Hepatic Resection as the Primary Treatment Method for Hepatocellular Carcinoma After Orthotopic Liver Transplantation.

BACKGROUND: Liver transplantation (LT) is the treatment of choice for end-stage liver disease and certain malignancies such as hepatocellular carcinoma (HCC). Data on the surgical management of de novo or recurrent tumors that develop in the transplanted allograft are limited. This study aimed to investigate the perioperative and long-term outcomes for patients undergoing hepatic resection for de novo or recurrent tumors after liver transplantation. METHODS: The study enrolled adult and pediatric patients from 12 centers across North America who underwent hepatic resection for the treatment of a solid tumor after LT. Perioperative outcomes were assessed as well as recurrence free survival (RFS) and overall survival (OS) for those undergoing resection for HCC. RESULTS: Between 2003 and 2023, 54 patients underwent hepatic resection of solid tumors after LT. For 50 patients (92.6 %), resection of malignant lesions was performed. The most common lesion was HCC (n = 35, 64.8 %), followed by cholangiocarcinoma (n = 6, 11.1 %) and colorectal liver metastases (n = 6, 11.1 %). The majority of the 35 patients underwent resection of HCC did not receive any preoperative therapy (82.9 %) or adjuvant therapy (71.4 %), with resection their only treatment method for HCC. During a median follow-up period of 50.7 months, the median RFS was 21.5 months, and the median OS was 49.6 months. CONCLUSION: Hepatic resection following OLT is safe and associated with morbidity and mortality rates that are comparable to those reported for patients undergoing resection in native livers. Hepatic resection as the primary and often only treatment modality for HCC following LT is associated with acceptable RFS and OS and should be considered in well selected patients.

Professionalism of Admitting and Consulting Services and Trauma Patient Outcomes.

OBJECTIVE: To determine whether trauma patients managed by an admitting or consulting service with a high proportion of physicians exhibiting patterns of unprofessional behaviors are at greater risk of complications or death. SUMMARY BACKGROUND DATA: Trauma care requires high-functioning interdisciplinary teams where professionalism, particularly modeling respect and communicating effectively, is essential. METHODS: This retrospective cohort study used data from 9 level I trauma centers that participated in a national trauma registry linked with data from a national database of unsolicited patient complaints. The cohort included trauma patients admitted January 1, 2012 through December 31, 2017. The exposure of interest was care by 1 or more high-risk services, defined as teams with a greater proportion of physicians with high numbers of patient complaints. The study outcome was death or complications within 30 days. RESULTS: Among the 71,046 patients in the cohort, 9553 (13.4%) experienced the primary outcome of complications or death, including 1875 of 16,107 patients (11.6%) with 0 high-risk services, 3788 of 28,085 patients (13.5%) with 1 high-risk service, and 3890 of 26,854 patients (14.5%) with 2+ highrisk services (P < 0.001). In logistic regression models adjusting for relevant patient, injury, and site characteristics, patients who received care from 1 or more high-risk services were at 24.1% (95% confidence interval 17.2% to 31.3%; P < 0.001) greater risk of experiencing the primary study outcome. CONCLUSIONS: Trauma patients who received care from at least 1 service with a high proportion of physicians modeling unprofessional behavior were at an increased risk of death or complications.

Prediction of Postoperative Deterioration in Cardiac Surgery Patients Using Electronic Health Record and Physiologic Waveform Data.

BACKGROUND: Postoperative hemodynamic deterioration among cardiac surgical patients can indicate or lead to adverse outcomes. Whereas prediction models for such events using electronic health records or physiologic waveform data are previously described, their combined value remains incompletely defined. The authors hypothesized that models incorporating electronic health record and processed waveform signal data (electrocardiogram lead II, pulse plethysmography, arterial catheter tracing) would yield improved performance versus either modality alone. METHODS: Intensive care unit data were reviewed after elective adult cardiac surgical procedures at an academic center between 2013 and 2020. Model features included electronic health record features and physiologic waveforms. Tensor decomposition was used for waveform feature reduction. Machine learning-based prediction models included a 2013 to 2017 training set and a 2017 to 2020 temporal holdout test set. The primary outcome was a postoperative deterioration event, defined as a composite of low cardiac index of less than 2.0 ml min-1 m-2, mean arterial pressure of less than 55 mmHg sustained for 120 min or longer, new or escalated inotrope/vasopressor infusion, epinephrine bolus of 1 mg or more, or intensive care unit mortality. Prediction models analyzed data 8 h before events. RESULTS: Among 1,555 cases, 185 (12%) experienced 276 deterioration events, most commonly including low cardiac index (7.0% of patients), new inotrope (1.9%), and sustained hypotension (1.4%). The best performing model on the 2013 to 2017 training set yielded a C-statistic of 0.803 (95% CI, 0.799 to 0.807), although performance was substantially lower in the 2017 to 2020 test set (0.709, 0.705 to 0.712). Test set performance of the combined model was greater than corresponding models limited to solely electronic health record features (0.641; 95% CI, 0.637 to 0.646) or waveform features (0.697; 95% CI, 0.693 to 0.701). CONCLUSIONS: Clinical deterioration prediction models combining electronic health record data and waveform data were superior to either modality alone, and performance of combined models was primarily driven by waveform data. Decreased performance of prediction models during temporal validation may be explained by data set shift, a core challenge of healthcare prediction modeling.

Delay in Hip Fracture Repair in the Elderly: A Missed Opportunity Towards Achieving Better Outcomes.

BACKGROUND: Hip fractures are a major cause of morbidity and mortality in the elderly. The American Academy of Orthopedic Surgeons (AAOS) recommends surgical repair within 48 hours of admission, as this is associated with lower postoperative mortality and complications. This study demonstrates the association between patient demographics, level of care, and hospital region to delay in hip fracture repair in the elderly. METHODS: The National Trauma Data Bank (NTDB) was queried for elderly patients (age >65 years) who underwent proximal femoral fracture repair. Identified patients were subcategorized into two groups: hip fracture repair in <48 hours, and hip fracture repair > 48 hours after admission. Patient and hospital characteristics were collected. Outcome variables were timed from the day of admission to surgery and inpatient mortality. RESULTS: Out of 69,532 patients, 28,031 were included after inclusion criteria were applied. 23,470 (83.7%) patients underwent surgical repair within 48 hours. The overall median time to procedure was 21 (interquartile range [IQR] 7-38) hours. Females were less likely to undergo a delay in hip fracture repair (odds ratio [OR; 95% confidence interval {CI}]: 0.82 [0.76-0.88], P< 0.05), and patients with higher Injury Severity Score (ISS ≥25) had higher odds of delay in surgical repair (OR; 95% CI: 1.56 [1.07-2.29], P< 0.05). Patients treated at hospitals in the Western regions of the United States had lower odds of delay, and those treated in the Northeast and the South had higher odds of delay compared to the hospitals in the Midwest (taken as standard). There was no association between trauma level designation and odds of undergoing delay in hip fracture repair. CONCLUSION: Variables related to patient demographic and hospital characteristics are associated with delay in hip fracture repair in the elderly. This study delineates key determinants of delay in hip fracture repair in the elderly patients.

Valproic Acid Protects Against Acute Kidney Injury in Hemorrhage and Trauma.

INTRODUCTION: Trauma is the leading cause of death among young people. These patients have a high incidence of kidney injury, which independently increases the risk of mortality. As valproic acid (VPA) treatment has been shown to improve survival in animal models of lethal trauma, we hypothesized that it would also attenuate the degree of acute kidney injury. METHODS: We analyzed data from two separate experiments where swine were subjected to lethal insults.  Model 1: hemorrhage (50% blood volume hemorrhage followed by 72-h damage control resuscitation). Model 2: polytrauma (traumatic brain injury, 40% blood volume hemorrhage, femur fracture, rectus crush and grade V liver laceration). Animals were resuscitated with normal saline (NS) +/- VPA 150 mg/kg after a 1-h shock phase in both models (n = 5-6/group). Serum samples were analyzed for creatinine (Cr) using colorimetry on a Liasys 330 chemistry analyzer. Proteomic analysis was performed on kidney tissue sampled at the time of necropsy. RESULTS: VPA treatment significantly (P < 0.05) improved survival in both models. (Model 1: 80% vs 20%; Model 2: 83% vs. 17%). Model 1 (Hemorrhage alone): Cr increased from a baseline of 1.2 to 3.0 in NS control animals (P < 0.0001) 8 h after hemorrhage, whereas it rose only to 2.1 in VPA treated animals (P = 0.004). Model 2 (Polytrauma): Cr levels increased from baseline of 1.3 to 2.5 mg/dL (P = 0.01) in NS control animals 4 h after injury but rose to only 1.8 in VPA treated animals (P = 0.02). Proteomic analysis of kidney tissue identified metabolic pathways were most affected by VPA treatment. CONCLUSIONS: A single dose of VPA (150 mg/kg) offers significant protection against acute kidney injury in swine models of polytrauma and hemorrhagic shock.

Assessment of the Cytoprotective Effects of High-Dose Valproic Acid Compared to a Clinically Used Lower Dose.

OBJECTIVE: Valproic acid (VPA) treatment improves survival in animal models of injuries on doses higher than those allowed by Food and Drug Administration (FDA). We investigated the proteomic alterations induced by a single high-dose (140mg/kg) of VPA (VPA140) compared to the FDA-approved dose of 30mg/kg (VPA30) in healthy humans. We also describe the proteomic and transcriptomic changes induced by VPA140 in an injured patient. We hypothesized that VPA140 would induce cytoprotective changes in the study participants. METHODS: Serum samples were obtained from healthy subjects randomized to two groups; VPA140 and VPA30 at 3 timepoints: 0h(baseline), 2h, and 24h following infusion(n = 3/group). Samples were also obtained from an injured patient that received VPA140 at 0h, 6h and 24h following infusion. Proteomic analyses were performed using liquid chromatography-mass spectrometry (LC-MS/MS), and transcriptomic analysis was performed using RNA-sequencing. Differentially expressed (DE) proteins and genes were identified for functional annotation and pathway analysis using iPathwayGuide and gene set enrichment analysis (GSEA), respectively. RESULTS: For healthy individuals, a dose comparison was performed between VPA140 and VPA30 groups at 2 and 24 h. Functional annotation showed that top biological processes in VPA140 versus VPA30 analysis at 2 h included regulation of fatty acid (P = 0.002) and ATP biosynthesis (P = 0.007), response to hypoxia (P = 0.017), cell polarity regulation (P = 0.031), and sequestration of calcium ions (P = 0.031). Top processes at 24 h in VPA140 versus VPA30 analysis included amino acid metabolism (P = 0.023), collagen catabolism (P = 0.023), and regulation of protein breakdown (P = 0.023). In the injured patient, annotation of the DE proteins in the serum showed that top biological processes at 2 h included neutrophil chemotaxis (P = 0.002), regulation of cellular response to heat (P = 0.008), regulation of oxidative stress (P = 0.008) and regulation of apoptotic signaling pathway (P = 0.008). Top biological processes in the injured patient at 24 h included autophagy (P = 0.01), glycolysis (P = 0.01), regulation of apoptosis (P = 0.01) and neuron apoptotic processes (P = 0.02). CONCLUSIONS: VPA140 induces cytoprotective changes in human proteome not observed in VPA30. These changes may be responsible for its protective effects in response to injuries.

Surgery Provider Perceptions on Telehealth Visits During the COVID-19 Pandemic: Room for Improvement.

BACKGROUND: COVID-19 has mandated rapid adoption of telehealth for surgical care. However, many surgical providers may be unfamiliar with telehealth. This study evaluates the perspectives of surgical providers practicing telehealth care during COVID-19 to help identify targets for surgical telehealth optimization. MATERIALS AND METHODS: At a single tertiary care center with telehealth capabilities, all department of surgery providers (attending surgeons, residents, fellows, and advanced practice providers) were emailed a voluntary survey focused on telehealth during the pandemic. Descriptive statistics and Mann-Whitney U analyses were performed as appropriate on responses. Text responses were thematically coded to identify key concepts. RESULTS: The completion rate was 41.3% (145/351). Providers reported increased telehealth usage relative to the pandemic (P < 0.001). Of respondents, 80% (116/145) had no formal telehealth training. Providers estimated that new patient video visits required less time than traditional visits (P = 0.001). Satisfaction was high for several aspects of video visits. Comparatively lower satisfaction scores were reported for the ability to perform physical exams (sensitive and nonsensitive) and to break bad news. The largest barriers to effective video visits were limited physical exams (55.6%; 45/81) and lack of provider or patient internet access/equipment/connection (34.6%; 28/81). Other barriers included ineffective communication and difficulty with fostering rapport. Concerns regarding video-to-telephone visit conversion were loss of physical exam/visual cues (34.3%; 24/70), less personal interactions (18.6%; 13/70), and reduced efficiency (18.6%; 13/70). CONCLUSIONS: Telehealth remains a new experience for surgical providers despite its expansion. Optimization strategies should target technology barriers and include specialized virtual exam and communication training.

The impact of intraoperative fluid management during laparoscopic donor nephrectomy on donor and recipient outcomes.

BACKGROUND: Intraoperative fluid management during laparoscopic donor nephrectomy (LDN) may have a significant effect on donor and recipient outcomes. We sought to quantify variability in fluid management and investigate its impact on donor and recipient outcomes. METHODS: A retrospective review of patients who underwent LDN from July 2011 to January 2016 with paired kidney recipients at a single center was performed. Patients were divided into tertiles of intraoperative fluid management (standard, high, and aggressive). Donor and recipient demographics, intraoperative data, and postoperative outcomes were analyzed. RESULTS: Overall, 413 paired kidney donors and recipients were identified. Intraoperative fluid management (mL/h) was highly variable with no correlation to donor weight (kg) (R = 0.017). The aggressive fluid management group had significantly lower recipient creatinine levels on postoperative day 1. However, no significant differences were noted in creatinine levels out to 6 months between groups. No significant differences were noted in recipient postoperative complications, graft loss, and death. There was a significant increase (P < 0.01) in the number of total donor complications in the aggressive fluid management group. CONCLUSIONS: Aggressive fluid management during LDN does not improve recipient outcomes and may worsen donor outcomes compared to standard fluid management.

Intestinal alkaline phosphatase to treat necrotizing enterocolitis.

BACKGROUND: Intestinal alkaline phosphatase (IAP) activity is decreased in necrotizing enterocolitis (NEC), and IAP supplementation prevents NEC development. It is not known if IAP given after NEC onset can reverse the course of the disease. We hypothesized that enteral IAP given after NEC induction would not reverse intestinal injury. MATERIALS AND METHODS: NEC was induced in Sprague-Dawley pups by delivery preterm followed by formula feedings with lipopolysaccharide (LPS) and hypoxia exposure and continued up to 4 d. IAP was added to feeds on day 2 until being sacrificed on day 4. NEC severity was scored based on hematoxylin and eosin-stained terminal ileum sections, and AP activity was measured using a colorimetric assay. IAP and interleukin-6 expression were measured using real time polymerase chain reaction. RESULTS: NEC pups' alkaline phosphatase (AP) activity was decreased to 0.18 U/mg compared with controls of 0.57 U/mg (P < 0.01). Discontinuation of LPS and hypoxia after 2 d increased AP activity to 0.36 U/mg (P < 0.01). IAP supplementation in matched groups did not impact total AP activity or expression. Discontinuing LPS and hypoxia after NEC onset improved intestinal injury scores to 1.14 compared with continued stressors, score 2.25 (P < 0.01). IAP supplementation decreased interleukin-6 expression two-fold (P < 0.05), though did not reverse NEC intestinal damage (P = 0.5). CONCLUSIONS: This is the first work to demonstrate that removing the source of NEC improves intestinal damage and increases AP activity. When used as a rescue treatment, IAP decreased intestinal inflammation though did not impact injury making it likely that IAP is best used preventatively to those neonates at risk.

Premalignant Lesions in the Kidney Transplant Candidate.

End-stage kidney disease patients who are referred for transplant undergo an extensive evaluation process to ensure their health prior to transplant due in part to the shortage of available organs. Although management and surveillance guidelines exist for malignancies identified in the transplant and waitlist populations, less is written about the management of premalignant lesions in this population. This review covers the less common premalignant lesions (intraductal papillary mucinous neoplasm, gastrointestinal stromal tumor, thymoma, and pancreatic neuroendocrine tumor) that can be found in the transplant candidate population. High-level evidence for the management of these rarer premalignant lesions in the transplant population is lacking, and this review extrapolates evidence from the general population and should not be a substitute for a multidisciplinary discussion with medical and surgical oncologists.

Nodular regenerative hyperplasia and liver transplantation: a systematic review.

Nodular regenerative hyperplasia (NRH) is a primary disease of the liver that may cause noncirrhotic portal hypertension. Common causes include autoimmune, hematologic, immune deficiency, and myeloproliferative disorders. Given the limited data regarding the development of NRH in contemporary immunosuppressive protocols and the occurrence of NRH post-liver transplantation, we systematically reviewed NRH as it pertains to liver transplantation. We performed a comprehensive search for NRH and transplantation. Nineteen studies were identified with relevant data for NRH as an indication for a liver transplant. Thirteen studies were identified with relevant data pertaining to NRH development after liver transplant. Pooled analysis revealed 0.9% of liver transplant recipients had NRH. A total of 113 patients identified with NRH underwent liver transplantation. Most series report transplants done after the failure of endoscopic banding and TIPS management of portal hypertension. Reported 5-year graft and patient survival ranged from 73%-78% and 73%-90%. The pooled incidence of NRH after liver transplant for all indications was 2.9% and caused complications of portal hypertension. Complications related to portal hypertension secondary to NRH are a rare indication for a liver transplant. NRH can develop at any time after liver transplantation often without an identifiable cause, which may lead to portal hypertension requiring treatment or even re-transplantation.

Prediction of postoperative cardiac events in multiple surgical cohorts using a multimodal and integrative decision support system.

Postoperative patients are at risk of life-threatening complications such as hemodynamic decompensation or arrhythmia. Automated detection of patients with such risks via a real-time clinical decision support system may provide opportunities for early and timely interventions that can significantly improve patient outcomes. We utilize multimodal features derived from digital signal processing techniques and tensor formation, as well as the electronic health record (EHR), to create machine learning models that predict the occurrence of several life-threatening complications up to 4 hours prior to the event. In order to ensure that our models are generalizable across different surgical cohorts, we trained the models on a cardiac surgery cohort and tested them on vascular and non-cardiac acute surgery cohorts. The best performing models achieved an area under the receiver operating characteristic curve (AUROC) of 0.94 on training and 0.94 and 0.82, respectively, on testing for the 0.5-hour interval. The AUROCs only slightly dropped to 0.93, 0.92, and 0.77, respectively, for the 4-hour interval. This study serves as a proof-of-concept that EHR data and physiologic waveform data can be combined to enable the early detection of postoperative deterioration events.

Early Treatment With a Single Dose of Mesenchymal Stem Cell Derived Extracellular Vesicles Modulates the Brain Transcriptome to Create Neuroprotective Changes in a Porcine Model of Traumatic Brain Injury and Hemorrhagic Shock.

BACKGROUND: Cell-based therapies using mesenchymal stem cell derived extracellular vesicles (EVs) improve neurologic outcomes in animal models of traumatic brain injury (TBI), stroke, and hemorrhage. Using a porcine 7-day survival model of TBI and hemorrhagic shock (HS), we previously demonstrated that EV-treatment was associated with reduced brain lesion size, neurologic severity score, and cerebral inflammation. However, the underlying cellular and genomic mechanisms remain poorly defined. We hypothesize that EV treatment modulates the brain transcriptome to enhance neuroprotection and neurorestoration following TBI + HS. METHODS: Swine were subjected to severe TBI (8-mm cortical impact) and HS (40% blood volume). After 1 h of shock, animals were randomized (n = 4/group) to treatment with either lactated Ringer's (LR) or LR + EV. Both groups received fluid resuscitation after 2 h of shock, and autologous packed red blood cells 5 h later.After 7-days, brains were harvested and RNA-sequencing was performed. The transcriptomic data were imported into the iPathway pipeline for bioinformatics analyses. RESULTS: 5,273 genes were differentially expressed in the LR + EV group versus LR alone (total 9,588 measured genes). Genes with the greatest upregulation were involved in synaptic transmission and neuronal development and differentiation, while downregulated genes were involved in inflammation. GO-terms experiencing the greatest modulation were involved in inflammation, brain development, and cell adhesion. Pathway analysis revealed significant modulation in the glutamatergic and GABAergic systems. Network analysis revealed downregulation of inflammation, and upregulation of neurogenesis, and neuron survival and differentiation. CONCLUSIONS: In a porcine model of TBI + HS, EV treatment was associated with an attenuation of cerebral inflammatory networks and a promotion of neurogenesis and neuroplasticity. These transcriptomic changes could explain the observed neuroprotective and neurorestorative properties associated with EV treatment.