Acceptability and feasibility of screening with a pediatric care provider-led social determinants of health identification tool.

BACKGROUND: Complex social determinants of health may not be easily recognized by health care providers and pose a unique challenge in the vulnerable pediatric population where patients may not be able to advocate for themselves. The goal of this study was to examine the acceptability and feasibility of health care providers using an integrated brief pediatric screening tool in primary care and hospital settings. METHODS: The framework of the Child and Adolescent Needs and Strengths (CANS) and Pediatric Intermed tools was used to inform the selection of items for the 9-item Child and Adolescent Needs and Strengths-Pediatric Complexity Indicator (CANS-PCI). The tool consisted of three domains: biological, psychological, and social. Semi-structured interviews were conducted with health care providers in pediatric medical facilities in Ottawa, Canada. A low inference and iterative thematic synthesis approach was used to analyze the qualitative interview data specific to acceptability and feasibility. RESULTS: Thirteen health care providers participated in interviews. Six overarching themes were identified: acceptability, logistics, feasibility, pros/cons, risk, and privacy. Overall, participants agreed that a routine, trained provider-led pediatric tool for the screening of social determinants of health is important (n = 10, 76.9%), acceptable (n = 11; 84.6%), and feasible (n = 7, 53.8%). INTERPRETATION: Though the importance of social determinants of health are widely recognized, there are limited systematic methods of assessing, describing, and communicating amongst health care providers about the biomedical and psychosocial complexities of pediatric patients. Based on this study's findings, implementation of a brief provider-led screening tool into pediatric care practices may contribute to this gap.

Epigenetic priming by hypomethylation enhances the immunogenic potential of tolinapant in T-cell lymphoma.

Programmed cell death mechanisms are important for the regulation of tumor development and progression. Evasion of and resistance to apoptosis are significant factors in tumorigenesis and drug resistance. Bypassing apoptotic pathways and eliciting another form of regulated cell death, namely necroptosis, an immunogenic cell death (ICD), may override apoptotic resistance. Here, we present the mechanistic rationale for combining tolinapant, an antagonist of the inhibitor of apoptosis proteins (IAP), with decitabine, a hypomethylating agent (HMA), in T-cell lymphoma (TCL). Tolinapant treatment alone of TCL cells in vitro and in syngeneic in vivo models demonstrated that ICD markers can be upregulated, and we have shown that epigenetic priming with decitabine further enhances this effect. The clinical relevance of ICD markers was confirmed by the direct measurement of plasma proteins from peripheral TCL patients treated with tolinapant. We showed increased levels of necroptosis in TCL lines, along with the expression of cancer-specific antigens (such as cancer testis antigens) and increases in genes involved in interferon signaling induced by HMA treatment, together deliver a strong adaptive immune response to the tumor. These results highlight the potential of a decitabine and tolinapant combination for TCL and could lead to clinical evaluation.

TiME OUT: Time-specific machine-learning evaluation to optimize ultramassive transfusion.

BACKGROUND: Ultramassive transfusion (UMT) is a resource-demanding intervention for trauma patients in hemorrhagic shock, and associated mortality rates remains high. Current research has been unable to identify a transfusion ceiling or point where UMT transitions from lifesaving to futility. Furthermore, little consideration has been given to how time-specific patient data points impact decisions with ongoing high-volume resuscitation. Therefore, this study sought to use time-specific machine learning modeling to predict mortality and identify parameters associated with survivability in trauma patients undergoing UMT. METHODS: A retrospective review was conducted at a Level I trauma (2018-2021) and included trauma patients meeting criteria for UMT, defined as ≥20 red blood cell products within 24 hours of admission. Cross-sectional data were obtained from the blood bank and trauma registries, and time-specific data were obtained from the electronic medical record. Time-specific decision-tree models predicating mortality were generated and evaluated using area under the curve. RESULTS: In the 180 patients included, mortality rate was 40.5% at 48 hours and 52.2% overall. The deceased received significantly more blood products with a median of 71.5 total units compared with 55.5 in the survivors ( p < 0.001) and significantly greater rates of packed red blood cells and fresh frozen plasma at each time interval. Time-specific decision-tree models predicted mortality with an accuracy as high as 81%. In the early time intervals, hemodynamic stability, undergoing an emergency department thoracotomy, and injury severity were most predictive of survival, while, in the later intervals, markers of adequate resuscitation such as arterial pH and lactate level became more prominent. CONCLUSION: This study supports that the decision of "when to stop" in UMT resuscitation is not based exclusively on the number of units transfused but rather the complex integration of patient and time-specific data. Machine learning is an effective tool to investigate this concept, and further research is needed to refine and validate these time-specific decision-tree models. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Detection of traumatic stress in the presence of traumatic experiences: the role of resilience factors in foster care children five years or younger.

BACKGROUND: Children less than five years of age comprised approximately 30% in 2020 of foster care entries in the United States, and they are consistently the largest foster care entry group. Very young children can respond differently to the same adverse life events. Detection of complex interpersonal traumas is core to providing appropriate interventions and prevention of reoccurring negative outcomes in these children. METHODS: Children who (1) were identified as having experienced complex interpersonal trauma, but (2) who did not have traumatic stress symptoms were identified using Child and Adolescent Needs and Strengths data in a large midwestern state from 2010 to 2021. A logistic model was fit to determine the effect of cumulative traumatic exposures (e.g., adverse childhood experiences such that increased events were hypothesized to predict an increased likelihood of symptomatic detection. We conducted a latent class analysis to understand the relationship between traumatic experiences, asset-based factors, and the detection of traumatic stress in children aged five years and under who had exposure to traumatic events but did not have detectable traumatic stress symptoms. RESULTS: We detected three classes within this population of very young children, who were described as "resilient" (demonstrating asset-based resilience when faced with traumatic experiences), "missed" (those who exhibit behavioral and mental health types like those with detected traumatic stress symptoms but who were not detected as such), and "unfolding". Very young children do demonstrate asset-based resilience when faced with traumatic experiences. CONCLUSIONS: Detection of traumatic stress may be more difficult in young children. It is important to assess both traumatic stress and strengths to ensure that children who are resilient after exposure to traumatic experiences (i.e., do not demonstrate traumatic stress symptoms) are not referred to unnecessary interventions. Additional educational approaches are needed to help caseworkers identify symptoms of traumatic stress that mirror symptoms of other behavioral and emotional challenges. Precision medicine approaches are required to best match the interventions to specific needs of young children. Recognition of resilience in very young children is critical for designing systems that customize approaches of trauma-informed care.

Ap-type dopable ultrawide-bandgap oxide.

A major shortcoming of ultrawide-bandgap (UWBG) semiconductors is unipolar doping, in which eithern-type orp-type conductivity is typically possible, but not both within the same material. For UWBG oxides, the issue is usually thep-type conductivity, which is inhibited by a strong tendency to form self-trapped holes (small polarons) in the material. Recently, rutile germanium oxide (r-GeO2), with a band gap near 4.7 eV, was identified as a material that might break this paradigm. However, the predicted acceptor ionization energies are still relatively high (∼0.4 eV), limitingp-type conductivity. To assess whether r-GeO2is an outlier due to its crystal structure, the properties of a set of rutile oxides are calculated and compared. Hybrid density functional calculations indicate that rutile TiO2and SnO2strongly trap holes at acceptor impurities, consistent with previous work. Self-trapped holes are found to be unstable in r-SiO2, a metastable polymorph that has a band gap near 8.5 eV. Group-III acceptor ionization energies are also found to be lowest among the rutile oxides and approach those of GaN. Acceptor impurities have sufficiently low formation energies to not be compensated by donors such as oxygen vacancies, at least under O-rich limit conditions. Based on the results, it appears that r-SiO2has the potential to exhibit the most efficientp-type conductivity when compared to other UWBG oxides.

Child Mental Health Services Access and Efficacy Post-Disaster: A Scoping Review.

INTRODUCTION: The increased threat of natural disasters makes understanding the relationship between community resources and children's mental health critical. Mental health care efficacy and access are crucial to assessing the quality of community mental health care availability. OBJECTIVES: The primary objective of this scoping review is to investigate the relationship between children's mental health and community mental health resource efficacy and accessibility after a major disaster. METHODS: Conducted a systematic search to identify epidemiologic and health service utilization studies assessing the relationship between disasters and subsequent health service utilization amongst children and adolescents. RESULTS: The research returned 1682 potentially relevant studies and 31 articles were selected based on identified criteria from pre-selected databases. CONCLUSION: The studies conclude a gender and age-based disparity in access and efficiency of children's mental health services. The studies also identify the need for greater resource distribution and organizational structure.

Creating the necessary infrastructure for a trauma-informed system of care for children and youth.

Understanding and addressing the impact of adverse life events is an important priority in the design of helping systems. However, creating trauma-informed systems requires efforts to embed effective trauma-informed work in routine practice. This article discusses a model for developing trauma-informed systems using the Transformational Collaborative Outcomes Management (TCOM) framework, a strategy for engineering person-centered care. Person-centered care is naturally congruent with trauma-informed care. We describe the initial stages of implementation of a trauma-informed standardized assessment process to support the sustained evolution of trauma-informed care. Distinguishing between traumatic experiences and traumatic stress is fundamental to an effective trauma-informed system. We describe two sets of analyses-one in a statewide child welfare system and the other in a statewide behavioral health system. These projects found opportunities in the analysis of the detection of traumatic stress based on traumatic experiences to inform practice and policy. Being trauma-informed in child welfare is distinct from being trauma-informed in behavioral health. In child welfare, it appears that a number of children are resilient in the face of traumatic experiences and do not require trauma treatment interventions. However, delayed and missed traumatic stress responses are common. In behavioral health, misses often occur among adolescents, particularly boys, who engage in acting out behavior. Opportunities for the ongoing development of trauma-informed systems using the TCOM framework are discussed.

Is There Really a Difference in Outcomes between Men and Women with Hepatocellular Cancer?

Hepatocellular carcinoma (HCC) is a male-dominated disease. Currently, gender differences remain incompletely defined. Data from the state tumor registry were used to investigate differences in demographics, comorbidities, treatment patterns, and cancer-specific survival (HSS) among HCC patients according to gender. Additional analyses were performed to evaluate racial differences among women with HCC. 2627 patients with HCC were included; 498 (19%) were women. Women were mostly white (58%) or African American (39%)-only 3.8% were of another or unknown race. Women were older (65.1 vs. 61.3 years), more obese (33.7% vs. 24.2%), and diagnosed at an earlier stage (31.7% vs. 28.4%) than men. Women had a lower incidence of liver associated comorbidities (36.1% vs. 43%), and more often underwent liver-directed surgery (LDS; 27.5% vs. 22%). When controlling for LDS, no survival differences were observed between genders. African American women had similar HSS rates compared to white women (HR 1.14 (0.91,1.41), p = 0.239) despite having different residential and treatment geographical distributions. African American race and age >65 were predictive for worse HSS in men, but not in women. Overall, women with HCC undergo more treatment options-likely because of the earlier stage of the cancer and/or less severe underlying liver disease. However, when controlling for similar stages and treatments, HCC treatment outcomes were similar between men and women. African American race did not appear to influence outcomes among women with HCC as it did in men.

SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling.

The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity. Accordingly, we performed a high-throughput screening matrix to identify synergistic drug combinations with birinapant. SMAC mimetics in combination with an HDAC inhibitor showed remarkable synergy and was, therefore, selected for further evaluation. We show here that this synergy observed both in vitro and in vivo results from multiple convergent pathways to include increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling. These findings provide a rationale for the integration of SMAC mimetics and HDAC inhibitors in clinical trials for recurrent ovarian cancer where treatment options are still limited.

Safe and Appropriate Minimally Invasive and Robotic Esophagectomy in a Community Cancer Center.

OBJECTIVES: Minimally invasive esophagectomy is a technically challenging procedure that been associated with better outcomes at high-volume tertiary care centers. Louisiana is one of the most impoverished states, and travel to a "destination center" is not an option for many patients. We hypothesize that patients can obtain excellent surgical outcomes following MIE in a comprehensive community cancer center. METHODS: We identified all patients who underwent totally robotic MIE by a single surgeon at our center from July 2018 to November 2020. All cases were performed using totally robotic Ivor Lewis technique with intrathoracic isoperistaltic esophagogastrostomy. Incidence, demographics, treatment, and outcomes were compared before and after first 10 cases using Student's t-test. RESULTS: We identified 21 patients: 16 male and 5 female. Mean age 65 (49-85). 19 patients underwent MIE for malignancy; 18 of these received neoadjuvant therapy. OR time decreased following the first 10 cases (502 vs. 408 minutes, P = 0.0127). Average lymph node harvest was 14 (4-23 nodes). Positive margin rate was 0%. Mean length of stay trended towards a decrease after the first 10 cases (11 vs. 9 days, P = NS). There were no leaks or strictures. Thirty-day readmission was five patients. Ninety-day mortality was 0%. CONCLUSION: These outcomes rival those of high-volume referral centers and demonstrate that totally robotic MIE can be performed with excellent outcomes in community center. These data call into question the need for all patients to travel to "destination centers" to receive complex oncologic surgery.

Evaluation of Telehealth in Child Behavioral Health Services Delivery During the COVID-19 Pandemic.

OBJECTIVE: The authors quantified the impact of the use of telehealth services on patient-level clinical outcomes among children with complex behavioral and emotional needs in Idaho during the COVID-19 pandemic by comparing data collected in 2020 with data for the same months in 2019. METHODS: Longitudinal statewide data of Child and Adolescent Needs and Strengths (CANS) assessments were extracted from Idaho's mental and behavioral health system. Prepandemic assessments were matched to midpandemic assessments. A linear mixed-effect model was used to explore four child-level outcomes: psychosocial strengths-building rate, rate of need resolution within a life-functioning domain, rate of need resolution within a behavior-emotional domain, and rate of need resolution within a high-risk behaviors domain. RESULTS: The number of new patients admitted to Idaho's state-funded mental and behavioral health program decreased almost twofold from April-December 2019 to April-December 2020 (N=4,458 vs. 2,794). For most children with complex needs, the use of telehealth was as effective in terms of strengths building and needs resolution as in-person services; for children whose caregivers had issues with access to transportation, availability of telehealth services improved outcomes for the children. CONCLUSIONS: The COVID-19 pandemic in 2020 was associated with a dramatic drop in the number of children served by Idaho's mental health program. Telehealth may effectively bridge mental health service delivery while patients and providers work toward the resolution of transportation issues or may serve as a more acceptable permanent format of service delivery for some populations.

The RIPK3 Scaffold Regulates Lung Inflammation During Pseudomonas Aeruginosa Pneumonia.

RIPK3 (receptor-interacting protein kinase 3) activity triggers cell death via necroptosis, whereas scaffold function supports protein binding and cytokine production. To determine if RIPK3 kinase or scaffold domains mediate pathology during Pseudomonas aeruginosa infection, control mice and those with deletion or mutation of RIPK3 and associated signaling partners were subjected to Pseudomonas pneumonia and followed for survival or killed for biologic assays. Murine immune cells were studied in vitro for Pseudomonas-induced cytokine production and cell death, and RIPK3 binding interactions were blocked with the viral inhibitor M45. Human tissue effects were assayed by infecting airway epithelial cells with Pseudomonas and measuring cytokine production after siRNA inhibition of RIPK3. Deletion of RIPK3 reduced inflammation and decreased animal mortality after Pseudomonas pneumonia. RIPK3 kinase inactivation did neither. In cell culture, RIPK3 was dispensable for cell killing by Pseudomonas and instead drove cytokine production that required the RIPK3 scaffold domain but not kinase activity. Blocking the RIP homotypic interaction motif (RHIM) with M45 reduced the inflammatory response to infection in vitro. Similarly, siRNA knockdown of RIPK3 decreased infection-triggered inflammation in human airway epithelial cells. Thus, the RIPK3 scaffold drives deleterious pulmonary inflammation and mortality in a relevant clinical model of Pseudomonas pneumonia. This process is distinct from kinase-mediated necroptosis, requiring only the RIPK3 RHIM. Inhibition of RHIM signaling is a potential strategy to reduce lung inflammation during infection.

Cell death proteins in sepsis: key players and modern therapeutic approaches.

Cell death proteins play a central role in host immune signaling during sepsis. These interconnected mechanisms trigger cell demise via apoptosis, necroptosis, and pyroptosis while also driving inflammatory signaling. Targeting cell death mediators with novel therapies may correct the dysregulated inflammation seen during sepsis and improve outcomes for septic patients.

Palliative care reduces emergency room visits and total hospital days among patients with metastatic HPB and GI cancers.

Palliative care services (PCS) have improved quality of life for patients across various cancer subtypes. Minimal data exists regarding PCSfor metastatic hepatopancreaticobiliary (HPB) and gastrointestinal (GI) cancers. We assessed the impact of PCS on emergency department visits, hospital admissions, and survival among these patients. Patients with metastatic HPB and GI cancer referred to outpatient PCS between 2014 and 2018 at a single institution were included. We compared the demographics, outcomes, and end-of-life indicators between those who did and did not receive PCS. The study included 183 patients, with 118 (64.5%) having received PCS. There were no significant differences in age, gender, race, marital status, or insurance. Those receiving PCS were more likely to have colorectal cancer (p = 0.0082) and receive chemotherapy (p = 0.0098). On multivariate analysis, PCS was associated with fewer ED visits (p = 0.0319), hospital admissions (p = 0.0002), and total inpatient hospital days (p < 0.0001) per 30 days of life. Overall survival was greater among patients receiving PCS (HR: 0.65 (0.46-0.92)). Outpatient PCS for patients with metastatic HPB and GI cancer is associated with fewer emergency department visits, hospital admissions, and inpatient hospital days, and improved overall survival.

The Impact of the COVID-19 Pandemic on the Transplant Pharmacist Workforce.

Background: The COVID-19 pandemic has placed an unprecedented strain on the US healthcare system, greatly impacting transplant centers. Objective: The purpose of this survey was to evaluate the impact of the COVID-19 pandemic on the transplant pharmacist workforce. Methods: A survey was disseminated electronically to assess the impact of the COVID-19 pandemic on the transplant pharmacist workforce. Respondents were asked to give background regarding transplant center, patient, population, and departmental staffing. Results: There were 67 total respondents from 56 transplant centers. In response to the COVID-19 pandemic, 55% of centers reported stopping non-life saving transplants, and a majority (89%) stopped living donor transplants altogether. The banning of caregivers on-site during education, reduction of bedside education teaching, and cancelling of group teaching classes occurred at 46%, 40%, and 22% of centers, respectively. Consequently, 42% of pharmacists surveyed felt that their confidence in patient and caregiver's understanding of medications had decreased since these changes have been implemented. Conclusions: Pharmacist perception of patient and caregiver understanding of transplant medications has decreased since before the COVID-19 pandemic. As health systems strategize resource allocation throughout the pandemic, the importance of patient education must be prioritized to sustain and improve transplant outcomes.

Junctional adhesion molecule-A deletion increases phagocytosis and improves survival in a murine model of sepsis.

Expression of the tight junction-associated protein junctional adhesion molecule-A (JAM-A) is increased in sepsis, although the significance of this is unknown. Here, we show that septic JAM-A -/- mice have increased gut permeability, yet paradoxically have decreased bacteremia and systemic TNF and IL-1ß expression. Survival is improved in JAM-A-/- mice. However, intestine-specific JAM-A-/- deletion does not alter mortality, suggesting that the mortality benefit conferred in mice lacking JAM-A is independent of the intestine. Septic JAM-A-/- mice have increased numbers of splenic CD44hiCD4+ T cells, decreased frequency of TNF+CD4+ cells, and elevated frequency of IL-2+CD4+ cells. Septic JAM-A-/- mice have increased numbers of B cells in mesenteric lymph nodes with elevated serum IgA and intraepithelial lymphocyte IgA production. JAM-A-/- × RAG-/- mice have improved survival compared with RAG-/- mice and identical mortality as WT mice. Gut neutrophil infiltration and neutrophil phagocytosis are increased in JAM-A-/- mice, while septic JAM-A-/- mice depleted of neutrophils lose their survival advantage. Therefore, increased bacterial clearance via neutrophils and an altered systemic inflammatory response with increased opsonizing IgA produced through the adaptive immune system results in improved survival in septic JAM-A-/- mice. JAM-A may be a therapeutic target in sepsis via immune mechanisms not related to its role in permeability.

Impact of catch-up vaccinations on anti-HLA antibody response in pediatric kidney transplant candidates.

BACKGROUND: Efforts have been concentrated on improving vaccination administration during the pretransplant evaluation period. However, concern for human leukocyte antigen (HLA) sensitization subsequent to vaccination exists. METHODS: A retrospective review of pediatric kidney transplant candidates (PKTCs) ≤18 years old who had received vaccinations between February 1, 2017 and November 30, 2019 was conducted. Emergence of de novo anti-HLA antibody (HLA-Ab) 3-4 weeks postvaccinations detected by the Luminex single antigen bead assay (SAB) was evaluated. Outcomes assessed included change in the HLA-Ab mean fluorescence intensity (MFI) ≥25% from baseline, and change in preexisting HLA-Ab MFI strength, categorized as weak: 1000-2999; moderate: 3000-9999; and strong: ≥10 000. RESULTS: Sixty vaccinations were administered to 14 patients. Forty-one potential de novo HLA-Ab were detected in five patients. After additional antibody panel testing, 5/41 potential de novo HLA-Ab were determined to be HLA specific; the remaining 36 were deemed nonspecific. The 5 de novo HLA-Ab were observed in three patients and were deemed weak antibody (Ab). Median MFI showed a significant increase for nonspecific Ab, but not de novo HLA-Ab. Median MFI values were deemed transient at 7-10 week follow-up. No HLA-donor-specific Ab developed posttransplant in the patients who developed de novo HLA-Ab. CONCLUSION: Vaccination resulted in a transient increase in non-HLA-specific Ab. The majority of responses were non-HLA specific, hypothesized to be related to denatured antigens on single antigen beads. These data suggest limited clinical impact of vaccinations on the emergence of de novo HLA-Ab.

NIR-Based Intelligent Sensing of Product Yield Stress for High-Value Bioresorbable Polymer Processing.

PLA (polylactide) is a bioresorbable polymer used in implantable medical and drug delivery devices. Like other bioresorbable polymers, PLA needs to be processed carefully to avoid degradation. In this work we combine in-process temperature, pressure, and NIR spectroscopy measurements with multivariate regression methods for prediction of the mechanical strength of an extruded PLA product. The potential to use such a method as an intelligent sensor for real-time quality analysis is evaluated based on regulatory guidelines for the medical device industry. It is shown that for the predictions to be robust to processing at different times and to slight changes in the processing conditions, the fusion of both NIR and conventional process sensor data is required. Partial least squares (PLS), which is the established 'soft sensing' method in the industry, performs the best of the linear methods but demonstrates poor reliability over the full range of processing conditions. Conversely, both random forest (RF) and support vector regression (SVR) show excellent performance for all criteria when used with a prior principal component (PC) dimension reduction step. While linear methods currently dominate for soft sensing of mixture concentrations in highly conservative, regulated industries such as the medical device industry, this work indicates that nonlinear methods may outperform them in the prediction of mechanical properties from complex physicochemical sensor data. The nonlinear methods show the potential to meet industrial standards for robustness, despite the relatively small amount of training data typically available in high-value material processing.

Outcomes of Breast-Conserving Surgery Plus Radiation vs Mastectomy for All Subtypes of Early-Stage Breast Cancer: Analysis of More Than 200,000 Women.

BACKGROUND: Recent large retrospective studies suggest that breast-conserving therapy (BCT) plus radiation yielded better outcomes than mastectomy (MST) for women with early-stage breast cancer (ESBC). Whether this is applicable to the different subtypes is unknown. We hypothesize that BCT yielded better outcomes than MST, regardless of subtypes of ESBC. STUDY DESIGN: Data on women diagnosed with first primary stage I to II breast cancer between 2010 and 2017 who underwent either BCT or MST were from the population-based 18 Surveillance, Epidemiology, and End Results cancer registries. The Kaplan-Meier method was used to estimate unadjusted 5-year overall survival and cause-specific survival. Univariable and multivariable Cox proportional regression models were used to determine the impact of surgical approaches on the hazard ratios adjusted for relevant demographic and clinical variables for molecular subtype (luminal A, luminal B, triple-negative, and HER2 enriched). RESULTS: Of the 214,128 patients with breast cancer, 41.6% received MST. For the different subtypes, BCT yielded better 5-year overall survival and cause-specific survival than MST. After adjusting for demographic and clinical factors, the risk of overall survival and cause-specific survival was still statistically significantly higher among MST recipients than BCT recipients for all subtypes. CONCLUSIONS: BCT yielded better survival rates than mastectomy for women with all subtypes of ESBC. The role of mastectomy for women with ESBC should be reassessed in future clinical trials.

Expression of the preadipocyte marker ZFP423 is dysregulated between well-differentiated and dedifferentiated liposarcoma.

BACKGROUND: Well-differentiated and dedifferentiated liposarcomas are rare soft tissue tumors originating in adipose tissue that share genetic abnormalities but have significantly different metastatic potential. Dedifferentiated liposarcoma (DDLPS) is highly aggressive and has an overall 5-year survival rate of 30% as compared to 90% for well-differentiated liposarcoma (WDLPS). This discrepancy may be connected to their potential to form adipocytes, where WDLPS is adipogenic but DDLPS is adipogenic-impaired. Normal adipogenesis requires Zinc Finger Protein 423 (ZFP423), a transcriptional coregulator of Perixosome Proliferator Activated Receptor gamma (PPARG2) mRNA expression that defines committed preadipocytes. Expression of ZFP423 in preadipocytes is promoted by Seven-In-Absentia Homolog 2 (SIAH2)-mediated degradation of Zinc Finger Protein 521 (ZFP521). This study investigated the potential role of ZFP423, SIAH2 and ZFP521 in the adipogenic potential of WDLPS and DDLPS. METHODS: Human WDLPS and DDLPS fresh and paraffin-embedded tissues were used to assess the gene and protein expression of proadipogenic regulators. In parallel, normal adipose tissue stromal cells along with WDLPS and DDLPS cell lines were cultured, genetically modified, and induced to undergo adipogenesis in vitro. RESULTS: Impaired adipogenic potential in DDLPS was associated with reduced ZFP423 protein levels in parallel with reduced PPARG2 expression, potentially involving regulation of ZFP521. SIAH2 protein levels did not define a clear distinction related to adipogenesis in these liposarcomas. However, in primary tumor specimens, SIAH2 mRNA was consistently upregulated in DDLPS compared to WDLPS when assayed by fluorescence in situ hybridization or real-time PCR. CONCLUSIONS: These data provide novel insights into ZFP423 expression in adipogenic regulation between WDLPS and DDLPS adipocytic tumor development. The data also introduces SIAH2 mRNA levels as a possible molecular marker to distinguish between WDLPS and DDLPS.