Faculty Bibliography

Classic Hodgkin lymphoma (cHL) associated with Epstein-Barr virus (EBV) positivity as well as non-nodular sclerosis (non-NS) histologic subtypes have demonstrated poorer outcomes compared to EBV-negative and nodular sclerosis cases. We report a prespecified subset analysis of patients enrolled in the phase III SWOG S1826 trial to evaluate outcomes based on EBV status and histologic subtype in patients treated with nivolumab-AVD (N-AVD) or brentuximab vedotin (BV)-AVD. In the phase III SWOG S1826 trial, patients with stage III-IV cHL were randomized to N-AVD or BV-AVD. Of 970 eligible patients, 522 had known EBV status. N-AVD improved 3-year progression-free survival (PFS) in EBV-positive (91% v 70%; HR, 0.30; P = 0.01) and EBV-negative patients (90% v 84%; HR, 0.64; P = 0.09). Among 664 patients with slides available for histology review, 102 (15.4%) had non-NS subtypes. N-AVD prolonged 3-year PFS in patients with non-NS (86% v 63%; HR, 0.33; P = 0.006) and NS histologic subtype (93% v 86%; HR, 0.53; P = 0.01). Non-NS histology independently was associated with inferior outcomes (HR, 2.54; P < 0.0001) after adjusting for treatment in the entire cohort. However, N-AVD treatment still had favorable PFS within this high-risk group. In addition, patients with EBV positivity or non-NS histology cHL treated with BV-AVD had significantly worse PFS (HR, 1.97; P = 0.03 for EBV; and HR, 3.08; P < 0.0001 for histology). N-AVD substantially abrogated the historically poor prognosis associated with EBV positivity and non-NS histology in advanced-stage cHL. These results support N-AVD as frontline standard of care, particularly in high-risk biologic subgroups. (NCT03907488).

STUDY DESIGN/METHODS:Retrospective cohort study. OBJECTIVES/OBJECTIVE:This study aimed to determine whether substance abuse among adolescent idiopathic scoliosis (AIS) patients is associated with increased odds of subsequent new-onset mental health disease (MHD). SUMMARY OF BACKGROUND DATA/BACKGROUND:MHD prevalence in patients with a substance abuse history has been well-described. However, the impact of current or historical substance abuse/dependence in AIS patients on the risk of subsequent development of new-onset MHDs is unknown. METHODS:The New York SPARCS database was reviewed to identify all 10-25-year-old AIS patients and stratified by prior or concurrent substance abuse (AIS-Sub) versus no history of substance abuse (AIS-NoSub). Cohorts were 1:1 propensity score-matched, and various comparisons were made, including incidence of subsequent MHDs. Binary stepwise logistic regressions were utilized to calculate odds ratios (OR) of developing any MHDs based on baseline substance abuse. RESULTS:386 AIS patients were included (193 AIS-Sub and 193 AIS-NoSub). At baseline, there were no significant differences between patient cohorts in demographic factors. AIS-Sub patients had higher rates of new-onset subsequent overall MHDs (16.1% vs. 3.6%, P<0.001), with only depressive disorder showing a significantly higher incidence when examining individual MHDs (10.9% vs. 0.5%, P<0.001). Logistic regression analyses revealed that baseline substance abuse was independently associated with subsequent diagnosis of either any MHD (OR=6.8, 95% CI: 2.6-17.3, P=0.001), or new-onset depressive disorder (OR=47.0, 95% CI: 3.9-568.7, P=0.002); but was not associated with the development of anxiety, stress, sleep, or eating disorders. CONCLUSIONS:AIS patients with prior or current substance abuse/dependence were at increased 2-year risk of developing any new-onset MHD, specifically depressive disorders. This data may guide preoperative screening and optimization efforts for surgeons, as MHDs have been associated with poor outcomes following spine surgery. LEVEL OF EVIDENCE/METHODS:Level III-retrospective cohort study.

BACKGROUND/UNASSIGNED:Re-recurrent rectal cancer (RRRC) represents a highly complex disease following curative-intent treatment of recurrent rectal cancer (RRC). While management principles for primary and locally recurrent rectal cancer (RRC) have been defined by expert collaborations, no specific guidelines currently outline the perioperative management of RRRC. This systematic review aimed to appraise the reported perioperative strategies and oncological outcomes of patients undergoing curative-intent treatment for RRRC. METHODS/UNASSIGNED:Eligibility criteria, Studies reporting perioperative management and outcomes of adult patients undergoing curative-intent treatment for RRRC were included. Non-English articles, letters, abstracts, and studies lacking surgical or oncological data were excluded. Information sources, The review was conducted according to PRISMA guidelines and registered in PROSPERO (CRD420251244390). MEDLINE (PubMed), Cochrane Library, Web of Science, and Scopus were searched for relevant articles. Risk of bias, Methodological quality was assessed using the Newcastle-Ottawa Scale for cohort studies. Synthesis of results, Given heterogeneity in treatment strategies and outcome reporting, results were synthesized narratively. RESULTS/UNASSIGNED:Included studies, Three retrospective cohort studies comprising 169 patients treated with curative intent surgery for RRRC were included. Synthesis of results, Neoadjuvant therapy was administered in 20-92% of included patients, depending on the previous cumulative radiation dose. Pelvic exenteration was frequently required, with total exenteration performed in 6-20% and sacrectomy in up to 15% of cases; reconstructive procedures were reported in less than 16%. IORT was used in 44-77% of patients in centers where it was available. R0 resection rates ranged from 33% to 62%, with oncological outcomes directly associated with margin status. DISCUSSION/UNASSIGNED:Limitations of evidence, Evidence was limited to retrospective observational studies with small sample sizes, heterogeneous management, and varied institutional resources, precluding meta-analysis. Interpretation, Curative-intent surgery for RRRC is feasible in highly selected patients, with R0 being the principal prognostic determinant of oncological outcome. However, significant variability in perioperative pathways, margin definition, MRI-based classification, and reconstructive strategies underlines the necessity for the development of standardized, consensus-based recommendations to optimize multidisciplinary treatment. SYSTEMATIC REVIEW REGISTRATION/UNASSIGNED:https://www.crd.york.ac.uk/PROSPERO/view/CRD420251244390, identifier CRD420251244390.

BackgroundManagement of moderate-to-large (1-2.9 cm²) osteochondral lesions of the talus (OLT) remains challenging due to the transition from reparative to replacement surgical strategies and the absence of high-level comparative evidence guiding treatment selection.MethodsAn international panel of experts participated in a modified Delphi consensus process during the International Congress on Cartilage Repair of the Ankle (ICCRA) meetings held in 2017 and 2025. Survey rounds and structured discussions were used to generate and refine consensus statements. Consensus strength was categorized as consensus (51%-74%), strong consensus (75%-99%), or unanimous (100%), and levels of evidence were graded according to established criteria.ResultsConsensus statements were developed for autologous osteochondral transplantation (AOT), osteochondral allograft transplantation (OCA), scaffold-based cartilage restoration techniques, and emerging extracellular matrix and juvenile cartilage allograft strategies. Autologous osteochondral transplantation was supported as a primary treatment option for cystic, uncontained, and revision lesions, with emphasis on graft continuity and appropriate depth. Osteochondral allograft transplantation was recommended for larger or uncontained lesions and in cases where autograft is contraindicated, with preference for fresh, size-matched grafts used within 28 days. Scaffold-based techniques were identified as viable alternatives in select primary and revision settings, although not superior to AOT for larger lesions. Extracellular matrix cartilage allograft (ECMA) and particulate juvenile cartilage allograft transplantation (PJCAT) potentially enhance cartilage restoration.ConclusionThe ICCRA consensus provides a structured, evidence-informed framework for the surgical management of moderate-to-large OLT. Although multiple treatment strategies demonstrate clinical utility, the current literature remains heterogeneous with limited high-level evidence. Further prospective and comparative studies are warranted to better define optimal indications and long-term outcomes for each approach.Level of Evidence:V, Expert consensus.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality. While for Stage IA LUAD surgery is often curative, recurrence rates remain significant. Liquid biopsy enables monitoring residual disease and predicts recurrence, however utility in Stage IA LUAD is not well-established. Tumor-informed whole genome sequencing (WGS) represents a highly sensitive liquid biopsy method for the analysis of circulating-tumor cell-free DNA (ctDNA) without designing and maintaining patient-specific probes. We aimed to determine the prognostic value of genome-wide tumor-informed minimal residual disease (MRD) monitoring in Stage IA NSCLC using WGS of ctDNA. WGS was performed on 42 patients with Stage IA NSCLC. Tumor was sequenced at 40x and germline DNA and plasma derived ctDNA at 20x and patient specific mutational signatures were developed from the tumor-normal comparison and applied to ctDNA WGS at each time point using AI-supported pattern recognition algorithm. ctDNA results were compared with clinical recurrence. WGS ctDNA was able to predict recurrence with 0.75 sensitivity and 0.83 specificity, with median 16.7 months lead time compared to clinical or imaging recurrence. ctDNA WGS was able to distinguish between a second primary and recurrence in histologically or clinically challenging cases. Whole genome sequencing of ctDNA can predict recurrence in the earliest clinical stage of NSCLC, identifying patients who will recur, and providing information to help guide radiological follow-up and adjuvant therapy.

State sequence analysis of longitudinal categorical data seeks to synthesize pathways through different dimensions of the life course for descriptive, associative and predictive purposes. Given the number and variety of patterns in such data, measures of the dynamic features of sequences are used to characterize them. One, based on the information-theoretic notion of entropy, measures the uncertainty in the state that will be active at a given time. We customize its use to establish the extent to which we are ignorant, or unsure, of what happens next in a dynamic process, conditional on its past. Relying on different Markov chain models for nominal state sequences, we establish multiple measures of uncertainty that allow us to adjust expectations to reflect individual-specific differences and historical information. We establish complementary measures to assess the predictive power of the models in the context of this uncertainty. In so doing, we can summarize and contrast the change in uncertainty associated with different models. As is common in this field, we consider ways in which data can be stratified through demographics and clustering, and how this additional level of partitioning builds a more complete narrative of the social process.

INTRODUCTION/BACKGROUND:Meal-related symptoms are commonly identified in disorders of gut-brain interaction (DGBIs). Gastroduodenal low-grade inflammation involving mucosal eosinophils and/or mast cells has been previously described in patients with DGBIs. In children with DGBIs, we sought to determine potential relationships between gastric and duodenal mucosal eosinophils and mast cells with specific meal-related and non-GI somatic symptoms. METHODS:Two hundred eight youth with AP-DGBI were evaluated. All patients underwent esophagogastroduodenoscopy (EGD) with biopsies taken from the gastric antrum and duodenum. Patients completed symptom and BASC-3 questionnaires to evaluate somatization and the presence of specific meal-related and non-GI somatic symptoms. A single observer blinded to clinical data reported maximum density of eosinophils and mast cells. KEY RESULTS/RESULTS:Mucosal eosinophil and mast cell counts did not differ between FD and IBS nor between FD subtypes. After correction for multiple comparisons, there were no associations between eosinophil or mast cell counts with meal-related symptoms. In contrast, duodenal mast cells were positively associated with headaches, dizziness, fatigue, and rhinitis, with predominantly medium effect sizes. CONCLUSIONS AND INFERENCES/CONCLUSIONS:Meal-related symptoms are common in youth with DGBIs, but do not appear to be associated with mucosal eosinophils and mast cell counts. The positive associations of duodenal mast cells with non-GI somatic complaints suggest future studies should determine whether treatments targeting mast cells are beneficial for ameliorating these symptoms in youth with DGBIs.

Mechanical thrombectomy (MT) is superior to medical therapy for anterior circulation proximal large-vessel occlusion (LVO) stroke, including in imaging-selected patients treated 6 to 24 h after their last known well (LKW) time. Beyond 4.5 h, the role of intravenous thrombolysis (IVT) has become more relevant because many health systems lack the ability to provide timely thrombectomy access for eligible late-window patients. Recent late-window IVT trials, including TRACE-III and HOPE, have demonstrated benefit in imaging-selected patients in whom thrombectomy was not planned or not effectively deliverable, addressing a critical systems-of-care gap. We review these trials alongside emerging evidence and situate each within a systems-of-care framework, distinguishing bridging scenarios from settings where MT is unavailable or substantially delayed. However, we argue that their results should not be taken to imply therapeutic equivalence with MT, a comparison that is misleading on methodological grounds. No randomized, head-to-head late-window trial of IVT versus MT exists. Comparing treated-arm outcomes across these separate trials as a proxy for therapeutic equivalence is vulnerable to differences in baseline prognosis, occlusion site, imaging selection, access to rescue therapy, and control-group outcomes. In this Perspective, we argue that these trials should be read one at a time. Each treated arm should be judged against its own control group and against the clinical and angiographic profile of the patients enrolled, not against treated arms from trials that enrolled very different strokes.

Animals can initiate movements either in response to external cues or from internal drive, yet how the brain flexibly supports both remains unclear. Disorders such as Parkinson's disease disrupt these modes differently, suggesting distinct underlying mechanisms. These differences could arise from specialized circuits or from shared neuronal populations that shift their dynamics across contexts. To distinguish between these possibilities, we performed two-photon calcium imaging in the dorsolateral striatum as mice executed the same lever press either spontaneously or in response to a cue. Unsupervised clustering identified neurons modulated during cue, movement, or postaction periods. Critically, the same neurons encoded movement across initiation contexts, but their population dynamics diverged before movement. Both D1- and D2-expressing spiny projection neurons contributed to these dynamics, with D1-SPNs more active at the time of the sensory stimulus. These results show that context shapes neural dynamics within a shared movement-encoding population, revealing a context-generalizable striatal code that supports flexible movement initiation across internal and external drives.