Direct thrombin inhibitors fail to reverse the negative effects of heparin on lung growth and function after murine left pneumonectomy.

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.

A pneumonectomy model to study flow-induced pulmonary hypertension and compensatory lung growth.

In newborns, developmental disorders such as congenital diaphragmatic hernia (CDH) and specific types of congenital heart disease (CHD) can lead to defective alveolarization, pulmonary hypoplasia, and pulmonary arterial hypertension (PAH). Therapeutic options for these patients are limited, emphasizing the need for new animal models representative of disease conditions. In most adult mammals, compensatory lung growth (CLG) occurs after pneumonectomy; however, the underlying relationship between CLG and flow-induced pulmonary hypertension (PH) is not fully understood. We propose a murine model that involves the simultaneous removal of the left lung and right caval lobe (extended pneumonectomy), which results in reduced CLG and exacerbated reproducible PH. Extended pneumonectomy in mice is a promising animal model to study the cellular response and molecular mechanisms contributing to flow-induced PH, with the potential to identify new treatments for patients with CDH or PAH-CHD.

Inequities in Thyroid Cancer Care: Populations Most at Risk for Delays in Diagnosis and Treatment.

Background: Delays in treatment for thyroid cancer (TC) have been associated with higher overall mortality rates. However, few studies have explored the impact of health disparities on delayed presentation and treatment for TC. This study aims to investigate what patient sociodemographic factors contribute to delays in presentation and treatment of TC. Methods: Using the National Cancer Database, we identified patients diagnosed with well-differentiated TC between 2004 and 2016 who underwent thyroidectomy. Multivariable regression analyses were conducted to examine the impact of race, insurance status, income, and distance from treatment facility on time to surgical treatment, stage, the presence of distant metastases, and tumor size. Results: We identified 89,105 patients diagnosed with well-differentiated TC who underwent thyroidectomy. Nonwhite patients who were uninsured or had Medicare or Medicaid insurance were more likely to experience delays in care, present with higher stages at diagnosis, and have distant metastases and larger tumors at presentation. Distance from treatment facility was associated with delays in surgical treatment and higher stage at presentation. Conclusion: Delays in TC presentation and surgical treatment vary by race, insurance status, and patient location. Health care policies should focus on targeting at-risk individuals to reduce health care disparities in this disease.

A Digestive Cartridge Reduces Parenteral Nutrition Dependence and Increases Bowel Growth in a Piglet Short Bowel Model.

OBJECTIVE: To determine whether the use of an immobilized lipase cartridge (ILC) to hydrolyze fats in enteral nutrition (EN) reduces parenteral nutrition (PN) dependence in a porcine model of short bowel syndrome with intestinal failure (SBS-IF). BACKGROUND: SBS-IF occurs after intestinal loss resulting in malabsorption and PN dependence. Limited therapeutic options are available for achieving enteral autonomy. METHODS: Eleven Yorkshire piglets underwent 75% jejunoileal resection and were randomized into control (n=6) and treatment (n = 5) groups. PN was initiated postoperatively and reduced as EN advanced if predefined clinical criteria were fulfilled. Animals were studied for 14 days and changes in PN/EN calories were assessed. Intestinal adaptation, absorption, and nutrition were evaluated at the end of the study (day 15). Comparisons between groups were performed using analysis of covariance adjusted for baseline. RESULTS: ILC animals demonstrated a 19% greater reduction in PN calories ( P < 0.0001) and higher mean EN advancement (66% vs 47% of total calories, P < 0.0001) during the 14-day experiment. Treatment animals had increased intestinal length (19.5 vs 0.7%, P =0.03) and 1.9-fold higher crypt cell proliferation ( P =0.02) compared with controls. By day 15, ILC treatment resulted in higher plasma concentrations of glucagon-like peptide-2 ( P = 0.02), eicosapentaenoic acid ( P < 0.0001), docosahexaenoic acid ( P = 0.004), vitamin A ( P = 0.02), low-density lipoprotein ( P = 0.02), and high-density lipoprotein ( P = 0.04). There were no differences in liver enzymes or total bilirubin between the two groups. CONCLUSIONS: ILC use in conjunction with enteral feeding reduced PN dependence, improved nutrient absorption, and increased bowel growth in a porcine SBS-IF model. These results support a potential role for the ILC in clinical SBS-IF.

Delay in Surgery and Papillary Thyroid Cancer Survival in the United States: A SEER-Medicare Analysis.

INTRODUCTION: Delays in surgery and their impact on survival in papillary thyroid cancer (PTC) is unclear. We sought to investigate the association between time to surgery and survival in patients with PTC. METHODS: A total of 8170 Medicare beneficiaries with PTC who underwent thyroidectomy were identified within the Surveillance, Epidemiology, and End Results-Medicare linked data files between 1999 and 2018. Disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan-Meir analysis, and Cox proportional hazards models were specified to estimate the association between time to surgery and survival. RESULTS: Among 8170 patients with PTC, mean age 69.3 (SD+/- 11.4), 89.8% had surgery within the first 90 days, 7.8% had surgery 91 to 180 days from diagnosis, and 2.4% had surgery after 180 days. Increasing time to surgery was associated with increased mortality for OS in the >180-day group [adjusted hazard ratio (aHR) 1.24; 95% CI, 1.01-1.53]. Moreover, on stratification by summary stage, those with localized disease in the 91- to 180-day group increased risk by 25% (aHR 1.25; 95%CI, 1.05-1.51), and delaying over 180 days increased risk by 61% (aHR 1.61; 95%CI, 1.19-2.18) in OS. Those with localized disease in the >180-day group had almost 4 times the estimated rate of DSS mortality (aHR3.51; 95%CI, 1.68-7.32). When stratified by T stage, those with T2 disease in the >180 days group had double the estimated rate of all-cause mortality (aHR 2.0; 95% CI, 1.1-3.3) and almost triple the estimated rate of disease-specific mortality (aHR 2.7; 95% CI, 1.05-6.8). CONCLUSIONS: Delays in surgery for PTC may impact OS and DSS in localized disease, prior to nodal metastasis.

Effects of systemic anticoagulation in a murine model of compensatory lung growth.

BACKGROUND: Neonates with congenital diaphragmatic hernia (CDH) suffer from pulmonary hypoplasia (PH) and may require extracorporeal membrane oxygenation (ECMO) and anticoagulation, often with unfractionated heparin (UFH). UFH interacts with vascular endothelial growth factor (VEGF), a factor important in lung development. We investigated the effects of UFH, low molecular weight heparin (LMWH), and bivalirudin (BV) on a murine model of compensatory lung growth (CLG). METHODS: Proliferation and apoptosis were assessed in microvascular lung endothelial cells (HMVEC-L) treated with anticoagulants. Eight-week-old C57Bl/6J mice underwent left pneumonectomy and anticoagulation with low- or high-dose UFH, LMWH, BV, or saline control. Lung volume, pulmonary function tests, morphometrics, treadmill exercise tolerance, and pulmonary protein expression were examined. RESULTS: UFH and LMWH inhibited HMVEC-L proliferation. BV promoted proliferation and decreased apoptosis. UFH and LMWH-treated mice had reduced lung volume, total lung capacity, alveolar volume, and septal surface area compared to controls, while BV did not affect these measures. UFH and LMWH-treated mice had lower exercise tolerance compared to controls. CONCLUSIONS: UFH and LMWH impair pulmonary growth, alveolarization, and exercise tolerance, while BV does not. Alternative anticoagulants to heparin may be considered to improve functional outcomes for neonates with CDH and pulmonary hypoplasia. IMPACT: Unfractionated heparin and low molecular weight heparin may modify compensatory lung growth by reducing microvascular lung endothelial cell proliferation and affecting pulmonary angiogenic signaling. Functional effects of unfractionated heparin and low molecular weight heparin on murine compensatory lung growth include reduction in exercise tolerance. Bivalirudin, a direct thrombin inhibitor, may increase microvascular lung endothelial cell proliferation and preserves lung volume, alveolarization, and exercise tolerance in a murine compensatory lung growth model. Anticoagulants alternative to heparin should be further investigated for use in neonates with pulmonary hypoplastic diseases to optimize lung growth and development and improve outcomes.

Incidence and development of cholestasis in surgical neonates receiving an intravenous mixed-oil lipid emulsion.

BACKGROUND: Intestinal failure-associated liver disease (IFALD), initially manifesting as cholestasis, is a complication in neonates receiving parenteral nutrition (PN). Soybean oil lipid emulsion (SOLE), though implicated in IFALD, was the only US Food and Drug Administration (FDA)-approved initial intravenous lipid emulsion (ILE) for infants and children in the United States. A mixed-oil lipid emulsion (MOLE) gained popularity in patients at risk for IFALD and was recently FDA approved as an initial ILE in children. Given the presence of soybean oil in MOLE, we hypothesized that MOLE would not be effective at preventing cholestasis in surgical neonates. METHODS: Neonates with gastrointestinal surgical conditions necessitating PN for ≥14 days and receiving MOLE (SMOFlipid) from July 2016 to July 2019 were analyzed retrospectively. Unpaired and pair-matched historical surgical neonates treated with SOLE (Intralipid) served as controls. The primary outcome measure was development of cholestasis (direct bilirubin ≥2 mg/dl). RESULTS: Overall, 63% (10 of 16) of MOLE patients and 22% (30 of 136) of SOLE patients developed cholestasis after ≥14 days of therapy (P = 0.005). The latency to developing cholestasis was significantly shorter in MOLE patients compared with SOLE patients. CONCLUSION: In surgical neonates, MOLE may not prevent cholestasis and should not be considered hepatoprotective. Regardless of ILE source, all surgical neonates should be closely monitored for development of IFALD. To date, there is still no ILE able to prevent IFALD.

Targeting the lung endothelial niche to promote angiogenesis and regeneration: A review of applications.

Lung endothelial cells comprise the pulmonary vascular bed and account for the majority of cells in the lungs. Beyond their role in gas exchange, lung ECs form a specialized microenvironment, or niche, with important roles in health and disease. In early development, progenitor ECs direct alveolar development through angiogenesis. Following birth, lung ECs are thought to maintain their regenerative capacity despite the aging process. As such, harnessing the power of the EC niche, specifically to promote angiogenesis and alveolar regeneration has potential clinical applications. Here, we focus on translational research with applications related to developmental lung diseases including pulmonary hypoplasia and bronchopulmonary dysplasia. An overview of studies examining the role of ECs in lung regeneration following acute lung injury is also provided. These diseases are all characterized by significant morbidity and mortality with limited existing therapeutics, affecting both young children and adults.

Time to Surgery and Thyroid Cancer Survival in the United States.

BACKGROUND: Longer time to surgery worsens survival in multiple malignancies, including lung, colorectal, and breast cancers, but limited data exist for well-differentiated thyroid cancer. We sought to investigate the impact of time to surgery on overall survival in patients with papillary thyroid cancer. METHODS: In a retrospective cohort study of the National Cancer Database, we used Cox proportional hazard models to investigate overall survival as a function of time between diagnosis and surgery for adults with papillary thyroid cancer, adjusting for demographic, patient, and cancer-related variables. Time to surgery was investigated both as a continuous variable and as intervals of 0-90 days, 90-180 days, and > 180 days. Subgroup analyses were conducted by T stage. RESULTS: Overall, 103,812 adults with papillary thyroid cancer were included from 2004 to 2016. Median follow-up was 55.2 months (interquartile range 28.4-89.5). Increasing time to surgery was associated with increased mortality: delaying by 91-180 days increased the risk by 30% (adjusted hazard ratio [aHR] 1.30, 95% CI 1.19-1.43) and delaying by over 180 days increased the risk by 94% (aHR 1.94, 95% CI 1.68-2.24). Five-year overall survival was 95.7% for 0-90 days, 93.0% for 91-180 days, and 87.9% for over 180 days. On subgroup analysis, increasing delay was associated with worse overall survival for T1, T2, and T3 tumors, but not T4 tumors. CONCLUSIONS: Increasing time to surgery in papillary thyroid cancer is associated with reduced overall survival. Further research is necessary to assess the impact of surgical delay on disease-specific survival.

Time to surgery in thoracic cancers and prioritization during COVID-19: a systematic review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has overwhelmed hospital resources worldwide, requiring widespread cancellation of non-emergency operations, including lung and esophageal cancer operations. In the United States, while hospitals begin to increase surgical volume and tackle the backlog of cases, the specter of a "second wave," with a potential vaccine months to years away, highlights the ongoing need to triage cases based upon the risk of surgical delay. We synthesize the available literature on time to surgery and its impact on outcomes along with a critical appraisal of the released triage guidelines in the United States. METHODS: We performed a systematic literature review using PubMed according to preferred reporting items for systematic reviews and meta-analyses guidelines evaluating relevant literature from the past 15 years. RESULTS: Out of 679 screened abstracts, 12 studies investigating time to surgery in lung cancer were included. In stage I-II lung cancer, delayed resection beyond 6 to 8 weeks is consistently associated with lower survival. No identified evidence justifies a 2 cm cutoff for immediate versus delayed surgery. For stage IIIa lung cancer, time to surgery greater than 6 weeks after neoadjuvant therapy is similarly associated with worse survival. For esophageal cancer, 254 abstracts were screened and 23 studies were included. Minimal literature addresses primary esophagectomy, but time to surgery over 8 weeks is associated with lower survival. In the neoadjuvant setting, longer time to surgery is associated with increased pathologic complete response, but also decreased survival. The optimal window for esophagectomy following neoadjuvant therapy is 6 to 8 weeks. CONCLUSIONS: In the setting of the COVID-19 pandemic, timely resection of lung and esophageal cancer should be prioritized whenever possible based upon local resources and disease-burden.

Gastrointestinal Malignancies and the COVID-19 Pandemic: Evidence-Based Triage to Surgery.

BACKGROUND: The COVID-19 pandemic has led to widespread cancelation of electively scheduled surgeries, including for colorectal, pancreatic, and gastric cancer. The American College of Surgeons and the Society of Surgical Oncology have released guidelines for triage of these procedures. We seek to synthesize available evidence on delayed resection and oncologic outcomes, while also providing a critical assessment of the released guidelines. METHODS: A systematic review was conducted to identify literature between 2005 and 2020 investigating the impact of time to surgery on oncologic outcomes in colorectal, pancreatic, and gastric cancer. RESULTS: For colorectal cancer, 1066 abstracts were screened and 43 papers were included. In primarily resected colon cancer, delay over 30 to 40 days is associated with lower survival. In rectal cancer, time to surgery over 7 to 8 weeks following neoadjuvant therapy is associated with decreased survival. Three hundred ninety-four abstracts were screened for pancreatic cancer and nine studies were included. Two studies demonstrate increased unexpected progression with delayed surgery over 30 days. Out of 633 abstracts screened for gastric cancer, six studies were included. No identified study demonstrated worse survival with increased time to surgery. CONCLUSION: Moderate evidence suggests that delayed resection of colorectal cancer worsens survival; the impact of time to surgery on gastric and pancreatic cancer outcomes is uncertain. Early resection of gastrointestinal malignancies provides the best chance for curative therapy. During the COVID-19 pandemic, prioritization of procedures should account for available evidence on time to surgery and oncologic outcomes.

Parathyroid hormone as a marker for hypoperfusion in trauma: A prospective observational study.

BACKGROUND: Hyperparathyroidism is common in critical illness. Intact parathyroid hormone has a half-life of 3 minutes to 5 minutes due to rapid clearance by the liver, kidneys, and bone. In hemorrhagic shock, decreased clearance may occur, thus making parathyroid hormone a potential early marker for hypoperfusion. We hypothesized that early hyperparathyroidism predicts mortality and transfusion in trauma patients. METHODS: A prospective observational study was performed at a Level I trauma center in consecutive adult patients receiving the highest level of trauma team activation. Parathyroid hormone and lactic acid were added to the standard laboratory panel drawn in the trauma bay on arrival, before the administration of any blood products. The primary outcomes assessed were transfusion in 24 hours and mortality. RESULTS: Forty-six patients were included. Median age was 47 years, 82.6% were men, 15.2% suffered penetrating trauma, and 21.7% died. Patients who were transfused in the first 24 hours (n = 17) had higher parathyroid hormone (182.0 pg/mL vs. 73.5 pg/mL, p < 0.001) and lactic acid (4.6 pg/mL vs. 2.3 pg/mL, p = 0.001). Patients who did not survive to discharge (n = 10) also had higher parathyroid hormone (180.3 pg/mL vs. 79.3 pg/mL, p < 0.001) and lactic acid (5.5 mmol/L vs. 2.5 mmol/L, p = 0.001). For predicting transfusion in the first 24 hours, parathyroid hormone has an area under the receiver operating characteristic curve of 0.876 compared with 0.793 for lactic acid and 0.734 for systolic blood pressure. Parathyroid hormone has an area under the receiver operating characteristic curve of 0.875 for predicting mortality compared with 0.835 for lactic acid and 0.732 for systolic blood pressure. CONCLUSION: Hyperparathyroidism on hospital arrival in trauma patients predicts mortality and transfusion in the first 24 hours. Further research should investigate the value of parathyroid hormone as an endpoint for resuscitation. LEVEL OF EVIDENCE: Prognostic, level II.