The Outcome of A Centralization Program in Biliary atresia: 20 years and beyond.

OBJECTIVE: Biliary atresia (BA) is a rare disease and reported outcomes of surgical management, typically a Kasai portoenterostomy (KPE), vary considerably across the world. Centralization has been proposed to improve this. SUMMARY BACKGROUND DATA: A national centralization programme was started in Jan. 1999, involving 3 English units with co-located liver transplant facilities. As the program has now reached the 20-year point, the main aim was to update outcome statistics and identify trends. METHODS: Prospective registry and database. The main measures of outcome were (i) time to KPE, (ii) Clearance of Jaundice (CoJ), defined as reaching a bilirubin value of <20µmol/L (≈1.5 mg/dL), and (iii) actuarial native liver survival (NLS) and overall survival (OS). Data are quoted as median (IQR) and non-parametric statistical comparison used with P<0.05 regarded as significant. RESULTS: 867 infants were born with BA and managed between January 1999 and December 2019. Death occurred without intervention (n=10, 1.1%) or were subject to primary transplant (n=26, 3.0%); leaving 831 (95.9%) infants who underwent KPE at median age of 51 (IQR 39-64) days. Age at KPE reduced over the period (P=0.0001) becoming 48(35-57) days in the last 5-year era. CoJ was achieved in 505/831 (60.6%), also increasing over the period (P=0.002). 42 (5.0%) died post-KPE and 384 were transplanted, leaving 405 alive with their native livers at last follow-up. Of the 412 children transplanted, there were 23 (5.6%) deaths, leaving 387 alive. 5-year and 10-year native liver survival were 51.3% (95% CI 54.8-47.8) and 46.5% (95% CI 50.1 - 42.9) and overall survival were 91.5% (95% CI 93.2 - 89.4) and 90.5% (95% CI 92.3 - 88.2%) respectively. CONCLUSIONS: There have been continued improvements in efficiency over the period of centralization with a significant reduction in time to KPE and improved CoJ following KPE. Overall survival in this disease remains >90%.

Early and Long-term Complications of Robotic Assisted Laparoscopy in Infants and Children.

BACKGROUND: Robotic-assisted laparoscopy still lacks wide acceptance in infants and children. We developed the service and report the largest single institution experience of complications over a period of 11 years. METHODS: Between March 2006 and May 2017, consecutive infants and children who underwent robotic assisted laparoscopy under the care of two laparoscopic surgeons were studied. Data for patients, surgeons, year of surgery, operation, and timing, nature, grades of complications were assessed. RESULTS: A total of 601 robotic procedures (45 different types) were carried out in 539 patients. Of these 31 (5.8%) were converted, none for operative complications. These and another 4 with complicated co-morbidity were excluded, leaving 504 patients for further analysis. There were 60 (11.9%) complications in 57 (11.3%) patients. Mean (SD) age was 7.7 years -/+5.1 with the youngest being 4 weeks. Concomitant or bilateral robotic and non-robotic procedures took place in 8.1% and 13.3% of patients respectively. Significant medical co-morbidity and abdominal scarring were present in 29% and 14.9% of patients respectively. Complications occurred in theatre 1.6%, hospital 5.6%, 28 days 1.2%, and late 3.6%. Mean follow up was 7.6 years -/+ 3.1 SD. Over-all postoperative complication rate was 10.3%: CD grade I 6.5% (33), II 0.6% (3), and IIIa/b 3.2% (16) which included 1.4% (7) re-do surgery. Most (11/16) grade III occurred late. There were no bleeding, grade IV or V complications, surgical mortality, or technology related complications. CONCLUSIONS: Complications are low even during the learning phase and while developing the new technique. Most complications occurred early and were minor. Most high-grade complications presented late. LEVELS OF EVIDENCE: 2B.

Incidence of Isolated Biliary Atresia during the COVID Lockdown in Europe: Results from a Collaborative Project by RARE-Liver.

BACKGROUND: Biliary atresia (BA) is a rare cholangiopathy where one of the proposed aetiological mechanisms is an infectious viral trigger. Coronavirus disease-19 (COVID) lockdown restrictions were implemented to reduce the transmission of infections. Strictness of lockdown varied across European countries. This study aimed to investigate if there was an association between strictness of lockdown and change in isolated BA (IBA) incidence in Europe. METHODS: We approached European centres involved in the European Reference Network RARE-LIVER. We included IBA patients born between 2015 and June 2020. We calculated the number of IBA patients born per centre per month. The Stringency Index (SI) was used as lockdown strictness indicator. The association between percentage change of mean number of IBA patients born per month and the SI was assessed. RESULTS: We included 412 IBA patients from thirteen different centres. The median number of patients per month did not change: 6 (1-15) pre-lockdown and 7 (6-9) during lockdown (p = 0.34). There was an inverse association between SI and percentage change in IBA (B = -0.73, p = 0.03). Median age at Kasai portoenterostomy (days) did not differ between time periods (51 (9-179) vs. 53 (19-126), p = 0.73). CONCLUSION: In this European study, a stricter COVID-lockdown was seemingly accompanied by a simultaneous larger decrease in the number of IBA patients born per month in the lockdown. Results should be interpreted with caution due to the assumptions and limitations of the analysis.

Toward systems-informed models for biologics disposition: covariates of the abundance of the neonatal Fc Receptor (FcRn) in human tissues and implications for pharmacokinetic modelling.

Biologics are a fast-growing therapeutic class, with intertwined pharmacokinetics and pharmacodynamics, affected by the abundance and function of the FcRn receptor. While many investigators assume adequacy of classical models, such as allometry, for pharmacokinetic characterization of biologics, advocates of physiologically-based pharmacokinetics (PBPK) propose consideration of known systems parameters that affect the fate of biologics to enable a priori predictions, which go beyond allometry. The aim of this study was to deploy a systems-informed modelling approach to predict the disposition of Fc-containing biologics. We used global proteomics to quantify the FcRn receptor [p51 and ß2-microglobulin (B2M) subunits] in 167 samples of human tissue (liver, intestine, kidney and skin) and assessed covariates of its expression. FcRn p51 subunit was highest in liver relative to other tissues, and B2M was 1-2 orders of magnitude more abundant than FcRn p51 across all sets. There were no sex-related differences, while higher expression was confirmed in neonate liver compared with adult liver. Trends of expression in liver and kidney indicated a moderate effect of body mass index, which should be confirmed in a larger sample size. Expression of FcRn p51 subunit was approximately 2-fold lower in histologically normal liver tissue adjacent to cancer compared with healthy liver. FcRn mRNA in plasma-derived exosomes correlated moderately with protein abundance in matching liver tissue, opening the possibility of use as a potential clinical tool. Predicted effects of trends in FcRn abundance in healthy and disease (cancer and psoriasis) populations using trastuzumab and efalizumab PBPK models were in line with clinical observations, and global sensitivity analysis revealed endogenous IgG plasma concentration and tissue FcRn abundance as key systems parameters influencing exposure to Fc-conjugated biologics.

Reduced Presentation of Biliary Atresia During the COVID-19 Lockdown: A Population Based Observational Study.

OBJECTIVE: The aim of this study was to assess whether there has been a change in presentations of biliary atresia (BA) in England and Wales during the first and second coronavirus disease 2019 (COVID-19) lockdowns (January-June 2020 and 2021). DESIGN: This population study assessed all confirmed cases of BA, from January 2020 to December 2021 across the 3 UK pediatric liver centers originating from England and Wales. Data was then compared to the incidence of confirmed BA cases from January to December 2017, 2018, and 2019. RESULTS: During January-June 2020 and 2021, there were only 8 and 12 presenting cases of BA in England and Wales, compared to 16, 13, and 18 for the same time periods in 2017, 2018, and 2019, respectively. This difference was significant in a two-sided t test for 2020 ( P = 0.035) but not for 2021 ( P = 0.385). There was no difference in the mean days to Kasai procedure in January-June 2020 and 2021 compared to 2017-2019; however average time to Kasai after the lockdown periods was significantly higher. CONCLUSIONS: There was a significant reduction in the presenting cases of BA during the first COVID-19 lockdown, with an increased time for BA referrals after the pandemic lockdowns were lifted in England and Wales.

Hepatic benign and malignant masses in children: a single UK tertiary centre experience.

PURPOSE: The aim of this study was to review the incidence, spectrum and investigation of liver masses presenting to our tertiary liver unit. METHODS: A retrospective single-centre cohort study of paediatric patients (age < 16 years) diagnosed with a liver mass who were investigated at a UK paediatric hepatobiliary tertiary referral centre. Data relating to the clinical findings at presentation, source of referral, diagnostic investigations and histopathology findings were recorded and analysed. RESULTS: 107 patients were identified between July 2012 and July 2019 (55 females). 69 (64%) patients had benign liver lesions, whereas the remaining 38 (36%) were found to have malignant masses. The liver lesions were most commonly detected incidentally (33%) with the second most common presentation being with palpable mass (29%). 82 (77%) patients were referred from other hospitals. All patients underwent USS, 74% MRI, 36% CT, 5% CEUS, 1% PET and 5% HIDA scan with 47% ultimately undergoing biopsy. 72% of patients had AFP measured. The most common benign liver masses were haemangioma 33 (48%), hepatic cyst 17 (25%) and FNH 12 (19%). Amongst the malignant lesions, 29 (76%) were hepatoblastoma and 3 (8%) were hepatocellular carcinoma. CONCLUSIONS: This large review series demonstrates that just over 1/3 of patients presenting to a paediatric tertiary referral centre with a focal liver lesion had neoplastic liver lesions, despite the published literature commonly stating that 2/3 of paediatric liver masses are malignant.

Extubation strategies after esophageal atresia repair.

BACKGROUND/PURPOSE: Early extubation following repair of esophageal atresia (EA) is desirable unless the anastomosis is under tension, in which case paralysis and post-operative ventilation may reduce the risk of anastomotic leakage. However, complications from emergency reintubations do occur with either strategy. We aim to examine the risk/benefit balance of early and delayed extubation following EA repair. METHODS: A seven-year retrospective review of all babies that underwent EA repair was performed. Babies extubated within 24 h of surgery were classified as early extubation (EE). Babies intubated beyond the first 24 h were classified as delayed extubation (DE). The EE group was subdivided into babies extubated in operating room (EIOR), and babies who returned to the neonatal intensive care unit (NICU) intubated but extubated within 24 h (EW24). RESULTS: Forty-six babies were analyzed, and overall 15 (32.6%) required 24 reintubation episodes. Eight (28.6%) babies in the EE group required reintubation. The EIOR group (n = 12) had significantly increased risk of requiring reintubation (OR:7, 95%CI:1.08 to 45.16:p = 0.04) compared to the EW24 group (n = 16). Seven (38.9%) babies in the DE group required reintubation. The complication rate from reintubation after EA repair was 17%. CONCLUSIONS: Extubation on the NICU within 24 h of surgery carried the lowest risk of reintubation. For babies with a tight anastomosis, elective postoperative ventilation appeared to confer a protective benefit without incurring a high risk of complications from reintubation.

Conversions in pediatric robot-assisted laparoscopic surgery.

BACKGROUND: New technology attracts necessary concerns regarding safety and effectiveness, including the risk and circumstances of conversions. This study analyses our 11-year experience of conversions from a dedicated pediatric robot-assisted laparoscopic surgery service. METHODS: Consecutive patients were evaluated from a prospective database for the period March 2006 to May 2017. Descriptive and quantitative data for conversions were analysed. Variables were investigated including year of surgery, patient age, operation type, surgeon, and experience. RESULTS: A total of 539 children underwent 601 procedures. There were 45 different types of procedures. Mean (± SD) age was 7.0 ± 5.2 years, and youngest 4 weeks old. There were 31 conversions (5.8%). Conversion rates were significantly higher in younger children, with rates of 10.0%, 6.1% and 4.2% for age groups 0-2, 2-6, and 6-18 years respectively (p = 0.01). There was a significant difference in conversion rates amongst procedures (p<0.001). Intravesical (9/26, 34.6%), liver cyst (2/8, 25.0%) and choledochal cyst (8/60, 13.3%) procedures were the highest. The most frequent reason for conversion was anesthetic related issues caused by dilated intestine and/or inadequate muscle relaxation (16/31, 52%). Three conversions were attributable to mechanical failures, none attributed to intraoperative complication. CONCLUSIONS: Conversion rates are low even in the learning phase and comparable favourably to conventional laparoscopy, supporting the safety and effectiveness of robot-assisted technology for advanced laparoscopy in children. The importance of optimization of surgical conditions cannot be overemphasised.

Enterocolic lymphocytic phlebitis: a rare pathology in children.

Enterocolic lymphocytic phlebitis (ELP) is a rare pathology, usually seen in the adult population. The condition affects the venous vasculature of the intestine sparing the arteries and lymphatics. It is commonly identified histologically after surgical resection making the preoperative diagnosis a clinical challenge. As the condition can lead to intestinal ischaemia and necrosis, surgical resection of the affected segment is the treatment of choice. We report the case of a 9-year-old girl who presented with a 2-day history of lower abdominal pain and anorexia. The initial diagnosis of appendicitis was made clinically and the patient underwent a diagnostic laparoscopy . The appendix was macroscopically normal and there were no other obvious intra-abdominal pathologies to account for her presenting complaints . The appendix was removed, as per the preoperative discussion and consent from parents. She recovered well and was discharged home the following day. The histological examination of the appendix demonstrated ELP. We describe this rare clinical entity in a child especially in view of the scarce published literature in the paediatric population.

Dose adjustment in orphan disease populations: the quest to fulfill the requirements of physiologically based pharmacokinetics.

INTRODUCTION: While the media is engaged and fascinated by the idea of 'Precision Medicine', the nuances related to 'Precision Dosing' seem to be largely ignored. Assuming the 'right drug' is selected, clinicians still need to decide on the 'right dose' for individuals. Ideally, optimal dosing should be studied in clinical trials; however, many drugs on the market lack evidence-based dosing recommendations, and small groups of patients (orphan disease populations) are dependent on local guidance and clinician experience to determine drug dosage adjustments. Areas Covered: This report explores the current understanding of dosing adjustment in special populations and examines the requirements for developing 'in silico' models for pediatric, elderly and pregnant patients. The report also highlights current use of modeling to provide evidence-based recommendations for drug labeling in the absence of complete clinical trials in orphan disease populations. Expert Opinion: Physiologically based pharmacokinetics (PBPK) is an attractive prospect for determining the best drug dosage adjustments in special populations. However, it is not sufficient for individualized, or even stratified dosing, unless the systems (drug-independent) data required to build robust PBPK models are obtained. Such models are not a substitute for clinical trials, but they are an alternative to undocumented and inconsistent guesswork.

Outcomes of laparoscopic Kasai portoenterostomy for biliary atresia: A systematic review.

AIMS: Biliary atresia (BA) is a rare disease for which mainstay of treatment consists of open Kasai portoenterostomy. The aim of this review was to assess the outcomes of laparoscopic Kasai portoenterostomy, which offers potential benefits of minimally invasive surgery. Outcomes identified were postoperative cholangitis rates, incidence of adhesions at subsequent liver transplantation, native liver survival rates and actuarial survival rates. METHODS: A comprehensive systematic literature search was conducted in the PubMed and Cochrane databases using the keywords hepatic portoenterostomy, biliary atresia and laparoscopy. Robotic cases were excluded. RESULTS: Ten studies (n=149 patients) were included in this review. The mean age at the time of operation was 66 (range 14-119) days. The mean operative time was 261 (range 120-662) minutes. The rate of postoperative cholangitis was 34% (range 11%-50%). The mean native liver survival rate was 57% (range 33%-78%) at 6months and 47% (range 8%-76%) at 2years. Mean actuarial survival rate was 87% (range 54%-100%) at 2years. Subsequent adhesions were reported in 4 patients. Two patients had dense adhesions and 2 had no adhesions. CONCLUSIONS: Although laparoscopic Kasai portoenterostomy is a feasible operation, outcomes in terms of native liver survival rates and actuarial survival rates are unfavourable compared to conventional surgery. There is no evidence that laparoscopic Kasai is associated with fewer adhesions at subsequent liver transplantation. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Treatment study.

Robot-assisted resection of choledochal cysts and hepaticojejunostomy in children.

PURPOSE: Choledochal cysts have traditionally been treated as an open procedure. However, recent publications from some large volume centres show that minimally invasive surgery has become their standard approach. Robotic surgical systems facilitate a surgeon's ability to undertake complex procedures. We present our experience of using robot assistance to treat choledochal cysts. METHODS: Children admitted with a choledochal cyst from March 2009 to Nov 2012 were included. There were 27 patients (20 females). Mean age 5.4 years (range 0.3-15.9). Mean weight 21.9 kg (range 5.9-78.8); 10 weighed <10 kg. The choledochal cysts were types 1c(12), 1f(10) and 4(5). The da vinci Surgical System was used for the robot-assisted resection of the choledochal cyst and hepaticojejunostomy. Roux loop was fashioned extra-corporeally. Mean follow-up is 2.7 years (range 0.9-4.7). RESULTS: 22 cases were completed successfully with robotic assistance. Five open conversions were for anatomical concerns or technical reasons. One child had three complications (omental hernia, anastomotic stricture and subsequent bile leak). Patients were on full feeds by a median of 5 days (range 3-6) and discharged after 6 days (range 4-7). CONCLUSION: Robotic-assisted resection of choledochal cysts in children is safe. They made a rapid recovery with a good cosmetic outcome.

Biliary atresia in England and Wales: results of centralization and new benchmark.

INTRODUCTION: Biliary atresia (BA) is a rare, potentially life-threatening condition of the newborn presenting with conjugated jaundice. Typically, it is treated by an initial attempt to restore bile flow (the Kasai portoenterostomy [KP]) as soon as possible after diagnosis and, if this fails, liver transplantation. Since 1999, the treatment of BA has been centralized to 3 centers in England and Wales able to offer both treatment options. The aim of this study was to review the outcome of this policy change and provide a national benchmark. METHODS: The management of all infants born within England and Wales during the period January 1999 to December 2009 was assessed using 3 key performance indicators such as median time to KP, percentage clearance of jaundice (≤20 mol/L) post-KP, and 5- and 10-year native liver and true survival estimates. Data are quoted as median (range), and P < .05 was considered significant. RESULTS: A total of 443 infants had confirmed BA; and of these, most were isolated BA (n = 359), with 84 having other significant anomalies (but predominantly BA splenic malformation syndrome). Four infants died before any biliary intervention. Kasai portoenterostomy was performed in 424 infants (median age, 54 [range 7-209] days), and a primary liver transplant was performed in 15. Clearance of jaundice post-KP was achieved in 232 (55%). There were 41 deaths, including 4 (10%) without any intervention, 24 (58%) post-KP usually because of end-stage liver disease and mostly on a transplant waiting list, and 13 (32%) post-LT usually because of multiorgan failure. Overall, the 5- and 10-year native liver survival estimates were 46% (95% confidence interval [CI], 41-51) and 40% (95% CI, 34-46), respectively. The 5- and 10-year true patient survival estimates were 90% (95% CI, 88-93) and 89% (95% CI, 86-93), respectively. Outcome was worse for those with other anomalies (lower clearance of jaundice post-KP [43% vs 57%; odds ratio, 1.7; 95% CI, 1.04-2.8]; P = .02) and an increased mortality overall (eg, at 5 years, 72 [95% CI, 64-83] vs 94 [95% CI, 91-96]; χ(2) = 33; P < .0001). CONCLUSIONS: National outcome measures in BA appear better than those from previously published series from comparable countries and may be attributed to centralization of surgical and medical resources.

Robot-assisted resection of choledochal cysts and hepaticojejunostomy in children less than 10 kg.

BACKGROUND/PURPOSE: Laparoscopic resection of choledochal cysts and hepaticojejunostomy have been described in children since 1995, but these can be technically demanding procedures. Robotic surgical systems can facilitate complex minimal-access procedures. In 2009, we made the transition from conventional laparoscopic to robotic-assisted choledochal cyst excision with hepaticojejunostomy. We present our experience in children weighing less than 10 kg. METHODS: During 2009, 5 children weighing less than 10 kg underwent robotic resections of choledochal cysts and hepaticojejunostomy using the da Vinci surgical system. The Roux loop was fashioned extracorporeally. Mean age was 1 year (range, 0.5-1.4), and mean weight was 8.5 kg (range, 7.6-9.5). All 5 had type 1c cysts, and 3 were very large. RESULTS: All 5 cases were treated successfully by robotic resection of the cyst and hepaticojejunostomy. Feeding was established by a median of 4 days (range, 3-6), and patients were discharged after a median of 6 days (range, 5-7) with no postoperative complications. CONCLUSION: The technique is safe and effective in children weighing less than 10 kg. The authors found ergonomic advantages in using robotic-assisted surgery for this complex minimal-access procedure.

Is cholecystectomy really an indication for concomitant splenectomy in mild hereditary spherocytosis?

BACKGROUND/AIM: The British Committee for Standards in Haematology currently recommends concomitant splenectomy in children with mild hereditary spherocytosis (HS) undergoing cholecystectomy for symptomatic gallstones. However, splenectomy is associated with a risk of life-threatening infection, particularly in young children. The aim of this study was to audit the outcome of the practice of uncoupling splenectomy and cholecystectomy in such patients. METHODS: Children referred with symptomatic gallstones complicating HS between April 1999 and April 2009 were prospectively identified and reviewed retrospectively. During this period, the policy was to undertake concomitant splenectomy only if indicated for haematological reasons and not simply because of planned cholecystectomy. RESULTS: A total of 16 patients (mean age 10.4, range 3.7 to 16 years, 11 women) with HS and symptomatic gallstones underwent cholecystectomy. Three patients subsequently required a splenectomy for haematological reasons 0.8-2.5 years after cholecystectomy; all three splenectomies were performed laparoscopically. There were no postoperative complications in the 16 patients; postoperative hospital stay was 1-3 days after either cholecystectomy or splenectomy. The 13 children with a retained spleen remain under regular review by a haematologist (median follow-up 4.6, range 0.5 to 10.6 years) and are well and transfusion independent. CONCLUSIONS: The advice to perform a concomitant splenectomy in children with mild HS undergoing cholecystectomy for symptomatic gallstones needs revisiting. In the era of minimal access surgery, the need for splenectomy in such children should be judged on its own merits.

Preoperative imaging of left portal vein at the Rex recess for Rex shunt formation using wedged hepatic vein carbon dioxide portography.

BACKGROUND: In children with extrahepatic portal vein obstruction (EHPVO), formation of a mesentericoportal bypass (Rex shunt) restores hepatopetal flow, relieves portal hypertension, and reduces variceal bleeding and hypersplenism. The Rex shunt is created by inserting a vein graft between the superior mesenteric vein and the umbilical segment (Rex) of the left portal vein within the Rex recess of the liver. The preoperative evaluation of a patient with EHPVO includes an accurate assessment of the venous inflow and outflow. The inflow portal vein is readily assessed by ultrasound and magnetic resonance imaging. The outflow intrahepatic portal vein is harder to assess. We report our experience of patients evaluated with wedged hepatic vein carbon dioxide portography (WHVCP). METHOD: All children referred for venography from October 2001 to October 2007 were prospectively identified, and clinical and radiologic data were reviewed retrospectively. The imaging findings were correlated to findings at surgery. RESULTS: Eleven children (range, 3-14 years, median, 6 years) were referred for preoperative wedged hepatic venography. The left portal vein at the Rex recess was clearly identified in 9 patients (82%). In the other 2 patients (18%), the Rex segment was not identified despite opacification of left and right intrahepatic portal veins; this was taken to indicate an occluded segment. Wedged venography was performed with carbon dioxide in 10 patients (91%). Carbon dioxide was contraindicated in the final patient because of the presence of a ventricular septal defect. CONCLUSION: Our series demonstrates the use of WHVCP as a diagnostic tool in preoperative assessment of the Rex segment of left portal vein in children with extrahepatic portal vein obstruction.

Mesenchymal hamartoma of the liver: a systematic review.

Mesenchymal hamartoma of the liver is the second commonest benign liver tumor in children, yet its biology and pathogenesis are poorly understood. Cytogenetic studies have suggested that the tumor may be a neoplasm rather than a hamartoma. Typically, it presents as a large benign multicystic liver mass in a child younger than 3 years amenable to complete resection. However, its imaging characteristics are variable, ranging from a few large cysts to a solid mass occupying one or both lobes of the liver. In addition, the tumor occasionally contains angiomatous elements or is multifocal. Most tumors gradually increase in size, some reaching enormous proportions, which can make surgery challenging. Paradoxically, a few undergo incomplete spontaneous regression and, on rare occasions, others have shown malignant transformation to undifferentiated (embryonal) sarcoma. These unusual pathological and biological features must be taken into account when considering the management of affected individuals.