Citations

Abstract Background X and Y chromosome analysis is a critical component of genetic testing, used both diagnostically and as a quality control (QC) metric. Discordances between expected and observed sex chromosome data can arise due to mislabeling, demographic data errors, transplant history, or biological variations. Such discordances pose challenges to laboratories and affect patient care, particularly in marginalized populations and unique clinical contexts. Methods We reviewed cases of sex chromosome discordance identified at our laboratory from January 2021 through August 2023. Cases spanned various testing methods and were categorized by the root cause, including mislabeling, sample mix-ups, transgender individuals, stem cell transplants, and unexplained causes. Case outcomes were assessed, and potential resolutions were analyzed. Results Among 65 cases identified, the leading cause of discordance was mislabeling (n = 20, 31%), followed by other/not identified (n = 16, 25%), sample mix-ups (n = 13, 20%), transgender individuals (n = 9, 14%), and stem cell transplants (n = 7, 11%). Cases required additional QC processes such as reanalysis, clinician contact, and occasionally sample re-collection. The process extended turnaround times by up to 13 business days. Detailed case reviews highlighted the challenges and implications of managing these discordances, emphasizing the importance of accurate data transmission and inclusive practices. Conclusion Using X and Y chromosome data as a QC metric can identify critical errors but also introduces limitations and bias. Improved standardization, inclusive practices, and alternative QC methods are necessary to ensure accuracy and equitable patient care. Collaborative efforts are required to address demographic complexities and reduce testing delays.

Abstract Purpose: Isocitrate dehydrogenase (IDH) 1/2–isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance. Patients and Methods: This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin–gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed. Results: Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma. Conclusions: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.

ABSTRACT Introduction Sinonasal sarcomas are exceedingly rare entities, constituting less than 7% of head and neck sarcomas. Their complex histology needs specialized treatment, which is often based on multimodal approaches including surgery, radiation therapy, and/or chemotherapy. This manuscript aims to gather expert opinions to establish common management principles for sinonasal sarcomas. Methods This international consensus followed a modified Delphi method in seven steps, including statements definition by the core group, expert panel recruitment, and a two‐round survey. Sixty‐two statements on sinonasal sarcoma management were developed. Experts from multiple continents participated, and results were anonymized and analyzed between March and May 2025. Results A total of 44 invited experts were recruited, 43.2% otorhinolaryngologists/head and neck surgeons, 31.8% medical oncologists, and 25% radiation oncologists. Participants varied in age and experience, representing Europe (70.5%), North America (18.2%), South America (6.8%), and Asia (4.5%). Among all histologies, biphenotypic sarcoma, chondrosarcoma, leiomyosarcoma, and myofibrosarcoma are principally treated with an upfront surgical management, differently from Ewing sarcoma and rhabdomyosarcoma in which chemotherapy, eventually associated with radiotherapy, is often chosen. In the remaining histologies (angiosarcoma, liposarcoma, malignant peripheral nerve sheath tumor [MPNST], osteosarcoma, and synovial sarcoma), a precise multimodal treatment is less standardized and needs to be discussed on a case‐by‐case basis. Conclusion Sinonasal sarcomas require a histology‐driven approach to determine upfront treatment, whether surgical, medical, or multimodal. Despite this structured strategy, prognosis remains highly variable across subtypes. Multidisciplinary evaluation and individualized management in referral centers are crucial to address the biological diversity and anatomical complexity of these rare malignancies.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.

Optimal management of hyperglycemia during illness has been hindered by a lack of comprehensive sick-day guidance, particularly for adults with diabetes. Managing glycemia can be challenging during illness because of adaptive counterregulatory hormonal changes, acute stress of illness, altered dietary intake, and effects of medications. People with diabetes may be at risk for severe hypoglycemia and hyperglycemic crisis during illness unless mitigated by close monitoring and medication adjustment. This article provides practical guidance to health care professionals and people with diabetes for safe glycemic management during illness, including considerations for insulin and noninsulin medications, use of insulin technologies, prevention of hypoglycemia and ketoacidosis, steroid use, and pregnancy.

Abstract Dobbs, WC, Almonroeder, TG, Carpenter, M, Schmitt, RE, Jacobson, AK, Luedke, JA, Roberts, BM, and Jagim, AR. Relationships between the Army Combat Fitness Test scoring structure and laboratory measurements of physical fitness in reserve officer training corps cadets. J Strength Cond Res 39(7): 798–808, 2025—The Army Combat Fitness Test (ACFT) assesses aerobic and anaerobic fitness capabilities in the U.S. Army. The aim of this study was to evaluate the association between raw and composite ACFT scores and laboratory-based measurements of fitness. Nineteen Reserve Officers' Training Corp cadets performed a battery of laboratory-based fitness testing. Tests included a movement screening (Fusionetics), countermovement jumps, and maximal isometric mid-thigh pulls on portable force plates to determine power and strength. A Wingate test involving maximal cycling for 30 seconds was used to determine peak and mean power. On a separate day, cadets completed body composition and a graded exercise test on a motorized treadmill to determine peak oxygen uptake (V̇ o 2 peak). Pearson correlations and partial corrections with 2000 bootstraps were used to compare ACFT scores (raw, composite, gender-neutral composite, and z -scores) with laboratory results. Significant associations were identified as 95% confidence intervals, not including zero. The results indicated that V̇ o 2 peak ( r = 0.61, [0.08–0.84]), body fat percentage ( r = −0.4, [−0.72 to −0.06]), and relative peak power ( r = 0.38, [0.02–0.68]) were associated with the total ACFT composite score when partialled by sex. All laboratory tests, except the movement screening, showed meaningful associations with total ACFT z -scores and gender-neutral ACFT scores ( r > 0.54). However, most relationships were eliminated when partialled out by sex, which may be due to a low sample size of women. This suggests the current scoring structure utilized for men is representative of aerobic and anaerobic fitness parameters and may be able to discriminate performance levels.

Background Intracranial occlusions in embolic stroke of undetermined source are histopathologically similar to cardiac sources of embolism. Whether patients with embolic stroke of undetermined source and intracranial occlusion benefit from anticoagulation is unknown. Methods A multicenter retrospective cohort of adults with cryptogenic stroke was queried for patients with proximal or medium/distal vessel occlusion. The primary outcome was recurrent ischemic stroke, which was assessed in unadjusted and adjusted Cox proportional hazards models and repeated following 1:1 propensity score matching and biweight kernel density matching. Results Of the 2328 patients who were followed over a median of 1.31 years (interquartile range, 0.34–2.85), 999 (42.6%) had an intracranial occlusion. When compared with patients without an intracranial occlusion, those with an occlusion had fewer atherosclerotic vascular risk factors, more severe symptoms, and less severe cerebral microvascular disease. The rate of recurrent stroke was similar between patients with versus without an intracranial occlusion (6.8%/year [95% CI, 5.7–8.2] versus 7.0%/year [95% CI 6.0–8.1]; adjusted hazard ratio [HR], 1.09 [95% CI, 0.77–1.55]). There was no association between occlusion and recurrent stroke in the adjusted propensity score matching (HR, 1.01 [95% CI, 0.64–1.59]) or kernel density models (HR, 0.95 [95% CI, 0.62–1.45]). There was no interaction between occlusion and treatment with anticoagulation, sex, age, or high‐risk sources of embolism for the primary outcome in the unmatched and matched analyses. Conclusions Intracranial occlusion in patients with embolic stroke of undetermined source is not associated with a greater risk of recurrence when compared with patients without an intracranial occlusion. There was no difference in rate of recurrent stroke with anticoagulation when stratified by presence or absence of occlusion.

ABSTRACTBackgroundPrimary progressive apraxia of speech is a neurodegenerative disorder characterized by early, isolated speech impairment due to impairment of motor speech planning and programming. Patients with PPAOS have varying disease durations from the estimated onset of the first symptom to death. Clinicopathological and neuroimaging features related to disease duration are unknown for PPAOS. We determine whether clinical, neuroimaging, or pathological features are associated with disease duration in primary progressive apraxia of speech (PPAOS).MethodsWe analyzed data from 41 PPAOS participants who were enrolled and longitudinally followed to death in NIH‐funded studies over 15 years. Demographic, clinical, and genetic features were abstracted. Brain volumes of cortical, subcortical, and brainstem regions were calculated. Regional tau lesion count (burden) was assessed histologically. Spearman rank correlations were performed between disease duration and variables of interest, followed by multiple regression analyses.ResultsDisease duration did not correlate with any baseline demographic, clinical, or pathologic features. Shorter disease duration correlated with a faster rate of behavioral change and of apraxia of speech severity over time, smaller baseline volumes of the superior frontal lobe and supplementary motor cortex, and higher tau burden in the locus ceruleus (ρ = −0.5, p = 0.03). Multiple regression analysis identified rate of behavioral change and volume loss in the superior frontal lobe as key clinical and neuroimaging variables, respectively.ConclusionIn patients with PPAOS, we found shorter disease duration to be related to behavioral dyscontrol and involvement of the frontal lobe, as well as a higher burden of 4‐repeat tau lesions in the locus ceruleus.

Abstract INTRODUCTION Research is limited regarding meaningful change thresholds for individual patients on clinical outcome assessments (COAs) frequently used in clinical trials for Alzheimer's disease and related dementias (ADRD), particularly in population‐based studies early in the disease course. METHODS There were 646 study participants in the population‐based Mayo Clinic Study of Aging (MCSA), 54–99 years old (47% females), who developed the clinical syndromes of mild cognitive impairment (MCI) with complete data to establish clinically meaningful within‐patient change thresholds in cognitive and functional COAs. RESULTS Using the diagnosis of incident MCI as the anchor, mean (95% confidence interval [CI]) annualized estimates of change were: Clinical Dementia Rating (CDR) scale Sum of Boxes (SB) 0.49 (0.43, 0.55), Mini‐Mental State Examination (MMSE) −1.01 (−1.12, −0.91), and Functional Activities Questionnaire (FAQ) score 1.04 (0.82, 1.26). DISCUSSION This study provides within‐patient estimates of clinically meaningful change early in disease progression in a community‐based sample. Highlights We studied incident mild cognitive impairment (MCI) participants from a population‐based study. Within‐patient change thresholds were estimated for clinical outcome assessments (COAs) used in clinical trials for Alzheimer's disease and related dementia (ADRD). These estimates may be used to plan and evaluate clinical trials involving disease‐modifying therapies (DMTs).