Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Gynecological cancers represent 10% to 15% of cancers in women, but brain metastases (BM) are uncommon, with limited evidence regarding their management. This study investigates the role of stereotactic radiosurgery (SRS) for BM from primary gynecological cancers. METHODS:Institutions of the International Radiosurgery Research Foundation participated in this study. Inclusion criteria required histological diagnosis of epithelial ovarian, cervical, or endometrial cancer, SRS between 2000 and 2020, and at least 1 imaging or clinical follow-up. RESULTS:A total of 276 patients having SRS for 977 BM were included. Median age at SRS was 62 years (IQR, 55-70). Primary cancer origin was ovarian in 128 (46%), cervical in 43 (16%), and endometrial in 105 patients (38%). Median Karnofsky Performance Scale was 80%, and systemic disease was active in 124 (45%) of patients. A median of 1 metastasis was treated (IQR, 1-3) per patient. Median individual metastasis volume was 0.27 cc (IQR, 0.05-1.59 cc). The majority (91%) received single-fraction SRS, using a median margin dose of 18 Gy (IQR, 16-20 Gy). Actuarial overall survival was 77%, 65%, and 44% at 6, 12, and 24 months, respectively. Predictors of worsened survival included older age, cervical and endometrial primary, previous whole-brain radiation therapy (WBRT), active systemic disease, worsened Karnofsky Performance Scale, absence of subsequent surgery, and increasing number of BM. Actuarial local control was 94% at 6 months, 89% at 12 months, and 78% at 24 months. Previous SRS or WBRT, tumor bed treatment, and cervical histology increased the risk of local failure. New remote BM and leptomeningeal dissemination occurred in 44% and 11% of patients, respectively. Adverse radiation effects (ARE) occurred in 13% of cases but were symptomatic in only 3%. Previous WBRT or SRS and increased tumor diameter increased the risk of ARE. CONCLUSION/CONCLUSIONS:SRS is an effective management for BM from gynecological cancers with low risks of symptomatic ARE.

Precision-targeted ultrasonic neuromodulation offers immense potential for studying brain function and treating neurological diseases. Yet, its application has been limited by challenges in achieving precise spatio-temporal control and monitoring of ultrasound effects on brain circuits. Here we show that transcranial ultrasound elicits direct and highly focal responses, which can be dynamically steered at spatio-temporal scales relevant for neural function. Furthermore, holographic transcranial ultrasound stimulation allows direct control of the stimulated volume and actively modulates local and mid-range network projections, effectively lowering the activation threshold by an order of magnitude. To better understand this previously unexplored excitability regime not fully explained by the conventional pressure-frequency dyad, we developed a dual modelling framework, where both an empirical and a mechanistic model were constructed to capture the intricacies of holographic transcranial ultrasound stimulation. These models achieve qualitative agreement with our experimental results, suggesting that these findings are predominantly driven by putative network interactions. Our results bring insight on the complex interaction mechanisms of ultrasound with neural tissue and highlight its potential for the noninvasive interfacing of distributed brain networks.

OBJECTIVES/OBJECTIVE:Multicenter research of geriatric emergency department (GED) care remains limited. Our objectives were to: 1. Prospectively collect data prioritized by the Geriatric Emergency care Applied Research (GEAR) network, a transdisciplinary taskforce for GED care, and create a multicenter GED research repository of prospective and electronic health record (EHR) data, 2. Assess concordance between prospective and EHR data. METHODS:The GEAR Standardization Study (GEARSS) is a multicenter, prospective study of older emergency department (ED) patients (65+) focusing on the 4Ms of age-friendly care (mobility, medication safety, mentation, what matters) and elder mistreatment. Demographic and clinical data were collected via interviews by trained research assistants (RA) on Days 0, 4, 30, and 90 and linked to EHR. Prevalence of chronic comorbidities and incident delirium were measured and reported using descriptive statistics. Prospective and EHR data concordance was assessed with Cohen's Kappa. RESULTS:999 participants were recruited from 5 EDs (3/25/2021-6/30/2022) across 3 institutions: Grady Health System, Northwestern Memorial Hospital, and Yale New Haven Health. The cohort was 57.0% female, 55.2% White, 39.1% Black, and 3.4% Hispanic, and the mean age was 75.1 years. For rheumatologic disease, peptic ulcer disease, diabetes, renal disease, and cancer, prevalence differed between prospective and EHR data by > 10%. About two-thirds of participants were at risk for falls. Concordance between prospective and EHR data was good for ethnicity (K = 0.73); excellent for sex (K = 1.00), age (K = 1.00), and race (K = 0.98); fair for disposition (K = 0.53); slight for ED observation status (K = 0.33) and dementia diagnosis (K = 0.24); poor for delirium presence (K = 0.07). CONCLUSION/CONCLUSIONS:In GEARSS, demographic variables aligned strongly between prospective and EHR data, while diagnosis, disposition, and mentation factors did not. This multicenter data source provides preliminary findings for common geriatric syndromes and conditions. Choice of measures using these data should be driven by GED research questions.

BACKGROUND AND AIMS/OBJECTIVE:receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). In this post hoc analysis, induction and maintenance efficacy of etrasimod 2 mg vs placebo were assessed by baseline Mayo endoscopic subscore (ES) in ELEVATE UC 52 and ELEVATE UC 12. METHODS:Moderate and severe endoscopic disease were defined as a centrally-read ES of 2 and 3, respectively. Efficacy endpoints were evaluated at Weeks 12 (pooled population) and 52 (ELEVATE UC 52). Subgroup analyses were stratified by baseline modified Mayo score (4-6 vs 7-9) and prior biologic/Janus kinase inhibitor exposure. RESULTS:Overall, 235 patients with moderate and 292 with severe endoscopic disease received etrasimod; 112 and 148 patients, respectively, received placebo. At both time points, significantly greater proportions of patients receiving etrasimod compared with placebo achieved clinical remission in the moderate (Week 12: 38.3% vs 17.9%; Week 52: 36.5% vs 14.3%; both P < .001) and severe (Week 12: 18.2% vs 6.1%; Week 52: 29.4% vs 3.4%; both P < .001) endoscopic disease subgroups. Similar efficacy was observed at Weeks 12 and 52 for most endpoints. The proportion of etrasimod-treated patients with severe endoscopic disease achieving endpoints was generally numerically higher at Week 52 vs Week 12, relative to placebo. Subgroup analysis findings were generally similar. CONCLUSIONS:Etrasimod demonstrated significant induction and maintenance efficacy over placebo in both moderate and severe endoscopic disease. Response to etrasimod in patients with severe endoscopic disease may continue to improve beyond 12-week induction therapy (ClinicalTrials.gov: NCT03945188; NCT03996369).

BACKGROUND:High-risk infant follow-up (HRIF) lacks universal definition. The aim of this study was to report current practice and factors used to identify eligibility for HRIF, yielding information which may provide a basis for future consensus. METHODS:A survey was prepared for a workshop at the 15th International Newborn Brain Conference on prediction of outcome, which was subsequently distributed to all attendees (n = 426). RESULTS:Follow-up was offered by 97% of respondents (n = 113/116). HRIF was offered to infants born <28 weeks by 47%, to those <32 weeks by two-thirds (66%) and to preterms based on neuroimaging by 54%. For infants born full-term, HRIF was offered by 88% in neonatal encephalopathy (NE) and 86% in neonatal stroke. HRIF continued most frequently until 24 months corrected (33.6%). For guiding prognosis in preterm infants, 22% (n = 25) selected neuroimaging as the most important factor. For NE, 54% (n = 63) selected neuroimaging findings as the most important factor in guiding prognosis and 14% (n = 16) selected EEG/aEEG. Social factors are not considered by 46% in determining HRIF eligibility. CONCLUSION/CONCLUSIONS:Significant variability in HRIF exists, without consensus. Awareness of factors predicting prognosis and the importance of social risk-factors must improve to allow accurate identification of those at highest risk. This information may act as a basis for future consensus on HRIF. IMPACT/CONCLUSIONS:There is no clear consensus on eligibility or duration of high-risk infant follow-up. We report current practice in, and factors used to identify eligibility for same, amongst attendees of the International Newborn Brain Conference. This information on international practice may provide a basis for future consensus. Given the importance of accurate prognostication in risk-stratification, we report participants' awareness of the most important factors guiding prognosis. A disconnect between the impact of social factors on outcome and their consideration for eligibility of high-risk infant follow-up is noted. We propose the need for guidelines on follow-up of socially disadvantaged, medically high-risk infants.

Dental enamel protects against the invasion of bacterial pathogens deep into the innervated layers of the tooth. Hereditary enamel disorders referred to as amelogenesis imperfecta (AI) can severely affect the development and mineralization of dental enamel compromising these functions. This rare disorder is often visible, carries a significant psychological and financial burden, and cosegregates with disease in other organs. Pathological variants in over 100 genes affect the enamel formation. Here, we describe the biology of enamel formation focusing on pathogenic variants underlying AI. We provide a computational model encapsulating new advances in calcium regulation during enamel formation. We also describe the psychological and financial burden of AI, its impact in systemic health, and discuss recent developments in diagnostic panels to detect AI.

BACKGROUND AND AIMS/OBJECTIVE:Endoscopic full-thickness resection (EFTR) is an established, safe technique for the resection of appendiceal orifice (AO) neoplasms. Post-EFTR appendicitis is a recognised adverse event. There are no systematic reviews and a paucity of literature which has assessed outcomes especially with respect to delayed appendicitis, mucocele, or fistula formation. We aimed to evaluate efficacy of EFTR for AO lesions. PATIENTS AND METHODS/METHODS:Consecutive AO lesions referred for consideration of EFTR were prospectively studied. Multiple data points were recorded including technical success, EFTR histopathological data, adverse events, and follow-up surveillance data by colonoscopy. Surveillance CT was performed due to concern of potential mucocele from the obstructed remnant appendix. RESULTS:Over a 4 year period to July 2023, 37 AO lesions were referred to a tertiary center for consideration of EFTR. EFTR was attempted in 35 (95%) lesions. Most lesions were small [median size 10mm, interquartile range (IQR) 10-15mm], Paris 0-IIa morphology (n=32, 91%) with serrated histopathology (n=17, 49%). R0 resection was achieved in most EFTR cases (n=30/35, 86%). Adverse events included appendicitis (n=4, 11%) and delayed bleeding (n=2, 6%). At 6-month (IQR 4-6 months) surveillance colonoscopy, there was 1 (3%) case of residual lesion. This was successfully treated endoscopically, confirmed on a second surveillance colonoscopy. There was one case of appendicitis of the remnant at 7 months. At surveillance CT abdomen/pelvis (median 15 months, IQR 7-37 months), 2/17 (12%) fistulas were identified. Both of these patients had presumed adhesions due to abdominal surgery prior to EFTR. CONCLUSIONS:In conclusion, EFTR is an effective technique for the curative resection of select, small (<15mm) Paris 0-IIa AO lesions. Appendicitis is a relatively common adverse event but often managed conservatively. The long-term significance post-EFTR fistulas remains unclear. Caution should be exercised when considering EFTR in a patient with prior regional surgery.

OBJECTIVES/OBJECTIVE:Despite its high negative predictive value (NPV) for clinically significant prostate cancer (csPCa), MRI suffers from a substantial number of false positives, especially for intermediate-risk cases. In this work, we determine whether a deep learning model trained with PI-RADS-guided representation learning can disambiguate the PI-RADS 3 classification, detect csPCa from bi-parametric prostate MR images, and avoid unnecessary benign biopsies. MATERIALS AND METHODS/METHODS:This study included 28,263 MR examinations and radiology reports from 21,938 men imaged for known or suspected prostate cancer between 2015 and 2023 at our institution (21 imaging locations with 34 readers), with 6352 subsequent biopsies. We trained a deep learning model, a representation learner (RL), to learn how radiologists interpret conventionally acquired T2-weighted and diffusion-weighted MR images, using exams in which the radiologists are confident in their risk assessments (PI-RADS 1 and 2 for the absence of csPCa vs. PI-RADS 4 and 5 for the presence of csPCa, n=21,465). We then trained biopsy-decision models to detect csPCa (Gleason score ≥7) using these learned image representations, and compared them to the performance of radiologists, and of models trained on other clinical variables (age, prostate volume, PSA, and PSA density) for treatment-naïve test cohorts consisting of only PI-RADS 3 (n=253, csPCa=103) and all PI-RADS (n=531, csPCa=300) cases. RESULTS:On the 2 test cohorts (PI-RADS-3-only, all-PI-RADS), RL-based biopsy-decision models consistently yielded higher AUCs in detecting csPCa (AUC=0.73 [0.66, 0.79], 0.88 [0.85, 0.91]) compared with radiologists (equivocal, AUC=0.79 [0.75, 0.83]) and the clinical model (AUCs=0.69 [0.62, 0.75], 0.78 [0.74, 0.82]). In the PIRADS-3-only cohort, all of whom would be biopsied using our institution's standard of care, the RL decision model avoided 41% (62/150) of benign biopsies compared with the clinical model (26%, P<0.001), and improved biopsy yield by 10% compared with the PI-RADS ≥3 decision strategy (0.50 vs. 0.40). Furthermore, on the all-PI-RADS cohort, RL decision model avoided 27% of additional benign biopsies (138/231) compared to radiologists (33%, P<0.001) with comparable sensitivity (93% vs. 92%), higher NPV (0.87 vs. 0.77), and biopsy yield (0.75 vs. 0.64). The combination of clinical and RL decision models further avoided benign biopsies (46% in PI-RADS-3-only and 62% in all-PI-RADS) while improving NPV (0.82, 0.88) and biopsy yields (0.52, 0.76) across the 2 test cohorts. CONCLUSIONS:Our PI-RADS-guided deep learning RL model learns summary representations from bi-parametric prostate MR images that can provide additional information to disambiguate intermediate-risk PI-RADS 3 assessments. The resulting RL-based biopsy decision models also outperformed radiologists in avoiding benign biopsies while maintaining comparable sensitivity to csPCa for the all-PI-RADS cohort. Such AI models can easily be integrated into clinical practice to supplement radiologists' reads in general and improve biopsy yield for any equivocal decisions.

OBJECTIVE:The CDC recommends initiating opioids for pain treatment at the lowest effective dose and duration. We examine how interactions between dose, duration, and other medication factors (e.g., drug type) influence opioid use disorder (OUD) risk-a gap not considered by CDC guidelines. SUBJECTS/METHODS:Using Medicaid claims data (2016-2019) from 25 states, we analyzed opioid-naïve adults, newly diagnosed with musculoskeletal pain who initiated opioids within three months of diagnosis. A 6-month washout confirmed no prior opioid exposure or musculoskeletal diagnosis. METHODS:Initial opioids were categorized by "dose-days supplied" (low [>0-20 mg MME] to very high [>90 mg MME] dose, and short [1-7 days] to moderate [>7-30 days] supply), and by opioid type; physical therapy (PT) sessions were also recorded. Using Poisson regression models, we estimated the OUD risk associated with dose-days categories, adjusting for baseline demographics, clinical characteristics, and medications. We separately examined opioid dose-days and PT, and assessed PT's moderating effect on dose-days' impact. RESULTS:Among 30,536 patients, half initiated opioids at 20-50 MME for 1-7 days, and 20% received PT. OUD risk was 2-3 times higher for opioids initiated for >7-30 days compared to 1-7 days across doses, and 5.5 times higher for opioids initiated for >7-30 days at > 90 MME versus 1-7 days at < 20 MME. PT alone, neither affected OUD risk nor mitigated the increased risk from longer or higher-dose opioids. CONCLUSIONS:Our findings support the need for careful opioid prescribing and alternative pain management strategies, as the observed associations between initial prescription characteristics and OUD were not mitigated by adjunctive PT. PERSPECTIVE/CONCLUSIONS:This study demonstrated that initial opioid prescriptions of 7-30 days, especially above 90 MME/day, increased OUD risk in opioid-naïve patients with musculoskeletal pain; physical therapy did not mitigate the risk. Different opioids posed varied risks, even at the same dose and duration. Careful prescribing and alternative pain management are essential.