European Society of Pediatric Radiology survey of perioperative imaging in pediatric liver transplantation: (1) pre-transplant evaluation.

BACKGROUND: Liver transplantation is the state-of-the-art curative treatment in end-stage liver disease. Imaging is a key element for successful organ-transplantation to assist surgical planning. So far, only limited data regarding the best radiological approach to prepare children for liver transplantation is available. OBJECTIVES: In an attempt to harmonize imaging surrounding pediatric liver transplantation, the European Society of Pediatric Radiology (ESPR) Abdominal Taskforce initiated a survey addressing the current status of imaging including the pre-, intra-, and postoperative phase. This paper reports the responses on preoperative imaging. MATERIAL AND METHODS: An online survey, initiated in 2021, asked European centers performing pediatric liver transplantation 48 questions about their imaging approach. In total, 26 centers were contacted and 22 institutions from 11 countries returned the survey. From 2018 to 2020, the participating centers collectively conducted 1,524 transplantations, with a median of 20 transplantations per center per annum (range, 8-60). RESULTS: Most sites (64%) consider ultrasound their preferred modality to define anatomy and to plan surgery in children before liver transplantation, and additional cross-sectional imaging is only used to answer specific questions (computed tomography [CT], 90.9%; magnetic resonance imaging [MRI], 54.5%). One-third of centers (31.8%) rely primarily on CT for pre-transplant evaluation. Imaging protocols differed substantially regarding applied CT scan ranges, number of contrast phases (range 1-4 phases), and applied MRI techniques. CONCLUSION: Diagnostic imaging is generally used in the work-up of children before liver transplantation. Substantial differences were noted regarding choice of modalities and protocols. We have identified starting points for future optimization and harmonization of the imaging approach to multicenter studies.

European Society of Pediatric Radiology survey of perioperative imaging in pediatric liver transplantation: (2) intraoperative imaging.

BACKGROUND: Liver transplantation is the state-of-the-art curative treatment for end-stage liver disease. Imaging is a key element in the detection of intraoperative and postoperative complications. So far, only limited data regarding the best radiological approach to monitor children during liver transplantation is available. OBJECTIVE: To harmonize the imaging of pediatric liver transplantation, the European Society of Pediatric Radiology Abdominal Taskforce initiated a survey addressing the current status of imaging including the pre-, intra- and postoperative phase. This paper reports the responses related to intraoperative imaging. MATERIALS AND METHODS: An online survey, initiated in 2021, asked European centers performing pediatric liver transplantation 48 questions about their imaging approach. In total, 26 centers were contacted, and 22 institutions from 11 countries returned the survey. RESULTS: Intraoperative ultrasound (US) is used by all sites to assess the quality of the vascular anastomosis in order to ensure optimal perfusion of the liver transplant. Vessel depiction is commonly achieved using color Doppler (95.3%). Additional US-based techniques are employed by fewer centers (power angio mode, 28.6%; B-flow, 19%; contrast-enhanced US, 14.3%). Most centers prefer a collaborative approach, with surgeons responsible for probe handling, while radiologists operate the US machine (47.6%). Less commonly, the intraoperative US is performed by the surgeon alone (28.6%) or by the radiologist alone (23.8%). Timing of US, imaging frequency, and documentation practices vary among centers. CONCLUSION: Intraoperative US is consistently utilized across all sites during pediatric liver transplantation. However, considerable variations were observed in terms of the US setup, technique preferences, timing of controls, and documentation practices. These differences provide valuable insights for future optimization and harmonization studies.

European Society of Pediatric Radiology survey of perioperative imaging in pediatric liver transplantation: (3) postoperative imaging.

BACKGROUND: Liver transplantation is the state-of-the-art curative treatment for end-stage liver disease. Imaging is a key element in the detection of postoperative complications. So far, limited data is available regarding the best radiologic approach to monitor children after liver transplantation. OBJECTIVE: To harmonize the imaging of pediatric liver transplantation, the European Society of Pediatric Radiology Abdominal Taskforce initiated a survey addressing the current status of imaging including the pre-, intra-, and postoperative phases. This paper reports the responses related to postoperative imaging. MATERIALS AND METHODS: An online survey, initiated in 2021, asked European centers performing pediatric liver transplantation 48 questions about their imaging approach. In total, 26 centers were contacted, and 22 institutions from 11 countries returned the survey. RESULTS: All sites commence ultrasound (US) monitoring within 24 h after liver transplantation. Monitoring frequency varies across sites, ranging from every 8 h to 72 h in early, and from daily to sporadic use in late postoperative phases. Predefined US protocols are used by 73% of sites. This commonly includes gray scale, color Doppler, and quantitative flow assessment. Alternative flow imaging techniques, contrast-enhanced US, and elastography are applied at 31.8%, 18.2%, and 63.6% of sites, respectively. Computed tomography is performed at 86.4% of sites when clarification is needed. Magnetic resonance imaging is used for selected cases at 36.4% of sites, mainly for assessment of biliary abnormalities or when blood tests are abnormal. CONCLUSION: Diagnostic imaging is extensively used for postoperative surveillance of children after liver transplantation. While US is generally prioritized, substantial differences were noted in US protocol, timing, and monitoring frequency. The study highlights potential areas for future optimization and standardization of imaging, essential for conducting multicenter studies.

Ultrasonography of the bone surface in children: normal and pathological findings in the bone cortex and periosteum.

Ultrasound (US) is widely used in pediatric musculoskeletal pathology at all ages. Although the focus is often on soft tissues, joints and cartilage, the examiner might be confronted with changes in the underlying bone surface that are important to understand and integrate in the diagnosis. This article illustrates the normal US aspects of the cortical bone surface and periosteum, as well as the most common US anomalies seen in infections, trauma and bone tumors in children.

Novel insights into the assessment of risk of upper gastrointestinal bleeding in decompensated cirrhotic children.

OBJECTIVES: Cirrhotic children wait-listed for liver transplant are prone to bleeding from gastrointestinal varices. Grade 2-3 esophageal varices, red signs, and gastric varices are well-known risk factors. However, the involvement of hemostatic factors remains controversial because of the rebalanced state of coagulation during cirrhosis. METHODS: Children suffering from decompensated cirrhosis were prospectively included while being on waitlist. Portal hypertension was assessed by ultrasound and endoscopy. Coagulopathy was evaluated through conventional tests, thromboelastometry, and platelet function testing. The included children were followed up until liver transplantation, and all bleeding episodes were recorded. Children with or without bleeding were compared according to clinical, radiological, endoscopic, and biological parameters. In addition, validation of a predictive model for risk of variceal bleeding comprising of grade 2-3 esophageal varices, red spots, and fibrinogen level <150 mg/dL was applied on this cohort. RESULTS: Of 20 enrolled children, 6 had upper gastrointestinal bleeding. Significant differences were observed in fibrinogen level, adenosine diphosphate, and thrombin-dependent platelet aggregation. The model used to compute the upper gastrointestinal bleeding risk had an estimated predictive performance of 81.0%. Platelet aggregation analysis addition improved the estimated predictive performance up to 89.0%. CONCLUSIONS: We demonstrated an association between hemostatic factors and the upper gastrointestinal bleeding risk. A low fibrinogen level and platelet aggregation dysfunction may predict the risk of bleeding in children with decompensated cirrhosis. A predictive model is available to assess the upper gastrointestinal bleeding risk but needs further investigations. Clinicaltrials.gov number: NCT03244332.

Angiosarcoma arising from congenital primary lymphedema.

We herein report the case of a 3-year-old girl with atypical congenital right upper limb lymphedema who developed an angiosarcoma. Only a few cases have been reported following congenital form of lymphedema and only 4 in such a young child. We also summarize all cases of angiosarcoma associated with congenital lymphedema reported in the literature.

Liver and systemic hemodynamics in children with cirrhosis: Impact on the surgical management in pediatric living donor liver transplantation.

Cirrhosis in adults is associated with modifications of systemic and liver hemodynamics, whereas little is known about the pediatric population. The aim of this work was to investigate whether alterations of hepatic and systemic hemodynamics were correlated with cirrhosis severity in children. The impact of hemodynamic findings on surgical management in pediatric living donor liver transplantation (LT) was evaluated. Liver and systemic hemodynamics were studied prospectively in 52 children (median age, 1 year; 33 with biliary atresia [BA]). The hemodynamics of native liver were studied preoperatively by Doppler ultrasound and intraoperatively using invasive flowmetry. Portosystemic gradient was invasively measured. Systemic hemodynamics were studied preoperatively by Doppler transthoracic echocardiography and intraoperatively by using transpulmonary thermodilution. Hemodynamic parameters were correlated with Pediatric End-Stage Liver Disease (PELD) score and the histological degree of fibrosis (collagen proportionate area [CPA]). Cirrhosis was associated with a 60% reduction of pretransplant total liver flow (n = 46; median, 36 mL/minute/100 g of liver) compared with noncirrhotic livers (n = 6; median, 86 mL/minute/100 g; P = 0.002). Total blood flow into the native liver was negatively correlated with PELD (P < 0.001) and liver CPA (P = 0.005). Median portosystemic gradient was 14.5 mm Hg in children with cirrhosis and positively correlated with PELD (P < 0.001). Portal vein (PV) hypoplasia was observed mainly in children with BA (P = 0.02). Systemic hemodynamics were not altered in our children with cirrhosis. Twenty-one children met the intraoperative criteria for PV reconstruction using a portoplasty technique during the LT procedure and had a smaller PV diameter at pretransplant Doppler ultrasound (median = 3.4 mm; P < 0.001). Cirrhosis in children appears also as a hemodynamic disease of the liver, correlated with cirrhosis severity. Surgical technique for PV reconstruction during LT was adapted accordingly. Liver Transplantation 23 1440-1450 2017 AASLD.

Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey.

PURPOSE: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. METHODS: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. RESULTS: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. CONCLUSIONS: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.

Isolated bilateral transverse agenesis of the distal segments of the lower limbs at the level of the knee joint in a human fetus.

Congenital limb anomalies occur in Europe with a prevalence of 3.81/1,000 births and can have a major impact on patients and their families. The present study concerned a female fetus aborted at 23 weeks of gestation because she was affected by non-syndromic bilateral absence of the zeugopod (leg) and autopod (foot). Autopsy of the aborted fetus, X-ray imaging, MRI, and histochemical analysis showed that the distal extremity of both femurs was continued by a cartilage-like mass, without joint cavitation. Karyotype was normal. Moreover, no damaging variant was detected by exome sequencing. The limb characteristics of the fetus, which to our knowledge have not yet been reported in humans, suggest a developmental arrest similar to anomalies described in chicks following surgical experiments on the apical ectodermal ridge of the lower limbs.

Ultrasound of the duodenum in children.

Ultrasound is well suited for examining the pediatric duodenum, given the small size of the patients, the lack of ionizing radiation and high-resolution imaging potential. Technical considerations, normal anatomy, congenital and acquired pathology of the duodenum, and the advantages and limitations of US are discussed and illustrated in this review.

Living Donor Liver Transplantation in Children: Surgical and Immunological Results in 250 Recipients at Université Catholique de Louvain.

OBJECTIVES: To evaluate the outcome of pediatric living donor liver transplantation (LDLT) regarding portal vein (PV) reconstruction, ABO compatibility, and impact of maternal donation on graft acceptance. BACKGROUND: LDLT and ABO-mismatched transplantation constitute feasible options to alleviate organ shortage in children. Vascular complications of portal hypoplasia in biliary atresia (BA) and acute rejection (AR) are still major concerns in this field. METHODS: Data from 250 pediatric LDLT recipients, performed at Cliniques Universitaires Saint-Luc between July 1993 and June 2012, were collected retrospectively. Results were analyzed according to ABO matching and PV complications. Uni- and multivariate analyses were performed to study the impact of immunosuppression, sex matching, and maternal donation on AR rate. RESULTS: Overall, the 10-year patient survival rate was 93.2%. Neither patient or graft loss nor vascular rejection, nor hemolysis, was encountered in the ABO nonidentical patients (n = 58), provided pretransplant levels of relevant isoagglutinins were below 1/16. In BA recipients, the rate of PV complications was lower after portoplasty (4.6%) than after truncal PV anastomosis (9.8%) and to jump graft interposition (26.9%; P = 0.027). In parental donation, maternal grafts were associated with higher 1-year AR-free survival (55.2%) than paternal grafts (39.8%; P = 0.041), but only in BA patients. CONCLUSIONS: LDLT, including ABO-mismatched transplantation, constitutes a safe and efficient therapy for liver failure in children. In BA patients with PV hypoplasia, portoplasty seems to constitute the best technique for PV reconstruction. Maternal donation might be a protective factor for AR.

Risk factors and surgical management of anastomotic biliary complications after pediatric liver transplantation.

Biliary complications (BCs) still remain the Achilles heel of liver transplantation (LT) with an overall incidence of 10% to 35% in pediatric series. We hypothesized that (1) the use of alternative techniques (reduced size, split, and living donor grafts) in pediatric LT may contribute to an increased incidence of BCs, and (2) surgery as a first treatment option for anastomotic BCs could allow a definitive cure for the majority of these patients. Four hundred twenty-nine primary pediatric LT procedures, including 88, 91, 47, and 203 whole, reduced size, split, and living donor grafts, respectively, that were performed between July 1993 and November 2010 were retrospectively reviewed. Demographic and surgical variables were analyzed, and their respective impact on BCs was studied with univariate and multivariate analyses. The modalities of BC management were also reviewed. The 1- and 5-year patient survival rates were 94% and 90%, 89% and 85%, 94% and 89%, and 98% and 94% for whole, reduced size, split, and living donor liver grafts, respectively. The overall incidence of BCs was 23% (n = 98). Sixty were anastomotic complications [47 strictures (78%) and 13 fistulas (22%)]. The graft type was not found to be an independent risk factor for the development of BCs. According to a multivariate analysis, only hepatic artery thrombosis and acute rejection increased the risk of anastomotic BCs (P < 0.001 and P = 0.003, respectively). Anastomotic BCs were managed primarily with surgical repair in 59 of 60 cases with a primary patency rate of 80% (n = 47). These results suggest that (1) most of the BCs were anastomotic complications not influenced by the type of graft, and (2) the surgical management of anastomotic BCs may constitute the first and best therapeutic option.

Postendoscopic duodenal hematoma in children: ultrasound diagnosis and follow-up.

Intramural duodenal hematomas have most frequently been reported in children in a traumatic setting. We present two cases of duodenal hematoma that occurred after upper gastrointestinal tract endoscopy with biopsy in children without significant prior medical history. The diagnosis was made by ultrasound, in correlation with the clinical presentation. Because the patients were hemodynamically stable, they were treated conservatively and the regression of the hematoma was followed up with ultrasound until its complete resolution. These cases demonstrate the risks of endoscopy, which are not to be neglected even in children without impaired coagulation, and the manner in which ultrasound can provide the correct diagnosis and follow-up.

Targeted treatment in complex lymphatic anomaly: a case of synergistic efficacy of trametinib and sirolimus.

Repurposing anticancer drugs to vascular malformations has significantly improved patient outcomes. Complex Lymphatic Anomalies (CLA) are part of the spectrum of lymphatic malformations (LMs) that share similar oncogenic mutations to cancer. We report the case of a young patient with highly symptomatic CLA who was initially treated with sirolimus, due to the frequent involvement of the PI3K-AKT-mTOR pathway in CLA pathogenesis. Despite an initial reduction in symptoms, sirolimus progressively lost its effectiveness. After an unsuccessful attempt with trametinib alone, sirolimus was added to trametinib and resulted in a significant, rapid and sustained improvement in symptoms. This suggests that, contrary to current dogmas, combination therapy using sub-therapeutic doses targeting both the PI3K and RAS pathways retains efficacy without generating the toxicity known for combination therapies, and is beneficial in the management of CLAs and potentially other vascular anomalies.

RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation.

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n = 100), common CM(s) (port-wine stain; n = 100), Sturge-Weber syndrome (n = 37), or isolated AVM(s) (n = 24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the "second-hit" hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up.

Deoxyguanosine kinase deficiency and recurrent spontaneous pneumothorax: a case report.

BACKGROUND: Deoxyguanosine kinase deficiency is mainly manifested by hepatic and neurological damage, hence it belongs to the hepatocerebral form of mitochondrial deoxyribonucleic acid depletion syndrome. The association between deoxyguanosine kinase deficiency and recurrent spontaneous pneumothorax has not currently been reported. CASE PRESENTATION: A 12-year-old Russian boy with deoxyguanosine kinase deficiency, a recipient of a liver transplant with amyotrophy secondary to his mitochondriopathy, presented with recurrent spontaneous bilateral pneumothorax refractory to drainage and surgery. CONCLUSION: To our knowledge, this is the first documented case of deoxyguanosine kinase deficiency associated with recurrent spontaneous pneumothorax, which could be considered a late complication of deoxyguanosine kinase deficiency. At this point, this is only an association and further studies and research need to be performed to help confirm the pathogenesis of this association.

A pregnant patient with ALK-positive non-small cell lung cancer treated with alectinib: A case report and review of the literature.

Oncogenic rearrangements in the anaplastic lymphoma kinase (ALK) gene account for 5% of non-small cell lung cancer (NSCLC) cases. ALK inhibitors have markedly improved the outcome of metastatic ALK-positive NSCLC (ALK+ mNSCLC) by increasing long-term overall survival. Although a diagnosis of NSCLC during pregnancy or the peripartum period is rare, ALK+ NSCLC accounts for 38% of NSCLC cases in women of childbearing age (18-45 years old). The younger age and prolonged survival of patients with ALK+ mNSCLC bring new challenges for lung cancer and obstetrics research, and raises questions related to pregnancy and family planning. The present study described normal fetal development and no obstetric complications in a patient infected with HIV diagnosed with ALK+ mNSCLC, who became pregnant during treatment with alectinib, a third-generation ALK inhibitor.

A case report of sirolimus use in early fetal management of lymphatic malformation.

Sirolimus, by targeting the mammalian target of rapamycin (mTOR) pathway, has demonstrated efficacy on lymphatic malformations (LMs) in adults and neonates. The current hypothesis is that the earlier the lesion is treated, the better it responds. This has prompted the idea that sirolimus administration might be efficacious to treat fetal LMs as well. Here we report a successful management of a cervicofacial fetal LM with sirolimus taken orally by the mother from the 22nd week of pregnancy until 2 weeks before planned delivery. Repeated cordocentesis recorded a 30% transplacental crossing of sirolimus. Continuation of sirolimus after birth allowed resection of the residual mass. We have followed the physical and neurological evolution of the child for 6 years since the fetal administration of sirolimus. We conclude that early administration of sirolimus during pregnancy with maternal serum monitoring may be proposed to high-risk fetal LMs in selected cases.

Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations.

BACKGROUNDSlow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODSThe Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTSThirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3-4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSIONSirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATIONClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDINGThe Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR grant 21CVD03), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.