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Dissecting discrepancies in head and neck margin assessment: frozen versus permanent sections
No full textConcordance between intraoperative frozen section (FS) and subsequent corresponding permanent section (PS) diagnoses is essential for quality patient care. Reported FS-PS discrepancy rates for head and neck (HN) cases average 3% to 4%, mostly due to inadequate sampling and interpretation errors. We sought to review our experience with FS and concordant PS from HN pathology cases diagnosed at a high-volume university medical center.
A concordance review was performed for intraoperative FS and corresponding PS of HN surgical pathology cases over a 3-year period. A focused analysis was performed on FS-PS discordances related to margin status (MS) control. The FS-PS discrepancies were classified as due to "sampling" or "interpretation."
In total, 2337 HN cases yielded 11 108 intraoperative FS diagnoses. The FS-PS concordance review identified 143 (1.29%) discrepancies. Of these, 82 (57.4%) were for MS control, with just over half due to "sampling." The FS slides generally represented a single top section taken from the tissue, with "sampling" discrepancies due to discordant diagnoses identified on a deeper cut of tissue on the PS slides. Common "interpretation" discrepancies included overlooking high-grade squamous dysplasia (HGD) present on the FS.
Our institutional intraoperative FS-PS discrepancy rate for HN pathology cases is 1.29% and well within the national quality standards. Our FS-PS discrepancy rate for HN cases related to MS control was mostly due to "sampling." Interpretation discordances included failure to report HGD on the FS slide. Based on our review, the FS-PS discrepancies for MS control did not have a major clinical impact on most patients
Causal machine learning reveals age-dependent radiation dose effects on mandibular osteoradionecrosis
No full textDistinguishing causal relationships from statistical correlations remains a fundamental challenge in clinical research, limiting the translation of observational findings into interventional treatment guidelines. Here we apply causal machine learning to establish causal effects of radiation dose parameters on mandibular osteoradionecrosis (ORN) in 931 head and neck cancer patients treated with volumetric-modulated arc therapy. Using generalized random forests, we demonstrate that all examined dosimetric factors exhibit significant positive causal effects on ORN development (average treatment effects: 0.092-0.141). Integration with explainable machine learning reveals substantial treatment effect heterogeneity, with patients aged 50-60 years showing the strongest causal dose-response relationships (conditional average treatment effects up to 0.229), while patients over 70 years demonstrate minimal effects. These results suggest that age-stratified treatment optimization and personalized treatment planning for the dosimetric factors could reduce ORN risk. Our findings demonstrate that causal inference methods can transform clinical retrospective radiotherapy data into personalized treatment recommendations, providing a methodological framework applicable to toxicity prediction across oncology and other clinical domains where treatment decisions depend on complex dose-response relationships
Magnetic Field-Guided Magnetic Nanoparticles as Neurotherapeutics for Neurological Disorders and Glioblastoma
No full textNeurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke, are among the most devastating neurological disorders worldwide. Glioblastoma (GBM) is a rapidly growing cancer that originates in astrocytes in the brain. It invades and damages the nervous system. Current treatment options remain limited, primarily due to poor blood–brain barrier penetration, lack of targeted delivery, and limited efficacy in slowing disease progression or promoting functional recovery. In recent years, magnetic fields (MFs) have emerged as a promising therapeutic approach, with mechanisms of action that include direct neuromodulation and the guidance of magnetically responsive nanocarriers to the lesion. Magnetic nanoparticles (MNPs), owing to their unique magnetic properties, biocompatibility, and responsiveness to external MFs, have emerged as promising therapeutic agents for the treatment of neurological diseases and glioblastoma. Exosome–magnetic complexes combine biological carriers with magnetic responsiveness to enhance targeting and biocompatibility for the treatment of neurological diseases and glioblastoma. This review highlights recent advances in magnetic field- and MNP-based neuroprotective strategies and explores new methods for targeted intervention and translational research using exosome–MNP complexes
Abstract PS1-07-08: Association of Prior Thoracic Radiation with Clinical Outcomes in Patients Hospitalized for Atrial Tachyarrhythmias
No full textMitochondrial Haplogroups and Left Ventricular Diastolic Dysfunction in People Living with and without HIV
No full textCardiac dysfunction is more common in people with HIV (PWH) than those without HIV (PWoH), with mitochondrial dysfunction implicated in pathogenesis. We investigated whether variations in mitochondrial DNA (mtDNA) and certain dideoxynucleoside analogues (D-drugs) relate to left ventricular diastolic dysfunction (LVDD) in PWH.
We included individuals with echocardiograms from the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. LVDD was defined using Characterizing Heart Function on Antiretroviral Therapy criteria. mtDNA haplogroups were inferred using HaploGrep. Separate exploratory multivariable logistic regressions examined associations between LVDD and African (L0L1, L2, L3 or "other") or European haplogroups (UK, H, JT, or "other"), D-drugs, and their interactions. No adjustments were made for multiple comparisons.
Among 842 men (455 PWH, 387 PWoH) and 898 women (620 PWH, 278 PWoH), LVDD prevalence was 29% in women and 24% in men. Among non-Hispanic White men with HIV, European haplogroup H was associated with lower odds of LVDD (odds ratio [OR], 0.50; 95% CI, 0.26-0.93), while haplogroup clade JT was associated with increased odds (OR, 2.09; 95% CI, 1.00-4.36). In men with HIV, D-drug exposure was associated with increased odds of LVDD (OR, 1.94; 95% CI, 1.21-3.13). No significant associations were observed between haplogroups and LVDD in women. HIV serostatus modified the association of haplogroup L2 (pinteraction=0.036) and L3 (pinteraction=0.045) with LVDD in women.
Mitochondrial genetic variation and D-drug use were associated with altered LVDD risk in men with HIV, highlighting potential biological mechanisms that may be targeted for surveillance or therapeutic strategies
Family‐Based Treatment + Unified Protocol for Avoidant/Restrictive Food Intake Disorder: An Exploratory Feasibility and Treatment Response Study in a Case Series of Adolescents
No full textAdolescents with ARFID commonly seek treatment for eating difficulties as well as cooccurring emotional concerns The study demonstrates initial evidence for FBT + UP‐A as a flexible treatment for adolescent ARFID and cooccurring emotional concerns A larger controlled study is needed to establish the effectiveness of FBT + UP‐A for adolescent ARFID
Abstract PS1-02-24: Physical activity level differences among Non-Hispanic White and Chinese American breast cancer survivors
No full textImpact of Alkaline Phosphatase Normalization on Complication-Free Survival in Primary Biliary Cholangitis
No full textDespite the widespread use of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC), many patients remain at risk for progression. Emerging data suggest that normalization of alkaline phosphatase (ALP) and total bilirubin (TB) - particularly when TB <0.6 times the upper limit of normal (xULN) - is associated with improved outcomes compared to ALP reduction to <1.5 xULN. This study investigated the association between ALP normalization in response to UDCA and long-term clinical outcomes in a real-world cohort of patients with PBC.
We compared complication-free survival in patients achieving an ALP >ULN and <1.5 xULN (adequate response) to those with an ALP <ULN on UDCA monotherapy. Complication-free survival was defined as the absence of serious liver-related clinical events. Restricted mean survival time was used to quantify survival time gained.
Patients achieving normal ALP and/or TB ≤0.6 xULN demonstrated significantly improved complication-free survival compared to those with an adequate ALP response. Event-free survival was extended by 1.34 years (95% CI:0.56, 2.11; p=0.001) for ALP normalization alone, 3.7 years (95% CI:3.11, 4.29; p< 0.001) for TB ≤ 0.6 xULN, and 4.51 years (95% CI:4.13, 4.88; p<0.001) for those meeting both criteria. The risk of severe clinical events was reduced in patients achieving ALP normalization (HR 0.34; 95% CI:0.15, 0.80; p=0.01), TB ≤ 0.6 × ULN (HR 0.23; 95% CI:0.09, 0.55; p=0.001), or both (HR 0.14; 95% CI:0.05, 0.38; p<0.001). High-risk patients, defined by LSM ≥10 kPa or clinical, histological, or laboratory evidence of cirrhosis or portal hypertension, derived the greatest benefit.
Achieving normal ALP and TB ≤0.6xULN is associated with significantly improved complication-free survival, particularly in high-risk patients. These findings highlight the potential of biochemical thresholds as a meaningful therapeutic goal in PBC management
Patient-reported outcomes in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia receiving standard chemotherapy plus quizartinib or placebo (QuANTUM-First): a global, randomised, placebo-controlled, phase 3 trial
No full textBackgroundQuANTUM-First is a randomised phase 3 trial in individuals with newly diagnosed acute myeloid leukaemia (AML) that is FLT3 internal tandem duplication (ITD) positive, showing a survival advantage for quizartinibversus placebo plus standard induction and consolidation chemotherapy with or without transplantation, followed by single-agent maintenance therapy. We evaluated the impact of quizartinib on patient-reported outcomes and healthrelated quality of life using the European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life Questionnaire.MethodsIn this global, multicentre, randomised, placebo-controlled, phase 3 trial, we recruited adults aged 18–75 years, with FLT3-ITD-positive newly diagnosed AML or AML secondary to myelodysplastic syndrome or myeloproliferative neoplasm, and with an Eastern Cooperative Oncology Group performance status of 0–2. Participants were randomly allocated (1:1) to quizartinib (40 mg/day) or placebo plus standard 7+3 induction chemotherapy, and then received standard consolidation chemotherapy with high-dose cytarabine plus quizartinib (40 mg/day) or placebo, allogeneic haematopoietic cell transplantation (allo-HCT), or both, followed by maintenance with single-agent quizartinib (30–60 mg/day) or placebo for up to 36 cycles. Randomisation was managed via an interactive web and voice response system. Patient-reported outcome endpoints, assessed using the European Organisation for Research and Treatmentof Cancer 30-item Core Quality of Life Questionnaire, were exploratory and analyses were based on the patient-reported outcome intention-to-treat analysis set. Treatment effects on patient-reported outcomes were assessed using the mixedeffects model for repeated measures, time to sustained improvement, and time until definitive deterioration analyses. A minimal clinically important difference score of 10 or higher for each subscale was defined as clinically meaningful. This trial is registered with ClinicalTrials.gov, NCT02668653, and is completed.FindingsParticipants were enrolled between Sept 27, 2016, and Aug 14, 2019. Of 539 randomly allocated participants, 509 (278 [55%] female and 231 [45%] male) were included in the patient-reported outcome analysis set, 254 in the quizartinib group and 255 in the placebo group. The overall median follow-up was 39·2 months (IQR 31·9–45·8). Baseline patient-reported outcome scores were similar between groups. The change in global health status and quality of life score (GHS–QoL) from baseline was above the minimal clinically important difference from consolidation onwards in both groups. The treatment difference (quizartinib minus placebo) in change from baseline for GHS–QoL (by mixed-effects model for repeated measures) was −2·0 (95% CI −4·8 to 0·7, nominal p=0·15), indicating no substantial difference between groups, further confirmed by time to sustained improvement (subdistribution hazard ratio [SHR] 1·126 [95% CI 0·904 to 1·403], nominal p=0·28) and time until definitive deterioration (hazard ratio 0·81[95% CI 0·51 to 1·28], nominal p=0·37) analyses. Longitudinal analyses of the functional and symptom subscales showed no substantially different patterns between groups. For the functional subscales, the SHR ranged from 0·940 to 1·148 (0·737–1·544, nominal p=0·36–0·90). For the symptom subscales, the SHR ranged from 0·965 to 1·407 (0·720–1·989, nominal p=0·28–0·99).InterpretationThe results indicate that quizartinib plus standard chemotherapy prolongs overall survival withoutadversely affecting patient-reported outcomes and health-related quality of life, with no substantial differences between groups. Future research in real-world settings is warranted to assess the generalisability of these patient-reported outcome results.FundingDaiichi Sankyo
Suicidality at Epilepsy Diagnosis and Future Treatment Resistance in Adults With Focal Epilepsy
No full textPsychiatric disturbances are common in epilepsy and are associated with increased risk of premature mortality, lower quality of life, and poor response to antiseizure medications (ASMs).
To evaluate the role of psychiatric disturbances at the time of epilepsy diagnosis in predicting risk of future treatment resistance in focal epilepsy.
The Human Epilepsy Project (HEP) is a prospective, observational, international, and multicenter cohort study with follow-up for up to 6 years. Participants with newly diagnosed focal epilepsy, enrolled within 4 months of initiating ASM treatment, between the ages 18 and 60 years, and without significant other comorbidities were recruited during the open period of 2012 to 2020. Data analysis was performed from January to September 2025.
Presence of a psychiatric diagnosis.
Presence of psychiatric diagnosis (mood/anxiety disorders) measured by Mini International Neuropsychiatric Interview (MINI) and/or suicidality measured by Columbia-Suicide Severity Rating Scale (C-SSRS) at enrollment. Treatment response included the following outcomes: treatment resistant (TR), defined as failure of first 2 adequate ASM trials (ongoing seizures at/above therapeutic doses); treatment sensitive (TS), defined by a minimum period of seizure freedom on first 2 adequate ASM trials (12 months/3-fold greatest pretreatment seizure-free interval, whichever is longer); and indeterminate (neither TR/TS).
Of 376 enrolled adults, 347 (median [IQR] age at seizure onset, 33 [23-44] years; 209 female [60.2%]) completed the MINI and C-SSRS at enrollment. Of these individuals, 191 (55%) were TS, 83 (24%) TR, and 73 (21%) indeterminate. The rate of psychiatric disturbance (mood/anxiety disorder; suicidality) at epilepsy diagnosis was 38% (n = 133). Fifty-seven (16%) had mood/anxiety disorder(s) without suicidality, and 75 (22%) expressed suicidality with or without a psychiatric disorder. Suicidality at epilepsy diagnosis was associated with greater than 2-fold risk of developing TR (relative risk [RR], 2.02; 95% CI, 1.32-3.09; P = .001). There were no significant overall associations between mood/anxiety disorders and TR. Suicidality alone significantly increased TR probability from 16.3% (95% CI, 11.3%-21.3%) in those with no psychiatric disturbance to 47.1% (RR, 2.89; 95% CI, 1.65-5.05; P < .001). Anxiety disorder alone increased TR probability to 32.9% (RR, 2.02; 95% CI, 1.10-3.71; P = .02), although this was not statistically significant after correcting for multiple comparisons. There was no significant change in TR probability when mood disorder alone was present; however, presence of mood disorder with suicidality increased TR probability to 39.6% (RR, 2.43; 95% CI, 1.26-4.68; P = .008).
Results of this cohort study reveal that suicidality at the time of focal epilepsy diagnosis was associated with future drug resistance and may be a marker of more severe neuropathology. Psychiatric screening at time of diagnosis may facilitate early identification of patients at risk for treatment refractory epilepsy syndromes