IRF5 suppresses metastasis through the regulation of tumor-derived extracellular vesicles and pre-metastatic niche formation.

Metastasis is driven by extensive cooperation between a tumor and its microenvironment, resulting in the adaptation of molecular mechanisms that evade the immune system and enable pre-metastatic niche (PMN) formation. Little is known of the tumor-intrinsic factors that regulate these mechanisms. Here we show that expression of the transcription factor interferon regulatory factor 5 (IRF5) in osteosarcoma (OS) and breast carcinoma (BC) clinically correlates with prolonged survival and decreased secretion of tumor-derived extracellular vesicles (t-dEVs). Conversely, loss of intra-tumoral IRF5 establishes a PMN that supports metastasis. Mechanistically, IRF5-positive tumor cells retain IRF5 transcripts within t-dEVs that contribute to altered composition, secretion, and trafficking of t-dEVs to sites of metastasis. Upon whole-body pre-conditioning with t-dEVs from IRF5-high or -low OS and BC cells, we found increased lung metastatic colonization that replicated findings from orthotopically implanted cancer cells. Collectively, our findings uncover a new role for IRF5 in cancer metastasis through its regulation of t-dEV programming of the PMN.

Management of Persistent Low-Suspicion Cervical Lymphadenopathy in Pediatric Patients.

INTRODUCTION: Cervical lymphadenopathy in children is typically self-limited; however, the management of persistent lymphadenopathy remains unclear. This study aimed to evaluate the management and outcomes of patients with persistent cervical lymphadenopathy. METHODS: Single-institution, retrospective review of children <18 years undergoing ultrasound (US) for cervical lymphadenopathy from 2013 to 2021 was performed. Patients were stratified into initial biopsy, delayed biopsy, or no biopsy groups. Clinical characteristics and workup were compared, and multivariate analyses were performed to assess predictors of delayed biopsy. RESULTS: 568 patients were identified, with 493 patients having no biopsy, 41 patients undergoing initial biopsy, and 34 patients undergoing delayed biopsy. Presenting symptoms differed: no biopsy patients were younger, were more likely to present to the emergency department, and had clinical findings often associated with acute illness. Patients with USs revealing abnormal vascularity or atypical architecture were more likely to be biopsied. History of malignancy, symptoms >1 week but <3 months, and atypical or change in architecture on US was associated with delayed biopsy. Patients with long-term follow-up (LTF) were followed for a median of 99.0 days. Malignancies were identified in 12 patients (2.1%). All malignancies were diagnosed within 14 days of presentation, and no malignancies were identified in LTF. CONCLUSIONS: Patients with persistent low suspicion lymphadenopathy are often followed for long durations; however, in this cohort, no malignancies were diagnosed during LTF. We propose an algorithm of forgoing a biopsy and employing primary care surveillance and education, which may be appropriate for these patients in the proper setting.

Pediatric, Adolescent and Young Adult (AYA) Peritoneal and Pleural Mesothelioma: A National Cancer Database Review.

PURPOSE: Malignant peritoneal and pleural mesothelioma are rare in young patients, with a paucity of data regarding clinical characteristics and outcomes. We aimed to describe the clinical characteristics, treatment strategies, and outcomes for pediatric and adolescent/young adult (AYA) patients. METHODS: The National Cancer Database (NCDB) was queried for malignant peritoneal and pleural mesothelioma in pediatric and AYA patients (ages 0-39) from 2004 to 2019. Stratification was performed for pediatric (age 0-21) and young adult (age 22-39) patients. Chi-squared, multivariable cox regression, and Kaplan-Meier analyses were performed. RESULTS: We identified 570 total patients, 46 pediatric and 524 young adult, with mesothelioma (363 peritoneal and 207 pleural). There were significant differences in sex distribution as patients with peritoneal mesothelioma were more frequently female (63.1%). Patients with peritoneal mesothelioma were more likely to have radical surgery compared to pleural mesothelioma (56.7% v. 24.6%, respectively). A majority of patients with peritoneal and pleural mesothelioma received chemotherapy (66.4% and 61.4%, respectively). For peritoneal mesothelioma, surgical resection was associated with improved overall survival, whereas male sex, neoadjuvant chemotherapy, and radiation were associated with worse overall survival. For pleural mesothelioma, intraoperative chemotherapy was associated with improved overall survival, whereas Black race was associated with worse overall survival. Mean overall survival was greater for patients with peritoneal mesothelioma (125 months) compared to those with pleural mesothelioma (69 months), which remained significant after stratification of pediatric and young adult patients. CONCLUSION: By analyzing a large cohort of pediatric and AYA mesothelioma, this study highlights clinical, prognostic, and survival differences between peritoneal and pleural disease. LEVEL OF EVIDENCE: Level III. TYPE OF STUDY: Retrospective.

Role of interferon regulatory factor 5 (IRF5) in tumor progression: Prognostic and therapeutic potential.

Canonically, the transcription factor interferon regulatory factor 5 (IRF5) is a key mediator of innate and adaptive immunity downstream of pathogen recognition receptors such as Toll-like receptors (TLRs). Hence, dysregulation of IRF5 function has been widely implicated in inflammatory and autoimmune diseases. Over the last few decades, dysregulation of IRF5 expression has been also reported in hematologic malignancies and solid cancers that support a role for IRF5 in malignant transformation, tumor immune regulation, clinical prognosis, and treatment response. This review will provide an in-depth overview of the current literature regarding the mechanisms by which IRF5 functions as either a tumor suppressor or oncogene, its role in metastasis, regulation of the tumor-immune microenvironment, utility as a prognostic indicator of disease, and new developments in IRF5 therapeutics that may be used to remodel tumor immunity.

Trends and Disparities in Firearm Deaths Among Children.

BACKGROUND AND OBJECTIVES: In 2020, firearm injuries became the leading cause of death among US children and adolescents. This study aimed to evaluate new 2021 data on US pediatric firearm deaths and disparities to understand trends compared with previous years. METHODS: Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research was queried for firearm mortalities in children/adolescents from 2018 to 2021. Absolute mortality, death rates, and characteristics were reported. Death rates were defined per 100 000 persons in that population per year. Death rates across states were illustrated via geographic heat maps, and correlations with state poverty levels were calculated. RESULTS: In 2021, firearms continued to be the leading cause of death among US children. From 2018 to 2021, there was a 41.6% increase in the firearm death rate. In 2021, among children who died by firearms, 84.8% were male, 49.9% were Black, 82.6% were aged 15 to 19 years, and 64.3% died by homicide. Black children accounted for 67.3% of firearm homicides, with a death rate increase of 1.8 from 2020 to 2021. White children accounted for 78.4% of firearm suicides. From 2020 to 2021, the suicide rate increased among Black and white children, yet decreased among American Indian or Alaskan Native children. Geographically, there were worsening clusters of firearm death rates in Southern states and increasing rates in Midwestern states from 2018 to 2021. Across the United States, higher poverty levels correlated with higher firearm death rates (R = 0.76, P < .001). CONCLUSIONS: US pediatric firearm deaths increased in 2021, above the spike in 2020, with worsening disparities. Implementation of prevention strategies and policies among communities at highest risk is critical.

Surgical Rehabilitation for Research Residents: A Pilot Program to Offset Surgical Skill Decay.

OBJECTIVE: Select general surgery residents in the surgeon-scientist pipeline dedicate time away from clinical residency to conduct research. However, these research residents (RR) are vulnerable to operative skill decay. The aim of this study is to assess the feasibility of implementation and impact of an organized intervention designed to combat skill decay experienced by RR. DESIGN: RR were enrolled in a pilot Surgical Rehabilitation Program (SRP). The SRP is comprised of 12 cadaver-based simulation sessions and supplemented with Fundamentals of Laparoscopic Surgery-based simulation workouts. The RR were integrated with the clinical residents (CR) during the cadaver sessions and were subsequently performance tested, surveyed, and interviewed. SETTING: One academic general surgery residency program graduating 8 chief residents yearly in New York. PARTICIPANTS: General surgery CR and residents on dedicated research years. RESULTS: Data were collected for all local RR (n = 8) and 77% (n = 37) of CR. Local RR conducted research within the same health system that sponsors the residency. RR experienced gaps in training ranging from 2 to 4 years. All RR were permitted to moonlight on surgical services, however performed 0 operations and only 0.88 procedures on average per shift. Although RR performed similarly to level-matched CR on basic laparoscopic tasks, they required significantly more time on laparoscopic suturing-based skills than CR (p < 0.001). RR had significantly lower confidence levels precadaver sessions but gained confidence postcadaver sessions (p < 0.05), whereas CR confidence was unchanged. Regarding the SRP, qualitative interviews revealed major themes emphasizing the integration of RR, exposure to CR and faculty, technical skill development, maintenance of surgical know-how, and improved confidence for RR. CONCLUSIONS: The implementation of such structured interventions, like our SRP, aimed at supporting RR over gap years is essential to help residents maintain skills and confidence needed to achieve their goals of becoming surgeon scientists.

Hospital-Based Violence Intervention Programs to Reduce Firearm Injuries in Children: A Scoping Review.

INTRODUCTION: Hospital-based violence intervention programs (HVIPs) have shown promise in preventing reinjury and enhancing recovery from violent injuries, including those related to firearms. Historically, HVIPs have primarily focused on at-risk adolescents and young adults. The aim of this study is to perform a scoping review of HVIPs targeting children under the age of 18, describe the evidence supporting these programs, and deduce the potential impact of expanding HVIPs to younger children. METHODS: A scoping review was performed utilizing PubMed database with search terms "violence intervention program" and pediatric, or children, or youth. Articles were screened for youth-inclusive violence programs, and the literature was analyzed for program descriptions, evidence supporting interventions, and barriers to evaluation. RESULTS: 36 studies (covering 23 programs) were identified that met criteria (including patients ≤18 years old), with only 4 programs including children under 10. Many HVIPs utilize brief hospital interventions with longitudinal wraparound outpatient services. Despite heterogeneity in programs and studied outcomes, many HVIPs demonstrated positive outcomes, such as reduction of risk factors, decreased reinjury, decreased violent behaviors, decreased criminal justice involvement, and positive attitude or behavioral changes. Only a few studies reported increased odds of enrollment and positive impact in younger patients specifically. CONCLUSIONS: Children are an impressionable population in which HVIPs may have significant impact; however, there remains a gap in targeted programs. Given that firearm injuries are the leading cause of death in children and adolescents, priority should be given to piloting, implementing, and evaluating HVIPs among younger age groups. LEVEL OF EVIDENCE: Level IV.

Recovery of Skill Decay After COVID-19 Redeployments and Implications for Competency Attainment.

INTRODUCTION: The COVID-19 pandemic immediately interrupted procedural training. The lasting impact of reduced caseloads and service redeployments on procedural-resident training has been underexplored. This longitudinal study investigated the long-term perspectives of skill decay after short breaks in training and implications for ensuring resident competency attainment. METHODS: Web-based cross-sectional surveys distributed immediately after (June 2020) compared to 1 y after (July 2021) COVID-19 redeployments at two tertiary academic medical centers of an integrated health system in New York. Participants included general surgery, surgical subspecialty, and anesthesiology residents and faculty. RESULTS: Fifty-five residents and 33 faculty completed the survey. Ninety-point nine percent of residents and 36.4% of faculty were redeployed to COVID-ICUs. Sixty-three-point seven percent of residents and 75.0% of faculty reported a reduction in resident technical skills in the short-term, with significantly less (45.5% of residents and 21.2% of faculty) reporting persistent reduction in technical skill after 1 y (P = 0.001, P < 0.001). Seventy-five percent of residents and 100% of faculty were confident residents would be able to practice independently at the conclusion of their training. Sixty-five-point five percent of residents and 63.6% of faculty felt that residents experienced a durable improvement in critical care skills. Residents also reported a positive long-term impact on professional core competencies at 1 y. CONCLUSIONS: Longitudinal surveillance of residents after COVID-19 redeployments suggests washout of temporary skill decay and return of resident confidence upon resumption of traditional training. This may provide insight into the impact of other short-term training interruptions on resident skill and promote greater resident support upon training resumption to ensure competency attainment.

Prenatal Recognition of Hepatopulmonary Fusion in Right-Sided Congenital Diaphragmatic Hernia for Successful Operative Planning.

INTRODUCTION: Hepatopulmonary fusion (HPF) is a rare anomaly specifically associated with right-sided congenital diaphragmatic hernia (CDH). Fewer than 50 cases of HPF have been reported, most at the time of surgery or postmortem with an associated high morbidity and mortality rate. Prenatal diagnosis and optimal management of these rare cases have not been established. CASE PRESENTATION: We present a case of HPF diagnosed prenatally by fetal ultrasound and magnetic resonance imaging allowing postnatal and intraoperative planning leading to successful HPF separation and repair of the CDH. DISCUSSION: The prenatal recognition allowed the use of preoperative computed tomography angiogram and right cardiac catheterization to plan the surgical approach. Intraoperative ultrasound confirmed abnormal vasculature associated with the HPF facilitating a successful complete HPF separation and CDH repair was performed. The patient survived and continues to do well on long-term follow-up. Prenatal recognition may help reduce the high morbidity and mortality associated with HPF.