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Patients with dextro-transposition of the great arteries (d-TGA) require surgical repair as neonates. These patients are at risk for post-operative chylothorax. We sought to describe the presentation, imaging, and outcomes after intervention for patients with d-TGA with post-operative chylothorax. A retrospective chart review was performed in patients with repaired d-TGA who were referred from 1/1/2013 to 4/1/2020 for evaluation of chylothorax. Patient history, lymphatic imaging, and interventional data were collected. Impact of intervention on lymphatic drainage was evaluated with a student’s t-test. Eight patients met inclusion criteria for this study. Five patients had a history of central venous thrombus leading to thoracic duct outlet occlusion. Five patients underwent intervention, two were managed conservatively, and one was not a candidate for intervention. Chylothorax resolved in six patients. There was a significant difference in output from 7 days prior to first intervention (114 mL/kg/day) compared to 28 days following final intervention (27 mL/kg/day, p = 0.034). There were no procedural complications. Chylothorax in patients with repaired transposition of the great arteries is often amenable to intervention. Early surveillance and management of central venous thrombosis may reduce the burden of lymphatic disease in these patients.

ObjectivesTo characterize hepatic to systemic lymphatic connections in patients with systemic lymphatic disease using intra-hepatic lymphangiography and to compare outcomes after lymphatic intervention.MethodsIn this retrospective study, patients with intra-hepatic lymphangiography from May 2014 – April 2019 at our institution were included. Imaging review was performed and hepatic lymphatic connections and flow patterns were characterized. Clinical data were reviewed and comparisons between patients undergoing lymphatic intervention with or without abnormal hepatic lymphatics were performed.ResultsDuring the study period, 105 patients underwent intra-hepatic lymphangiography. Primary clinical presentation included ascites (19/105), chylothorax (27/105), plastic bronchitis (PB) (17/105), and protein losing enteropathy (PLE) (42/105). Five categories of hepatic lymphatic connections and flow patterns were identified (%): normal (25%, 26/105), hepatoperitoneal (12%, 13/105), hepatopulmonary (10.5%, 11/105), hepatomesenteric (7.5%, 8/105), and hepatoduodenal (41%, 43/105) with four patients having more than one abnormal pattern. A comparison between clinical presentation and imaging category revealed an increased likelihood of having ascites with hepatoperitoneal (p< .0001), chylothorax/PB with hepatopulmonary (p= .01), and PLE with hepatoduodenal (p< .001) connections. Seventy-six patients had a lymphatic intervention, 24% with normal, and 76% with abnormal liver lymphatics. There was no difference in length of hospital stay or mortality between the two groups, but there was a prolonged time to symptom resolution (p= .006) and persistent symptoms after 6 months (5% vs 44%,p= .002) in the group with abnormal liver lymphatics.ConclusionWe identified five liver lymphatic imaging categories with a substantial correlation to presenting lymphatic disease. Abnormal imaging patterns correlated with increased morbidity. Evaluation of liver lymphatics should be considered in patients with a systemic lymphatic disease if central lymphatic imaging is normal.Key Points•We identified five liver lymphatic imaging patterns: normal, hepatoperitoneal, hepatomesenteric, hepatopulmonary, and hepatoduodenal.•Imaging patterns were correlated with disease presentation (normal – chylothorax/PB, hepatoperitoneal – ascites/chylothorax, hepatopulmonary – chylothorax/PB, hepatoduodenal – PLE).•Abnormal imaging patterns correlated with increased morbidity.

Lymphatic flow disorders include a broad spectrum of abnormalities that can originate in the lymphatic or the venous system. The development of these disorders is multifactorial and is most commonly associated with congenital heart diseases and palliative surgeries that these patients undergo. Central lymphatic disorders might be secondary to traumatic leaks, lymphatic overproduction, conduction abnormalities or lymphedema, and they can progress to perfusion anomalies. Several imaging modalities have been used to visualize the lymphatic system. However, the imaging of central lymphatic flow has always been challenging. Dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) allows for visualization of central lymphatic flow disorders and has been recently applied for the assessment of plastic bronchitis, protein-losing enteropathy, chylothorax and chylopericardium, among other lymphatic disorders. The hepatic and mesenteric accesses are innovative and promising techniques for better identification and understanding of these abnormalities. The main objectives of this review are to discuss the physiology and anatomy of the lymphatic system and review the current uses of DCMRL in the diagnosis and management of lymphatic flow disorders.

Neonatal chylothorax (NCTx) and central lymphatic flow disorder (CLFD) are historically challenging neonatal disorders with high morbidity and mortality. METHODS We conducted a retrospective study of 35 neonates with pulmonary lymphatic abnormalities at our institution who underwent lymphatic evaluation between December 2015 and September 2018. Patients with only pulmonary lymphatic perfusion syndrome were classified as NCTx and those with multiple flow abnormalities were classified as CLFD. Demographics, clinical characteristics, and outcomes were compared using t-tests/Wilcoxon rank sum tests and Fisher's exact tests. RESULTS All 35 patients had intranodal MR lymphangiography and 14 (40%) also had conventional fluoroscopic lymphangiography. Fifteen (42.8%) patients were diagnosed with NCTx and 20 (57.1%) were diagnosed with CLFD. Thirty-four (97.1%) patients had pleural effusions. None of the NCTx group had ascites, anasarca, or dermal backflow compared to 17 (85%) (p

To report on our initial experience with intramesenteric (IM) dynamic contrast magnetic resonance lymphangiography (DCMRL) for evaluation of the lymphatics in patients with concern for mesenteric lymphatic flow disorders and to compare IM-DCMRL with intrahepatic (IH) and intranodal (IN) DCMRL. This is a retrospective review of imaging findings in 15 consecutive patients who presented with protein losing enteropathy (PLE) and/or ascites undergoing IM-DCMRL, IH-DCMRL, and IN-DCMRL. The IM-DCMRL technique involves the injection of a gadolinium contrast agent into the mesenteric lymphatic ducts or lymph nodes followed by imaging of the abdomen and chest with dynamic time-resolved MR lymphangiography. IM-DCMRL was successfully performed in 14/15 (93%) of the patients. When comparing IN-DCMRL with IM-DCMRL, there was a significant difference in the visualization of dermal backflow (p = 0.014), duodenal perfusion (p = 0.003), duodenal leak (p = 0.014), and peritoneal leak (p = 0.003). IM-DCMRL demonstrated peritoneal leak in 7 patients in contrast to IH-DCMRL which demonstrated leak in 4 patients and IN-DCMRL which did not demonstrate any peritoneal leaks. Duodenal leaks were seen by IH-DCMRL in 9 patients versus 5 with IM-DCMRL and none with IN-DCMRL. In one patient with congenital PLE, the three modalities showed different disconnected flow patterns with duodenal leak only seen by IM-DCMRL. There were no short-term complications from the procedures. IM-DCMRL is a feasible imaging technique for evaluation of the mesenteric lymphatics. In certain mesenteric lymphatic flow abnormalities, such as PLE and ascites, this imaging may be helpful for diagnosis and the planning of interventions and warrants further studies. • Intramesenteric dynamic contrast magnetic resonance lymphangiography (IM-DCMRL) is a new imaging technique to evaluate mesenteric lymphatic flow disorders such as ascites. • IM-DCMRL is able to image lymphatic leaks in patients with ascites and protein losing enteropathy not seen with intranodal (IN-DCMRL) imaging.

The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient's lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.

To describe the technique and report on our initial experience with the use of intrahepatic dynamic contrast magnetic resonance lymphangiography (IH-DCMRL) for evaluation of the lymphatics in patients with hepatic lymphatic flow disorders. This is a retrospective review of the imaging and clinical findings in six consecutive patients undergoing IH-DCMRL. The technique involves injection of a gadolinium contrast agent into the intrahepatic lymphatic ducts followed by imaging of the abdomen and chest with both heavily T2-weighted imaging and dynamic time-resolved imaging. In six consecutive patients, IH-DCMRL was technically successful. There were four patients with protein-losing enteropathy (PLE) and two with ascites in this study. In the four patients with PLE, IH-DCMRL demonstrated hepatoduodenal connections with leak of contrast into the duodenal lumen not seen by conventional lymphangiography. In one patient with ascites, IH-DCMRL demonstrated lymphatic leakage into the peritoneal cavity not seen by intranodal lymphangiography. In the second patient with ascites, retrograde lymphatic perfusion of mesenteric lymphatic networks and nodes was seen. Venous contamination was seen in two patients. No biliary contamination was identified. There were no short-term complications. IH-DCMRL is a cross-sectional technique which successfully evaluated hepatic lymphatic flow disorders and warrants further investigation. • Intrahepatic dynamic contrast magnetic resonance lymphangiography (IH-DCMRL) is a new imaging technique to evaluate hepatic lymphatic flow disorders such as protein-losing enteropathy. • In comparison to conventional liver lymphangiography, IH-DCMRL offers a 3D imaging technique and better distal lymphatic contrast distribution and does not use ionizing radiation.

Central conducting lymphatic anomaly (CCLA) is a heterogenous disorder caused by disruption of central lymphatic flow that may result in dilation or leakage of central lymphatic channels. There is also a paucity of known genetic diagnoses associated with CCLA. We hypothesized that specific genetic syndromes would have distinct lymphatic patterns and this would allow us to more precisely define CCLA. As a first step toward "precision lymphology", we defined the genetic conditions associated with CCLA by performing a retrospective cohort study. Individuals receiving care through the Jill and Mark Fishman Center for Lymphatic Disorders at the Children's Hospital of Philadelphia between 2016 and 2019 were included if they had a lymphangiogram and clinical genetic testing performed and consented to a clinical registry. In our cohort of 115 participants, 26% received a molecular diagnosis from standard genetic evaluation. The most common genetic etiologies were germline and mosaic RASopathies, chromosomal abnormalities including Trisomy 21 and 22q11.2 deletion syndrome, and PIEZO1-related lymphatic dysplasia. Next, we analyzed the dynamic contrast magnetic resonance lymphangiograms and found that individuals with germline and mosaic RASopathies, mosaic KRASopathies, PIEZO1-related lymphatic dysplasia, and Trisomy 21 had distinct central lymphatic flow phenotypes. Our research expands the genetic conditions associated with CCLA and genotype-lymphatic phenotype correlations. Future descriptions of CCLA should include both genotype (if known) and phenotype to provide more information about disease (gene-CCLA). This should be considered for updated classifications of CCLA by the International Society of Vascular Anomalies.

Stenosis of the pulmonary arteries frequently occurs during staged palliation of hypoplastic left heart syndrome and variants, often necessitating stent angioplasty. A complication of stent angioplasty is compression of the ipsilateral mainstem bronchus. Following such a case, we re-evaluated our approach to PA stent angioplasty in these patients. The incident case is described. A retrospective observational study of children and adults with superior (SCPC) and/or total cavopulmonary connection (TCPC) undergoing left pulmonary artery (LPA) stent angioplasty between January 1, 2005 and January 5, 2014 and subsequent chest CT was performed to assess the incidence of bronchial compression. The current strategy of employing bronchoscopy to assess bronchial compression during angioplasty is described with short-term results. Sixty-five children and adults underwent LPA stent angioplasty. Other than the incident case, none had symptomatic bronchial compression. Of the total study population, 12 % had subsequent CT, of which one subject had moderate bronchial compression. To date, seven subjects have undergone angioplasty of LPA stenosis and bronchoscopy. In one case, stent angioplasty was not performed because of baseline bronchial compression, exacerbated during angioplasty. In the rest of cases, mild-moderate compression was seen during angioplasty. Following stent angioplasty, the resultant compression was not worse than that seen on test angioplasty. Bronchial compression is a rare complication of stent angioplasty of the pulmonary arteries in children and adults with SCPC/TCPC. Angioplasty of the region of interest with procedural bronchoscopy can help to identify patients at risk of this complication.

Radiofrequency perforation and valvuloplasty (RFV) is an effective initial treatment in patients with pulmonary atresia and intact ventricular septum (PA-IVS) and mild to moderate right ventricle and tricuspid valve hypoplasia. Outcomes and risk factors for the need for additional interventions in these patients are poorly defined. All patients with PA-IVS who underwent RFV at our center between January 2000 and July 2011 were reviewed. Twenty-three patients met the inclusion criteria. All patients underwent successful valvuloplasty with no procedural deaths and one major complication. Excluding two patients with limited follow-up, 6 (29 %) patients underwent no subsequent interventions, whereas 9 (42 %) patients underwent surgical right-ventricular outflow tract augmentation. All except one patient with adequate follow-up have a biventricular circulation with saturation >92 %. Patients who did not undergo any right-ventricular outflow tract intervention after valvuloplasty had a significantly lower gradient across the pulmonary valve after valvuloplasty (9.9 mmHg ± 8.4 vs. 19.1 mmHg ± 10.4, p = 0.05). Significantly more patients who received a supplemental source of pulmonary blood flow had a tricuspid valve z-score