PARC: a phase I/II study evaluating the safety and activity of pegylated recombinant human arginase BCT-100 in relapsed/refractory cancers of children and young adults.

Background: The survival for many children with relapsed/refractory cancers remains poor despite advances in therapies. Arginine metabolism plays a key role in the pathophysiology of a number of pediatric cancers. We report the first in child study of a recombinant human arginase, BCT-100, in children with relapsed/refractory hematological, solid or CNS cancers. Procedure: PARC was a single arm, Phase I/II, international, open label study. BCT-100 was given intravenously over one hour at weekly intervals. The Phase I section utilized a modified 3 + 3 design where escalation/de-escalation was based on both the safety profile and the complete depletion of arginine (defined as adequate arginine depletion; AAD <8µM arginine in the blood after 4 doses of BCT-100). The Phase II section was designed to further evaluate the clinical activity of BCT-100 at the pediatric RP2D determined in the Phase I section, by recruitment of patients with pediatric cancers into 4 individual groups. A primary evaluation of response was conducted at eight weeks with patients continuing to receive treatment until disease progression or unacceptable toxicity. Results: 49 children were recruited globally. The Phase I cohort of the trial established the Recommended Phase II Dose of 1600U/kg iv weekly in children, matching that of adults. BCT-100 was very well tolerated. No responses defined as a CR, CRi or PR were seen in any cohort within the defined 8 week primary evaluation period. However a number of these relapsed/refractory patients experienced prolonged radiological SD. Conclusion: Arginine depletion is a clinically safe and achievable strategy in children with cancer. The RP2D of BCT-100 in children with relapsed/refractory cancers is established at 1600U/kg intravenously weekly and can lead to sustained disease stability in this hard to treat population. Clinical trial registration: EudraCT, 2017-002762-44; ISRCTN, 21727048; and ClinicalTrials.gov, NCT03455140.

Living bioethics, theories and children's consent to heart surgery.

Background: This analysis is about practical living bioethics and how law, ethics and sociology understand and respect children's consent to, or refusal of, elective heart surgery. Analysis of underlying theories and influences will contrast legalistic bioethics with living bioethics. In-depth philosophical analysis compares social science traditions of positivism, interpretivism, critical theory and functionalism and applies them to bioethics and childhood, to examine how living bioethics may be encouraged or discouraged. Illustrative examples are drawn from research interviews and observations in two London paediatric cardiac units. This paper is one of a series on how the multidisciplinary cardiac team members all contribute to the complex mosaic of care when preparing and supporting families' informed consent to surgery. Results: The living bioethics of justice, care and respect for children and their consent depends on theories and practices, contexts and relationships. These can all be undermined by unseen influences: the history of adult-centric ethics; developmental psychology theories; legal and financial pressures that require consent to be defined as an adult contract; management systems and daily routines in healthcare that can intimidate families and staff; social inequalities. Mainstream theories in the clinical ethics literature markedly differ from the living bioethics in clinical practices. Conclusion: We aim to contribute to raising standards of respectful paediatric bioethics and to showing the relevance of virtue and feminist ethics, childhood studies and children's rights.

Crisis care for children and young people with mental health problems: national mapping, models of delivery, sustainability and experience (CAMH-Crisis2). A study protocol.

Background: One in six five 16-year-olds have a probable mental health difficulty. Of these, almost half of older teenagers and a quarter of 11-16-year-olds report having self-harmed or attempted suicide. Currently, there is little research into mental health crisis services for young people, with little understanding of what services exist, who uses them, or what works best. Question: 'How are mental health crisis responses for children and young people up to the age of 25 sustained, experienced and integrated within their local systems of services'? Objectives:     1.    To describe National Health Service (NHS), local authority, education and third sector approaches to the implementation and organisation of crisis care for children and young people across England and Wales.    2.   To identify eight contrasting case studies in which to evaluate how crisis services have developed and are currently organised, sustained, experienced and integrated within the context of their local systems of services.    3.   To compare and contrast these services in the context of the available international evidence, drawing out and disseminating clear implications for the design and delivery of future crisis responses for children and young people and their families. Methods: A sequential mixed methods approach, underpinned by normalisation process theory will be employed. A survey will create a detailed record of how crisis responses across England and Wales are organised, implemented and used. Subsequently, eight contrasting services in relation to geographic and socioeconomic setting, populations served, and service configuration will be identified as case studies. Interviews will be conducted with children, young people and parents/carers who have used the service, as well as commissioners, managers and practitioners. Operational policies and service usage data will also be examined. Analysis of how each service is provided, experienced, implemented and sustained will be conducted both inductively and deductively, reflecting normalisation process theory constructs.

BACKGROUND: There has been a sharp increase in children and young people experiencing extreme emotional distress and/or self-harm, which is also known as 'crisis'. Services for young people in crisis are a priority in the UK but little is currently known about what crisis services exist, who uses them, or what type of service works best. AIM AND OBJECTIVES: This project aims to explore the types of mental health crisis services currently available to children and young people up to the age of 25 in England and Wales, and to examine how they are organised, perceived and integrated within other local care systems. The objectives are to: 1. Find out what NHS, local authority, education and charity sector crisis services exist for children and young people across England and Wales, to describe the services and to create a database of them. 2. Identify eight contrasting services from the database and evaluate how these services are organised, perceived and integrated within local care systems. 3. Compare and contrast these services with the available international evidence, drawing out clear implications for the design and delivery of future crisis responses for children and young people and their families. METHODS: We will use a survey to create a database of crisis response services across England and Wales. From the database we will identify eight contrasting services and we will conduct interviews with children, young people and parents/carers who have used the service as well as managers and staff. We will look at how the services work and explore how they are used and by whom. We will compare and contrast each case study and consider findings of other research studies from around the world to draw clear, actionable, lessons for the future provision of high-quality crisis services for children and young people.

Identifying Optimal Acute Care Comparators to Inform the Evaluation of an Advanced Care at Home Pilot Program.

BACKGROUND: Hospital at Home (H@H) programs-which seek to deliver acute care within a patient's home-have become more prevalent over time. However, existing literature exhibits heterogeneity in program structure, evaluation design, and target population size, making it difficult to draw generalizable conclusions to inform future H@H program design. OBJECTIVE: The objective of this work was to develop a quality improvement evaluation strategy for a H@H program-the Kaiser Permanente Advanced Care at Home (KPACAH) program in Northern California-leveraging electronic health record data, chart review, and patient surveys to compare KPACAH patients with inpatients in traditional hospital settings. METHODS: The authors developed a 3-step recruitment workflow that used electronic health record filtering tools to generate a daily list of potential comparators, a manual chart review of potentially eligible comparator patients to assess individual clinical and social criteria, and a phone interview with patients to affirm eligibility and interest from potential comparator patients. RESULTS: This workflow successfully identified and enrolled a population of 446 comparator patients in a 5-month period who exhibited similar demographics, reasons for hospitalization, comorbidity burden, and utilization measures to patients enrolled in the KPACAH program. CONCLUSION: These initial findings provide promise for a workflow that can facilitate the identification of similar inpatients hospitalized at traditional brick and mortar facilities to enhance outcomes evaluations for the H@H programs, as well as to identify the potential volume of enrollees as the program expands.

In Memoriam: Professor Marc R. de Leval (April 16, 1941-June 26, 2022) - a tribute.

This manuscript is a personal tribute to Professor Marc de Leval from two of his colleagues: Professor Martin J. Elliott and Professor John E. Deanfield. As stated by the authors: "Marc's career history is presented in the accompanying eulogy from the current Heart & Lung Team at Great Ormond Street Hospital (GOSH), allowing us to highlight Marc's personal qualities that made him such an inspirational colleague. … Marc was, as we have said, the cardiologist's surgeon. He was also the surgeon's cardiologist, bridging the two disciplines and fusing the team. He was delighted by the advent of interventional cardiology and did not see it as a threat or competition, but instead, as appropriate for the well-being of his patients. He recognised how traumatic surgery could be for patients and their families and sought to avoid it whenever possible by alternative treatments. Marc will be remembered with love and admiration by his many patients and their families, whose lives he changed. His technical skill, energy, devotion, humour, intellect and influence will be sorely missed. May he rest in peace."

Living bioethics, clinical ethics committees and children's consent to heart surgery.

This discussion paper considers how seldom recognised theories influence clinical ethics committees. A companion paper examined four major theories in social science: positivism, interpretivism, critical theory and functionalism, which can encourage legalistic ethics theories or practical living bioethics, which aims for theory-practice congruence. This paper develops the legalistic or living bioethics themes by relating the four theories to clinical ethics committee members' reported aims and practices and approaches towards efficiency, power, intimidation, justice, equality and children's interests and rights. Different approaches to framing ethical questions are also considered. Being aware of the four theories' influence can help when seeking to understand and possibly change clinical ethics committee routines. The paper is not a research report but is informed by a recent study in two London paediatric cardiac units. Forty-five practitioners and related experts were interviewed, including eight members of ethics committees, about the work of informing, preparing and supporting families during the extended process of consent to children's elective heart surgery. The mosaic of multidisciplinary teamwork is reported in a series of papers about each profession, including this one on bioethics and law and clinical ethics committees' influence on clinical practice. The qualitative social research was funded by the British Heart Foundation, in order that more may be known about the perioperative views and needs of all concerned. Questions included how disputes can be avoided, how high ethical standards and respectful cooperation between staff and families can be encouraged, and how minors' consent or refusal may be respected, with the support of clinical ethics committees.

Data resource profile: children looked after administrative records in Wales.

Introduction: Children who are 'looked after' by the State are considered one of the most vulnerable groups in society. Being in State care is associated with poor social, educational and health outcomes. Exploring how to improve the system and better support children in care is key to improving these outcomes. When children and young people come to the attention of children's social services a significant amount of information about their care experience is routinely collected by local authorities. In Wales, routine data are captured in the 'Children Looked After' Census which is submitted annually to the Welsh Government and has recently been shared with the Secure Anonymised Information Linkage (SAIL) Databank. Method: The aim of this paper is to provide an overview of the main 'Children Looked After' Census dataset and its subsets. These datasets contain rich, situational and individual level data on children looked after, such as information on placement types, education and leaving care. We outline the strengths and limitations of the available information and how to access the data. Results: The 'Children Looked After' Census has recently been made available for research purposes and access to it will enable researchers to explore and understand at population level the journey through the care system and outcomes of leaving care. There is also the opportunity, through the SAIL Databank, for data linkage to health, education and family justice datasets, allowing research to holistically explore other factors associated with being in care. Conclusion: These data provide a rich source of information about children and young people who have been in care in Wales. They offer researchers opportunities to better understand the care system and outcomes for this within it. Findings will have important implications for making improvements in children's social care policy and practice.

The involvement and autonomy of young children undergoing elective paediatric cardiac surgery: a qualitative study.

BACKGROUND: Standards generally reported in the literature about informing children and respecting their consent or refusal before elective heart surgery may differ from actual practice. This research aims to summarize the main themes in the literature about paediatric anaesthesia and compare these with research findings on how health professionals counsel young children before elective heart surgery, respect their consent or refusal, and maintain patient-centred care. METHODS: This qualitative research involved: literature reviews about children's consent to surgery and major interventions; observations of wards, clinics and medical meetings in two paediatric cardiology departments, October 2019 to February 2020; audio-recorded semi-structured interviews with 45 hospital staff, including 5 anaesthetists, and related experts, November 2019 to April 2021; interviews with 16 families, with children aged 6- to 15-years and their parents shortly after elective heart surgery, and some months later (reported in other papers); thematic data analysis; and research reports on how different professions contribute to children's informed decisions for heart surgery. RESULTS: The medical, ethics and English legal literature tend to assume legal minors cannot refuse major recommended treatment, and cannot consent until they are 12 years or older. Little is said about informing pre-competent children. If children resist, some anaesthetists rely on sedation and distraction, and avoid much informed discussion, aiming to reduce peri-operative anxiety. However, interviewees reported informing young children, and respecting their consent or refusal before elective surgery. They may delay elective surgery and provide further information and support, aiming to reduce fear and promote trust. Six years of age was commonly cited as the threshold for respecting consent to heart transplantation. CONCLUSION: Differing views about younger children's competence, anxiety and best interests support different reactions to children's consent and refusal before elective heart surgery. This paper reports the zero-restraint policy followed for over a decade in at least one leading surgery centre. The related law and literature need to be updated, to take more account of evidence of actual practice.

Data resource: Children receiving care and support and children in need, administrative records in Wales.

Introduction: In Wales, the Children in Need (CIN) dataset includes information relating to needs of children and social care support. Before the Social Services and Well-being (Wales) Act 2014 came into force in April 2016, this data collection was named the Children in Need census, changing to Children Receiving Care and Support (CRCS) after this date to reflect better the children eligible for inclusion. This paper describes these datasets, their potential for research and their limitations. We describe data that researchers can access via the Secure Anonymised Information Linkage (SAIL) Databank and exploratory linkages made to health records. Methods: CIN and CRCS data were transferred to the SAIL Databank using a standardised approach to provide de-identified data with Anonymised Linking Fields (ALF) for successfully matched records. The linkage method relies on the use of Unique Pupil Numbers (UPN). As such, no records are currently available for children without a UPN, which includes most under age three. ALFs enabled linkage to individual-level health data within SAIL. Health service use was compared to non-CIN/CRCS populations. Results: CRCS data held within the SAIL Databank comprises 25,972 records, 81% of the total number of records reported by the Welsh Government. The CIN data contains 108,449 records, 79% of the Welsh Government's records for this data collection. Health service use of children in need, and children receiving care and support, was roughly equal to that of the non-CIN/CRCS population, except GP visits, where children in need had fewer consultations, and children receiving care and support had more consultations than the comparison population. Conclusion: Researchers can access Welsh CIN and CRCS datasets through the SAIL Databank, enabling research opportunities. Work is ongoing to improve records and to understand better the health and health service use among children captured by CIN and CRCS censuses.

Cardiac surgery and congenital heart disease: reflections on a modern revolution.

The success of cardiac surgery has transformed the prospects of children with congenital heart disease with over 90% now surviving to adulthood. The early pioneering surgeons took on significant risk, whilst current surgical practice emphasises safety and consistency. In this article we review important British contributions to the field and consider challenges for the future, specifically how to better manage and reduce the adverse sequelae of congenital cardiac surgery by continuing to innovate safely.

Intrathoracic prosthesis in children in preventing post pneumonectomy syndrome: Its role in congenital single lung and post pneumonectomy situations.

BACKGROUND: Postpneumopnectomy syndrome (PPS) is an extreme rotation and malposition of mediastinum causing dynamic and symptomatic central airway compression, arisingafter pneumonectomy or more uncommonly, in congenital single lung physiology. Affected patients present with severe respiratory compromise. Intrathoracic prosthesis placement is an evolving technique in children that mitigate the effects of thoracic dead space. RESEARCH QUESTION: Assessment of clinical recovery and functional benefit in children undergoing placement of intrathoracic prosthesis following pneumonectomy or in congenital single lung situations. STUDY DESIGN AND METHODS: Retrospective chart review of patients at Great Ormond Street Hospital from 2010 to 2020 was performed of all patients who underwent intrathoracic tissue expander placement. We summarize the outcomes of twenty four children, including those with both congenital and postpneumonectomy PPS etiology. RESULTS: 24 Children who underwent placement of intrathoracic prosthesis for PPS in the study period with median age of 3.5 months and weight of 5 kg. Single lung etiology was congenital in 15 children (6 agenesis, 9 hypoplasia), and postpneumonectomy in 9 children. In seven patients, there was associated long segment tracheal stenosis. Pre operative ECMO was required in 2 patients, and pre operative ventilation was required in 12 patients all of whom had congenital single lung. Intrathoracic prosthesis placement was concurrent with intracardiac repair in 5 patients. There were no operative deaths, but one early postoperative death related to septicaemia. Median follow up was 75 months with 10 patients on continued respiratory support and 3 on nocturnal support with good quality of life. Two children needed reoperations for replacement of prosthesis. CONCLUSION: The use of tissue expanders is within the armamentarium of most plastic surgeons' practice. We also therefore advocate for a collaborative team approach involving Plastic and Cardiothoracic Surgery for surgical treatment of these patients. This multidisciplinary strategy has improved management of this rare and debilitating condition of PPS, thereby offering significant improvements in general progress of these sick children having single lung physiology. Evidence is still lacking on functional outcomes in these children and further work is necessary to prove that this is indeed achievable.

Nomenclature for Pediatric and Congenital Cardiac Care: Unification of Clinical and Administrative Nomenclature - The 2021 International Paediatric and Congenital Cardiac Code (IPCCC) and the Eleventh Revision of the International Classification of Diseases (ICD-11).

Substantial progress has been made in the standardization of nomenclature for paediatric and congenital cardiac care. In 1936, Maude Abbott published her Atlas of Congenital Cardiac Disease, which was the first formal attempt to classify congenital heart disease. The International Paediatric and Congenital Cardiac Code (IPCCC) is now utilized worldwide and has most recently become the paediatric and congenital cardiac component of the Eleventh Revision of the International Classification of Diseases (ICD-11). The most recent publication of the IPCCC was in 2017. This manuscript provides an updated 2021 version of the IPCCC.The International Society for Nomenclature of Paediatric and Congenital Heart Disease (ISNPCHD), in collaboration with the World Health Organization (WHO), developed the paediatric and congenital cardiac nomenclature that is now within the eleventh version of the International Classification of Diseases (ICD-11). This unification of IPCCC and ICD-11 is the IPCCC ICD-11 Nomenclature and is the first time that the clinical nomenclature for paediatric and congenital cardiac care and the administrative nomenclature for paediatric and congenital cardiac care are harmonized. The resultant congenital cardiac component of ICD-11 was increased from 29 congenital cardiac codes in ICD-9 and 73 congenital cardiac codes in ICD-10 to 318 codes submitted by ISNPCHD through 2018 for incorporation into ICD-11. After these 318 terms were incorporated into ICD-11 in 2018, the WHO ICD-11 team added an additional 49 terms, some of which are acceptable legacy terms from ICD-10, while others provide greater granularity than the ISNPCHD thought was originally acceptable. Thus, the total number of paediatric and congenital cardiac terms in ICD-11 is 367. In this manuscript, we describe and review the terminology, hierarchy, and definitions of the IPCCC ICD-11 Nomenclature. This article, therefore, presents a global system of nomenclature for paediatric and congenital cardiac care that unifies clinical and administrative nomenclature.The members of ISNPCHD realize that the nomenclature published in this manuscript will continue to evolve. The version of the IPCCC that was published in 2017 has evolved and changed, and it is now replaced by this 2021 version. In the future, ISNPCHD will again publish updated versions of IPCCC, as IPCCC continues to evolve.

Nomenclature for Pediatric and Congenital Cardiac Care: Unification of Clinical and Administrative Nomenclature - The 2021 International Paediatric and Congenital Cardiac Code (IPCCC) and the Eleventh Revision of the International Classification of Diseases (ICD-11).

Substantial progress has been made in the standardization of nomenclature for paediatric and congenital cardiac care. In 1936, Maude Abbott published her Atlas of Congenital Cardiac Disease, which was the first formal attempt to classify congenital heart disease. The International Paediatric and Congenital Cardiac Code (IPCCC) is now utilized worldwide and has most recently become the paediatric and congenital cardiac component of the Eleventh Revision of the International Classification of Diseases (ICD-11). The most recent publication of the IPCCC was in 2017. This manuscript provides an updated 2021 version of the IPCCC.The International Society for Nomenclature of Paediatric and Congenital Heart Disease (ISNPCHD), in collaboration with the World Health Organization (WHO), developed the paediatric and congenital cardiac nomenclature that is now within the eleventh version of the International Classification of Diseases (ICD-11). This unification of IPCCC and ICD-11 is the IPCCC ICD-11 Nomenclature and is the first time that the clinical nomenclature for paediatric and congenital cardiac care and the administrative nomenclature for paediatric and congenital cardiac care are harmonized. The resultant congenital cardiac component of ICD-11 was increased from 29 congenital cardiac codes in ICD-9 and 73 congenital cardiac codes in ICD-10 to 318 codes submitted by ISNPCHD through 2018 for incorporation into ICD-11. After these 318 terms were incorporated into ICD-11 in 2018, the WHO ICD-11 team added an additional 49 terms, some of which are acceptable legacy terms from ICD-10, while others provide greater granularity than the ISNPCHD thought was originally acceptable. Thus, the total number of paediatric and congenital cardiac terms in ICD-11 is 367. In this manuscript, we describe and review the terminology, hierarchy, and definitions of the IPCCC ICD-11 Nomenclature. This article, therefore, presents a global system of nomenclature for paediatric and congenital cardiac care that unifies clinical and administrative nomenclature.The members of ISNPCHD realize that the nomenclature published in this manuscript will continue to evolve. The version of the IPCCC that was published in 2017 has evolved and changed, and it is now replaced by this 2021 version. In the future, ISNPCHD will again publish updated versions of IPCCC, as IPCCC continues to evolve.

Randomized Trial of Two Induction Therapy Regimens for High-Risk Neuroblastoma: HR-NBL1.5 International Society of Pediatric Oncology European Neuroblastoma Group Study.

PURPOSE: Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]). PATIENTS AND METHODS: Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged < 1 year with MYCN amplification were eligible for random assignment to rCOJEC or MSKCC-N5. Random assignment was stratified according to national group and metastatic sites. Following induction, therapy comprised primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with ch14.18/CHO (dinutuximab beta) antibody with or without interleukin-2 immunotherapy. The primary end points were mCR rate and 3-year EFS. RESULTS: A total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age with MYCN amplification. mCR rate following rCOJEC induction (32%, 86/272 evaluable patients) was not significantly different from 35% (99/281) with MSKCC-N5 (P = .368), and 3-year EFS was 44% ± 3% for rCOJEC compared with 47% ± 3% for MSKCC-N5 (P = .527). Three-year overall survival was 60% ± 3% for rCOJEC compared with 65% ± 3% for MSKCC-N5 (P = .379). Toxic death rates with both regimens were 1%. However, nonhematologic CTC grade 3 and 4 toxicities were higher with MSKCC-N5: 68% (193/283) versus 48% (129/268) (P < .001); infection 35% versus 25% (P = .011); stomatitis 25% versus 3% (P < .001); nausea and vomiting 17% versus 7% (P < .001); and diarrhea 7% versus 3% (P = .011). CONCLUSION: No difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.

Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1).

PURPOSE: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. MATERIALS AND METHODS: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). RESULTS: Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P < .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. CONCLUSION: Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.

Income inequality and child welfare interventions in England and Wales.

BACKGROUND: Previous research has identified a relationship between income inequality and child abuse and neglect in the USA. This association has received limited exploration outside the USA. METHODS: Administrative data on child protection (CP) in 172 English and Welsh local authorities between 2013 and 2018 were combined with data on deprivation, ethnic density and education from publicly available data sources. Commercial income data were used for Gini coefficient estimation. We tested whether similar evidence for three key findings from a US study could be found in England and Wales. These included whether there was evidence of a relationship between income inequality and child maltreatment, whether this relationship was non-linear and whether this relationship varied dependent on the level of poverty. RESULTS: There was a significant non-linear relationship between income inequality and state care rates in England and Wales. Predicted state care rates were higher as income inequality increased, up until around average levels where the effect flattens. However, there was no significant relationship for models predicting CP plan/register rates. Income inequality, income deprivation, ethnic density and higher education were able to explain around 75% of the variance in English and Welsh state care rates. CONCLUSIONS: There is some evidence to support the claim of a relationship between income inequality and child maltreatment beyond the USA in England and Wales, and a case for further comparative research, but there are significant limitations in the comparability of data.

Influence of Surgical Excision on the Survival of Patients With Stage 4 High-Risk Neuroblastoma: A Report From the HR-NBL1/SIOPEN Study.

PURPOSE: To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial. PATIENTS AND METHODS: Patients recruited between 2002 and 2015 with stage 4 disease > 1 year or stage 4/4S with MYCN amplification < 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome. RESULTS: A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patients (9.7%), and nephrectomy was performed in 124 (8.8%). Five-year event-free survival (EFS) ± SE (0.40 ± 0.01) and overall survival (OS; 0.45 ± 0.02) were significantly higher with CME compared with IME (5-year EFS, 0.33 ± 0.03; 5-year OS, 0.37 ± 0.03; P < .001 and P = .004). The cumulative incidence of local progression (CILP) was significantly lower after CME (0.17 ± 0.01) compared with IME (0.30 ± 0.02; P < .001). With immunotherapy, outcomes were still superior with CME versus IME (5-year EFS, 0.47 ± 0.02 v 0.39 ± 0.04; P = .038); CILP was 0.14 ± 0.01 after CME and 0.27 ± 0.03 after IME (P < .002). A hazard ratio of 1.3 for EFS associated with IME compared with CME was observed before and after the introduction of immunotherapy (P = .030 and P = .038). CONCLUSION: In patients with stage 4 high-risk neuroblastoma who have responded to induction therapy, CME of the primary tumor is associated with improved survival and local control after HDT, local radiotherapy (21 Gy), and immunotherapy.

Site-Specific Protein Photochemical Covalent Attachment to Carbon Nanotube Side Walls and Its Electronic Impact on Single Molecule Function.

Functional integration of proteins with carbon-based nanomaterials such as nanotubes holds great promise in emerging electronic and optoelectronic applications. Control over protein attachment poses a major challenge for consistent and useful device fabrication, especially when utilizing single/few molecule properties. Here, we exploit genetically encoded phenyl azide photochemistry to define the direct covalent attachment of four different proteins, including the fluorescent protein GFP and a ß-lactamase binding protein (BBP), to carbon nanotube side walls. AFM showed that on attachment BBP could still recognize and bind additional protein components. Single molecule fluorescence revealed that on attachment to SWCNTs function was retained and there was feedback to GFP in terms of fluorescence intensity and improved resistance to photobleaching; GFP is fluorescent for much longer on attachment. The site of attachment proved important in terms of electronic impact on GFP function, with the attachment site furthest from the chromophore having the larger effect on fluorescence. Our approach provides a versatile and general method for generating intimate protein-CNT hybrid bioconjugates. It can be potentially applied to any protein of choice; the attachment position and thus interface characteristics with the CNT can easily be changed by simply placing the phenyl azide chemistry at different residues by gene mutagenesis. Thus, our approach will allow consistent construction and modulate functional coupling through changing the protein attachment position.