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Lymphatic anomalies comprise a spectrum of disorders ranging from common localized microcystic and macrocystic lymphatic malformations (LMs) to rare complex lymphatic anomalies, including generalized lymphatic anomaly, Kaposiform lymph-angiomatosis, central conducting lymphatic anomaly, and Gorham-Stout disease. Imaging diagnosis of cystic LMs is generally straightforward, but complex lymphatic anomalies, particularly those with multiorgan involvement or diffuse disease, may be more challenging to diagnose. Complex lymphatic anomalies are rare but associated with high morbidity. Imaging plays an important role in their diagnosis, and radiologists may be the first clinicians to suggest the diagnosis. Furthermore, radiologists are regularly involved in management given the frequent need for image-guided interventions. For these reasons, it is crucial for radiologists to be familiar with the spectrum of entities comprising complex lymphatic anomalies and their typical imaging findings. In this article, we review the imaging findings of lymphatic anomalies, including LMs and complex lymphatic anomalies. We discuss characteristic imaging findings, multimodality imaging techniques used for evaluation, pearls and pitfalls in diagnosis, and potential complications. We also review recently discovered genetic changes underlying lymphatic anomaly development and the advent of new molecularly targeted therapies.

Children and adolescents undergoing posterior spinal fusion for scoliosis experience high rates of bleeding and blood product transfusion. Antifibrinolytic therapy is one key strategy to decrease blood loss and transfusion in pediatric scoliosis surgery. Here we review 172 pediatric scoliosis patients (birth to 21 y) who underwent posterior spinal fusion at our institution from 2017 to 2018. We reported rates of blood loss and transfusion, compared patients receiving tranexamic acid to a e-aminocaproic acid, and evaluated antifibrinolytic agent and laboratory parameters as predictors of blood loss and transfusion. Intraoperatively, 62% received tranexamic acid and 38% received e-aminocaproic acid. Overall, blood loss (mean intraoperative estimated blood loss=14.9±9.7 mL/kg, 22% with clinically significant blood loss [>20 mL/kg], and mean calculated hemoglobin mass loss=175.9±70.1 g) and transfusion rates (15% with intraoperative allogeneic red blood cell transfusion and mean intraoperative allogeneic red blood cell transfusion volume=12.5±7.1 mL/kg) were similar to previous cohorts studying intraoperative antifibrinolytics. There was no difference in intraoperative estimated blood loss, clinically significant blood loss, calculated hemoglobin mass loss, or transfusion rates between the antifibrinolytic groups. Antifibrinolytic choice was not predictive of blood loss or transfusion. Routine hematologic laboratory parameters and antifibrinolytic choice were insufficient to predict blood loss or other outcomes. Future prospective laboratory-based studies may provide a more comprehensive model of surgical-induced coagulopathy in scoliosis surgery and provide a better tool for predicting blood loss and improving outcomes.

The goal of this report is to describe, through a series of 5 cases, the clinical response and safety of alpelisib (BYL719) use in children and adults withWe reviewed clinical records of 5 patients from October 2019 through September 2021 followed by the pediatric hematology and multidisciplinary vascular anomalies teams at the Monroe Carell Jr. Children's Hospital at Vanderbilt (MCJCHV). All patients carried a clinical or genetic diagnosis of PROS and were treated with alpelisib provided by a Novartis managed access program.We highlight improvement in reported symptoms, objective overgrowth measurements, and quality of life to varying degrees in all patients. We note dose-dependent hyperglycemia and gastrointestinal side effects in 2 of the 5 patients. No patients experienced any serious side effects.This case series reports on the real-world use of PI3K-α inhibition in the management of PROS. Ongoing clinical trials will provide efficacy and safety data as these drugs become more widely used in patients with vascular anomalies and syndromes secondary to somatic

Overgrowth syndromes encompass a number of rare genetic diseases with heterogeneous clinical phenotypes. Accordingly, there is a strong imperative to collect data and classify these disorders to aid in diagnosis and management. Recent advances in the genetics of overgrowth syndromes have identified mutations in the PIK3CA gene. These somatic mutations manifest in progressive segmental overgrowth of fibrous and adipose tissue and bone, vascular malformations, and in some cases, increased risk for malignancy. Targeted medical therapy is under investigation for the management of PROS, but treatment of overgrowth relies on surgical debulking. Macrotia in PIK3CA-related overgrowth spectrum (PROS) has not been reported in the literature. In this case, we discuss a novel approach to reductive otoplasty and facial soft tissue debulking in a pediatric patient with PROS.

Dural arteriovenous fistulae (dAVF) are an uncommon feature of PTEN hamartoma tumor syndrome (PHTS). We report a case of an adolescent male diagnosed with PHTS following the treatment of multiple intracranial dAVF to emphasize the association of vascular anomalies with this disorder and discuss potential implications. An adolescent male presented with bilateral proptosis secondary to intracranial venous hypertension. Workup revealed the presence of a complex intracranial dAVF which was treated with several embolization procedures. Following treatment, a de novo dAVF was identified on surveillance imaging. A genetic workup revealed a pathogenic mutation in PTEN consistent with a diagnosis of PHTS. Recognition that PHTS may be associated with dAVF, and potentially delayed spontaneous formation of dAVF, is critically important due to the potential for devastating yet preventable neurologic sequelae.

The care of patients with vascular anomalies is quickly becoming a complex field requiring high-quality, coordinated multidisciplinary care. In this article, we review the history of multidisciplinary care in this field, discuss the benefits of this model of care, and outline some of the essential components and structure of a successful vascular anomalies team. We provide an overview of two example programs and a roadmap for other centers to develop their own multidisciplinary vascular anomalies teams.

ImportanceVascular malformations (VMs) are rare disorders of vasculogenesis associated with substantial morbidity. Improved understanding of their genetic basis is increasingly guiding management, but logistical barriers to obtaining genetic testing in patients with VM may constrain treatment options.ObjectivesTo examine the institutional mechanisms for and obstacles to obtaining genetic testing for VM.Design, Setting, and ParticipantsThis survey study invited members of the Pediatric Hematology-Oncology Vascular Anomalies Interest Group, representing 81 vascular anomaly centers (VACs) serving individuals up to 18 years of age, to complete an electronic survey. Respondents were mostly pediatric hematologists-oncologists (PHOs) but included geneticists, genetic counselors, clinic administrators, and nurse practitioners. Responses that were received between March 1 and September 30, 2022, were analyzed with descriptive methods. Requirements for genetic testing by several genetics laboratories were also reviewed. Results were stratified by size of the VAC.Main Outcomes and MeasuresVascular anomaly center and associated clinician characteristics and practice patterns for ordering and obtaining insurance approval for genetic testing for VMs were collected.ResultsResponses were received from 55 of 81 clinicians, for a response rate of 67.9%. Most respondents were PHOs (50 [90.9%]). Most respondents (32 of 55 respondents [58.2%]) replied that they order genetic testing on 5 to 50 patients per year and reported a genetic testing volume increase of 2- to 10-fold over the past 3 years (38 of 53 respondents [71.7%]). Most testing was ordered by PHOs (35 of 53 respondents [66.0%]), followed by geneticists (28 [52.8%]) and genetic counselors (24 [45.3%]). In-house clinical testing was more common at large and medium-sized VACs. Small VACs were more likely to use oncology-based platforms, which potentially miss low-frequency allelic variants in VM. Logistics and barriers varied by size of the VAC. Obtaining prior authorization was the duty shared among PHOs, nurses, and administrative staff, but the burden of insurance denials and appeals were on PHOs (35 of 53 respondents [66.0%]). Lack of administrative support; unclear institutional, insurance, and laboratory requirements; and lack of clinician education were barriers to genetic testing at VACs of all sizes. The effort to obtain genetic testing for patients with VM, compared with patients with cancer, was perceived as excessive, despite genetic testing being considered standard of care for this population.Conclusions and RelevanceResults of this survey study showed the barriers to genetic testing for VM across VACs, described differences between VACs based on size, and proposed multiple interventions to support clinicians ordering genetic testing for VM. The results and recommendations should have broader application to clinicians caring for patients for whom molecular diagnosis is important to medical management.

PURPOSE: Posterior spinal fusion (PSF) activates the fibrinolytic protease plasmin, which is implicated in blood loss and transfusion. While antifibrinolytic drugs have improved blood loss and reduced transfusion, variable blood loss has been observed in similar PSF procedures treated with the same dose of antifibrinolytics. However, both the cause of this and the appropriate measures to determine antifibrinolytic efficacy during high-blood-loss spine surgery are unknown, making clinical trials to optimize antifibrinolytic dosing in PSF difficult. We hypothesized that patients undergoing PSF respond differently to antifibrinolytic dosing, resulting in variable blood loss, and that specific diagnostic markers of plasmin activity will accurately measure the efficacy of antifibrinolytics in PSF. METHODS: A prospective study of 17 patients undergoing elective PSF with the same dosing regimen of TXA was conducted. Surgery-induced plasmin activity was exhaustively analyzed in perioperative blood samples and correlated to measures of inflammation, bleeding, and transfusion. RESULTS: While markers of in vivo plasmin activation (PAP and D-dimer) suggested significant breakthrough plasmin activation and fibrinolysis (P < 0.01), in vitro plasmin assays, including TEG, did not detect plasmin activation. In vivo measures of breakthrough plasmin activation correlated with blood loss (R(2) = 0.400, 0.264; P < 0.01), transfusions (R(2) = 0.388; P < 0.01), and complement activation (R(2) = 0.346, P < 0.05). CONCLUSIONS: Despite all patients receiving a high dose of TXA, its efficacy among patients was variable, indicated by notable intra-operative plasmin activity. Markers of in vivo plasmin activation best correlated with clinical outcomes. These findings suggest that the efficacy of antifibrinolytic therapy to inhibit plasmin in PSF surgery should be determined by markers of in vivo plasmin activation in future studies. LEVEL OF EVIDENCE: Level II-diagnostic.

Posterior spinal fusion (PSF) activates the fibrinolytic protease plasmin, which is implicated in blood loss and transfusion. While antifibrinolytic drugs have improved blood loss and reduced transfusion, variable blood loss has been observed in similar PSF procedures treated with the same dose of antifibrinolytics. However, both the cause of this and the appropriate measures to determine antifibrinolytic efficacy during high-blood-loss spine surgery are unknown, making clinical trials to optimize antifibrinolytic dosing in PSF difficult. We hypothesized that patients undergoing PSF respond differently to antifibrinolytic dosing, resulting in variable blood loss, and that specific diagnostic markers of plasmin activity will accurately measure the efficacy of antifibrinolytics in PSF.A prospective study of 17 patients undergoing elective PSF with the same dosing regimen of TXA was conducted. Surgery-induced plasmin activity was exhaustively analyzed in perioperative blood samples and correlated to measures of inflammation, bleeding, and transfusion.While markers of in vivo plasmin activation (PAP and D-dimer) suggested significant breakthrough plasmin activation and fibrinolysis (P 0.01), in vitro plasmin assays, including TEG, did not detect plasmin activation. In vivo measures of breakthrough plasmin activation correlated with blood loss (RDespite all patients receiving a high dose of TXA, its efficacy among patients was variable, indicated by notable intra-operative plasmin activity. Markers of in vivo plasmin activation best correlated with clinical outcomes. These findings suggest that the efficacy of antifibrinolytic therapy to inhibit plasmin in PSF surgery should be determined by markers of in vivo plasmin activation in future studies.Level II-diagnostic.

Complex cranial vault reconstruction (CCVR) for pediatric craniosynostosis is a high blood loss surgery, for which antifibrinolytic agents have been shown to reduce bleeding and transfusion requirements. The relative efficacy of ε-aminocaproic acid (EACA) versus tranexamic acid (TXA) has not yet been evaluated in this population. The aim of this retrospective study was to compare perioperative blood loss and transfusion in CCVR patients receiving EACA versus TXA. In a CCVR cohort of 95 children, 47 received EACA and 48 received TXA. We found no differences in demographics, adverse outcomes, calculated blood loss (CBL), or transfusion requirements between the two antifibrinolytic groups.

Dural arteriovenous fistulae (dAVF) are an uncommon feature of PTEN hamartoma tumor syndrome (PHTS). We report a case of an adolescent male diagnosed with PHTS following the treatment of multiple intracranial dAVF to emphasize the association of vascular anomalies with this disorder and discuss potential implications.An adolescent male presented with bilateral proptosis secondary to intracranial venous hypertension. Workup revealed the presence of a complex intracranial dAVF which was treated with several embolization procedures. Following treatment, a de novo dAVF was identified on surveillance imaging. A genetic workup revealed a pathogenic mutation in PTEN consistent with a diagnosis of PHTS.Recognition that PHTS may be associated with dAVF, and potentially delayed spontaneous formation of dAVF, is critically important due to the potential for devastating yet preventable neurologic sequelae.

Objectives: Spinal fusion is often complicated by high blood loss and the clinically observed phenomenon of increased bleeding times throughout the case. Although the pathophysiology of this phenomenon involves hyperfibrinolysis and occurs to a lesser extent in the presence of antifibrinolytics (e.g. TXA), we hypothesize that perioperative changes in platelet function also contribute to this continued observation. Methods: Blood samples were acquired from patients undergoing posterior spinal fusion for correcting scoliosis (5 neuromuscular, 3 idiopathic ). Samples were obtained immediately before the procedure, at 2, 4, and 6 hours post-incision, and the subsequent morning (POD1). Platelet activation in response to stimulation with an intravascular agonist, thrombin, and an extravascular agonist, convulxin, was measured by flow cytometry. Activation of the fibrin-binding integrin glycoprotein IIb/IIIa (GpIIb/IIIa) was reported by PAC-1 binding and expression of the alpha-granule component P-selectin was reported by CD62p binding. CBCs and Thromboelastography (TEG) were performed on samples in parallel. Estimated blood loss (EBL) was calculated using a hematocrit-based analysis of red cell mass. Results:All 5 neuromuscular patients exhibited a marked and progressive decline in platelet count and activity throughout surgery and early postoperative period. Reductions were most notable for thrombin-stimulated GpIIb/IIIa activation (Th PAC1) at 4 hrs (mean 41.7%, p=0.0056) and 6 hrs (50.9%, p=0.0096). Similar trends in mean reductions were observed for thrombin stimulated P- selectin expression (Th P-Selectin) at 6 hrs (22.5%, p=0.0112) and on POD1 (39.2%, p=0.0274). Patients with idiopathic scoliosis demonstrated significant reductions in convulxin-stimulated GpIIb/IIIa activation (32.8%, p=0.0087) and P-selectin expression (35.1%, p=0.0147) at 2 hrs, which recovered to or increased beyond baseline thereafter. These trends also manifested on TEG for all neuromuscular patients as the average time to maximum clot strength increased by 48.8% at 6 hrs (p=0.0058). Furthermore, platelet activity correlated with the calculated EBL for all 8 patients (Th PAC1 at 4 hrs R= -0.673, p=0.146 and 6 hrs: R= -0.623, p=0.099; Th P-Selectin at 6 hrs: R= -0.694 p = 0.056 and POD1: R= -0.713, p=0.047). EBL also significantly correlated with reductions in platelet count at 6 hrs (R= -0.919, p=0.010) and absolute platelet count on POD1 (R= -0.858, p=0.006). Conclusions: We have observed a progressive reduction in platelet activation and fibrin-dependent clot formation throughout scoliosis surgery, particularly in patients with neuromuscular disease. High endothelial injury related to achieving surgical exposure may account for the early drop in response to the extravascular collagen receptor agonist, convulxin. Measures associated with secondary hemostasis, such as the thrombin-stimulated platelet activation and time to maximum clot strength, both demonstrated exhaustion towards the post-operative period. These data suggest that surgically-induced disruption in platelet function may be a key component of the coagulopathic phenomenon described and closely associated with blood loss.

INTRODUCTION: Children undergoing complex cranial vault reconstruction (CCVR) for craniosynostosis experience high rates of bleeding and transfusion, increasing risk for perioperative complications. ε-Aminocaproic acid (EACA) and tranexamic acid (TXA) are antifibrinolytic agents that have been shown to reduce intraoperative hemorrhage and transfusion requirements during CCVR. However, the relative efficacy of these two agents has not yet been evaluated. The aim of this study was to compare perioperative blood loss and transfusion rates in children receiving EACA vs. TXA. METHODS: All patients who underwent CCVR from September 2015 to December 2019 at a single center were retrospectively evaluated. Primary outcome measures included intraoperative estimated blood loss, postoperative drain output, transfusion volumes, and calculated blood loss. Secondary outcome measures included hematologic and coagulation parameters. RESULTS: 95 patients were included, with 47 patients in the EACA cohort and 48 patients in the TXA cohort. There were no significant differences in demographics, surgical outcomes, blood loss, transfusion requirement, or perioperative hematologic and coagulation laboratory values between the two cohorts. Adverse events were similar between the groups, but did include two seizure events and two thromboembolic events related to vascular access devices. DISCUSSION: We found no significant difference in blood loss, transfusion requirements, hematologic parameters, or outcomes between pediatric CCVR patients who received EACA vs. TXA. Further research is needed to define optimal antifibrinolytic dosing and duration of therapy. While standard laboratory parameters were similar between groups, future studies investigating coagulation-based and inflammatory assays may be useful in defining surgical-induced coagulopathy.

The care of patients with vascular anomalies is quickly becoming a complex field requiring high quality, coordinated multidisciplinary care. In this article, we review the history of multidisciplinary care in this field, discuss the benefits of this model of care, and outline some of the essential components and structure of a successful vascular anomalies team. We provide an overview of two example programs and a roadmap for other centers to develop their own multidisciplinary vascular anomalies teams.

Background : Children undergoing complex cranial vault reconstruction (CCVR) for craniosynostosis experience high rates of bleeding and blood product transfusion, increasing the risk of perioperative complications. The most severe issues relate to the rate and extent of blood loss, which can be up to several times the patient's total blood volume and is often equated to controlled massive hemorrhage. ε-Aminocaproic acid (EACA) and tranexamic acid (TXA) are antifibrinolytic agents that have been shown to reduce intraoperative hemorrhage and transfusion requirements during CCVR. However, the relative efficacy of EACA vs. TXA in CCVR has not yet been evaluated. The aim of this study was to compare perioperative blood loss and need for transfusion in children receiving EACA and TXA. We hypothesized that TXA is associated with a greater decrease in blood loss and transfusion requirements when compared to EACA. Methods: All patients who underwent CCVR from September 2015 to December 2019 at our institution were retrospectively evaluated. The primary outcome measures included intraoperative estimated blood loss (EBL), red blood cell (RBC) transfusion volume (mL/kg), and calculated blood loss (CBL) (Kearney et al., Can J Anaesth 1989). Secondary outcome measures included hematologic and coagulation parameters. Study cohort demographic and outcome data were analyzed; Fisher's exact test was used for categorical data, student's t-test was used for continuous data. A p-value of < 0.05 was considered statistically significant. Results: 104 patients were included in the study with 48 patients in the EACA cohort and 56 patients in the TXA cohort. There were slightly more patients with syndromic craniosynostosis in the EACA group, but overall no significant differences in cohort characteristics (Table 1). Mean EBL (mL/kg) was slightly higher in the EACA group vs. the TXA group (21 ± 13 vs. 17 ± 10), but not statistically significant. Intraoperative mean CBL (34 ± 21mL/kg) and intraoperative percent blood volume lost (43 ± 26%) for the cohort were high, but these were equal between groups. Likewise, postoperative DO, CBL and percent blood volume lost were similar between groups. Overall, intraoperative RBC transfusion was required in 66 (64%) of patients and was similar between groups (69% of EACA patients vs. 59% of TXA patients). Intraoperative transfusion of other products was equal between groups. Postoperatively, 23 (22%) of patients required RBC transfusion. Postoperative blood product transfusions were equal between groups (Table 2). We compared routine hematologic and coagulation parameters peri-operatively and did not find any differences between the EACA and TXA group (Table 3). In the EACA group, there were 6 reported perioperative complications, including 2 suspected seizure events, as compared to 7 complications in the TXA group, which included 2 thromboembolic events. Discussion: Pediatric CCVR is a high blood loss surgery and this can lead to a consumptive coagulopathy for which intraoperative antifibrinolytic agents have been demonstrated to improve outcomes. We found no significant difference in blood loss, transfusion requirements, or hematologic parameters between patients who received EACA and TXA in our retrospective pediatric CCVR cohort. Overall there were 4 postoperative outcomes that could have been related to antifibrinolytic use (seizure, thromboembolism), but this was equal between groups and causality was not confirmed. Further research is needed to define optimal antifibrinolytic dosing and duration of therapy. While standard hematologic and coagulation parameters were similar between groups, the mechanisms of surgically induced coagulopathy in CCVR still need to be explored. Future studies investigating coagulation-based and inflammatory assays may be useful in defining surgical-induced coagulopathy. Disclosures No relevant conflicts of interest to declare.

High blood loss requiring transfusion is a common complication in pediatric scoliosis surgery. Bleeding in patients undergoing spinal surgery is exacerbated by the development of coagulopathy in response to extensive activation of the acute phase response (APR). Coagulopathy is characterized by consumption of coagulation factors, inflammation, and hyperfibrinolysis. Although the administration of antifibrinolytics (e.g. tranexamic acid, TXA) has significantly reduced transfusions, patients still experience high rates of blood loss, suggesting either that TXA dosing needs optimization or that plasmin-independent aspects of coagulopathy could be driving bleeding. Major orthopedic surgeries are characterized by a reduction in platelet counts indicating the coagulopathic conditions of surgery exert a tropism on the circulating platelet population. Indeed, platelet dysfunction concomitant with trauma-induced coagulopathy has been extensively described in literature. Platelet dysfunction during adult orthopedic surgery has been observed but has not been correlated with bleeding, and platelet function in pediatric spine surgery has yet to be assessed. To determine if pediatric patients also experience platelet dysfunction, we measured platelet activation by whole blood flow cytometry during the course of scoliosis surgery in 8 pediatric patients. In parallel, circulating markers of the APR (i.e. IL-6, IL-10, IL-8), products of fibrinolysis (D-dimer), and indicators of consumptive coagulopathy (Protein C) were measured by multiplex ELISA. Samples were collected preoperatively (Preop), intraoperatively (every 2 hours, Intraop 1 and Intraop 2), immediately after closure (Postop) and the following morning (POD1). Samples were stimulated with submaximal concentrations of thrombin, convulxin (GPVI agonist, collagen receptor), and ADP. Platelet integrin activation was measured by PAC1 binding (GPIIbIIIa activation) and platelet secretion was measured by CD62p binding (P-selectin surface expression). We observed a progressive and statistically significant reduction in the platelet response (GPIIbIIIa activation and P-selectin expression) to both thrombin and convulxin stimulation during the procedure but with distinct temporal patterns. The reduction in response to thrombin became significant at Postop, remaining down even at POD1 (PAC1 max reduction, Postop 1: 32.5%, p=0.0403; P-selectin max reduction, POD1: 33.9%, p=0.016). The reduction in response to convulxin, on the other hand developed almost immediately after the initiation of surgery, starting with Intraop1 and resolving by Postop (PAC1 max reduction, Intraop 1: 25.1%, p=0.0087; P-selectin max reduction, Intraop 1: 18.3%, p=0.0369). Intra-operative responses to thrombin (both PAC1 and CD62p binding) significantly correlated with estimates of blood loss based on red blood cell mass (Estimated Red Blood Cell Mass, ERCM def) and hemoglobin mass (Hg mass loss) (see Table I below). Although we observed a consistent and statistically significant reduction in platelet number it correlated with blood loss at POD1 only, suggesting platelet function is a better predictor of blood loss than platelet count. Despite all patients receiving a bolus of TXA with continuous low dose infusion, multiplex results indicated a progressive increase in circulating D-dimer, becoming statistically significant at Postop and persisting through POD 1. Elevations in D-dimer, the byproduct of plasmin degradation of fibrin, suggest elusive fibrinolysis despite administration of TXA. Significant intraoperative elevations in IL-6, IL-10, and IL-8 and consumption of Protein C were also noted that persisted through POD1, indicating the development of coagulopathy. In conclusion, pediatric scoliosis surgery is characterized by persistent fibrinolysis platelet dysfunction, activation of the APR, and coagulopathy despite administration of the anti-fibrinolytic TXA. Future studies will focus on altering the dose of TXA to determine if an optimal dosing can be achieved that effectively inhibits fibrinolysis and answer important questions about the dependence of the APR and platelet hypofunction on the persistent fibrinolysis seen in these patients. Figure Disclosures No relevant conflicts of interest to declare.

Pyridox(am)ine-5-phosphate oxidase deficiency is an inborn error of vitamin B(6) metabolism that is characterized by neonatal seizures, requiring lifelong therapy with pyridoxal-5-phosphate. We present the first case of a patient with pyridox(am)ine-5-phosphate oxidase deficiency and mild hemophilia A, whose bleeding symptoms were exacerbated by the vitamin B(6) therapy essential for his epileptic disorder. This report expands the spectrum of known vitamin B(6) toxicity and demonstrates a need for vigilance in monitoring for bleeding symptoms in patients requiring pyridoxine or pyridoxal-5-phosphate supplementation.

Background Pediatric patients undergoing liver transplant are at significant risk for bleeding and thrombotic complications due to the complex nature of rebalanced hemostasis in patients with liver disease. Methods/objectives We reviewed records of 92 pediatric liver and multivisceral transplant cases at Duke University Medical Center between January 2009 and December 2015. The goal was to define the nature and incidence of bleeding and thrombotic complications in this cohort and define potential risk factors. Results There were 24 major bleeding events in 19 transplants (incidence 20.7%) and 30 thrombotic events in 23 transplants (incidence 25%). Five of the 10 retransplantations were for vascular thrombotic complications. Thirty-day mortality was 4.9%, and three of these four deaths were due to vascular thrombosis. No bleeding events led to retransplantation or mortality. Prophylactic aspirin was associated with decreased risk of thrombosis without increased bleeding. Prophylactic heparin did not increase bleeding risk. Laboratory assays predicted events poorly, apparently failing to capture the nuanced and dynamic interplay between pro- and anticoagulant factors in the posttransplant patient. Conclusions Both bleeding and thrombosis are frequent in this population, but only thrombotic complications contributed to retransplantation and mortality. A standardized approach to coagulation testing and antithrombotic therapy may be useful in predicting and reducing adverse outcomes. Alternative approaches to monitoring hemostasis need to be prospectively investigated in this complex patient population.

Immune checkpoint inhibitors are a novel group of immunotherapeutic agents for the treatment of cancer. Immune-related adverse events, including neurological symptoms, have been associated with these agents. We present the case of an adolescent with refractory Hodgkin lymphoma treated with nivolumab, a PD1 inhibitor, who developed Hashimoto thyroiditis, posterior reversible encephalopathy syndrome causing seizures, as well as urinary retention, truncal/appendicular spasticity, dysphagia, and a progressive encephalopathy that was clinically consistent with a diagnosis of progressive encephalopathy with rigidity and myoclonus, a stiff-person-syndrome spectrum disorder. He showed response and ultimately full recovery to a combination of intravenous steroids, intravenous immunoglobulin, and plasma exchange. To our knowledge, this is the first documented report of an immune-related neurological reaction to nivolumab in an adolescent patient and expands the spectrum of known nivolumab-associated toxicities.

* Abbreviation: EBV — : Epstein-Barr virus Major advances have been made in the field of pediatric solid organ transplant, with significant improvements in long-term survival for children requiring this life-saving intervention.1 Developments in supportive care, organ allocation, HLA antigen matching, and immunosuppressive regimens have all contributed to this success.2–4 With more patients surviving longer, however, there has also been an increase in the long-term complications of transplantation.5 In addition to other organ toxicities, allograft loss, and impaired health-related quality of life,6,7 a dramatic increase in cancer incidence has been seen in organ transplant recipients.8,9 The overall increased incidence of malignancy in patients who have received solid organ transplants has been reported to range from a two- to six-fold increase above the general population,8,10 depending on the cohort and type of transplant. The cumulative incidence has been reported to be as high as 55% … Address correspondence to Daniel S. Wechsler, MD, PhD, Pediatric Hematology-Oncology, Duke University Medical Center, 397 Hanes House, DUMC Box 102382, Durham, NC 27710. E-mail: dan.wechsler{at}duke.edu

Background Primary lymphomas of the bone are rare in children, but have an excellent response to therapy. Evaluating patients for remission and recurrence can be challenging given the difficulties of distinguishing healing bone from residual tumor on imaging. A review of imaging in patients treated for primary bone lymphoma (PBL) in one center was performed in an effort to determine best practice. Methods Twelve cases of PBL diagnosed and treated from 2000 to 2011 at the Children's Hospital of Philadelphia were identified. Information about presentation, histology, imaging, treatment, and outcomes was collected. Results There were no recurrences of the primary bone tumor after therapy. One patient developed therapy-related AML. Although PET-avid lesions usually fell below a SUVmax of 3 within 3 months, low-level SUVmax lesions often remained up to 12 months post-therapy. At no point during therapy did radiographs, MRI, bone scans or CT of bones normalize, most remaining abnormal for several months to years. Patients were exposed to significant ionizing radiation, with estimated levels ranging from 9.5 to 183.1 mSv per patient. Over 10% of scans had incidental findings, which led to 17 extra imaging studies and 4 biopsies, but no clinically significant outcomes. Conclusions In our cohort, frequent imaging did not affect or improve outcome. Due to the low risk of relapse and high rate of repeated imaging for incidental findings, minimization of post-therapy imaging should be considered. This modification in practice will significantly reduce radiation exposure, as well as potentially decrease parent and patient anxiety. Pediatr Blood Cancer 2013;601281-1286. © 2013 Wiley Periodicals, Inc.

Background: Venous thromboembolism (VTE) is an uncommon but clinically significant postoperative complication in children. Incidence of VTE in pediatric patients ranges from 34-58 per 10,000 hospitalized children1. Due to rarity of these events, there is limited information about the factors predisposing children to VTE after surgery. We queried a national surgical database to identify risks and outcomes associated with VTE in pediatric surgical patients. Methods: The National Surgical Quality Improvement Program-Pediatric (NSQIP) is a prospectively collected database that records pediatric surgical information, surgical approaches, and 30 day patient outcomes. The database was queried for the years 2012-2013 to identify pediatric patients (age < 18) who had received surgical intervention and were diagnosed with postoperative VTE. Because of their separate coding in NSQIP, we defined VTE as including venous thromboembolism, or pulmonary embolism (PE) diagnosed radiographically within 30 days of operation. To reduce non-random differences between patients we used propensity scores based on age, sex, race, BMI, and ASA classification to match patients in a 1:2 ratio using the nearest neighbor method. Using univariate and multivariate analysis, we identified preoperative risk factors associated with VTE. Results: In total, 130 patients were identified who developed VTE postoperatively (VTE n=122, PE n=7, BOTH PE + VTE n= 1) from this database of 114,395 patients. There were 104 patients with VTE that also had complete entries and were subsequently analyzed in this study. Surgical specialties treating patients in this analysis included cardiothoracic surgery, general surgery, neurosurgery, orthopedic surgery, otolaryngology, plastic surgery, and urology. Eighty-one unique operative CPT codes were identified for patients with VTE. Patients who developed VTE had increased operative time, anesthesia time, and total length of stay (all p < 0.001). Multivariate analysis demonstrated that pneumonia (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.3 - 2.29), Central Line Associated Bloodstream Infection (CLABSI) (OR 1.69, 95% CI 1.18 - 2.42), sepsis (OR 1.47, 95% CI 1.18 - 1.82), septic shock (OR 1.36, 95% CI 1.06 - 1.75), and current solid or hematologic malignancy or active treatment of malignancy (OR 1.30, 95% CI 1.08 - 1.58) were all statistically significant risk factors associated with development of VTE (all p < 0.05). Conclusions: Postoperative VTE risk is significantly increased in children with malignancy or severe infections. Further research is needed to understand the mechanism between malignancy, systemic inflammation, and VTE risk in children. These findings may help to identify patients in need of prophylactic treatment in order to reduce postoperative thrombotic risk in pediatric patients. References: 1. Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics. 2009;124(4):1001-1008. Disclosures No relevant conflicts of interest to declare.

Purpose: Circulating cell-free DNA in blood may originate from cell necrosis, apoptosis, or NETosis. NETosis is a recently described inflammatory process in which neutrophils release a meshwork of DNA fibers called neutrophil extracellular traps (NETs) to attack microorganisms. Higher levels of cell-free DNA have been observed in patients with sepsis and malignancy, and it may be linked to arterial thrombosis as well. We examined changes in cell-free DNA in infants who experienced acute, iatrogenic thrombosis of the femoral artery after arterial catheterization to better understand the role of cell-free DNA in clot formation. Methods: Plasma samples were collected from infants < 1 year of age with congenital heart disease during cardiac catheterization. Post-procedurally, femoral artery thrombus formation at the site of sheath insertion was detected by ultrasound. Cell-free DNA was quantified at two time points (before and after arterial catheterization) in three infants who developed femoral artery thrombus after catheterization and three age-matched controls. Cell-free DNA was also quantified from plasma of normal adults as a comparison. Results: At baseline,cell-free DNA level for the infant cohort was similar to that in normal adults (13.9 ng/mL vs. 10.3 ng/mL, p = 0.20, Figure). After arterial catheterization, cell-free DNA was increased from baseline in all infants (51.0 ng/mL vs. 13.9 ng/ml, p = 0.004). However, infants who developed femoral artery thrombus after catheterization did not demonstrate higher cell-free DNA after arterial injury, compared to the control group (47.1 ng/mL vs. 54.9 ng/ml, p = 0.83). Conclusions: Cell-free DNA is significantly and consistently elevated in infants after arterial catheterization. As part of NETosis, cell-free DNA may serve as an inflammatory mediator in infants who experience arterial injury. We plan to confirm the findings of this pilot study in a larger human infant cohort as well as in a piglet model of vascular injury. Figure Cell-free DNA levels in infants, before and after arterial catheterization, in comparison to normal adults. Figure. Cell-free DNA levels in infants, before and after arterial catheterization, in comparison to normal adults. Disclosures No relevant conflicts of interest to declare.

Background: Due to underlying liver disease and the transplant process itself, pediatric abdominal transplant patients are at significant risk for bleeding and thrombotic complications. Hemostasis in these patients is nuanced, reflecting a balance of pro- and anti-coagulant factors not accurately captured by routine coagulation lab testing. Previous studies of pediatric liver transplant estimate thrombotic complications in up to 19% of patients and bleeding in 5-9%. These hematologic complications increase risk for graft failure, re-transplantation, or death. Methods: We retrospectively reviewed electronic medical records of consecutive pediatric liver andmultivisceraltransplants at Duke University Medical Center between January 2010 and December 2015 (one exclusion due to inability to access chart). We extracted data from 30 days pre-transplant to 90 days post-transplant. Thrombotic events were defined as any documented thrombus by imaging or direct observation during a surgical procedure. Major bleeding events included surgical bleeding requiring re-operation, CNS bleed, bleeding into an enclosed anatomic space, or blood loss resulting in > 3g/dl drop in hemoglobin. Data was entered into aRedCapDatabase and analyzed usingunivariablelogistic regression. Results: There were 84 transplants at Duke from 2010-2015 (Table 1). There were 103 major bleeding events in 65 patients (incidence 77.4%) and 27 thrombotic events in 21 patients (incidence 25%). Excluding events that were only a > 3g/dl drop in hemoglobin, there were 21 bleeding events in 17 patients (incidence 20.2%). Patients on prophylactic aspirin were less likely to have a thrombosis and were not more likely to have bleeding (Table 2). Patients who received prophylactic heparin (initiated prior to any event) did not have a decreased risk of thrombosis nor increased bleeding (Table 2). There was a higher rate of thrombosis and bleeding in patients who had prior GI surgery (Table 2). Use of an arterial conduit was associated with increased bleeding but not thrombosis (Table 2). Patients with a post-op fibrinogen nadir < 75mg/dl had increased bleeding whereas fibrinogen > 75mg/dl was associated with increased thrombosis (Table 2). Patient age, weight, donor to recipient weight ratio, and transplant type were not associated with bleeding or thrombosis. Maximum INR (pre, intra or post-operatively) or minimum antithrombin( Discussion: We found that bleeding events were more frequent than reported in previous cohorts, but notably less severe than thrombotic complications. In our cohort, many thrombotic complications were severe and potentiallylife-threatening. Practice changes aimed to decrease thrombosis may have led to an increase in recent bleeding events, but these events generally did not result in significant morbidity. Bleeding often required intervention, but did not contribute to re-transplantation or mortality during this period. Laboratory parameters predicted adverse events poorly, apparently failing to capture the nuanced and dynamic interplay between pro- and anti-coagulant factors in the post-transplant patient. A standard approach to coagulation testing combined with a protocol for use of anti-thrombotic therapies may be useful for prospective study. Regular review of outcomes can demonstrate changes that may impact future practice. Further study aimed at delineating parameters associated with adverse outcomes-possibly other than standard coagulation assays-is warranted. Disclosures No relevant conflicts of interest to declare.

Primary lymphomas of the bone are rare in children, but have an excellent response to therapy. Evaluating patients for remission and recurrence can be challenging given the difficulties of distinguishing healing bone from residual tumor on imaging. A review of imaging in patients treated for primary bone lymphoma (PBL) in one center was performed in an effort to determine best practice.Twelve cases of PBL diagnosed and treated from 2000 to 2011 at the Children's Hospital of Philadelphia were identified. Information about presentation, histology, imaging, treatment, and outcomes was collected.There were no recurrences of the primary bone tumor after therapy. One patient developed therapy-related AML. Although PET-avid lesions usually fell below a SUVmax of 3 within 3 months, low-level SUVmax lesions often remained up to 12 months post-therapy. At no point during therapy did radiographs, MRI, bone scans or CT of bones normalize, most remaining abnormal for several months to years. Patients were exposed to significant ionizing radiation, with estimated levels ranging from 9.5 to 183.1 mSv per patient. Over 10% of scans had incidental findings, which led to 17 extra imaging studies and 4 biopsies, but no clinically significant outcomes.In our cohort, frequent imaging did not affect or improve outcome. Due to the low risk of relapse and high rate of repeated imaging for incidental findings, minimization of post-therapy imaging should be considered. This modification in practice will significantly reduce radiation exposure, as well as potentially decrease parent and patient anxiety.