Faculty Bibliography

The mammalian interstitium is a body-wide network of fluid-filled, prelymphatic spaces. Recent studies demonstrate that it exists at three scales in continuity both within and between organs, comprising intercellular, pericapillary, and large (or fascial) interstitial spaces, the latter including fascia, dermis, organ submucosae and capsules, vascular adventitia, and perineurium. Hyaluronic acid fills all interstitial spaces, but large interstitial spaces also contain additional structurally complex and varied extracellular matrices that support soluble factor, mechanical, and potentially electrical signaling. Here we review areas where the new anatomic concept of the interstitium has led to the re-examination of previous findings, including data on interstitial matrix composition and cell trafficking. We also identify new questions arising specifically from the finding that the interstitium is multiscale and body-wide, including questions about the characteristics and drivers of interstitial fluid flow and the role of the interstitium as a rich and active basolateral signaling compartment.

Bereavement from loss related to drug poisoning, the leading cause of injury-related death in the United States, is associated with elevated risk for prolonged grief disorder, substance use, and poor mental health outcomes. Despite this, few interventions specifically target survivors of overdose loss. The Family Support Program (FSP) is a novel, social worker-delivered bereavement support service provided by the Drug Intelligence and Intervention Group of the New York City Office of Chief Medical Examiner for family, friends, and other close social network members bereaved by drug poisoning. The FSP integrates evidence-based components including motivational interviewing, psychoeducation, social support, and linkage to care to reduce grief-related distress and improve psychosocial functioning. This paper describes the development, implementation, and pilot-phase adaptations of the FSP, including program design, staffing strategies, data infrastructure, and lessons learned. This paper can guide medical examiner and coroner offices in developing responsive, trauma-informed services for individuals affected by drug poisoning loss.

BACKGROUND:Some centres advocate preoperative radiotherapy in patients with pancreatic cancer and arterial involvement despite a lack of Level 1 evidence on survival benefit. Although it has been suggested that preoperative radiotherapy may increase the risk of postpancreatectomy haemorrhage (PPH) and morbidity, evidence is again lacking. This study investigated the association between preoperative radiotherapy and both PPH and major morbidity following arterial divestment/resection during pancreatic adenocarcinoma resection after chemotherapy. METHODS:Consecutive patients diagnosed with pancreatic adenocarcinoma and > 180° arterial involvement who were treated with preoperative chemotherapy with or without radiotherapy followed by pancreatic resection with arterial divestment/resection were included in the study. Logistic regression analyses including propensity score-based overlap weighting were performed to investigate associations between radiotherapy and in-hospital PPH grade B/C and major morbidity, expressed as adjusted risk differences (aRDs). RESULTS:Overall, 246 patients undergoing pancreatic resection with arterial resection (169, 69%) or divestment (77, 31%) were included. Radiotherapy was not associated with PPH (aRD 6%; 95% confidence interval (c.i.) -3 to 14), regardless of arterial divestment (aRD 3%; 95% c.i. -5 to 11) or arterial resection (aRD 12%; 95% c.i. 1 to 23; Pinteraction = 0.189). Radiotherapy was associated with a 14% (95% c.i. 2 to 25) higher risk of major morbidity, especially after arterial resection (aRD 27%; 95% c.i. 11 to 43) compared with arterial divestment (aRD -12%; 95% c.i. -35 to 11; Pinteraction = 0.006) and after external beam radiotherapy (aRD 21%; 95% c.i. 8 to 32) compared with stereotactic body radiotherapy (aRD -12%; 95% c.i. -27 to 6; Pinteraction = 0.0001). Ninety-day mortality was increased, albeit not significantly, after preoperative radiotherapy (10 (8%) versus 3 (3%) deaths with versus without preoperative radiotherapy, respectively; P = 0.067). CONCLUSIONS:Radiotherapy before resection of pancreatic cancer with > 180° arterial involvement was associated with an increased risk of postoperative major morbidity when arterial resection, but not arterial divestment, was performed. This risk should be taken into account when considering preoperative radiotherapy in patients who may require arterial resection.

OBJECTIVE:ratio (TPR) imaging approach and evaluates its ability to characterize MS lesions alongside other quantitative MRI (qMRI) metrics. METHODS:and PD values were used to illustrate TPR contrast. Statistical analyses included Wilcoxon rank-sum tests and Spearman correlations (p < 0.05). RESULTS:* (92 ms) values but lower MTR (37.3%) and MTsat (1.57%) compared to hypointense lesions (1085 ms; 0.88 a.u.; 64 ms; 46%; 2.48%, respectively). QSM values varied across lesion types. INTERPRETATION/CONCLUSIONS:, PD, and MT metrics, consistent with demyelination. In contrast, hypointense lesions may reflect tissue changes associated with repair processes such as remyelination.

INTRODUCTION/UNASSIGNED:To ensure Alzheimer's disease-modifying treatments can be initiated in diverse populations, efficient pathways to obtain timely diagnoses are required. METHODS/UNASSIGNED:This interim sub-analysis of a multicenter US study included cross-sectional surveys and interviews with neurologists at 12 diverse sites to assess real-world lecanemab use. RESULTS/UNASSIGNED:testing to inform risk/benefit decisions. Infusions usually started within 6 months of diagnosis. Delayed/incomplete referrals were identified as the most significant barrier in the current patient pathway. DISCUSSION/UNASSIGNED:These findings demonstrate the feasibility of lecanemab integration in diverse clinical settings and highlight the importance of primary care physician engagement, optimization of referral pathways, and expanding BBM use in improving timely diagnosis, equitable access, and early treatment initiation.

INTRODUCTION/BACKGROUND:-variation with greater time post-9/11/2001 will be a mortality risk-factor associated with cross sectional BMI and longitudinal weight-variation. METHODS:-variation. RESULTS:-variation (OR = 1.18; 95% CI 1.06, 1.27 and OR = 1.17; 95% CI 1.07, 1.27 respectively). INTERPRETATION/CONCLUSIONS:-variation and weight-variation may reflect concurrent metabolic and pulmonary instability that increase vulnerability to death.

Hypomethylating agents (HMA) and allogeneic hematopoietic stem cell transplantation (alloHSCT) have both demonstrated remissions in VEXAS; however, comparative data is lacking. We conducted a multicenter, retrospective analysis of 66 patients diagnosed with VEXAS syndrome treated with HMA (n = 35) or alloHSCT (n = 31). Baseline characteristics such as genetics, co-morbidities, and performance status were balanced between the groups, except older age in the HMA group. Median follow-up from therapy initiation was 18 months (95% CI: 11-26), and 14 (21%) deaths were reported (alloHSCT n = 3; HMA n = 11). Among all evaluable patients within the alloHSCT cohort, all patients achieved molecular remission, and a substantial proportion of patients discontinued glucocorticoids (58%). In contrast, HMA therapy was associated with lower but meaningful rates of molecular remission (22%) and glucocorticoid discontinuation (6%). In a real-world setting, HMA therapy was associated with a high discontinuation rate related to toxicity or lack of response. On multivariable analysis adjusted for age and Charlson Comorbidity Index, alloHSCT was associated with improved overall survival (HR = 0.20, 95% CI: 0.05-0.81; p = 0.024). This association remained consistent across multiple ancillary sensitivity analyses, including restriction to transplant-eligible patients, patients aged ≤ 75 years, 1:1 matching, and propensity score-based weighted analyses. Although limited by retrospective design, these findings suggest that alloHSCT remains an attractive and potentially curative strategy in selected patients with VEXAS. Prospective validation of these findings is warranted.

BACKGROUND:Early detection of oral potentially malignant disorders (OPMDs) and oral cavity cancer can improve patient prognosis. In this guideline, the authors address the use of vital staining, specifically toluidine blue, as an adjunct to screen adults without mucosal abnormalities and to determine the need for biopsy among adults with mucosal abnormalities in the oral cavity. TYPES OF STUDIES REVIEWED/METHODS:The authors conducted systematic searches to identify evidence on the benefits and harms of using vital staining as an adjunct as well as patient and clinician values and preferences regarding the use of this adjunct. The guideline panel used the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework to formulate recommendations. As part of the framework, the panel also considered the resources required, equity, acceptability, and feasibility when formulating recommendations. RESULTS:The panel formulated 2 recommendations and 2 good practice statements. For adults with and without mucosal abnormalities, the panel recommend against the use of vital staining as an adjunct (conditional recommendation, very low certainty). The good practice statements encourage clinicians to perform a clinical oral examination in all adult patients. CONCLUSIONS AND PRACTICAL IMPLICATIONS/CONCLUSIONS:Biopsy remains the first choice for obtaining a definitive diagnosis of an OPMD and oral squamous cell carcinoma. Clinical oral examination should be performed in all asymptomatic adults with no clinically evident mucosal abnormality. When implementing or adapting these recommendations, local contexts should be taken into account to ensure equitable access to early detection.

BACKGROUND:Alpha-emitting radionuclides enable precise cancer therapy through high linear energy transfer and limited tissue penetration, damaging tumor cells while sparing healthy tissue. Diffusing Alpha-emitters Radiation Therapy (Alpha DaRT) features Ra-224 sources that are implanted directly into the tumor and emit alpha particles during radioactive decay. Alpha DaRT has demonstrated efficacy and safety in preclinical and early clinical trials across multiple tumor types, including skin, head and neck, and pancreatic cancers. PURPOSE/OBJECTIVE:Reliable and efficient methods for verifying Alpha DaRT source activity prior to treatment can help support accurate and consistent radiation delivery. The direct measurement of alpha particles from sources within an Alpha DaRT applicator is impractical due to their short range; however, gamma emissions from the Ra-224 sources can be used to infer radioactivity. This study established a protocol for verifying the source activity within Ra-224 Alpha DaRT applicators using a reentrant well-type ionization chamber, providing users with a practical method for detecting errors in source manufacturing or certificate paperwork without compromising applicator sterility. METHODS:Ra-224 Alpha DaRT sources in sterile packaging (Flex and Needle applicators with 1-4 sources) were assessed. Source energy spectra and activities were verified using a high-purity germanium (HPGe) radiation detector. Calibration factors (kBq/pA) were established using an IVB1000 well-type ionization chamber with measurements conducted by placing single applicator sterile packages into the chamber with sources centered in the chamber's sweet spot and corrected for temperature, pressure, and leakage current. Quality assurance was performed on 26 Flex applicators using the established calibrations before the first clinical procedure. RESULTS:HPGe measurements agreed with vendor-stated activities. The average calibration coefficient using the IVB1000 chamber was 233 ± 3 kBq/pA for Flex and 597 ± 7 kBq/pA for Needle applicators. Calibration coefficients were consistent across two IVB1000 chambers. Source number dependence was observed, with calibration factors increasing by 1.7% ± 0.7% per source (Needle) and 2.7% ± 0.6% per source (Flex). Measurement repeatability was 3.3%. Applying the calibration to 26 Flex applicators before the first patient treatment yielded a 1.1 ± 5.8% (range: -7.5% to 11.4%) difference relative to the vendor's stated activity. CONCLUSION/CONCLUSIONS:A reentrant well-type ionization chamber is suitable for pre-treatment quality assurance of Ra-224 Alpha DaRT applicators, enabling verification of the vendor-stated activity while maintaining sterility within sealed packaging.