Citations

Once considered rare and essentially untreatable with a grim prognosis and reduced life expectancy, hypertrophic cardiomyopathy (HCM) has evolved substantially over 6 decades. Ultimately, HCM has become a contemporary global disease with pharmacologic and interventional options offering effective personalized treatment for all adverse disease pathways. Striking reduction in HCM‐related mortality to ≤0.5%/year in optimally treated cohorts is now comparable to that expected in the US general population, lower than most other disease risks to living, and 10‐fold less than the earliest estimates. The few deaths directly related to HCM are now largely attributable to advanced (end‐stage) heart failure in patients with nonobstructive HCM. Determinants of this transformation to a lower risk disease are evident in hallmark clinical inflection points and breakthroughs, including dedicated HCM programs assembling large clinical databases in which focused (and unfunded) physician‐investigators have derived data directly from patients in clinical practice. Evidence‐based observational studies report emergence of contemporary treatment strategies enhancing survival: implantable defibrillators prevent arrhythmic sudden death globally with 95% sensitive patient selection using an American Heart Association/American College Cardiology risk stratification algorithm; low‐risk, high‐benefit surgical myectomy reverses outflow obstruction and heart failure in >90% with a long‐term survival benefit; and aggressive anticoagulation has reduced embolic strokes. Recent novel pharmacologic alternatives (cardiac myosin inhibitors) are proving effective in relieving obstruction/symptom burden and changing disease management. These principles and time‐tested patient‐centered research strategies uniquely tailored to the heterogeneous HCM clinical spectrum are pivotal in providing practice insights, offering a vulnerable population more optimistic prognosis including opportunity to achieve normal longevity not available to prior generations of patients.

Abstract Background While immunologic aging impacts immune responses to vaccination, consistent biomarkers associated with aging of the immune system and suboptimal serologic response to influenza vaccination have not been well-studied. Identification of readily measurable biomarkers of immunosenescence may have predictive clinical utility and inform targeted influenza vaccination strategies and future research into aging of the immune system. Methods We quantified multiple serum/plasma and cell-based parameters related to immune aging (CMV serostatus, plasma cytokines/chemokines, TREC, TERT, NK cell functionality, and DNA methylation clock) at baseline in an adult (age range 18-85) cohort of 2019-2020 influenza vaccine recipients (n=337) and evaluated their associations with vaccine-induced HAI response to influenza A/H1N1, A/H3N2 and B/Victoria strains. Results CMV IgG titers were significantly positively correlated with vaccine-induced increases in HAI antibody titers to influenza A/H1N1 ( p= 0.02) and A/H3N2 ( p =0.014). CMV IgG titers ( p= 0.00096) and CMV seropositivity ( p= 0.003) were also associated with Day 28 HAI seropositivity against influenza A/H3N2 in subjects seronegative at baseline. Conversely, plasma MCP-1 levels were negatively associated with HAI responses to the A/H3N2 ( p= 0.04) strain. These findings were significant independent of age, sex or vaccine type received (high vs standard-dose seasonal influenza vaccine) Conclusions Our identification of significant relationships between easily quantifiable immune markers and HAI responses to influenza A vaccine strains across sex and age enhances our knowledge of specific links between immune aging and influenza vaccine-induced immunity. These markers could be leveraged for predicting response to influenza immunization.

IMPORTANCE Neoadjuvant chemoimmunotherapy has high rates of pathologic response and improved prognosis among solid tumors. Its role in head and neck squamous cell carcinoma (HNSCC) remains understudied. OBJECTIVE To summarize the efficacy associated with neoadjuvant chemoimmunotherapy regimens in HNSCC and to compare the efficacy associated with neoadjuvant chemoimmunotherapy vs immunotherapy alone in locoregionally advanced resectable HNSCC prior to definitive surgery. DATA SOURCES A librarian-led systematic review was conducted using multiple electronic databases, including Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus, following Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. Databases were queried from inception to October 2024. STUDY SELECTION Inclusion criteria included prospective interventional trials that have completed accrual, with results published in English. Only trials of resectable, treatment-naive HNSCC were included. Exclusion criteria included lack of reporting on pathologic response or Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 response. DATA EXTRACTION AND SYNTHESIS Two investigators independently conducted title, abstract, and full-text reviews per PRISMA guidelines. Primary outcomes extracted were major pathologic response (MPR) and complete pathologic response (CPR) at surgery and complete response (CR) on imaging by RECIST 1.1. Secondary outcomes included 1-year overall survival (OS) and toxic effects. MAIN OUTCOMES AND MEASURES A meta-analysis was performed using a binary random-effects model to determine the pooled proportion of primary outcomes in the immunotherapy and chemoimmunotherapy groups. Heterogeneity was reported as I 2 . RESULTS A total of 751 patients (502 [77%] male; age range, 27-87 years) across 23 studies were included in the meta-analysis, including 357 patients (47%) who underwent chemoimmunotherapy, 102 patients (14%) who underwent dual-agent immunotherapy, and 292 patients (39%) who underwent single-agent immunotherapy. Pooled rates of MPR plus CPR were 66% (95% CI, 58%-73%; I 2 = 0.59) for chemoimmunotherapy, 18% (95% CI, 6%-29%; I 2 = 0.65) for dual-agent immunotherapy, and 6% (95% CI, 3%-9%; I 2 < 0.01) for single-agent immunotherapy. Across all groups, 1-year OS rates ranged from 88% to 96% for single-agent immunotherapy, 88% to 96% for dual-agent immunotherapy, and 88% to 100% for chemoimmunotherapy. Grade 3 to 5 adverse events were reported in 61 of 210 patients (29%), 2 of 67 patients (3.0%), and 36 of 210 patients (17%) among the reporting studies in the single-agent immunotherapy, dual-agent immunotherapy, and chemoimmunotherapy groups, respectively. CONCLUSIONS AND RELEVANCE These findings suggest that neoadjuvant chemoimmunotherapy regimens were associated with higher pathologic and radiographic response rates compared with immunotherapy alone in locoregionally advanced HNSCC. These results call for phase 3 trials comparing these neoadjuvant regimens head to head.

Abstract Background NRG/RTOG 1010 evaluated trastuzumab added to trimodality therapy for HER2+ localized esophageal adenocarcinoma (EAC) management. Secondary PRO objectives assessed improvement in the FACT‐Esophageal Cancer Subscale (ECS), version 4, with trastuzumab, and if improved ECS correlated with pathologic complete response (pCR). Methods Patients were randomized to weekly paclitaxel/carboplatin/radiation (chemoradiation, CRT) followed by surgery ± trastuzumab (CRT + Tras). Disease‐free survival (DFS) was the primary end point. The projected PRO sample size of 158 patients, based on an 80% participation rate of the DFS primary endpoint sample size of 197 HER2+ patients, would provide ≥ 89% power to detect ≥25% increase in the proportion of CRT + Tras patients with ECS improvement from baseline to 6–8 weeks post‐CRT; one‐sided α = 0.05, using a χ 2 test. Improvement in ECS and its swallowing index (SI) and eating index (EI) was defined as 5‐, 2‐, and 2‐point increases, respectively, from baseline to 6–8 weeks post‐CRT. Univariate logistic regression was assessed if pCR was associated with improved ECS. Results From 2010 to 2015, 203 HER2+ patients were randomized and 194 were eligible. Of 171 PRO consenting patients, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6–8 weeks, 82 (49%) 1 year, and 55 (33%) at 2 years. The proportion of patients with an improvement in 6–8 weeks ECS was higher on the CRT + Tras arm (46% vs. 38%), although not significantly different ( p = .39). There was no correlation between pCR and ECS scores at 1 year, with 39% and 37% of pCR and non‐pCR patients, respectively, having improved 1‐year ECS scores. Conclusions The addition of trastuzumab to CRT for localized HER2+ EAC did not improve PROs.

Caudal type homeobox 2 (CDX2) is an intestine-specific transcription factor that serves as a diagnostic marker of enteric differentiation and may also reflect tumor behavior and therapeutic susceptibility. Emerging evidence suggests that CDX2 expression may predict sensitivity to fluoropyrimidine-based therapy independent of tissue of origin. We report a retrospective case series of three patients with metastatic adenocarcinoma (aggressive variant prostate, minor salivary gland, and intestinal-type sinonasal tract) exhibiting strong CDX2 nuclear expression. In all cases, tumors were refractory to or lacked established standard systemic therapy. Treatment decisions were informed by the CDX2-positive enteric phenotype, leading to the initiation of fluoropyrimidine-based regimens. Response was assessed using PET-CT and MRI. All three patients achieved marked metabolic and clinical responses, including a sustained complete metabolic response in the prostate cancer case and durable disease control in the salivary gland and sinonasal tumors. These findings highlight CDX2 as a potential biomarker requiring validation, which may identify tumors intrinsically susceptible to fluoropyrimidines regardless of anatomical origin. CDX2 immunohistochemistry is widely available and inexpensive, and may complement genomic profiling in rare malignancies or in settings where standard treatment algorithms are limited. This report is hypothesis-generating and not intended to estimate response rates or treatment efficacy.

ABSTRACT Background Preoperative vascular embolization (PVE) is commonly used in managing juvenile nasopharyngeal angiofibroma (JNA) to improve outcomes. However, few studies have evaluated how embolization patterns and vascular features affect prognosis. Methods A 15‐year retrospective review was performed on 44 patients with JNA undergoing surgery at one institution. Data included demographics, vascular supply, embolization techniques, surgical outcomes, and recurrence. Results Forty‐three patients underwent PVE. Most tumors were embolized transarterially (93.0%) using polyvinyl alcohol‐based agents (79.1%). The internal maxillary artery was most commonly embolized (93.0%). Internal carotid artery supply was present in 34.9%, and more than two vessels were embolized in 23.3%. Postembolization tumor blush occurred in 60.5%, with a median of 5% of the pre‐embolization blush remaining after embolization. Neither internal carotid involvement, number of vessels embolized, nor residual blush significantly impacted operative time, surgical outcomes, or recurrence. Conclusion With effective embolization, vascular complexity might not affect JNA resection outcomes. Multicenter studies are required to confirm those findings.

Abstract Background Computed tomography (CT) is an essential imaging modality for disease diagnosis, treatment efficacy, and image‐based guidance of various medical procedures. The locally deposited radiation dose in tissues, as estimated by the computed tomography dose index (CTDI), can vary considerably across exposures delivered by CT scanners from different vendors, even if the scans are performed using similar technique factors, such as tube potential and tube current. The volumetric CTDI (CTDI vol ) is a common dose metric that reports an average radiation dose (in mGy) delivered to a specific volume within a test phantom. The CTDI vol is important in dosimetry applications as the organ absorbed dose within the patient has been shown to scale in near‐linear proportion, creating a basis for comparing organ doses across different scan protocols and scanner models. Purpose To develop a database of tube current‐time product (mAs) normalized CTDI vol values for currently utilized CT scanner models for each of the four primary CT vendors for use in the MIRDct organ dosimetry software available at MIRDsoft.org. This data forms the basis of the MIRDct code, which reports organ doses across a range of computational phantoms based upon axial organ dose coefficient libraries generated through Monte Carlo radiation transport for a reference CT scanner. Organ doses delivered by alternate CT scanner vendors and models may then be reported using ratios of normalized CTDI vol values under similar technique factors. Methods Scanners were selected from four major CT manufacturers: Philips Healthcare, GE Healthcare, Canon Medical Systems, and Siemens Healthineers. Technique parameters were also selected for each scanner that closely matched values used in the generation of an equivalent CT source term (small to large bowtie filters; 80–140‐kVp tube voltage; and 10‐mm to 40‐mm beam collimation). For each scanner chosen, the appropriate technique factors and protocols were selected, and the console‐reported CTDI vol values were recorded and normalized to a set value of 100 mAs. The normalized CTDI vol data collected for use within the MIRDct code were analyzed for noticeable patterns, features, and trends, and were compared to similar normalized CTDI vol datasets used within the National Cancer Institute NCICT software and the Virtual Phantoms, Inc. VirtualDose software. Results For all given CT scanner and technique factor combinations, there was strong agreement in normalized CTDI vol values across all three codes: between 0% and 12% difference for the compared scanners. Ratios of CTDI vol values for various CT scanner vendors and models to the corresponding CTDI vol values for the MIRDct reference scanner (Cannon Aquilion One Genesis) were also compared on the basis of either the 16‐cm head PMMA phantom or the 32‐cm body PMMA phantom. The mean quotient of these normalized CTDI vol ratios (head ratios to body ratios) was found to be approximately 1.06, and thus either ratio may be applied in reporting patient organ dose by MIRDct. Conclusions A database of normalized CTDI vol (mGy/100 mAs) was created for 17 models of CT scanners from four manufacturers at varying tube potentials, collimations, x‐ray bowtie filters, and phantom sizes for use in the MIRDct software.

Purpose This study assessed the association between holding an additional graduate degree beyond a Doctor of Medicine (MD) or Doctor of Osteopathic Medicine (DO) and residency match outcomes. Specifically, the authors examined graduate degree attainment trends among residency applicants and evaluated whether graduate degree holders experience lower match rates than non-holders. Methods A retrospective, observational analysis was conducted using publicly available data from the National Resident Matching Program's Charting Outcomes in the Match reports (2016-2024). The 10 specialties with the highest applicant volumes were analyzed, encompassing 80 136 matched and 6820 unmatched U.S. MD and DO senior applicants. Trends in graduate degree attainment were evaluated using linear regression models. Match rates were stratified by graduate degree status and compared using two-proportion z-tests based on aggregated matched and unmatched counts for each specialty and overall. Results From 2016 to 2024, the proportion of graduate degree holders entering the match increased significantly for MD (15.77% to 18.29%, P = .0008) and DO (19.93% to 23.31%, P = .0151) applicants. Across all 10 specialties, graduate degree holders matched at lower rates than non-holders. Among MD applicants, graduate degree holders matched at 92.57% compared with 94.12% for non-graduates (P < .0001), with specialty-specific differences ranging from 0.22% in Psychiatry to 4.61% in Anesthesiology; five specialties demonstrated statistically significant disparities. Among DO applicants, graduate degree holders matched at 84.54% compared with 88.64% for non-graduates (P < .0001), with specialty-specific differences ranging from 1.44% in Family Medicine to 10.48% in Obstetrics and Gynecology; five specialties also reached statistical significance. Conclusions The proportion of graduate degree holders in the residency match is increasing, and these applicants experience lower match rates than non-holders. These findings challenge the assumption that additional graduate education provides a competitive advantage and underscore the need for further research into the applicant-level factors contributing to these disparities.

837 Background: A recent randomized trial suggested that CR may influence ICI activity in patients with lung cancer. However, the same has not been established in GI cancers, where reports have shown mixed results with variable definitions of 'early' vs 'late' IT. We evaluated multiple approaches to assess the impact of CR on first-line ICI in GI malignancies. Methods: This retrospective study included patients from three Mayo Clinic sites (N=455). Both previously reported IT cutoffs and a new cutoff derived from ROC analysis were evaluated. Patients were categorized by the median of all ITs, the median of the first four ITs, and whether ≥20% of ITs occurred before the identified cutoff. Univariate and multivariate Cox regression (adjusting for age, MSI status, type of cancer, metastasis status, number of cycles, and receipt of chemotherapy with ICI) assessed associations with OS. KM analyses were performed to illustrate survival differences. The primary endpoint was OS. Results: When patients were categorized based on whether ≥20% of infusions occurred before 14:00 (ROC-derived cutoff), a significant association with OS was observed. On univariate analysis, early infusion timing was associated with improved survival (HR 2.30, 95% CI 1.58–3.32, p <0.001). This remained significant after multivariable adjustment (HR 2.11, 95% CI 1.41–3.16, p < 0.001). Median OS was 14.2 months in the early group vs 3.8 months in the late group (log-rank p < 0.001). Using previously defined cutoffs, categorization by the median IT of all infusions or the median of the first four infusions did not demonstrate a significant association with OS in either univariate or multivariate Cox regression analyses. Conclusions: These findings highlight the potential role of infusion timing as a chronotherapy factor in GI cancers. Given the retrospective design and heterogeneous population, prospective studies are warranted to validate this signal and clarify its clinical relevance. Baseline demographics of patients by infusion timing (early vs late). Variables Early N=412 (%) LateN=43(%) Total N=455(%) p-value Age <70 249(60.4) 21(48.8) 270 (59.3) 0.1 >70 163(39.6) 22(51.2) 185 (40.7) Gender F 118(28.6) 16(37.2) 134 (29.5) 0.3 M 294(71.4) 27(62.8) 321 (70.5) Cancer Type Gastroesophageal 109 (26.5) 8 (18.6) 117 (25.7) 0.1 Hepatocellular 159 (38.6) 24 (55.8) 183 (40.2) Biliary 86 (20.9) 4 (9.3) 90 (19.8) MSI-H 58 (14.1) 7 (16.3) 65 (14.3) Metastasis No 150 (36.4) 22 (51.2) 172 (37.8) 0.1 Yes 262 (63.6) 21 (48.8) 283 (62.2) Immunotherapy Cycle Number <6 189 (45.9) 33 (76.7) 222 (48.8) <0.001 >6 223 (54.1) 10 (23.3) 233 (51.2)