Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Feasibility and effectiveness of pre-operative inspiratory muscle training in patients undergoing oesophagectomy: a pilot study

Patients undergoing oesophageal surgery have a high risk for post-operative complications including pulmonary infections. Recently, physical therapy has shifted from the post-operative to the pre-operative phase to diminish post-operative complications and to shorten hospital stay. The purpose of this pilot study was to investigate the feasibility and initial effectiveness of pre-operative inspiratory muscle training (IMT) on the incidence of pneumonia in patients undergoing oesophagectomy. A pragmatic non-randomized controlled trial was conducted among all patients who underwent an oesophagectomy between January 2009 and February 2010. Patients in the intervention group received IMT prior to surgery. Feasibility was assessed on the basis of the occurrence of adverse effects during testing or training and patient satisfaction. Initial effectiveness on respiratory function was evaluated by maximal inspiratory pressure (MIP) and endurance, the incidence of post-operative pneumonia and length of hospital stay. Eighty-three patients were included, of which 44 received pre-operative IMT. No adverse effects were observed. IMT was well tolerated and appreciated. In the intervention group, the median MIP and endurance improved significantly after IMT by 32% and 41%, respectively (p < 0.001). The incidence of post-operative pneumonia and the length of hospital stay were comparable for the intervention and the conventional care groups (pneumonia, 25% vs. 23% [p = 0.84]; hospitalization, 13.5 vs. 12 days [p = 0.08]). Pre-operative IMT is feasible in patients with oesophageal carcinoma and significantly improves respiratory muscle function. This, however, did not result in a reduction of post-operative pneumonia in patients undergoing oesophagectom

Initial experiences of an enhanced recovery protocol in esophageal surgery

A recent development in gastrointestinal surgery is the implementation of enhanced recovery after surgery (ERAS) programs. Evidence regarding the benefit of these programs in patients undergoing esophageal surgery is scarce. We investigated the feasibility and possible benefit of a perioperative ERAS program in patients undergoing esophagectomy for malignant disease. The ERAS program was initiated in 2009. Patients who underwent esophagectomy and were treated according to the ERAS program were included. Items of ERAS included preoperative nutrition, early extubation, early removal of nasogastric tube, and early mobilization. Primary outcome parameters were hospital stay and the incidence of postoperative complications. Outcome parameters in the ERAS cohort were compared to a cohort of patients who underwent surgical resection in the year prior to the implementation of the ERAS protocol. A feasibility analysis was performed among a sample of ERAS patients to determine the number of achieved items per patient. Between 2008 and August 2010, 181 patients in our department underwent esophagectomy. Of these, 103 patients were included in the ERAS program (ERAS+ group) and were compared to 78 patients who had undergone an esophagectomy in 2008 (ERAS- group). Overall hospital stay was 14 days versus 15 days (ERAS+ and ERAS-, respectively; p = 0.013). There were no significant differences in the incidence of postoperative complications in either group. The percentage of achieved items varied between 42 and 93 % per item. The implementation of an ERAS program in esophageal surgery was feasible and resulted in a small but significant reduction in overall hospital stay, whereas overall morbidity was not affecte

Results of the introduction of a minimally invasive esophagectomy program in a tertiary referral center

Background: Esophagectomy is accompanied by a high postoperative complication rate. Minimally invasive esophageal surgery appears to be a promising technique that might be associated with a lower pulmonary morbidity rate. The objective of this study was to describe the implementation of minimally invasive esophageal surgery in a tertiary referral center and to compare the results of our first series of minimally invasive esophagectomies (MIE) to conventional open esophagectomies. Methods: MIE was implemented after several procedures had been proctored by a surgeon with extensive experience with MIE. Preoperative characteristics and the postoperative course of patients who underwent a transthoracic esophagectomy were prospectively registered. Morbidity and overall hospital stay were compared between minimally invasive and open resections performed in the same period. Results: A total of 90 consecutive esophageal cancer patients underwent a transthoracic resection, 41 patients by means of a minimally invasive approach. Preoperative characteristics were comparable for both groups. The duration of surgery was longer in the MIE group (6.0 vs. 5.2 hours, P <0.001) and median blood loss was lower [100 vs. 500 mL (P <0.001)]. There was only a trend towards a shorter hospital stay in the MIE group (11 vs. 13 days, P=0.072), pulmonary complications occurred in 20% of patients in the MIE group vs. 31% in the open group (P=0.229). The overall complication rate was 51% in the MIE group vs. 63% in the open group, P=0.249. Conclusions: Implementation of MIE in our center was successful and it appears to be a safe technique for patients with potentially curable esophageal carcinom

Interobserver Reproducibility of Diffusion-Weighted MRI in Monitoring Tumor Response to Neoadjuvant Therapy in Esophageal Cancer

OBJECTIVE: To investigate the reproducibility of diffusion-weighted magnetic resonance imaging (DW-MRI) in assessing tumor response early in the course of neoadjuvant chemoradiotherapy in patients with operable esophageal cancer. METHODS: Eleven male patients (mean age 54.8 years) with newly diagnosed esophageal cancer underwent DW-MRI before and 10 days after start of chemoradiotherapy. Reproducibility of apparent diffusion coefficient (ADC) measurements by manual (freehand) and semi-automated volumetric methods was assessed. RESULTS: Interobserver reproducibility for the assessment of mean tumor ADC by the manual measurement method was good, with an ICC of 0.69 (95% CI, 0.36 to 0.85; P = 0.001). Interobserver reproducibility for the assessment of mean tumor ADC by the semi-automated volumetric measurement method was very good, with an ICC of 0.96 (95% CI, 0.91 to 0.98; P<0.001). CONCLUSION: Semi-automated volumetric ADC measurements have higher reproducibility than manual ADC measurements in assessing tumor response to chemoradiotherapy in patients with esophageal adenocarcinoma

Feasibility of extended chemoradiotherapy plus surgery for patients with cT4b esophageal carcinoma

BACKGROUND: Treatment of cT4b esophageal carcinoma usually consists of definitive chemoradiotherapy (dCRT). However, outcome after dCRT in these patients is poor. Whether surgery should have a place in the treatment of cT4b esophageal cancer is still subject to debate. Goal of this study was to evaluate the feasibility of esophagectomy after extended chemoradiotherapy in patients with cT4b esophageal cancer. METHODS: Patients with cT4b esophageal carcinoma, as determined by endoscopic ultrasound and (PET-)CT, were eligible for this phase-2 study. Patients were treated with weekly carboplatin + paclitaxel with 50.4 Gy radiotherapy in 28 fractions for 5.5 weeks followed by an explorative thoracotomy and esophagectomy if deemed feasible. RESULTS: From July 2011 through March 2013, 16 patients were enrolled. Five patients did not undergo surgery because of detection of distant metastases during/after CRT (n = 3), unwillingness to undergo surgery (n = 1) or death before start of CRT (n = 1). Of the 13 patients who completed CRT, 3 patients experienced major hematologic toxicity (grade 3). A radical (R0) resection was achieved in 9 of 11 patients. Postoperative complications occurred in 9 patients. A reoperation was performed in 2 patients and 2 patients died in hospital after surgery. Three patients developed recurrent disease (1 locoregional and 2 systemic) after a mean interval of 17 months. Median overall survival of all included patients was 14.3 months. CONCLUSIONS: In certain patients with cT4b esophageal carcinoma a radical resection can be accomplished after chemoradiotherapy. However, this treatment is associated with considerable complications and should therefore be reserved for physically fit patients. NETHERLANDS TRIAL REGISTER NUMBER: NTR3060