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PURPOSE Predictive biomarkers to better tailor therapy for patients with early-stage human epidermal growth factor 2 (HER2)-positive breast cancer are a priority. We hypothesized that HER2 and immune-based biomarkers would be predictive of pathologic complete response (pCR) to preoperative trastuzumab/pertuzumab (HP). MATERIALS AND METHODS Patients with stage II/III, estrogen receptor (ER)-negative, HER2-positive breast cancer received neoadjuvant HP in the TBCRC026 clinical trial. The pCR after receiving HP alone was 22% (18/83). Tumor biopsies were performed at baseline. Secondary correlative objectives were to determine the relationship between HER2-based biomarkers and immune processes with pCR. NanoString code sets BC360 and IO360 were used to compare differential gene expression in baseline tumors that underwent pCR versus no pCR. NanoString GeoMx digital spatial profiling was used to assess immune protein abundance in intraepithelial and stromal segments. Stromal tumor-infiltrating lymphocytes and Ki67 were evaluated by hematoxylin and eosin and immunohistochemistry, respectively. RESULTS Intraepithelial HER2 protein abundance was significantly associated with pCR ( P = .001). Low HER2 abundance tumors were primarily basal-like, and essentially all (19/20) failed to achieve pCR. High HER2 abundance tumors that achieved pCR (14/51) exhibited a high degree of immune cell activity, whereas high HER2 abundance tumors that failed to achieve pCR tumors (37/51) were enriched for M-phase processes and epidermal growth factor receptor signaling. Baseline Ki67 was significantly higher in nonresponders ( P = .04). CONCLUSION ER-negative, HER2-positive breast cancer has unique molecular and immunologic features that may predict pCR after neoadjuvant HP. Validation of these potential biomarkers and composite biomarker analyses may guide design of future clinical trials.

Abstract Background and Aims Classification and risk stratification in aortic (AR), mitral (MR), and tricuspid regurgitation (TR) remains a significant clinical challenge. This study aimed to develop an artificial intelligence (AI) system to assess valvular regurgitation and stratify MR-progression risk. Methods Using transthoracic echocardiograms (TTEs) at two sites (internal development/test, external test), the DELINEATE-Regurgitation system was developed to classify AR, MR, and TR severity using colour Doppler videos. Methods of summating video-level classifications into study-level predictions were tested, comparing single-view with multiview approaches integrating predictions across multiple videos. Model agreement with cardiologists was assessed by weighted kappa. A separate AI system (DELINEATE-MR-Progression) analysing colour Doppler videos was developed to predict which patients with mild, mild–moderate, and moderate MR were most likely to progress to moderate–severe or severe MR with analysis by Kaplan–Meier and Cox proportional hazards models. Results A total of 71 660 TTEs with 1 203 980 colour Doppler videos were included. The weighted kappa in internal/external test sets for regurgitation classification was 0.81/0.76 for AR, 0.76/0.72 for MR, and 0.73/0.64 for TR using a multiview approach taking all colour Doppler videos in a study, demonstrating substantial agreement with cardiologist interpretation with superiority of multiview over single view approaches. In the progression analysis, the AI score stratified MR-progression risk even when controlled for clinical factors known to be associated with MR progression [internal test set hazard ratio 4.1 (95% confidence interval 2.5–6.6)]. Conclusions An AI system can accurately classify AR, MR, and TR and predict MR progression beyond currently known risk factors.

Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is due to a defect in metabolism of long-chain fatty acids. Infants with VLCADD may experience cardiomyopathy, hypoglycemia, or even death; thus, early detection and intervention is crucial. The spectrum of disease and natural variation in newborn metabolism, however, lead to overlap in acylcarnitine values between affected and unaffected individuals, which contributes to the difficulty in identifying true positive cases while minimizing false positive cases. VLCADD was added to the state of Wisconsin’s newborn screening (NBS) panel in 2000. A previous retrospective review of VLCADD screen positive cases identified between 2000 and 2014 resulted in a change to the screening algorithm. Following implementation, a reduction in the percentage of false positive screens from 25.3% to 20.4% was observed between 2015 and 2021. The overall PPV also decreased, from 37.2% to 28%, due to an increase in the number of carriers identified (27.5% of cases in 2000–2014 and 51.8% of cases in 2015–2021). A data review also identified three long-chain acylcarnitine elevations (C14:1, C14:1/C16, and C14:1/C2) that had statistically significant differences in concentrations in true positive populations versus false positive populations. Utilization of the C14:1, C14:1/C16, and C14:1/C2 values in newborn screening may provide clearer distinction between true positive and carrier populations and additionally increase the PPV of this screen.

Objectives/Goals: Digital recruitment can improve participant engagement in medical research, but its potential to introduce demographic and socioeconomic biases is unclear. This study investigates pathways participants took during a digital recruitment workflow in neurology, examining potential associations with socioeconomic and demographic factors. Methods/Study Population: As part of an ongoing study aiming to remotely capture speech from patients with neurologic disease, most participants seen in neurology on our campus are invited to complete a self-administered speech examination. We exported participant data from Epic (semi-automated identification and invitation), Qualtrics (eligibility screening), the participant tracking database (consent), and the recording platform (completion) for March to July 2024. Data visualization was performed using a Sankey diagram. Socioeconomic status was assessed using the housing-based socioeconomic status (HOUSES) index and area deprivation index (ADI) national rank. Kruskal–Wallis and Wilcoxon rank-sum tests were used to compare the median age, socioeconomic indices, and time taken to reach different steps of the study. Results/Anticipated Results: Of the 5846 invited participants, 57% were from urban areas, 23% from rural areas, and 20% from urban clusters. Most did not read/respond (2739) or declined (1749) the initial invitation via Epic. Of the 1358 interested participants, 415 completed the study. Participants from urban areas completed enrollment steps faster than those from rural areas and urban clusters, though the variance was large (42.6 ± 41.4 days vs. 50.6 ± 42.2 days and 50 ± 43.9 days, respectively; p = 0.030). Female participants took longer to complete enrollment than males (48.7 ± 44 days vs. 40.5 ± 38.8 days; p = 0.026). Participants who successfully finished the study had significantly lower ADI national ranks compared to other common pathways (40.6 ± 19; p = 0.0021). No associations were found with the HOUSES indices. Discussion/Significance of Impact: Our findings support differences in participant engagement, with urban participants and males more likely to complete enrollment steps. Those who finished the study were less disadvantaged suggesting potential bias in digital recruitment. These findings can inform strategies to improve digital recruitment in neurology research.

ImportanceCutaneous squamous cell carcinoma (CSCC) risk stratification is central to management, and physicians rely on tumor staging systems to estimate risk. The Brigham and Women’s Hospital (BWH) T staging system predicts risk based on 4 tumor risk factors (RFs). However, stage is not precisely associated with the number of RFs, as BWH stage T2b includes CSCCs with 2 and 3 RFs.ObjectiveTo determine how RF number is associated with the risk of recurrence, metastasis, and disease-related death.Design, Setting, and ParticipantsThis retrospective multination cohort study of CSCCs diagnosed between October 1, 1991, and July 19, 2023, was conducted at 12 centers in the US (10), Spain (1), and Brazil (1). Invasive CSCCs with confirmed negative margins longer than 14 days were included. Tumors were excluded if they were metastatic at presentation or received adjuvant therapy. Data were analyzed from October 2023 to August 2024.Interventions or ExposuresCSCCs were stratified by the number of the following RFs (0, 1, 2, 3, or 4): a diameter of 2 cm or larger, poorly differentiated histology, tumor extension beyond subcutaneous fat, and large caliber nerve invasion.Main Outcomes and MeasuresFive-year cumulative incidences of local recurrence, nodal metastasis, distant metastasis, and disease-specific death.ResultsA total of 16 844 CSCCs were included (5978 female individuals [35.5%]; median [IQR] age, 73.9 [65.7-81.8] years), with 0 (12 657 [75.1%]), 1 (2892 [17.2%]), 2 (1015 [6.0%]), 3 ( 225 [1.3%]) or 4 (55 [0.3%]) RFs. Median (IQ) follow up time was 33.6 (14.5-60.3) months. For local recurrence, the risk increased as the number of RF increased from 0 (1.7%; 95% CI, 1.5%-2.0%) to 1 (5.0%; 95% CI, 4.1%-5.9%) to 2 (8.8%; 95% CI, 7.0%-11.0%) to 3 (16.0%; 95% CI, 11.0%-22.0%) to 4 (33.0%; 95% CI, 19.0%-47.0%; P < .001 for between-group differences). This increase was also observed for nodal metastasis (0.6% [95% CI, 0.4%-0.7%] vs 3.6% [95% CI, 2.9%-4.4%] vs 11.0% [95% CI, 9.2%-13.0%] vs 20.0% [95% CI, 15.0%-26.0%] vs 28.0% [95% CI, 15.0%-42.0%], respectively; P < .001), distant metastasis (0.2% [95% CI, 0.1%-0.3%] vs 1.1% [95% CI, 0.7%-1.6%] vs 2.3% [95% CI, 1.4%-3.4%] vs 7.9% [95% CI, 4.6%-12.0%] vs 8.4% [95% CI, 2.6%-19.0%], respectively; P < .001), and disease-specific death (0.3% [95% CI, 0.2%-0.4%] vs 1.9% [95% CI, 1.4%-2.7%] vs 5.4% [95% CI, 4.0%-7.0%] vs 11.0% [95% CI, 6.7%-16.0%] vs 25% [95% CI, 12%-39%], respectively; P < .001). CSCCs with 3 RFs had higher cumulative incidences of local recurrence (1.6-fold), nodal metastasis (1.9-fold), distant metastasis (4.3-fold), and disease-specific death (1.9-fold) compared with those with 2 RFs.Conclusions and RelevanceThe results of this cohort study suggest that the number of RFs is an indicator of risk, and among BWH T2b tumors, those with 3 RFs represent a higher risk subset.

BACKGROUND AND OBJECTIVES: Schwannomas are benign, slow-growing peripheral nerve sheath tumors. Approximately 8% of intracranial schwannomas originate from the trigeminal nerve. No consensus exists regarding superiority of outcomes after resection vs stereotactic radiosurgery (SRS) in the treatment of trigeminal schwannomas (TS). The aim of this study was to compare the efficacy and outcomes of resection vs SRS for TS management. METHODS: Embase, PubMed, and SCOPUS databases were queried from the date of inception to July 2023 for primary data reporting TS treatment outcomes after SRS or resection. Risk of bias was reported under Newcastle-Ottawa Scale. RESULTS: Overall, 29 retrospective observational studies comprising 949 patients were included in the analysis. A total of 13 studies (n = 589) reported outcomes after SRS, and 16 studies (n = 360) reported outcomes after surgical resection, and 182 patients in the SRS group had previous resection. To ensure statistical validity of comparing the cohorts, 3 checkpoints were assessed: the median age (SRS: 48 vs surgery: 40 years old, P < .01), tumor volume (5.2 vs 8.9 cm 3 , P = .06), and median follow-up (53.9 vs 48.5 months, P = .59), which reflected the choice of treatment. Compared with surgical resection, the SRS group demonstrated significantly higher rates of facial hypesthesia improvement (44% vs 12%, P < .01) and lower rates of new onset (4% vs 15%, P = .051) at last follow-up. Facial pain was less likely to improve (58% vs 81%, P = .024) after SRS compared with surgery. However, worsened (5% vs 1%, P = .71) and new facial pain (2% vs 1%, P = .55) were comparable between cohorts. CONCLUSION: SRS seems to offer improvement in rates of hypesthesia and trigeminal motor deficits compared with surgical resection for TS. However, facial pain improvement was more favorable after surgery. These findings highlight the importance of individualized treatment decisions based on patient characteristics, tumor profile, and pretreatment symptoms.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Central Nervous System Cancers provide multidisciplinary diagnostic workup, staging, and treatment recommendations for diffuse high-grade gliomas and medulloblastomas in children and adolescents. This article summarizes the studies and panel discussion that serve as the rationale for comprehensive care recommendations included in the NCCN Guidelines for Pediatric Central Nervous System Cancers.

ABSTRACTObjectivesCeliac disease (CeD), an autoimmune disorder triggered by gluten ingestion, induces intestinal inflammation and varied symptoms. Treatment entails a strict gluten‐free diet (GFD), posing challenges for students, especially in schools with limited food choices. Nonadherence worsens symptoms, yet research on CeD's impact on students is scarce.MethodsThe CeliacKIDS study, conducted across 11 United States academic medical centers, evaluated gluten exposure risk in pediatric CeD patients via a cross‐sectional survey from August 2020 to August 2021. Participants recruited from treating institutions were approved by respective Institutional Review Boards.ResultsOne hundred and sixty children aged 5–18 (65% female, 34% male, 1% other) participated. Only 12% had GF food options at school, 31% brought their own for celebrations, and 41% lacked gluten free (GF) snacks after school. Thirty‐six percent lacked a 504 plan, with 5% misinformed. Hand hygiene concerns included 24% using sanitizer and 10% rarely washing hands before eating. Sixty‐two percent disclosed CeD, 35% when prompted, and 3% refused, mainly 13‐year‐old males. Two percent hesitated to request GF options, and 2% consumed potentially gluten‐containing food from friends.ConclusionMany US schools provide GF accommodations under the Americans with Disabilities Act (ADA) but lack national standards. Diverse GF options and education on GF‐safe practices are crucial for GFD adherence. Discrepancies in parent–child perceptions emphasize the need for better communication. Adolescents, particularly females aged 12–13 with 2+ years on a GF diet, face higher risks. Transparent family–school communication is vital for optimizing the school experience and ensuring GFD adherence. Comprehensive nationwide school training is essential for celiac patients' well‐being.

OBJECTIVE Stereotactic radiosurgery (SRS) is an effective treatment for refractory tremor. However, the lack of reliable patient-specific targeting biomarkers leads to varying outcomes. Although connectomic-based targeting is commonly used in deep brain stimulation, its application in SRS is limited. This study aimed to develop a new targeting approach by using patient-specific structural connectivity to improve outcomes after SRS. METHODS The authors performed a retrospective study of patients in a prospective trial for frameless virtual-cone SRS on a linear accelerator for essential tremor or tremor-dominant Parkinson disease. The primary endpoint was percentage improvement in Fahn-Tolosa-Marin tremor rating scale scores contralateral to the treatment side. Probabilistic tractography assessed connectivity from each thalamic voxel to the primary motor cortex (M1), primary sensory cortex (S1), and supplemental motor area/premotor cortex (SMA/PMC). Group-level comparisons were conducted to evaluate the relationship between the sweet spot for maximum contralateral tremor improvement and areas maximally connected to M1, S1, and SMA/PMC. Multiple regression analysis assessed the relationship between the lesion centerpoint coordinates and the maximally connected voxel to M1, S1, and SMA/PMC at the individual level. RESULTS The analysis included 27 patients with a mean follow-up of 17.9 ± 11.1 months. The sweet spot for maximal contralateral tremor improvement at the group level was in the region most connected to M1 cortex. Smaller y-distances (anterior-posterior) from the lesion center to the M1 maximally connected voxel significantly correlated with tremor improvement at the single-subject level (p < 0.001). However, the authors found no significant correlation between the lesion y-coordinate and the maximally connected voxel to SMA/PMC and S1, nor between the x-distances from the lesions to the SMA/PMC, M1, and S1 voxels (p > 0.07). CONCLUSIONS This study demonstrates that patient-specific connectivity between the treatment target and M1 correlates with treatment outcomes. The authors’ approach provides a practical targeting method for SRS thalamotomy for tremor.