR1 MAF changes with CB. Methods: ELAINE 2 patients with detectable ctDNA mutESR1 at baseline (BL) were analyzed. Oral LAS 5 mg/day and Abema 150 mg BID were taken until disease progression, death, unacceptable toxicity, or withdrawal from the study. ctDNA was assessed by the Sysmex-Inostics SafeSeq assay—which detects mutESR1 at low allele fractions—at BL, every 4 wks, and end of treatment. MAF changes from BL to wk 4 were characterized as decreased (decrease in ESR1 MAF or none detected [ND]), increased (increase in MAF), or equivocal (in polyclonal patients [&gt;1 mutESR1] with some MAF increasing and decreasing trends). Correlations of MAF change at 4 wks with CB at 24 wks were explored. Results: 29 patients (median of 2 prior metastatic therapies: 97% CDK4/6i, 79% fulvestrant, 48% chemotherapy) had BL mutESR1 of Y537S (66%), D538G (45%), Y537N (28%), and other less frequently detected mutations; 14 (48.3%) patients were polyclonal. 26 of 29 patients had evaluable BL and wk-4 ctDNA results: 21 patients had decreased MAF (81% [54% with ND]), 3 (12%) had increased, and 2 (8%) had equivocal ESR1 MAF changes (Table). CB at 24 wks was seen in 17 patients with a decrease, 2 with an increase, and 1 with equivocal MAF change. A sensitivity of 89.5% and specificity of 20% were calculated for predicting CB based on direction of ESR1 MAF change. The positive predictive value (PPV) for CB with decreased MAF was 81% and the negative predictive value (NPV) for an increased MAF was 33%. Of the 14 (54%) patients with ND ESR1 MAF, 13 had CB resulting in 87% sensitivity, 50% specificity, 93% PPV, and 33% NPV. Conclusion: In ELAINE 2, 81% of patients had decrease/cleared (ND) mutESR1 after 4 wks of LAS plus Abema, which correlated with clinical benefit. All mutESR1 detected appear targeted with this therapy. High sensitivity and favorable PPV were observed in patients with decreased MAF, and even more so in those with ND MAF; however, increased MAF was less specific and not as predictive of treatment failure. Our results indicate that ESR1 liquid biopsy evaluation may be an adequate non-invasive surrogate marker for monitoring patients on treatment. Further study in a larger population of women with endocrine-resistant mBC and acquired mutESR1 is warranted to explore this potential for monitoring treatment response or resistance to this novel LAS-Abema combination. Table. Change from baseline to week 4 in ESR1 MAF and clinical benefit at 24 weeks. CI, confidence interval; MAF, mutant allele fraction; ND, none detected; NPV, negative predictive value; PPV, positive predictive value. *Sensitivity and specificity analyses do not include equivocal results. Citation Format: Senthil Damodaran, Halle Moore, Ciara C. O’Sullivan, Paul V. Plourde, Gary Riordan, Hillary S. Sloane, Debu Tripathy, Dominic Carroll, David J Portman. Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA) from patients with ER+/HER2- metastatic breast cancer (mBC) treated with lasofoxifene plus abemaciclib in the ELAINE 2 study [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 P5-05-02.

Abstract Introduction: Acquired ESR1 mutations (mutESR1) after long-term endocrine therapy drive treatment resistance, metastasis, and poor prognosis for patients (pts) with ER+/HER2- metastatic breast cancer (mBC). Lasofoxifene (LAS), a selective estrogen receptor modulator, alone or with a CDK4/6 inhibitor (CDK4/6i) reduced tumor growth better than fulvestrant (Fulv) in mutESR1 BC xenograft models. ELAINE 1 is a randomized trial of LAS vs Fulv in pts with mutESR1 and prior progression on aromatase inhibitor and CDK4/6i. Preliminary results (ESMO 2022) showed that LAS prolonged median progression-free survival (mPFS) compared with Fulv with a favorable safety profile. Here, we report changes in ESR1 ctDNA mutant allele frequency (MAF) from baseline to 8 wks and their associations with clinical benefit (CB) and mPFS. Methods: ELAINE 1 pts were randomized to oral LAS 5 mg daily or IM Fulv 500 mg on days 1, 15, and 29, then every 4 wks, until disease progression or severe toxicity. ctDNA mutESR1 mutations (baseline and 8 wks) were assessed using the Sysmex Inostics OncoBeam or SafeSeq assays—which detect mutESR1 at low allele fractions. MAF changes from baseline to wk 8 were characterized as decreased (decrease in ESR1 MAF or fully cleared), increased (increase in MAF), or equivocal (polyclonal patients [&gt;1 mutESR1] with some increasing and decreasing MAF trends); correlations with PFS and CB were explored. Efficacy measures included objective response rate (ORR), PFS, and CB at 24 wks (CB defined as response or stable disease ≥24 wks). Results: 103 pts received LAS (n=52) or Fulv (n=51). Most common baseline ESR1 variants detected were D538G (56%), Y537S (39%), Y537N (29%), E380Q (22%); 56 (54%) pts were polyclonal. Of the 61 pts with evaluable baseline and wk 8 ctDNA, LAS decreased mutESR1 MAF in 29/35 pts (83% [11 complete clearance]) while Fulv decreased mutESR1 MAF in 16/26 pts (61.5% [6 complete clearance]) (Table). mPFS with LAS was 8 and 4 mos for pts with decreased/cleared MAF and increased MAF, respectively, and with Fulv was 4.5 and 2.8 mos, respectively (Table). LAS decreased the common mutESR1 variants more frequently than Fulv (median relative change -87.1% vs -14.7%). In pts with decreased MAF, CB was observed in 16/29 LAS pts (55%) and 4/16 Fulv pts (25%). The predictiveness of ESR1 MAF clearance for CB was also explored. Of 11 pts with ESR1 MAF clearance taking LAS, 10 achieved CB, yielding a positive predictive value (PPV) of 90.9%. In contrast, 2/6 pts with ESR1 MAF clearance taking Fulv had CB for a PPV of 33.3%. Sensitivity for predicting CB based on direction of ESR1 MAF change was 94% with LAS and 80% with Fulv. In pts with Y537S MAF (n=33), LAS decreased Y537S in 13/15 (87%), with a median relative MAF decrease of 89%. In marked contrast, Fulv increased Y537S MAF in 11/18 pts (61%), corresponding to an MAF relative increase of 82%. LAS and Fulv resulted in complete clearance of Y537S MAF in 33% and 6% of pts, respectively. Conclusion: Our data demonstrate that LAS more effectively decreased or cleared mutESR1 than Fulv. Further, mutESR1 clearance was associated with prolonged PFS and more CB in LAS but not Fulv pts, suggesting that LAS results in robust mutESR1 target engagement. Taken together, our data suggest mutESR1 as a potential liquid biomarker for predicting response to LAS in mutESR1, endocrine-resistant mBC pts. Table. Change from baseline to week 8 in ESR1 MAF and clinical benefit at 24 weeks. CI, confidence interval; MAF, mutant allele fraction; ND, none detected; PFS, progression-free survival. Citation Format: Matthew P. Goetz, Einav Gal-Yam, Daniel Stover, Sarah L. Sammons, Stephanie L. Graff, Grace Wang, Massimo Cristofanilli, Gary Riordan, Hillary S. Sloane, Dominic Carroll, Paul V. Plourde, David J Portman. Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA) from patients with ER+/HER2- metastatic breast cancer (mBC) treated with lasofoxifene or fulvestrant in the ELAINE 1 study [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 P5-05-04.

A biliary stricture is an abnormal narrowing in the ductal drainage system of the liver that can result in clinically and physiologically relevant obstruction to the flow of bile. The most common and ominous etiology is malignancy, underscoring the importance of a high index of suspicion in the evaluation of this condition. The goals of care in patients with a biliary stricture are confirming or excluding malignancy (diagnosis) and reestablishing flow of bile to the duodenum (drainage); the approach to diagnosis and drainage varies according to anatomic location (extrahepatic vs perihilar). For extrahepatic strictures, endoscopic ultrasound-guided tissue acquisition is highly accurate and has become the diagnostic mainstay. In contrast, the diagnosis of perihilar strictures remains a challenge. Similarly, the drainage of extrahepatic strictures tends to be more straightforward and safer and less controversial than that of perihilar strictures. Recent evidence has provided some clarity in multiple important areas pertaining to biliary strictures, whereas several remaining controversies require additional research. The goal of this guideline is to provide practicing clinicians with the most evidence-based guidance on the approach to patients with extrahepatic and perihilar strictures, focusing on diagnosis and drainage.

Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.