Faculty Bibliography

The management of brain metastases is challenging and should ideally be coordinated through a multidisciplinary approach. Stereotactic radiosurgery (SRS) has been the cornerstone of management for most patients with oligometastatic central nervous system involvement (one to four brain metastases), and several technological and therapeutic advances over the past decade have broadened the indications for SRS to include polymetastatic central nervous system involvement (>4 brain metastases), preoperative application and fractionated SRS, as well as combinatorial approaches with targeted therapy and immune-checkpoint inhibitors. For example, improved imaging and frameless head-immobilization technologies have facilitated fractionated SRS for large brain metastases or postsurgical cavities, or lesions in proximity to organs at risk. However, these opportunities come with new challenges and questions, including the implications of tumour histology as well as the role and sequencing of concurrent systemic treatments. In this Review, we discuss these advances and associated challenges in the context of ongoing clinical trials, with insights from a global group of experts, including recommendations for current clinical practice and future investigations. The updates provided herein are meaningful for all practitioners in clinical oncology.

BackgroundAdvances in STN-DBS technology, among which directional stimulation, improved Parkinson's disease (PD) treatment efficacy, while increasing the clinical programming complexity. Lead localization software may aid the stimulation contact selection process.ObjectiveWe aimed to assess the concordance between imaging-suggested (IGP) and conventional-programming (CP) selected stimulation contacts one year after surgery and its impact on motor outcomes.MethodsSixty-four PD patients with bilateral STN-DBS were enrolled. Lead localization was reconstructed with Brainlab^TM software. For each electrode, the vertical contact level and, when applicable, the directionality predicted by the lead reconstruction software to be the most effective were established and compared to the stimulation parameters clinically activated one-year post-surgery. IGP/CP concordance ratio was calculated for both stimulation level and directional contacts. Post-operative modifications of PD motor symptoms severity were compared among groups of concordant and discordant IGP/CP programming.ResultsOne-year post-surgery, IGP/CP concordance was 80% for active stimulation vertical contact level and 51% for directionality. No significant difference in motor outcomes was found between IGP/CP concordant and discordant patients for contact level activation, whereas patients with concordant IGP/CP active directional stimulation (c-Direction) showed superior motor outcomes at one-year follow-up than those discordant (d-Direction) (UPDRS-III stimulation-induced improvement: c-Direction = -25.66 ± 13.74 vs. d-Direction = -12.54 ± 11.86; p = 0.011).ConclusionsVisual reconstruction software correctly predicted the most clinically effective stimulation contact levels in most patients. Imaging therefore facilitates classic STN-DBS clinical programming while assuring similar outcomes. Moreover, better motor outcomes were reached by patients with concordant IGP/CP directional parameters, suggesting that visualization can represent an added value in particular for directional stimulation programming.

BACKGROUND/UNASSIGNED:With the introduction of sirolimus as medical therapy for lymphangioleiomyomatosis (LAM), an updated evaluation of LAM lung transplant (LT) outcomes and characterization of peritransplant sirolimus use is needed. METHODS/UNASSIGNED:We identified adult LT recipients from 2005-2021 using the Scientific Registry of Transplant Recipients database and stratified by diagnosis (LAM vs other). Multivariable Cox regression was performed to calculate the adjusted hazard ratio for LAM vs other diagnoses. A pharmacy claims database was linked to provide sirolimus prescription information, and a subgroup analysis comparing outcomes with pre- vs posttransplant sirolimus use was performed. RESULTS/UNASSIGNED: = .003). CONCLUSIONS/UNASSIGNED:This study supports lung transplant as a treatment for severe pulmonary LAM and identifies increased mortality associated with pre-LT sirolimus, though this may be due to uncharacterized baseline differences.

Existing deep learning algorithms for electrocardiogram (ECG) classification rely on supervised training approaches requiring large volumes of reliably labeled data. This limits their applicability to rare cardiac diseases like Brugada syndrome (BrS), often lacking accurately labeled ECG examples. To address labeled data constraints and the resulting limitations of supervised training approaches, we developed a novel deep learning model for BrS ECG classification using the Variance-Invariance-Covariance Regularization (VICReg) architecture for self-supervised pre-training. The VICReg model outperformed a state-of-the-art neural network in all calculated metrics, achieving an area under the receiver operating and precision-recall curves of 0.88 and 0.82, respectively. We used the VICReg model to identify missed BrS cases and hence refine the previously underestimated institutional BrS prevalence and patient outcomes. Our results provide a novel approach to rare cardiac disease identification and challenge existing BrS prevalence estimates offering a framework for other rare cardiac conditions.

BACKGROUND:Psoriatic arthritis (PsA) is a multi-domain, inflammatory disease impacting joints, soft tissues, and skin; tumor necrosis factor inhibitors (TNFi) are typically the first biologic following inadequate response (IR) to conventional therapies. Although guidance is lacking on therapy selection after initial TNFi failure, data suggest TNFi-IR PsA patients may benefit from switching to a different mechanism of action (MOA) vs. cycling to another TNFi. Guselkumab is a fully human monoclonal antibody targeting the interleukin-23p19 subunit. Emphasizing practicality and applicability to routine clinical practice, EVOLUTION will pragmatically evaluate whether switching to guselkumab is more effective than cycling to a second TNFi (subcutaneous [SC] golimumab) in TNFi-IR PsA patients. METHODS:The multicenter, longitudinal, prospective, observational Psoriatic Arthritis Research Consortium study guided eligibility criteria, outcome measures, and sample size estimates. Adults seen in clinical practice with active PsA (≥ 1 swollen joint) while receiving TNFi treatment will be eligible. Participants will be randomized (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at Week 0, Week 4, and Q8W; or SC golimumab 50 mg Q4W (no washout period). The novel primary composite endpoint is achievement of clinical Disease Activity in Psoriatic Arthritis (cDAPSA) low disease activity (≤ 13) and an Investigator's Global Assessment (IGA) of psoriasis score of 0/1 (scale: 0-4) at Month12. Secondary endpoints include cDAPSA + IGA 0/1 at Month 6; achievement of minimal disease activity, resolution of enthesitis and dactylitis (among patients affected at baseline) at Months 6/12; and mean changes at Months 6/12 in the 12-item PsA Impact of Disease, Dermatology Life Quality Index, Patient-Reported Outcomes Measurements Information System fatigue and depression questionnaires, and Bath Ankylosing Spondylitis Disease Activity Index (patients with physician-determined axial disease). The target sample size is 150 participants (50/treatment group); all analyses are considered exploratory. DISCUSSION/CONCLUSIONS:EVOLUTION will employ a pragmatic approach, including a novel primary endpoint relevant to clinical practice, to assess whether switching to an alternate MOA biologic with guselkumab is more effective than cycling to a second TNFi among TNFi-IR PsA patients. TRIAL REGISTRATION/BACKGROUND:This trial was registered at ClinicalTrials.gov, NCT05669833, on 3 January 2023, https://www. CLINICALTRIALS/RESULTS:gov/study/NCT05669833?term=%20NCT05669833&rank=1.

Early antibody therapy can prevent severe SARS-CoV-2 infection (COVID-19). However, the effectiveness of COVID-19 convalescent plasma (CCP) therapy in treating severe COVID-19 remains inconclusive. To test a hypothesis that some CCP units are associated with a coagulopathy hazard in severe disease that offsets its benefits, we tracked 304 CCP units administered to 414 hospitalized COVID-19 patients to assess their association with the onset of unfavorable post-transfusion D-dimer trends. CCP recipients with increasing or persistently elevated D-dimer trajectories after transfusion experienced higher mortality than those whose D-dimer levels were persistently low or decreasing after transfusion. Within the CCP donor-recipient network, recipients with increasing or persistently high D-dimer trajectories were skewed toward association with a minority of CCP units. In in vitro assays, CCP from "higher-risk" units had higher cross-reactivity with the spike protein of human seasonal betacoronavirus OC43. "Higher-risk" CCP units also mediated greater Fcγ receptor IIa signaling against cells expressing SARS-CoV-2 spike compared with "lower-risk" units. This study finds that post-transfusion activation of coagulation pathways during severe COVID-19 is associated with specific CCP antibody profiles and supports a potential mechanism of immune complex-activated coagulopathy.

Minoritized communities often experience worse health outcomes on the cancer continuum. Mainstream strategies may have limited reach and utility to populations experiencing inequities in real-world settings. Through the combined use of community-based participatory research (CBPR) and social marketing strategies, which highlight community-centered and culturally adapted processes, we provide an approach to inform future intervention research across various health topics that has been successful in engaging minoritized and understudied communities. We present two case studies that used participatory social marketing principles to culturally adapt evidence-based cancer screening programs for two communities in New York City. The first program is a campaign to increase screening and vaccination for hepatitis B among Korean and Chinese American immigrants. The second is a culturally adapted program to increase breast and cervical cancer screening among a multiracial and ethnic population of Muslim women. These case studies illustrate the benefits of integrating social marketing and CBPR approaches as a key strategy when developing public health campaigns to effectively reach and influence health behaviors in partnership with communities that have been socially marginalized and historically underserved.

High-dimensional multiplexed imaging can reveal the spatial organization of tumour tissues at the molecular level. However, owing to the scale and information complexity of the imaging data, it is challenging to discover and thoroughly characterize the heterogeneity of tumour microenvironments. Here we show that self-supervised representation learning on data from imaging mass cytometry can be leveraged to distinguish morphological differences in tumour microenvironments and to precisely characterize distinct microenvironment signatures. We used self-supervised masked image modelling to train a vision transformer that directly takes high-dimensional multiplexed mass-cytometry images. In contrast with traditional spatial analyses relying on cellular segmentation, the vision transformer is segmentation-free, uses pixel-level information, and retains information on the local morphology and biomarker distribution. By applying the vision transformer to a lung-tumour dataset, we identified and validated a monocytic signature that is associated with poor prognosis.

People with HIV are at increased risk of cardiovascular events; thus, care delivery strategies that increase access to comprehensive cardiovascular disease (CVD) risk management are a priority. We report the results of a multi-component telemedicine-based strategy to improve blood pressure control among people with HIV-Assess and Adapt to the Impact of COVID-19 on CVD Self-Management and Prevention Care in Adults Living with HIV (AAIM-High). The AAIM High strategy is a virtual adaptation of our previously published EXTRA-CVD strategy and consisted of hypertension education and six components: nurse-led care coordination (delivered by teleconference or telephone), home systolic blood pressure (SBP) monitoring, evidence-based treatment algorithms, electronic health records tools, technology coach, and communication preferences assessment. People with HIV (n = 74) with comorbid hypertension at three academic medical centers were enrolled in a single arm implementation study from January 2021 to December 2022. Over 12 months, the average patient-performed home SBP decreased by 7.7 mmHg (95% CI -11.5, -3.9). The percentage of patients at treatment goal, defined as average SBP <130 mmHg, increased from 46.0% to 72.5% at 12 months. By adapting to the growing use of telemedicine in healthcare delivery, our study effectively improved hypertension control in people with HIV through a virtual, nurse-led intervention.

BACKGROUND:Arthrofibrosis is a debilitating complication of total knee arthroplasty (TKA) and may benefit from arthroscopic lysis of adhesions (LOA) to improve range of motion and decrease pain. However, the rates of periprosthetic joint infection (PJI) and of the need for future revision TKA (rTKA) have only been studied in a limited capacity in the literature. In this study, we aimed to compare PJI and revision outcomes in patients who had undergone TKA between those who subsequently underwent arthroscopic LOA and those who did not undergo arthroscopic LOA. METHODS:The PearlDiver database was utilized to identify patients who had undergone primary TKA between 2016 and 2021. ICD-10 (International Classification of Diseases, Tenth Revision) and CPT (Current Procedural Terminology) codes were then used to identify patients who underwent LOA for arthrofibrosis. The rates of PJI and rTKA were compared between patients who did and did not undergo LOA. Multivariable logistic and Cox regressions, controlling for age, sex, Charlson Comorbidity Index, tobacco use, and a body mass index of >30 kg/m2, were performed to compare the rates of PJI and revision between the LOA and no-LOA groups. RESULTS:A total of 383,143 patients were identified, of whom 703 had undergone arthroscopic LOA. Patients who underwent LOA had higher overall rates of PJI (2.7% versus 1.3%; p = 0.001) and all-cause revision (9.8% versus 1.8%; p < 0.001) than those who did not. Patients who underwent LOA had significantly higher odds of PJI (odds ratio [OR], 2.00; p < 0.014), aseptic loosening-related revision (OR, 3.31; p = 0.002), and all-cause revision (OR, 5.32; p < 0.001) within 1 year after the initial TKA. There was no significant difference in 1-year PJI-related revisions between the groups (OR, 1.71; p = 0.193). In a time-to-event analysis, patients undergoing LOA had significantly higher risks of PJI (p = 0.003) and all-cause revision (p = 0.001) but not PJI-related revision (p = 0.322) or aseptic loosening-related revision (p = 0.111). CONCLUSIONS:Arthroscopic LOA after primary TKA was associated with higher rates of PJI and subsequent revision surgery. Surgeons should consider the results of these studies when counseling patients on the importance of early rehabilitation and improving modifiable risk factors after TKA. LEVEL OF EVIDENCE/METHODS:Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.