Combining immunotherapy with high-dose radiation therapy (HDRT) significantly inhibits tumor growth in a syngeneic mouse model of high-risk neuroblastoma.

Purpose: The mortality in patients with MYCN-amplified high-risk neuroblastoma remains greater than 50% despite advances in multimodal therapy. Novel therapies are urgently needed that requires preclinical evaluation in appropriate mice models. Combinatorial treatment with high-dose radiotherapy (HDRT) and immunotherapy has emerged as an effective treatment option in a variety of cancers. Current models of neuroblastoma do not recapitulate the anatomic and immune environment in which multimodal therapies can be effectively tested, and there is a need for an appropriate syngeneic neuroblastoma mice model to study interaction of immunotherapy with host immune cells. Here, we develop a novel syngeneic mouse model of MYCN-amplified neuroblastoma and report the relevance and opportunities of this model to study radiotherapy and immunotherapy. Materials and methods: A syngeneic allograft tumor model was developed using the murine neuroblastoma cell line 9464D derived a tumor from TH-MYCN transgenic mouse. Tumors were generated by transplanting 1 mm3 portions of 9464D flank tumors into the left kidney of C57Bl/6 mice. We investigated the effect of combining HDRT with anti-PD1 antibody on tumor growth and tumor microenvironment. HDRT (8 Gy x 3) was delivered by the small animal radiation research platform (SARRP). Tumor growth was monitored by ultrasound. To assess the effect on immune cells tumors sections were co-imuunostained for six biomarkers using the Vectra multispectral imaging platform. Results: Tumor growth was uniform and confined to the kidney in 100% of transplanted tumors. HDRT was largely restricted to the tumor region with minimal scattered out-of-field dose. Combinatorial treatment with HDRT and PD-1 blockade significantly inhibited tumor growth and prolonged mice survival. We observed augmented T-lymphocyte infiltration, especially CD3+CD8+ lymphocytes, in tumors of mice which received combination treatment. Conclusion: We have developed a novel syngeneic mouse model of MYCN amplified high-risk neuroblastoma. We have utilized this model to show that combining immunotherapy with HDRT inhibits tumor growth and prolongs mice survival.

Weight loss one year after laparoscopic roux-en-Y gastric bypass is not dependent on the type of gastrojejunal anastomosis.

BACKGROUND: Laparoscopic roux-en-Y gastric bypass (LRYGB) is the gold standard weight-loss procedure. There are different techniques to perform the gastrojejunal (GJ) anastomosis, but there is no consensus as to which one is superior for weight loss. Our goal in this study was to assess one-year weight loss after LRYGB comparing the three different techniques at our tertiary care center. METHODS: The American college of surgeons (ACS) Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP®) data for Montefiore Medical Center for years 2014-2017 were analyzed. Three surgeons were included in this study; each type of anastomosis was performed by a single surgeon. Patients were included if they underwent primary LRYGB. Patients were designated to one of three different groups depending of the type of gastrojejunal anastomosis performed: hand sewn, circular stapled, or linear stapled. One-year weight loss was assessed as primary endpoint of the study. A descriptive analysis of perioperative variables for each group was included as well. RESULTS: A total of 1011 patients underwent primary LRYGB. 429 (42.1%) were performed with circular-stapled GJ anastomosis, 433 (42.5%) with a hand-sewn GJ anastomosis, and 149 (14.6%) linear-stapled GJ anastomosis. The median BMI was 46.08  ±  6.43, with no difference between groups (p = .405). Procedure time was 106.70  ±  28.23 min for the circular group, 108.27  ±  28.59 min for the hand-sewn group, and 115.78  ±  36.11 min for the linear group (p > 0.005). There were no significant differences in complications except for the need of postoperative transfusions (p < 0.002). There was no statistically significant difference in %EWL one year after surgery: %EWL was 58.81  ±  16.54 kg for hand sewn, 58.86  ±  14.84 kg for circular, and 59.20  ±  17.58Kg for linear. (p = .595). CONCLUSION: There is no difference in weight loss one year after LRYGB based on the type of gastrojejunal anastomosis performed.

Incidence and effects of deep vein thrombosis on the outcome of patients with coronavirus disease 2019 infection.

BACKGROUND: Deep vein thrombosis (DVT) has been reported to occur at different rates in patients with coronavirus disease 2019 (COVID-19). Limited data exist regarding comparisons with non-COVID-19 patients with similar characteristics. Our objective was to compare the rates of DVT in patients with and without COVID-19 and to determine the effect of DVT on the outcomes. METHODS: We performed a retrospective, observational cohort study at a single-institution, level 1 trauma center comparing patients with and without COVID-19. The 573 non-COVID-19 patients (age, 61 ± 17 years; 44.9% male) had been treated from March 20, 2019 to June 30, 2019, and the 213 COVID-19 patients (age, 61 ± 16 years; 61.0% male) had been treated during the same interval in 2020. Standard prophylactic anticoagulation therapy consisted of 5000 U of heparin three times daily for the medical patients without COVID-19 who were not in the intensive care unit (ICU). The ICU, surgical, and trauma patients without COVID-19 had received 40 mg of enoxaparin daily (not adjusted to weight). The patients with COVID-19 had also received enoxaparin 40 mg daily (also not adjusted to weight), regardless of whether treated in the ICU. The two primary outcomes were the rate of deep vein thrombosis (DVT) in the COVID-19 group vs that in the historic control and the effect of DVT on mortality. The subgroup analyses included patients with adult respiratory distress syndrome (ARDS), pulmonary embolism (PE), and intensive care unit patients (ICU). RESULTS: The rate of DVT and PE for the non-COVID-19 patients was 12.4% (71 of 573) and 3.3% (19 of 573) compared with 33.8% (72 of 213) and 7.0% (15 of 213) for the COVID-19 patients, respectively. Unprovoked PE had developed in 10 of 15 COVID-19 patients (66.7%) compared with 8 of 497 non-COVID-19 patients (1.6%). The 60 COVID-19 patients with ARDS had had an incidence of DVT of 46.7% (n = 28). In contrast, the incidence of DVT for the 153 non-COVID-19 patients with ARDS was 28.8% (n = 44; P = .01). The COVID-19 patients requiring the ICU had had an increased rate of DVT (39 of 90; 43.3%) compared with the non-COVID-19 patients (33 of 123; 33.3%; P = .01). The risk factors for mortality included age, DVT, multiple organ failure syndrome, and prolonged ventilatory support with the following odd ratios: 1.030 (95% confidence interval [CI], 1.002-1.058), 2.847 (95% CI, 1.356-5.5979), 4.438 (95% CI, 1.973-9.985), and 5.321 (95% CI, 1.973-14.082), respectively. CONCLUSIONS: The incidence of DVT for COVID-19 patients receiving standard-dose prophylactic anticoagulation that was not weight adjusted was high, especially for ICU patients. DVT is one of the factors contributing to increased mortality. These results suggest a reevaluation is necessary of the present standard-dose thromboprophylaxis for patients with COVID-19.

SARS-Cov-2 Was Not Found in the Peritoneal Fluid of an Asymptomatic Patient Undergoing Laparoscopic Appendectomy.

BACKGROUND: The safety of laparoscopic surgery in SARS-CoV-2 positive patients remains unclear. The presence of the virus within peritoneal fluid and the peritoneal tissues is not known. We report an asymptomatic COVID-19 positive patient who underwent laparoscopic appendectomy with negative peritoneal sampling for SARS-CoV-2. MATERIALS AND METHODS: During a standard 3 port laparoscopic surgery samples peritoneal fluid, peritoneal brushings, and surgical smoke plum were collected. Specific real-time reverse transcriptase-polymerase chain reaction targeting SARS-CoV-2 were used to detect the presence of the virus in the samples. RESULTS: SARS-CoV-2 was not detected on multiple samples of the peritoneum in an asymptomatic patient. CONCLUSIONS: SARS-CoV-2 was not found in the peritoneum of a single patient with asymptomatic infection. Further studies comparing SARS-CoV-2 surgical candidates are needed to address safety concerns.

Asymptomatic Congenital Lung Malformations: Timing of Resection Does Not Affect Adverse Surgical Outcomes.

Background: Optimal timing for resection of asymptomatic congenital lung malformations (CLMs) remains controversial. The aim of this study is to define optimal timing for surgical intervention of patients with CLMs and define clinical variables that affect surgical outcomes. Methods: An IRB-approved retrospective analysis was conducted for patients undergoing surgery for CLMs between 2012 and 2017. Subjects were divided into cohorts based on timing of operative intervention. "Early intervention" was defined as surgery within 4 months of birth; "intermediate intervention"-between 4 and 6 months; and "late intervention"-6-12 months. Surgical outcomes including intraoperative estimated blood loss (EBL), surgical time, post-operative pneumothorax, length of time chest tube stayed in, and hospital length of stay were compared among the three groups using Fisher's exact test or Chi-squared test for categorical variables and one-way analysis of variance test for continuous variables. Results: We analyzed 63 patients who underwent surgery for CLM. There were no significant differences in baseline characteristics. Timing of surgery did not significantly correlate with post-operative outcomes. Specifically, there was no difference in operative time, EBL, post-operative pneumothorax, or length of hospital stay among the early, intermediate, and late intervention groups. Even after controlling for cyst-volume ratio (CVR), timing of surgery still did not affect post-operative outcomes. Conclusions: Surgical outcomes for resection of CLMs are not significantly affected by timing of surgery. We advocate for early intervention to decrease the incidence of associated complications that can occur with later intervention.

Characterization of Extracorporeal Membrane Oxygenation Support for Single Ventricle Patients.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) can provide crucial support for single ventricle (SV) patients at various stages of palliation. However, characterization of the utilization and outcomes of ECMO in these unique patients remains incompletely studied. METHODS: We performed a single-center retrospective review of SV patients between 2010 and 2017 who underwent ECMO cannulation with primary end point of survival to discharge and secondary end point of survival to decannulation or orthotopic heart transplantation (OHT). Multivariate analysis was performed for factors predictive of survival to discharge and survival to decannulation. RESULTS: Forty SV patients with a median age of one month (range: 3 days to 15 years) received ECMO support. The incidence of ECMO was 14% for stage I, 3% for stage II, and 4% for stage III. Twenty-seven (68%) patients survived to decannulation, and 21 (53%) patients survived to discharge, with seven survivors to discharge undergoing OHT. Complications included infection (40%), bleeding (40%), thrombosis (33%), and radiographic stroke (45%). Factors associated with survival to decannulation included pre-ECMO lactate (hazard ratio [HR]: 0.61, 95% confidence interval [CI]: 0.41-0.90, P = .013) and post-ECMO bicarbonate (HR: 1.24, 95% CI: 1.0-1.5, P = .018). Factors associated with survival to discharge included central cannulation (HR: 40.0, 95% CI: 3.1-500.0, P = .005) and lack of thrombotic complications (HR: 28.7, 95% CI: 2.1-382.9, P = .011). CONCLUSIONS: Extracorporeal membrane oxygenation can be useful to rescue SV patients with approximately half surviving to discharge, although complications are frequent. Early recognition of the role of heart transplant is imperative. Further study is required to identify areas for improvement in this population.

Comparative outcomes of right versus left congenital diaphragmatic hernia: A multicenter analysis.

BACKGROUND: Congenital diaphragmatic hernia (CDH) occurs in 1 out of 2500-3000 live births. Right-sided CDHs (R-CDHs) comprise 25% of all CDH cases, and data are conflicting on outcomes of these patients. The aim of our study was to compare outcomes in patients with right versus left CDH (L-CDH). METHODS: We analyzed a multicenter prospectively enrolled database to compare baseline characteristics and outcomes of neonates enrolled from January 2005 to January 2019 with R-CDH vs. L-CDH. RESULTS: A total of 588, 495 L-CDH, and 93 R-CDH patients with CDH were analyzed. L-CDHs were more frequently diagnosed prenatally (p=0.011). Lung-to-head ratio was similar in both cohorts. R-CDHs had a lower frequency of primary repair (p=0.022) and a higher frequency of need for oxygen at discharge (p=0.013). However, in a multivariate analysis, need for oxygen at discharge was no longer significantly different. There were no differences in long-term neurodevelopmental outcomes assessed at two year follow up. There was no difference in mortality, need for ECMO, pulmonary hypertension, or hernia recurrence. CONCLUSION: In this large series comparing R to L-CDH patients, we found no significant difference in mortality, use of ECMO, or pulmonary complications. Our study supports prior studies that R-CDHs are relatively larger and more often require a patch or muscle flap for repair. TYPE OF STUDY: Prognosis study LEVEL OF EVIDENCE: Level II.

Extracorporeal Cardiopulmonary Resuscitation (ECPR) in Infants and Children: A Single-Center Retrospective Study.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is increasingly used to rescue patients with cardiac arrest refractory to conventional therapy, necessitating evaluation of factors that may affect outcomes. METHODS: A single-center retrospective review of pediatric patients (<21 years old) who underwent ECPR from January 2010 to November 2017. Comparisons between nonsurvivors and survivors, to decannulation and discharge, were made. Factors associated with survival and rate of complications were examined. RESULTS: Seventy patients were supported with ECPR. Forty-nine (70%) patients survived to decannulation and 38 (54%) patients to discharge. There was no statistical difference between baseline characteristics of survivors and nonsurvivors, including age at cannulation, weight (kg), time to cannulation (minutes), and total time on extracorporeal membrane oxygenation (hours). Survivors to discharge had significantly higher pH prior to cannulation compared to nonsurvivors (7.11 ± 0.24 vs 6.97 ± 0.21, P = .01). Of all, 23.2% of patients received renal replacement therapy (RRT), 39.4% had significant bleeding, 22.5% had thrombotic complications, and 68.8% had neurologic injury on imaging studies. A greater number of nonsurvivors received RRT compared to survivors to discharge (35.5% vs 10.8%, P = .02). There were no differences in bleeding or thrombotic complications or radiographically established neurologic injury. CONCLUSIONS: Although ECPR effectively increases overall survival, a better characterization of long-term outcomes is needed.

Bariatric surgery in patients with left ventricular assist devices: a safe and effective method of weight loss as a gateway to heart transplantation.

BACKGROUND: Severe cardiac disease often warrants intervention to improve cardiac function, such as mechanical support via a left ventricular assist device (LVAD). While this is an effective way of improving myocardial activity, it works synergistically with weight loss. SETTING: Academic hospital. OBJECTIVE: The aim of this study was to evaluate bariatric surgery as an alternative means of weight loss to improve cardiac status. METHODS: Six patients with LVADs underwent sleeve gastrectomies (SG) over a 5-year study period (2014-2018). Patient characteristics, cardiac history, operative outcomes, and follow-up was evaluated by univariate analyses. RESULTS: Median age at operation was 49.8 years (range, 24-58 yr) with average weight at surgery of 126.6 kg. Average body mass index at time of SG was 41.4 kg/m2. Median hospital length of stay was 8.5 days (range, 4-13 d), with postoperative length of stay of 5.5 days (3-7 d). Total follow-up was 29 months (range, 7-51 mo). Postoperative readmission occurred in 2 patients (33%) without significant adverse outcomes. Four patients (67%) were listed for transplant, 3 within 1 year of LSG. Three patients (50%) underwent orthotopic heart transplant. All patients experienced improved cardiac co-morbidities after SG. CONCLUSION: We demonstrate that weight loss surgery as a bridge to transplantation for patients with implanted LVADs can be performed in young and middle-aged adults. Although it is limited by sample size, the reported results add to the existing literature highlighting the potential success of bariatric surgery in high-risk patient populations to achieve weight loss goals, impact cardiac co-morbidities, and improve overall quality of life.