Search

Introduction The COVID-19 pandemic resulted in the suspension of nonemergent surgeries throughout New York. Our tertiary care children’s hospital pivoted towards a brief trial of intravenous (IV) antibiotic therapy in all patients in order to limit operating room (OR) utilization and avoid prolonged hospital stays. We describe our pandemic-based strategy for non-operative management (NOM) of appendicitis but with a limited duration of IV antibiotics. Methods We performed a retrospective study of children treated for acute appendicitis at our center from 3/31/2020 to 5/3/2020 during the peak of the New York pandemic. We compared appendicitis volume to similar months in prior years. We evaluated failure of NOM, length of stay, and compared characteristics of children we successfully treated with our expanded NOM protocol to previously published inclusion criteria for NOM. Results 45.5% of children (25/55) with acute appendicitis underwent NOM. Of the 30 who underwent surgery, 13 had complicated appendicitis while 17 had simple appendicitis. Three patients were COVID-positive, although none had respiratory symptoms. The majority of patients presenting with acute appendicitis (78.2%) did not meet previously published criteria for NOM. Conclusions We treated a similar volume of children with acute appendicitis during the pandemic compared to prior years. We applied non-operative management to nearly half our patients, even as we expanded inclusion criteria for NOM to reduce OR utilization, but limited the duration of the antibiotic trial to avoid prolonged hospital stays. Type of study Retrospective study. Level of evidence IV.

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, and imposes significant morbidity and mortality in this population. The aggressive chemoradiotherapy required to treat high-risk NB results in survival of less than 50%, yet is associated with significant long-term adverse effects in survivors. Boosting efficacy and reducing morbidity are therefore key goals of treatment for affected children. We hypothesize that these may be achieved by developing strategies that both focus and limit toxic therapies to the region of the tumor. One such strategy is the use of targeted image-guided drug delivery (IGDD), which is growing in popularity in personalized therapy to simultaneously improve on-target drug deposition and assess drug pharmacodynamics in individual patients. IGDD strategies can utilize a variety of imaging modalities and methods of actively targeting pharmaceutical drugs, however in vivo imaging in combination with focused ultrasound is one of the most promising approaches already being deployed for clinical applications. Over the last two decades, IGDD using focused ultrasound with “microbubble” ultrasound contrast agents (UCAs) has been increasingly explored as a method of targeting a wide variety of diseases, including cancer. This technique, known as sonopermeation, mechanically augments vascular permeability, enabling increased penetration of drugs into target tissue. However, to date, methods of monitoring the vascular bioeffects of sonopermeation in vivo are lacking. UCAs are excellent vascular probes in contrast-enhanced ultrasound (CEUS) imaging, and are thus uniquely suited for monitoring the effects of sonopermeation in tumors. Methods: To monitor the therapeutic efficacy of sonopermeation in vivo, we developed a novel system using 2D and 3D quantitative contrast-enhanced ultrasound imaging (qCEUS). 3D tumor volume and contrast enhancement was used to evaluate changes in blood volume during sonopermeation. 2D qCEUS-derived time-intensity curves (TICs) were used to assess reperfusion rates following sonopermeation therapy. Intratumoral doxorubicin (and liposome) uptake in NB was evalauted ex vivo along with associated vascular changes. Results: In this study, we demonstrate that combining focused ultrasound therapy with UCAs can significantly enhance chemotherapeutic payload to NB in an orthotopic xenograft model, by improving delivery and tumoral uptake of long-circulating liposomal doxorubicin (L-DOX) nanoparticles. qCEUS imaging suggests that changes in flow rates are highly sensitive to sonopermeation and could be used to monitor the efficacy of treatment in vivo. Additionally, initial tumor perfusion may be a good predictor of drug uptake during sonopermeation. Following sonopermeation treatment, vascular biomarkers show increased permeability due to reduced pericyte coverage and rapid onset of doxorubicin-induced apoptosis of NB cells but without damage to blood vessels. Conclusion: Our results suggest that significant L-DOX uptake can occur by increasing tumor vascular permeability with microbubble sonopermeation without otherwise damaging the vasculature, as confirmed by in vivo qCEUS imaging and ex vivo analysis. The use of qCEUS imaging to monitor sonopermeation efficiency and predict drug uptake could potentially provide real-time feedback to clinicians for determining treatment efficacy in tumors, leading to better and more efficient personalized therapies. Finally, we demonstrate how the IGDD strategy outlined in this study could be implemented in human patients using a single case study.

Staphylococcus aureus infection is one of the leading causes of morbidity in hospitalized patients in the United States, an effect compounded by increasing antibiotic resistance. The secreted agent hemolysin alpha toxin (Hla) requires the receptor A Disintegrin And Metalloproteinase domain-containing protein 10 (ADAM10) to mediate its toxic effects. We hypothesized that these effects are in part regulated by Notch signaling, for which ADAM10 activation is essential. Notch proteins function in developmental and pathological angiogenesis via the modulation of key pathways in endothelial and perivascular cells. Thus, we hypothesized that Hla would activate Notch in vascular cells. Human umbilical vein endothelial cells were treated with recombinant Hla (rHla), Hla-H35L (genetically inactivated Hla), or Hank’s solution (HBSS), and probed by different methods. Luciferase assays showed that Hla (0.01 µg/mL) increased Notch activation by 1.75 ± 0.5-fold as compared to HBSS controls (p

Current surgical dogma dictates that tissue ischemia and hypoxia are major contributing factors in anastomotic leak despite scant evidence. The aim of this study was to determine if tissue hypoxia is a feature of anastomotic leakage in rats following colon resection and segmental devascularization. Rats were randomly assigned to undergo sham operation, segmental colon devascularization alone, colectomy alone, or segmental devascularization plus colectomy. Tissue hypoxia present at the colon anastomosis site across the various treatment groups was determined at sacrifice on postoperative day 6. Pimonidazole HCl was injected 30 min prior to sacrifice. Anastomotic tissues were examined and scored for healing versus leakage using an anastomotic healing score (AHS). Collagen content, hypoxia, enteric smooth muscle and periendothelial stromal patterning, and apoptosis were evaluated histologically. No differences in tissue hypoxia were noted in the 16% of anastomotic tissues with poor healing compared to the remaining 84% of rats whose anastomoses healed well. No significant changes were found in cell death in the submucosa of any group. Consistent with previous findings, poor healing was associated with lower collagen content. Submucosal thickness correlated with increased arteriole diameter (R 2 = 0.25, p

Background. Staphylococcus aureus infection is one of the leading causes of morbidity in hospitalized patients in the United States. The secreted agent hemolysin alpha toxin (Hla) requires the receptor A Disintegrin And Metalloproteinase domain-containing protein 10 (ADAM10) to mediate its toxic effects; ADAM10 in turn activates the Notch pathway. Notch proteins function in developmental and pathological angiogenesis via the modulation of key pathways in endothelial (EC) and perivascular cells. Thus, we hypothesized that Hla would activate Notch in EC in vitro and in vivo. Methods. Human umbilical vein endothelial cells (HUVEC) were treated with recombinant Hla (rHla), Hla-H35L (genetically inactivated Hla), 5mM EDTA (a known Notch activator), or HBSS, and probed with a Luciferase reporter regulated by a Notch promoter. Mice engineered to express yellow fluorescent protein (YFP) upon Notch activation received a non-lethal daily subcutaneous injection of rHla (0.025 µg/5µL) or vehicle (PBS) and their retinal endothelial YFP interrogated at p6. 6 week old male Notch reporter mice received a 1-4 × 107 50 µl subcutaneous inoculation of S. aureus strains USA300/LAC (WT), or its isogenic Δhla mutant lacking Hla, and their skin biopsies were analyzed by histology after 36 hours, 8 and 16 days. Notch activation in endothelial cells of human liver sections from patients whose blood cultures were positive or negative for S. aureus was evaluated by immunohistochemistry. Results. Luciferase assays demonstrated that Hla (0.01 µg/mL) increased Notch activation by 1.75±0.5-fold as compared to HBSS controls (p ±3.1x106 vs. 7.7x10-5 ±6x105 YFP area/ DAPI area, p=0.002). Increased EC Notch activation in response to Hla was maintained 8 and 16 days after inoculation. IHC showed EC in human liver had higher Notch expression than controls. In sum, our results demonstrate that the S. aureus toxin Hla can potently activate Notch in endothelial cells, an effect which could have effects in development and pathological angiogenesis such as cancer. Citation Format: Sonia L. Hernandez, Mildred Nelson, Georgia Sampedro, Bianca Lec, Jared Emolo, Naina Bagrodia, Ann M. Defnet, Lydia Wu, Juliane Bubeck-Wardenburg, Jessica Kandel. Staphylococcus aureus alpha toxin activates Notch in endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2055.

Splenectomy is a commonly performed operation; however, data from large series regarding operative outcomes to help guide decision making and informed consent are lacking.To evaluate clinical and pathologic variables associated with morbidity and mortality following elective splenectomy for benign and malignant hematologic conditions in the United States.A review of the American College of Surgeons National Surgical Quality Improvement Program data for elective splenectomy between January 1, 2005, and December 31, 2011, was performed, and 1715 eligible individuals were identified.Elective splenectomy for hematologic conditions.Complications and operative mortality were evaluated for the entire cohort and compared between patients with benign vs malignant diseases. Multivariable logistic regression was used to evaluate factors predictive of operative complications and death.Splenectomy was performed in 1344 patients (78.4%) for benign disease and in 371 patients (21.6%) for malignant disease. Two hundred ninety-one patients (17.0%) had a complication, and operative mortality occurred in 27 patients (mortality rate, 1.6%). Patients treated for malignant disease had a higher rate of overall complications (27.2%) compared with patients treated for benign disease (14.1%) (P .001). Several variables were independent predictors of complications, including malignant disease (vs benign) (Odds Ratio [OR], 1.86; 95% CI, 1.23-2.80; P = .003), independent performance status (vs dependent) (OR, 0.33; 95% CI, 0.07-1.52; P = .02), and increasing albumin level (OR, 0.75; 95% CI, 0.66-0.86; P .001). Increasing age (OR, 1.03; 95% CI, 1.00-1.06; P = .05) was an independent predictor of mortality while increasing albumin level (OR, 0.63; 95% CI, 0.46-0.86; P = .003) predicted lower risk of operative death. From these data, a patient older than 60 years with a low preoperative albumin level has a predicted probability for operative death as high as 10.0%.Preoperative performance and nutritional status are significant risk factors for complications and mortality following elective splenectomy. Although operative mortality continues to decrease over time, specific preoperative variables may help with patient selection before elective splenectomy for certain patients.