Implementing and Evaluating a National Integrated Digital Registry and Clinical Decision Support System in Early Intervention in Psychosis Services (Early Psychosis Informatics Into Care): Co-Designed Protocol.

BACKGROUND: Early intervention in psychosis (EIP) services are nationally mandated in England to provide multidisciplinary care to people experiencing first-episode psychosis, which disproportionately affects deprived and ethnic minority youth. Quality of service provision varies by region, and people from historically underserved populations have unequal access. In other disease areas, including stroke and dementia, national digital registries coupled with clinical decision support systems (CDSSs) have revolutionized the delivery of equitable, evidence-based interventions to transform patient outcomes and reduce population-level disparities in care. Given psychosis is ranked the third most burdensome mental health condition by the World Health Organization, it is essential that we achieve the same parity of health improvements. OBJECTIVE: This paper reports the protocol for the program development phase of this study, in which we aimed to co-design and produce an evidence-based, stakeholder-informed framework for the building, implementation, piloting, and evaluation of a national integrated digital registry and CDSS for psychosis, known as EPICare (Early Psychosis Informatics into Care). METHODS: We conducted 3 concurrent work packages, with reciprocal knowledge exchange between each. In work package 1, using a participatory co-design framework, key stakeholders (clinicians, academics, policy makers, and patient and public contributors) engaged in 4 workshops to review, refine, and identify a core set of essential and desirable measures and features of the EPICare registry and CDSS. Using a modified Delphi approach, we then developed a consensus of data priorities. In work package 2, we collaborated with National Health Service (NHS) informatics teams to identify relevant data currently captured in electronic health records, understand data retrieval methods, and design the software architecture and data model to inform future implementation. In work package 3, observations of stakeholder workshops and individual interviews with representative stakeholders (n=10) were subject to interpretative qualitative analysis, guided by normalization process theory, to identify factors likely to influence the adoption and implementation of EPICare into routine practice. RESULTS: Stage 1 of the EPICare study took place between December 2021 and September 2022. The next steps include stage 2 building, piloting, implementation, and evaluation of EPICare in 5 demonstrator NHS Trusts serving underserved and diverse populations with substantial need for EIP care in England. If successful, this will be followed by stage 3, in which we will seek NHS adoption of EPICare for rollout to all EIP services in England. CONCLUSIONS: By establishing a multistakeholder network and engaging them in an iterative co-design process, we have identified essential and desirable elements of the EPICare registry and CDSS; proactively identified and minimized potential challenges and barriers to uptake and implementation; and addressed key questions related to informatics architecture, infrastructure, governance, and integration in diverse NHS Trusts, enabling us to proceed with the building, piloting, implementation, and evaluation of EPICare. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50177.

The effectiveness of public health interventions, initiatives, and campaigns designed to improve pathways to care for individuals with psychotic disorders: A systematic review.

PURPOSE: Lengthy duration of untreated psychosis (DUP) and duration of untreated illness (DUI) in people at clinical high-risk for psychosis (CHR-P) and first episode psychosis (FEP) is associated with poorer outcomes. However, individuals with FEP often experience negative pathways to care involving contacts with police, crisis services and requiring compulsory admissions, and evidence suggests individuals with both FEP and CHR-P often experience lengthy delays to treatment. Early detection interventions, such as public health interventions, may be one way to reduce delays. This systematic review aimed to synthesise the available evidence on such interventions. METHODS: The EMBASE, PsychINFO, CINAHL, and MEDLINE databases were searched. Studies were included if they compared an intervention designed to improve timely access to treatment for individuals with FEP or CHR-P to standard treatment provision. Interventions may be targeted at potential patients, their families, the general public, or non-healthcare professionals. Outcomes of interest were DUP or DUI, and/or characteristics of pathways to care. RESULTS: Nineteen studies met the inclusion criteria. All consisted of FEP populations, none of CHR-P populations. Employing narrative synthesis, we found mixed results about the effectiveness of interventions at reducing DUP and interventions appeared to differentially impact groups. Pathways to care information was limited and mixed. CONCLUSION: Findings on the effectiveness of interventions designed to improve timely access to treatment were inconclusive. More research is warranted to better understand where delays occur and factors which may influence this for both FEP and CHR-P populations which may help to develop targeted interventions to address delays.

The effectiveness, implementation, and experiences of peer support approaches for mental health: a systematic umbrella review.

BACKGROUND: Peer support for mental health is recommended across international policy guidance and provision. Our systematic umbrella review summarises evidence on the effectiveness, implementation, and experiences of paid peer support approaches for mental health. METHODS: We searched MEDLINE, EMBASE, PsycINFO, The Campbell Collaboration, and The Cochrane Database of Systematic Reviews (2012-2022) for reviews of paid peer support interventions for mental health. The AMSTAR2 assessed quality. Results were synthesised narratively, with implementation reported using the CFIR (Consolidated Framework for Implementation Research). The protocol was registered with PROSPERO (registration number: CRD42022362099). RESULTS: We included 35 reviews (426 primary studies, n = 95-40,927 participants): systematic reviews with (n = 13) or without (n = 13) meta-analysis, or with qualitative synthesis (n = 3), scoping reviews (n = 6). Most reviews were low or critically low (97%) quality, one review was high quality. Effectiveness was investigated in 23 reviews. Results were mixed; there was some evidence from meta-analyses that peer support may improve depression symptoms (particularly perinatal depression), self-efficacy, and recovery. Factors promoting successful implementation, investigated in 9 reviews, included adequate training and supervision, a recovery-oriented workplace, strong leadership, and a supportive and trusting workplace culture with effective collaboration. Barriers included lack of time, resources and funding, and lack of recognised peer support worker (PSW) certification. Experiences of peer support were explored in 11 reviews, with 3 overarching themes: (i) what the PSW role can bring, including recovery and improved wellbeing for service users and PSWs; (ii) confusion over the PSW role, including role ambiguity and unclear boundaries; and (iii) organisational challenges and impact, including low pay, negative non-peer staff attitudes, and lack of support and training. CONCLUSIONS: Peer support may be effective at improving some clinical outcomes, self-efficacy, and recovery. Certain populations, e.g. perinatal populations, may especially benefit from peer support. Potential strategies to successfully implement PSWs include co-production, clearly defined PSW roles, a receptive hierarchical structure and staff, appropriate PSW and staff training with clinical and/or peer supervision alongside safeguarding. Services could benefit from clear, coproduced, setting specific implementation guidelines for PSW. PSW roles tend to be poorly defined and associations between PSW intervention content and impacts need further investigation. Future research should reflect the priorities of providers/service users involved in peer support.

Mental health in Europe during the COVID-19 pandemic: a systematic review.

The COVID-19 pandemic caused immediate and far-reaching disruption to society, the economy, and health-care services. We synthesised evidence on the effect of the pandemic on mental health and mental health care in high-income European countries. We included 177 longitudinal and repeated cross-sectional studies comparing prevalence or incidence of mental health problems, mental health symptom severity in people with pre-existing mental health conditions, or mental health service use before versus during the pandemic, or between different timepoints of the pandemic. We found that epidemiological studies reported higher prevalence of some mental health problems during the pandemic compared with before it, but that in most cases this increase reduced over time. Conversely, studies of health records showed reduced incidence of new diagnoses at the start of the pandemic, which further declined during 2020. Mental health service use also declined at the onset of the pandemic but increased later in 2020 and through 2021, although rates of use did not return to pre-pandemic levels for some services. We found mixed patterns of effects of the pandemic on mental health and social outcome for adults already living with mental health conditions.

A systematic review of the impact of carer interventions on outcomes for patients with eating disorders.

PURPOSE: Eating disorder (ED) prevalence and illness severity is rapidly increasing. The complicated interplay of factors contributing to the maintenance of EDs, including family/carer influences, highlights the importance of carer interventions within ED treatment. Carer interventions demonstrate positive outcomes for carers themselves, though are also hypothesised to benefit the patient indirectly. A systematic review was conducted to greater understand the impact of carer interventions on ED patient outcomes. METHODS: Eight databases, including CINAHL, MEDLINE and PsychINFO, were systematically searched. Intervention studies for parent(s)/carer(s) of a patient with an ED were included, provided they reported outcomes for the patient. No publication date restrictions were set. Included studies were quality appraised. RESULTS: Twenty-eight studies met inclusion for the review; all of which varied in intervention type, duration, content and setting. Patient diagnosis and treatment setting were mixed across studies, though the majority focused on Anorexia Nervosa within outpatient settings. Intervention content broadly included consideration of relationship issues and interactional patterns, psychoeducation, skill development, behavioural management, and peer support. Therapeutic models utilised were diverse, including but not limited to: family, interpersonal, cognitive, and psychodynamic approaches. CONCLUSION: Several carer interventions showed positive outcomes for patients with EDs, with small group treatment formats being commonly used and proving effective through intervention content alongside a peer support element. Separate family therapy was suggested to be of equal efficacy, if not better, than family therapy alongside the patient. Recommendations for clinical practice and future research are considered. LEVEL OF EVIDENCE: 1: Systematic review, evidence mostly obtained from randomised controlled trials.

Self-evaluation as an active ingredient in the experience and treatment of adolescent depression; an integrated scoping review with expert advisory input.

BACKGROUND: Negative self-perceptions is one of the most common symptoms of depression in young people, and has been found to be strongly associated with severity of depression symptoms. Psychological treatments for adolescent depression are only moderately effective. Understanding the role and importance of these self-perceptions may help to inform and improve treatments. The aim of this review was to examine self-evaluation as a characteristic of adolescent depression, and as an active ingredient in treatment for adolescent depression. METHODS: We conducted a scoping review which included quantitative and qualitative studies of any design that reported on self-evaluation as a characteristic of, or focus of treatment for, adolescent depression. Participants were required to be 11-24 years and experiencing elevated symptoms of depression or a diagnosis. We also met with 14 expert advisory groups of young people with lived experience, clinicians, and researchers, for their input. Findings from 46 peer-reviewed research studies are presented alongside views of 64 expert advisors, to identify what is known and what is missing in the literature. RESULTS: Three overarching topics were identified following the review and reflections from advisors: 1) What does it look like? 2) Where does it come from? and 3) How can we change it? The literature identified that young people view themselves more negatively and less positively when depressed, however expert advisors explained that view of self is complex and varies for each individual. Literature identified preliminary evidence of a bidirectional relationship between self-evaluation and depression, however, advisors raised questions regarding the influences and mechanisms involved, such as being influenced by the social environment, and by the cognitive capacity of the individual. Finally, there was a consensus from the literature and expert advisors that self-evaluation can improve across treatment. However, research literature was limited, with only 11 identified studies covering a diverse range of interventions and self-evaluation measures. Various barriers and facilitators to working on self-evaluation in treatment were highlighted by advisors, as well as suggestions for treatment approaches. CONCLUSIONS: Findings indicate the importance of self-evaluation in adolescent depression, but highlight the need for more research on which treatments and treatment components are most effective in changing self-evaluation.

Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma.

PURPOSE: We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma. EXPERIMENTAL DESIGN: The effects of the drug combination on cancer growth were examined in vitro and in animal models of MYCN-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction. RESULTS: The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination. CONCLUSIONS: The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.

Pathways to care in at-risk mental states: A systematic review.

AIM: Pathways to care are well studied in the First Episode Psychosis field, but less attention has been given to At-Risk Mental States or prodromal psychosis. This is important because accessing appropriate help at the earliest opportunity is likely to improve outcomes, particularly for those who make transition to psychosis. The present systematic review aimed to synthesize the available literature on pathways to care in ARMS or prodromal psychosis, and investigate the barriers and facilitators to receiving care for ARMS. METHODS: The CINAHL Complete, EMBASE, Medline Complete, PsycINFO and PubMED databases were searched. Studies were included if they were published in English between 1985 and 2019, where reported data came exclusively from an At-Risk Mental State population, and the study described or related to pathways to care. RESULTS: Ten studies met the inclusion criteria, of which 8 were quantitative. Screening tools and pathways to care instruments varied. Mental health professionals, and general practitioners played a key role in help seeking. Family involvement was also found to be an important factor. CONCLUSIONS: Pathways to care research in At-Risk Mental States are more scarce than in the field of First Episode Psychosis. More research is warranted, especially concerning the role of patient-level characteristics on pathways to care. A validated measure of pathways to care may also be of benefit.

The prevalence of common and stress-related mental health disorders in healthcare workers based in pandemic-affected hospitals: a rapid systematic review and meta-analysis.

Background: Healthcare workers (HCWs) are considered at elevated risk of experiencing mental health disorders in working with patients with COVID-19. Objective: To estimate the prevalence of common mental health disorders in HCWs based in hospitals where pandemic-affected patients were treated. Method: Databases were searched for studies published before 30 March 2020. Quantitative synthesis was used to obtain estimates of the prevalence of mental health disorders in four time windows, determined a priori (the acute phase, i.e. during and up to 1.5 months post-pandemic; 1.5-5.9 months; 6-11.9 months; 12 months and later). Results: Nineteen studies met the review criteria. They predominantly addressed the acute phase of the SARS outbreak in Asia. The most studied outcomes were clinically significant post-traumatic stress symptoms (PTSS) and general psychiatric caseness. For clinically significant PTSS in the acute phase, the prevalence estimate was 23.4% (95% CI 16.3, 31.2; N = 4147; I2 = 96.2%); in the 12 months plus window, the estimate was 11.9% (8.4, 15.8; N = 1136; I2 = 74.3%). For general psychiatric caseness, prevalence estimates were acute phase, 34.1% (18.7, 51.4; N = 3971; I2 = 99.1%); 6-12 months, 17.9% (13.1, 23.2; N = 223; I2 = 0.0%); 12 months plus, 29.3% (6.0, 61.0; N = 710; I2 = 97.8%). No differences between doctors and nurses with respective to PTSS and general psychiatric caseness were apparent in the acute phase. Conclusions: Mental health disorders are particularly common in HCWs working with pandemic-afflicted patients immediately following a pandemic, but the course of disorders following this period is poorly understood. There was considerable heterogeneity between studies, likely linked to methodological differences. More extended follow up of HCWs is needed.

Antecedentes: Se considera que los trabajadores de la salud (TS) tienen un riesgo elevado de experimentar trastornos de salud mental al trabajar con pacientes con COVID-19.Objetivo: Estimar la prevalencia de trastornos de salud mental comunes en los TS de los hospitales donde se trataron a pacientes afectados por una pandemia.Método: Se realizaron búsquedas en las bases de datos para estudios publicados antes del 30 de marzo de 2020. Se utilizó una síntesis cuantitativa para obtener estimaciones de la prevalencia de trastornos de salud mental en cuatro ventanas de tiempo, determinadas a priori (la fase aguda, es decir, durante y hasta 1,5 meses después de la pandemia; 1.5-5.9 meses; 6-11.9 meses; y después de 12 meses).Resultados: Diecinueve estudios cumplieron los criterios de esta revisión. Principalmente abordaron la fase aguda del brote de SARS en Asia. Los resultados más estudiados fueron los síntomas de estrés postraumático clínicamente significativos (SEPT) y casuística psiquiátrica general. Para los SEPT clínicamente significativo en la fase aguda, la estimación de prevalencia fue del 23,4% (IC del 95%: 16,3, 31,2; N = 4147; I2 = 96,2%); en los 12 meses adicionales, la estimación fue del 11,9% (8,4, 15,8; N = 1136; I2 = 74,3%). Para los casos de psiquiatría general, las estimaciones de prevalencia fueron: fase aguda, 34.1% (18.7, 51.4; N = 3971; I2 = 99.1%); 6-12 meses, 17.9% (13.1, 23.2; N = 223; I2 = 0.0%); después de 12 meses, 29.3% (6.0, 61.0; N = 710; I2 = 97.8%). No se observaron diferencias entre los médicos y las enfermeras con SEPT y casuística psiquiátrica general en la fase aguda.Conclusiones: Los trastornos de salud mental son particularmente comunes en los TS que trabajan con pacientes afectados inmediatamente después de la pandemia, pero el curso de los trastornos después de este período es poco conocido. Hubo una considerable heterogeneidad entre los estudios, probablemente vinculada a diferencias metodológicas. Se necesita un seguimiento más extenso de los TS.

Targeting metabolic activity in high-risk neuroblastoma through Monocarboxylate Transporter 1 (MCT1) inhibition.

Amplification of the MYCN oncogene occurs in ~25% of primary neuroblastomas and is the single most powerful biological marker of poor prognosis in this disease. MYCN transcriptionally regulates a range of biological processes important for cancer, including cell metabolism. The MYCN-regulated metabolic gene SLC16A1, encoding the lactate transporter monocarboxylate transporter 1 (MCT1), is a potential therapeutic target. Treatment of neuroblastoma cells with the MCT1 inhibitor SR13800 increased intracellular lactate levels, disrupted the nicotinamide adenine dinucleotide (NADH/NAD+) ratio, and decreased intracellular glutathione levels. Metabolite tracing with 13C-glucose and 13C-glutamine following MCT1 inhibitor treatment revealed increased quantities of tricarboxylic acid (TCA) cycle intermediates and increased oxygen consumption rate. MCT1 inhibition was highly synergistic with vincristine and LDHA inhibition under cell culture conditions, but this combination was ineffective against neuroblastoma xenografts. Posttreatment xenograft tumors had increased synthesis of the MCT1 homolog MCT4/SLC16A, a known resistance factor to MCT1 inhibition. We found that MCT4 was negatively regulated by MYCN in luciferase reporter assays and its synthesis in neuroblastoma cells was increased under hypoxic conditions and following hypoxia-inducible factor (HIF1) induction, suggesting that MCT4 may contribute to resistance to MCT1 inhibitor treatment in hypoxic neuroblastoma tumors. Co-treatment of neuroblastoma cells with inhibitors of MCT1 and LDHA, the enzyme responsible for lactate production, resulted in a large increase in intracellular pyruvate and was highly synergistic in decreasing neuroblastoma cell viability. These results highlight the potential of targeting MCT1 in neuroblastoma in conjunction with strategies that involve disruption of pyruvate homeostasis and indicate possible resistance mechanisms.

Early Intervention in Psychosis Treatment Components Utilization in Patients Aged Over 35.

Early Intervention in Psychosis (EIP) services have been youth-focused since their inception. In England, recent National Institute for Health and Care Excellence (NICE) guidelines and new National Health Service (NHS) Standards for EIP recommend the expansion of the age acceptability criterion from 14-35 to 14-65. In the Cambridgeshire and Peterborough EIP service (CAMEO), we ran a service evaluation to assess the initial impact of this policy change. It aimed to elicit EIP treatment components utilization by patients with first-episode psychosis (FEP) aged over 35, in comparison with those under 35. We found that the over-35s required more contacts from EIP healthcare professionals, especially from care coordinators (coefficient = .239; Robust SE = .102; Z = 6.42; p = 0.019) and social workers (coefficient = 18.462; Robust SE = .692; Z = .016; p < 0.001). These findings indicate that FEP patients aged over 35 may present with more complex and sustained clinical/social needs. This may have implications for EIP service development and commissioning.

Mindfulness-Based Interventions for University Students: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: University students are expressing an increased need for mental health support. Mindfulness-based interventions (MBIs) are being integrated into university stress-reduction programmes globally. We conducted a comprehensive systematic review and meta-analysis of randomised controlled trials (RCTs) assessing MBI effects on university students' mental and physical health. METHODS: We searched nine databases, including grey literature and trial registries. Two independent reviewers extracted data following a prospective public protocol. RESULTS: Fifty-one RCTs were included. In comparison with passive controls, and when measured shortly after intervention completion, MBIs improve distress, anxiety, depression, well-being, rumination, and mindfulness with small to moderate effect sizes, with no benefit found for blood pressure, sleep, life satisfaction, resilience, worry, and thought suppression. Evidence for self-compassion is inconclusive. Effects last beyond three months for distress and mindfulness, with no data on other outcomes. Compared with active control groups, MBIs significantly improve distress and state anxiety, but not mindfulness, depression, well-being, affect, trait anxiety, or emotion regulation. Results were robust to adjustment for multiple testing, but RCTs' risk of bias is generally high. Moderator analyses did not find differential intervention effects according to intervention duration, delivery mode, or sub-populations. CONCLUSIONS: MBIs may be helpful to students but higher-quality research is needed.

Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma.

Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as the key transporter involved in polyamine uptake in neuroblastoma. Knockdown of SLC3A2 in neuroblastoma cells reduced the uptake of the radiolabeled polyamine spermidine, and DFMO treatment increased SLC3A2 protein. In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway. Inhibiting polyamine uptake with the small-molecule drug AMXT 1501, in combination with DFMO, prevented or delayed tumor development in neuroblastoma-prone mice and extended survival in rodent models of established tumors. Our findings suggest that combining AMXT 1501 and DFMO with standard chemotherapy might be an effective strategy for treating neuroblastoma.

The over-35s: early intervention in psychosis services entering uncharted territory.

Aims and methodFollowing the introduction of new standards for early intervention in psychosis (EIP) in England, EIP services are accepting referrals for people aged 35-65. The Cambridgeshire and Peterborough EIP service (CAMEO) aimed to explore the immediate implications for the service, especially with regards to referral numbers and sources. Data were collected from April 2016 to June 2017. RESULTS: Referrals for over-35s represented 25.7% of all new referrals. Fifty per cent of referrals for over-35s were accepted onto caseload (40.2% for under-35s). The over-35s were more likely to be referred from acute and secondary mental health services (P < 0.01) and had longer durations of untreated psychosis than the under-35s (P = 0.02).Clinical implicationsCAMEO has received a significantly higher number of referrals as a result of age inclusivity, with an increased proportion of patients suffering from severe, acute psychotic presentations and existing mental health difficulties. This has implications for service planning.Declaration of interestNone.

Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo.

The ATP-binding cassette transporter ABCC4 (multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signalling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 strongly inhibited the growth of human neuroblastoma cells in vitro and impaired the growth of neuroblastoma xenografts. Loss of Abcc4 in the Th-MYCN transgenic neuroblastoma mouse model did not impact tumour formation; however, Abcc4-null neuroblastomas were strongly sensitised to the ABCC4 substrate drug irinotecan. Our findings demonstrate a role for ABCC4 in neuroblastoma cell proliferation and chemoresistance and provide rationale for a strategy where inhibition of ABCC4 should both attenuate the growth of neuroblastoma and sensitise tumours to ABCC4 chemotherapeutic substrates.