Faculty Bibliography

BACKGROUND:Soft tissue sarcoma (STS) is a rare and heterogeneous malignancy with more than 100 histologic subtypes that can arise in virtually any part of the body. Although surgical resection is the standard of care, complete surgical resection is often limited by involvement of critical anatomy, and most subtypes are resistant to systemic therapies. Histotripsy uses microsecond length, high-pressure ultrasound (US) pulses delivered externally to generate cavitation inside the target tumor to mechanically liquefy tissue to acellular homogenate. This study tested the effect of histotripsy in a variety of soft tissue tumors (STTs) including benign tumors and sarcomas. METHODS:Histotripsy was delivered to 45 surgically excised ex vivo human samples with a custom 1 MHz 8-element US transducer guided by US imaging. RESULTS:Histotripsy was successful in creating an identifiable treatment effect across all subtypes including adipocytic tumors, benign myxoid and nerve sheath tumors, aggressive fibrous sarcomas, and high-grade sarcomas. Immediately after histotripsy, B-mode and shear-wave elastography US imaging was shown to effectively evaluate the treatment. Tissue structure heterogeneity among the tumor subtypes dictated the variation in histologic treatment effects. CONCLUSIONS:The data demonstrate effective US-guided histotripsy ablation on a robust cohort of ex vivo STTs. The variable treatment effects observed across tumor subtypes highlight the need for histotripsy parameter optimization, with support for its potential as a promising non-invasive treatment modality for sarcoma patients who currently have limited therapeutic options.

BACKGROUND:Robotic surgery is increasingly used in emergency general surgery (EGS), but its adoption and outcomes after interhospital transfer remain unclear. We evaluated robotic adoption, hospital-level variation, predictors of use, and comparative outcomes among transferred EGS patients. STUDY DESIGN/METHODS:Using the Nationwide Readmissions Database (2016-2019), we identified adults transferred from acute-care hospitals who underwent EGS procedures. Mixed-effects models evaluated predictors and between-hospital variation in robotic use, summarized by intraclass correlation coefficients (ICC) and median odds ratios (MOR). Multivariable logistic and generalized linear models compared cost, length of stay (LOS), non-home discharge, complications, mortality, and 30-day readmission across robotic, laparoscopic, and open approaches. RESULTS:Robotics was used for ≥1 transferred patient in 8.5% of transfer-receiving hospital-years and 13.7% of robot-capable transfer-receiving hospital-years. Hospital-level variation was substantial for robotic vs laparoscopic selection (MOR 3.59; ICC 35.3%) but modest for robotic vs open selection (MOR 1.31; ICC 2.3%). Investor-owned hospitals and later years were associated with greater odds of robotic use, whereas extreme illness severity and rural residence were associated with lower odds. Compared with laparoscopy, robotics was associated with shorter LOS and higher cost, without statistically significant differences in adjusted clinical outcomes. Compared with open surgery, robotics was associated with shorter LOS, lower cost, and lower odds of non-home discharge and surgical complications. CONCLUSIONS:Robotic surgery after interhospital transfer was uncommon, with substantial hospital-level variation relative to laparoscopy despite similar adjusted clinical outcomes. These findings support defining selection criteria and evaluating equitable access to minimally invasive platforms.

Early-life enteric infection disrupts the developing microbiota-gut-brain (MGB) axis. Using a neonatal Enteropathogenic Escherichia coli (EPEC) model, we show that intestinal epithelial cell (IEC) nucleotide oligomerization domain (NOD)1 signaling coordinates neuroimmune outcomes throughout early development and into adulthood. Neonatal mice infected at postnatal day (P)7 exhibited ileal inflammation, with increased pro-inflammatory cytokines and monocyte/macrophage infiltration, and loss of myenteric neurons in wild-type mice but not in NOD1 conditional knockout (Nod1^ΔIEC) mice. These deficits persisted into adulthood (P56), with increased intestinal permeability, sustained inflammatory/repair signatures, neuroinflammation, altered neurogenesis, and impaired recognition memory, which were absent in Nod1^ΔIEC mice, establishing a crucial role for IEC NOD1 in long-term MGB remodeling. Last, bioactive peptidoglycan fragments (muropeptides) were isolated from probiotic Lactobacillus strains and tested as possible therapeutics. Excitingly, supplementation of muropeptides attenuated neonatal EPEC-induced mucosal inflammation and enteric neuron loss without altering bacterial burden, potentially via IEC NOD2. Together, these findings identify IEC NOD-dependent signaling linking early-life enteric infection to enduring gut-brain dysfunction and reveal probiotic-derived muropeptides as candidate therapeutics.

BACKGROUND:The majority of postoperative morbidity and mortality after partial pancreatectomy is attributable to postoperative pancreatic fistula. Several interventions to prevent postoperative pancreatic fistula have been assessed in randomized clinical trials but consensus on their efficacy is lacking. This is the first systematic review and meta-analysis of randomized trials focusing on strategies to prevent postoperative pancreatic fistula after all types of partial pancreatectomy. METHODS:Eligible randomized clinical trials assessing postoperative pancreatic fistula following partial pancreatectomy were included from the Evidence Map of Pancreatic Surgery database (2005-2025). As primary endpoint, both the 2005 and 2016 International Study Group for Pancreatic Surgery definitions of grade B/C postoperative pancreatic fistula were accepted. Interventions shown to reduce postoperative pancreatic fistula in at least one randomized trial were identified, and meta-analysis undertaken for those with at least three available trials, irrespective of their outcome. RESULTS:Overall, 193 RCTs were included with 29 408 patients from 24 countries. The pooled rate of postoperative pancreatic fistula grade B/C was 15.1%: 14.2% after pancreatoduodenectomy and 19.1% after left pancreatectomy. Overall, 24 trials identified 18 interventions as effective in reducing the rate of postoperative pancreatic fistula: 11 intraoperative and 7 postoperative. Eight interventions were eligible for meta-analysis, involving 46 trials. Following meta-analysis, three interventions remained effective: drain omission in left pancreatectomy, perioperative use of somatostatin analogues, and administration of perioperative corticosteroids. The certainty of evidence was high for drain omission, moderate for somatostatin analogues, and low for corticosteroids. Eleven trials focused specifically on high-risk patients and four on ongoing postoperative pancreatic fistula. No trial combined interventions. CONCLUSION/CONCLUSIONS:Omission of drains in left pancreatectomy, perioperative use of somatostatin analogues, and administration of perioperative corticosteroids are effective strategies to prevent postoperative pancreatic fistula after partial pancreatectomy. However, current evidence remains immature and further RCTs evaluating these interventions are warranted, as they are likely to change the conclusions of subsequent meta-analyses. Such trials could potentially focus on high-risk patient cohorts and/or assess combinations of interventions.

Leptomeningeal metastasis (LM) is a fatal neurological complication of cancer. Proton craniospinal irradiation (pCSI) has emerged as a promising life-prolonging intervention for patients with LM, but response to this treatment varies. Here, we aimed to characterize the molecular basis of pCSI resistance and response. Proteomic analysis of cerebrospinal fluid (CSF) collected from patients with LM at baseline (before pCSI), and at multiple time points posttreatment, identified the chemokine C-X-C-motif ligand 1, CXCL1, associated with LM growth. Higher CXCL1 levels in the CSF before pCSI correlated with worse response to this treatment. To define the role of CXCL1 in LM, we established syngeneic mouse models of LM-CSI. We found that both metastatic cancer and host cells generate CXCL1. Genetic interruption of Cxcl1 expression in metastatic cancer, but not host cells, impaired cancer cell growth within the leptomeninges. Moreover, we found that Cxcr2, the primary receptor for Cxcl1, was widely expressed within the LM microenvironment. A subset of LM cancer cells expressed Cxcr2, and this population was enriched over time in the leptomeninges. Transcriptomic profiling of this rare population revealed enrichment in pathways associated with cell cycle progression. In patients, we found that higher expression of CXCR2 before pCSI correlated with worse overall survival. Last, in preclinical models, interruption of Cxcl1-Cxcr2 signaling with intrathecally delivered Cxcr2 antagonist hampered LM growth and sensitized cancer cells to CSI. Our results demonstrate that the Cxcl1-Cxcr2 signaling axis mediates LM growth and identifies a potential actionable intervention to improve response to pCSI and halt LM progression.

AIMS/UNASSIGNED:To evaluate the clinical and economic value of onabotulinumtoxinA (onabotA) vs oral pharmacotherapies for adults with OAB inadequately managed with anticholinergics from a United States (US) Medicare + societal perspective over 1 year. MATERIALS AND METHODS/UNASSIGNED:A Markov model-based 1-year cost per responder (CPR) analysis was conducted for patients achieving complete response (100% reduction in urinary incontinence episodes [i.e. complete dryness]). Comparators included onabotA and oral therapies (vibegron [brand], mirabegron 25/50 mg [brand and generic], and anticholinergics [generic]), using inputs for efficacy, costs, and healthcare resource use. The primary outcome was CPR for a complete response, with secondary outcomes including number of urinary incontinence episodes per patient and number needed to treat (NNT). Uncertainty was evaluated through one-way and probabilistic sensitivity analyses. Scenario analyses assessed results using commercial costs and longer-term effects for selected outcomes. RESULTS/UNASSIGNED:In the base-case analysis, onabotA had the highest complete response rate (23.5%), resulting in the lowest NNT and CPR (4.3; $18,646) vs oral therapies (response 10.9-12.1%; NNT 8.3-9.2; CPR $21,941-$49,524). Scenario and sensitivity analyses were consistent with these findings and supported the base-case results. LIMITATIONS/UNASSIGNED:Model inputs were primarily based on clinical trial data and may not fully reflect real-world practice; differences across trials may limit comparability. The stringent responder definition, use of non-US productivity estimates, 1-year time horizon, and exclusion of neuromodulation therapies may further limit generalizability and scope. CONCLUSIONS/UNASSIGNED:OnabotA demonstrated favorable clinical and economic value relative to oral pharmacotherapies that was consistent across sensitivity and scenario analyses. About 1 in 4 patients treated with onabotA could achieve a 100% response over 1 year compared to 1 in at least 8 with oral pharmacotherapies. These findings support onabotA as a treatment option with demonstrated clinical and economic value for patients who do not achieve adequate symptom relief with oral OAB therapies.

BACKGROUND/UNASSIGNED:Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and is associated with an increased risk of adverse outcomes. Age is an important risk factor for AF with a sharp rise in prevalence after the age of 60 years. Despite a rising share of older adults in Africa, there is a paucity of data regarding AF burden in this demographic. OBJECTIVE/UNASSIGNED:This study aimed to determine the prevalence, clinical characteristics, and associated factors of AF among adults 60 years and older attending noncardiac outpatient clinics at a tertiary hospital in Tanzania. METHODS/UNASSIGNED:We conducted a cross-sectional study among consenting adults aged 60 years and older at noncardiac outpatient clinics of Muhimbili National Hospital from June 2021 to February 2022. A structured questionnaire was used to collect sociodemographic and clinical characteristics of participants. They were screened for AF using a smartphone-connected single-lead electrocardiography (ECG) device (KardiaMobile, AliveCor). Probable AF was confirmed by 12-lead ECG. Multivariable logistic regression was used to determine factors associated with AF. Data analysis was performed using Stata version 13 (StataCorp LLC). RESULTS/UNASSIGNED:< .001) were independently associated with AF. CONCLUSION/UNASSIGNED:AF is common and underdiagnosed and carries a high stroke risk among elderly outpatients in Tanzania. Opportunistic screening of the elderly for AF in low-resource countries with 1-lead ECG is feasible and has the potential to reduce the burden of stroke.

Spine surgery missions in low-resource settings can meaningfully close global gaps in access to care but require careful logistical and relational planning. Drawing on collaborative missions within 2 Jamaican hospital systems under the Back to Healing nonprofit initiative, we review financial realities, logistical barriers, ethical responsibilities, and human dimensions that define high-impact missions. Success depends on financial planning and transparency, equipment logistics, intraoperative adaptability, and operating room throughput, but equally on sustained partnership with host institutions and local teams. Patient selection carries particular ethical weight under resource constraints, and training and research opportunities further support long-term collaboration. Practical recommendations are offered for surgeons and institutions planning missions.

Aggression is an innate behavior conserved across species, serving as a critical means to compete for food, mating opportunities, and other essential resources. A central question in aggression research is the extent to which inter-individual variability in aggression is shaped by genetic factors. Here, we examine aggressive behaviors in naïve male mice across seven genetically defined strains and find large cross-strain differences. We find a tight correlation between aggressiveness and anxiety levels across strains, but not within the same strain, suggesting strong genetic control of both traits. Pharmacologically elevating anxiety in high-aggression strains reduces aggression, revealing a causal relationship between these behaviors. We further demonstrate that differences in the synaptic and cellular properties of neurons in the ventrolateral ventromedial hypothalamus (VMHvl) largely account for cross-strain variability in male aggression, and that chemogenetically increasing VMHvl excitability enhances attack behavior in a low-aggression strain. Together, these findings reveal the neuronal implementation of the genetic control of innate aggression level.