Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Congenital obstructive hydrocephalus (HCP) causes progressive, irreversible fetal brain damage through ventricular enlargement and increasing fetal cerebral tissue compression. Postnatal treatments of choice include ventriculoperitoneal shunting or endoscopic third ventriculostomy (ETV). Intrauterine treatments, such as ventriculoamniotic shunting, were attempted unsuccessfully 4 decades ago and failed to improve postnatal outcomes, likely due to inadequate fetal patient selection. The aim of this study was to evaluate the efficacy of prenatal ETV for early ventricular decompression and potential prevention of fetal brain damage in hydrocephalic fetal lambs. METHODS:HCP was induced in 24 fetal lambs by injecting BioGlue into the cisterna magna at E85. Three weeks later (E105-110), fetal ETV was successfully performed on 8 fetuses using a small rigid cystoscope. Fetal brain lateral ventricular diameters and cerebral mantle thicknesses were monitored by prenatal and postnatal ultrasounds and fetal MRI. RESULTS:According to the Cincinnati HCP Severity Scale, moderate and severe HCP subgroups responded positively to fetal ETV with reduced cerebral ventricular diameters. Ten days post-ETV, severe HCP fetal lambs improved to moderate levels, whereas those with moderate HCP normalized by birth. A similar improvement pattern was seen for the mechanical compression threshold (ventricular diameters/biparietal diameter). Biparietal diameter values did not significantly differ among nontreated, treated, and normal control groups during pregnancy. MRI revealed a significant increase in brain mantle thickness in the prenatally treated fetuses. CONCLUSION/CONCLUSIONS:Prenatal ETV is feasible in hydrocephalic fetal lambs and effectively reverses ventriculomegaly and brain compression in cases of severe or moderate fetal HCP in this ovine model.

INTRODUCTION/BACKGROUND:Management of relapsed mantle cell lymphoma (MCL) has included Bruton's tyrosine kinase (BTK) inhibitors for more than 10 years, but finding an optimal combination partner that meaningfully improves outcomes while limiting toxicity has been difficult. We conducted a phase 1/2 trial of ibrutinib and the proteasome inhibitor, ixazomib, in patients with relapsed/refractory MCL. PATIENTS AND METHODS/METHODS:Patients and Methods: The primary endpoint for the phase 1 study was to determine the recommended phase 2 dose (RP2D), and for the phase 2 study was the complete response (CR) rate, compared with the previously reported single-agent CR rate of ibrutinib. After the phase 1 portion of the study identified a recommended phase 2 dose of ixazomib 4 mg days 1, 8, and 15, of a 28-day cycle combined with ibrutinib 560 mg daily until progression or unacceptable toxicity. RESULTS:We enrolled 35 BTK-naïve patients to the phase 2 portion of the study. Overall response rate was 77%, and 37% of patients achieved a CR. The 2-year progression-free survival is 44%, and the duration of response is 47%. Treatment-related adverse events were common, resulting in treatment discontinuation for 37% of patients. CONCLUSION/CONCLUSIONS:Given that the progression-free survival (PFS) was not significantly improved compared to historical reports for single-agent BTK inhibitors and the high rate of treatment-related toxicity, this combination does not merit further study in this setting. Additional trials evaluating newer BTK inhibitors and alternative combination partners are warranted.

BACKGROUND:in participants with relapsed or refractory follicular lymphoma after at least one previous line of chemoimmunotherapy. METHODS:for up to 12 cycles. Epcoritamab was administered weekly in cycles 1-3 and every 4 weeks in cycles 4-12, lenalidomide once daily during cycles 1-12 (days 1-21), and rituximab weekly during cycle 1 and monthly in cycles 2-5. The dual primary endpoints were overall response rate and progression-free survival by independent review committee. The data reported here are from a planned interim analysis carried out after 78% of progression-free survival events had occurred. This study is registered with ClinicalTrials.gov, NCT05409066, and EudraCT, 2021-000169-34, and is ongoing (closed to recruitment). FINDINGS/RESULTS:(grade 1 in 28 [21%] participants and grade 2 in seven [5%] participants) and manageable, and all events were resolved. INTERPRETATION/CONCLUSIONS:as a new standard of care for second-line or subsequent treatment of follicular lymphoma. FUNDING/BACKGROUND:AbbVie and Genmab.

BACKGROUND:Facial trauma surgeons consulted by emergency departments (EDs) for mandible fractures must decide whether hospital admission is warranted. While admission may allow for closer monitoring and expedited surgery, many patients present with clinically stable injuries for which outpatient management is feasible. PURPOSE/OBJECTIVE:This study aims to identify biological, situational, and socioeconomic predictors of admission for mandible fractures presenting to EDs across the United States. STUDY DESIGN, SETTING, AND SAMPLE/UNASSIGNED:This was a retrospective cohort study of the 2022 Nationwide Emergency Department Sample. Subjects diagnosed with mandible fractures (International Classification of Diseases, 10th Revision, Clinical Modification S02.6-) were included. Subjects who died in the ED or left against medical advice were excluded. PREDICTOR VARIABLES/METHODS:The predictor variables consisted of a heterogeneous set of demographic, hospital-related, and injury-related risk factors. MAIN OUTCOME VARIABLES/METHODS:The outcome variables were admission status and ED charges. COVARIATES/UNASSIGNED:None. ANALYSES/METHODS:tests. A multivariable logistic model was used to identify independent predictors of admission. A P value <.05 was considered statistically significant. RESULTS:The sample was composed of 12,160 subjects with a mean age of 39 years (SD = 19), and 9,117 (75%) were male. A total of 5,236 (43%) subjects were admitted. Mandibular symphysis fractures had the highest likelihood of admission (P < .001), whereas body fractures had the lowest likelihood (P < .001). In a multivariable logistic model, male sex (OR: 1.23; 95% CI: 1.11 to 1.36), number of mandible fractures (OR: 2.81; 95% CI: 2.61 to 3.02), concomitant midface fractures (OR: 3.25; 95% CI: 2.89 to 3.65), and firearm injuries (OR: 16.16; 95% CI: 11.50 to 22.71) were associated with admission, whereas uninsured patients were less likely to be admitted (OR: 0.84; 95% CI: 0.75 to 0.94). Admissions were more costly than discharges ($15,511 vs $4,899, P < .001). CONCLUSION AND RELEVANCE/CONCLUSIONS:Disposition decisions for mandible fractures are influenced by not only injury severity (eg, multiple mandible fractures, concomitant facial fractures) but also patient characteristics and socioeconomic factors. These findings support the development of standardized admission criteria to improve equity and resource utilization.

De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here, we demonstrate that microglia, the resident macrophages of the brain, are required for metabolic coupling between endothelial cells, astrocytes, and neurons, which fuels protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, which increases glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit that is required for on-demand protein synthesis in mouse motor cortex.

OBJECTIVE:HPV vaccination recommendations have expanded to include both sexes and a broadened age range since approval in 2006. These changes and increasing HPV-related head and neck cancer rates support vaccination of older and male patients, necessitating changes in HPV education. We aim to analyze vaccination trends and to identify opportunities for increasing awareness. STUDY DESIGN/METHODS:Cross-sectional study analyzing vaccination trends between 2007 and 2023. SETTING/METHODS:US hospitals and clinics using Epic. METHODS:Using Epic Cosmos, a national database, vaccination trends for patients aged 9 to 45 were stratified by year, demographics, and administering provider specialty. RESULTS:19.6 million HPV vaccinations were administered between 2007 and 2023. The inclusion of males aged 9 to 21 in the recommendations beginning in 2009 corresponded with an 836% increase in vaccinations in this group from 2010 to 2016. Males comprised 49.9% of vaccinated patients aged 9 to 18 in 2023, a percentage that increased annually since 2010. Head and neck cancer prevention became a designated vaccine indication in 2020. Despite broadened indications, total vaccination declined by 47.1% from 2016 to 2023 in patients aged 9 to 26. In 2012, 74.8% of vaccinations were administered in pediatrics and 18.3% in family medicine. In 2023, pediatrics administered 46.6%, family medicine 33.3%, OBGYN 7.1%, and primary care 6.8%. CONCLUSION/CONCLUSIONS:Expanding guidelines have had inconsistent impacts on vaccination trends, as rates decreased in target populations since 2016. Males contribute equally to pediatric but not adult vaccinations. Departments administering vaccines are diversifying, though pediatrics predominates. Gendered and outdated education and marketing could contribute to disparities and discordance with guidelines.

Vertebral metastatic disease results from many types of cancer and can have a devastating impact on patient mobility, psychological health, quality of life, and ultimately overall patient survival. However, the development of radiotherapy and surgical techniques has rapidly surged in conjunction with ongoing advances in basic science and translational studies. In this review, we discuss the paradigm shift in our understanding of the epidemiology and treatment algorithms for spinal oncology, ranging from preoperative optimization strategies, radiation and surgical techniques, the utilization of molecular markers and targeted therapeutics in medical oncology, and prognostication tools that underscore a new multidisciplinary approach to spinal oncology care.

OBJECTIVE:receptor-related epilepsies. Here, we extend these observations with a retrospective observational study evaluating the response to vinpocetine in an additional seven patients. METHODS:Patients initiated treatment with vinpocetine between 2018 and 2025 at the Danish Epilepsy Centre or abroad. Clinical data were collected from medical records, seizure diaries, and neuropsychological assessments. The modulatory efficacy of vinpocetine was investigated using electrophysiological studies. RESULTS:receptor LoF variants were given add-on vinpocetine treatment. Electrophysiological analyses confirmed dose-dependent positive modulation by vinpocetine across tested variants. Six patients with a median age of 15.5 years (range = 6-29) continued treatment for a median of 24 months (range = 12-90), whereas three discontinued due to adverse effects (AEs) or lack of efficacy. The patients' level of function ranged from normal to moderate intellectual disability, psychiatric comorbidities, and behavioral disturbances. Four patients initiated vinpocetine due to uncontrolled seizures. One became seizure-free, and two experienced a 50%-55% reduction. Electroencephalograms demonstrated improved spike-wave indexes in four patients. Six showed improvement in nonseizure factors, and caregivers reported reduced aggressivity and better vocabulary in one. Vinpocetine was well tolerated, with only mild and reversible AEs reported. SIGNIFICANCE/CONCLUSIONS:receptor-related epilepsies, which should be investigated further in future N-of-1 trials.

BACKGROUND/UNASSIGNED:Bone metastases from breast cancer cause skeletal-related events (SREs), including pain, fractures, and the need for radiation or surgery. Denosumab and bisphosphonates (BP) reduce these complications, but their relative efficacy and safety remain unclear. METHODS/UNASSIGNED:PubMed, Scopus, Cochrane Library, and Google Scholar were searched through October 2025. Five publications (four unique studies: three randomized trials and one retrospective cohort) were included. Sensitivity analyses were limited to randomized trials when feasible. Outcomes included SRE incidence and skeletal endpoints, plus renal, metabolic, hematologic, musculoskeletal, gastrointestinal, infectious adverse events, osteonecrosis of the jaw (ONJ), and serious, grade ≥ 3, and treatment-related events. RESULTS/UNASSIGNED: = 0.04) were reduced. Other outcomes, including uNTx, ONJ, serious and grade ≥ 3 events, thrombocytopenia, infectious, gastrointestinal, and respiratory events, were comparable. Results were consistent in randomized-only analyses. CONCLUSION/UNASSIGNED:In breast cancer patients with bone metastases, denosumab may benefit those at higher risk of renal toxicity or skeletal complications, while treatment decisions should remain individualized. PROTOCOL REGISTRATION/UNASSIGNED:www.crd.york.ac.uk/PROSPERO identifier is CRD420251231881.