Burkitt lymphoma: The effect of age, sex and delay to diagnosis on treatment completion and outcome of treatment in 934 Patients in Cameroon.

INTRODUCTION: The role of age and sex in the presentation and outcome of endemic Burkitt lymphoma (BL) has not been studied recently. This study analysed these factors in 934 patients with BL who had received cyclophosphamide and intrathecal methotrexate as treatment. METHODS: Records of 934 children diagnosed with BL from 2004 to 2015 were obtained from our Paediatric Oncology Networked Database (POND) cancer registry. Age at diagnosis, sex, disease stage, time to diagnosis, delay in diagnosis, completion of treatment, rate of abandonment, and one-year survival rates were recorded and statistically analysed. RESULTS: The male to female ratio of 1.41 for the study population of 934. The median delay from onset of symptoms to diagnosis was 31 days. The St Jude stage distribution was I = 6.4%, II = 5.9%, III = 71.5% and IV = 16.2%. Significantly more patients presented with stage III disease in age groups 5-9 and 10-14 years than 0-4 years. The overall 1-year survival rate was 53.45%, respectively 77.1% for stage I, 67.9% for stage II, 55.1% for stage III and 32.4% for stage IV disease (p<0.001). There was no significant difference in survival by sex and age group. CONCLUSION: Patients aged under 5 years presented with less-advanced disease, but survival was not affected by age. Sex did not influence delay to diagnosis and overall survival. The long delay between the onset of symptoms and diagnosis emphasises the need for interventions to achieve an earlier diagnosis and a better survival rate.

Survey of the use of traditional and complementary medicine among children with cancer at three hospitals in Cameroon.

INTRODUCTION: There is lack of diagnostic and treatment resources with variable access to childhood cancer treatment in low- and middle-income countries (LMIC), which may lead to subsequent poor survival. The primary aim of this study was to determine the prevalence and types of traditional and complementary medicine (T&CM) used in Cameroon. Secondarily, we explored determinants of T&CM use, associated costs, perceived benefits and harm, and disclosure of T&CM use to medical team. METHODS: A prospective, cross-sectional survey among parents and carers of children younger than 15 years of age who had a cancer diagnosis and received cancer treatment at three Baptist Mission hospitals between November 2017 and February 2019. RESULTS: Eighty participants completed the survey. Median patient age was 8.1 years (IQR4.1-11.1). There was significant availability (90%) and use (67.5%) of T&CM, whereas 24% thought T&CM would be good for cancer treatment. Common T&CM remedies included herbs and other plant remedies or teas taken by mouth, prayer for healing purposes and skin cutting. Living more than five hours away from the treatment center (P = 0.030), anticipated costs (0.028), and a habit of consulting a traditional healer when sick (P = 0.006) were associated with the use of T&CM. T&CM was mostly paid for in cash (53.7%) or provided free of charge (29.6%). Of importance was the fact that nearly half (44%) did not want to disclose the use of TM to their doctor. CONCLUSION: Pediatric oncology patients used T&CM before and during treatment but were unlikely to disclose its use to the child's health care team.

Outcome of retinoblastoma treatment protocol in Cameroon as per SIOP-PODC recommendation for a low-income setting.

INTRODUCTION: The International Society of Paediatric Oncology-Paediatric Oncology in Developing Countries (SIOP-PODC) group recommended graduated-intensity retinoblastoma treatment for children in low- and middle-income countries with limited local resources. AIM: The aim was to improve outcome of children with retinoblastoma by means of a treatment protocol for low-income settings as recommended by the SIOP-PODC recommendation in Cameroon. METHODS: Children diagnosed with retinoblastoma between 2012 and 2016 were treated in two Baptist Mission hospitals in Cameroon, staging according to the International Retinoblastoma Staging System. Treatment included local therapy and combination chemotherapy (vincristine, cyclophosphamide, and doxorubicin) with or without surgery as per SIOP-PODC guidelines for low-income countries. Endpoint was survival at 24 months. Kaplan-Meier curves with log-rank (Mantel-Cox) chi-square (χ2 ) with respective p-values were prepared. RESULTS: Eighty-two children were included, of whom 79.3% had unilateral disease. The majority were males (61.0%) with median age 24 months (range 1-112 months; standard deviation [SD] 19). Limited disease was diagnosed in 58.5%, metastatic disease in 35.4%, and unknown stage in 6.1%. Overall survival (OS) was 50.0% at 24 months post diagnosis, but 68.8% for limited disease. Estimated cumulative survival at 24 months was 0.528 (standard error [SE] 0.056). Causes of death included disease progression/relapses (60.5%), neutropenic sepsis (15.9%), unknown causes (18.4%), unrelated infection (2.6%), and death post surgery (2.6%). Stage was significantly associated with OS (p < .001). CONCLUSION: Stage was the most significant factor for good OS and demonstrated the efficacy and feasibility of the SIOP-PODC-proposed management guidelines for retinoblastoma in a lower middle-income setting.

Treatment abandonment: A report from the collaborative African network for childhood cancer care and research-CANCaRe Africa.

BACKGROUND: 'Treatmentabandonment' is a common and preventable cause of childhood cancer treatment failure in low- and middle-income countries (LMIC). Risk factors and effective interventions in LMIC are reported. Poverty and costs of treatment are perceived as overriding causes in sub-Saharan Africa. The objective of this study was to study potential determinants of treatment abandonment, including aspects of treatment costs in sub-Saharan Africa, to be better informed for planned future interventions. METHODS: A multicentre, prospective, observational, cohort study was conducted in five hospitals in sub-Saharan Africa. Children younger than 16 years with newly diagnosed cancer treated as inpatient with curative intent were included. The occurrence of treatment abandonment and potential determinants including aspects of treatment costs were documented during the first 3 months of treatment. RESULTS: We included 252 patients (median age 6.0, range 0.2-15.0 years, 54% male). The most common cancer was Burkitt lymphoma (63/252, 25%). Seven percent of patients (18 of 252) abandoned treatment. Two thirds (65%, 163/252) of patients had to borrow money to reach the hospital for the diagnosis and start of treatment. Treatment abandonment occurred more frequently in families who had to borrow money (16/163, 10%) versus those who did not (2/89, 2%; p = .026). CONCLUSIONS: Limiting costs for families and improved counselling may reduce treatment abandonment. Development and implementation of interventions to reduce treatment abandonment are required in sub-Saharan Africa.

Fever and neutropenia outcomes and areas for intervention: A report from SUCCOUR - Supportive Care for Children with Cancer in Africa.

BACKGROUND: Death during paediatric cancer treatment is common in sub-Saharan Africa. Using the infrastructure of Supportive Care for Children with Cancer in Africa (SUCCOUR), our objective was to describe fever and neutropenia (FN) characteristics and outcomes in order to identify potential areas for future intervention. METHODS: A multicentre prospective, observational cohort study was conducted in sub-Saharan Africa. Data were collected from September 2019 to March 2020. Children below 16 years with newly diagnosed cancer treated with curative intent were included. Data were abstracted in real time using standardised case report forms by trained personnel. Characteristics and outcomes of FN during the first 3 months of treatment were documented. RESULTS: A total of 252 patients were included (median age 6.0, range 0.2-15.0 years, 54% male). The most common cancer was Burkitt lymphoma (63/252, 25%). Among 104 FN episodes, 21 (21%) were associated with prolonged neutropenia (>1 week) and 32 (31%) were associated with profound neutropenia (absolute neutrophil count <0.1 × 109 /L). In 10/104 (10%) episodes, empiric antibiotics were started within 1 hour following fever onset and in 16/104 (15%) episodes, a blood culture was obtained before starting antibiotics. Malaria parasitaemia was detected in four of 104 (4%). A total of 11/104 (11%) patients died in the FN episodes. CONCLUSIONS: Although in most, FN was not associated with prolonged or profound neutropenia, 11% resulted in death. Areas to target include blood cultures prior to antibiotics and earlier initiation of empiric antibiotics. Future efforts should modify FN practices to reduce treatment-related mortality.

Early death and treatment-related mortality: A report from SUCCOUR - Supportive Care for Children with Cancer in Africa.

BACKGROUND: Deaths during paediatric cancer treatment are common in Africa. It is often difficult to distinguish between treatment-related and disease-related causes. To prevent these deaths, it is important to study them and identify the cause. The Supportive Care for Children with Cancer in Africa (SUCCOUR) programme enabled a study with the objective to identify the reasons for early death during treatment. METHODS: We conducted a multicentre prospective, observational cohort study in sub-Saharan Africa. Children younger than 16 years with newly diagnosed cancer treated with curative intent were included from 1 September 2019 until 30 March 2020. Data were abstracted in real time by trained personnel using standardised case report forms. The treating clinician's assessment of the cause of death and signs, symptoms and laboratory values of patients who died during the first 3 months of treatment (early death) were documented. RESULTS: We included 252 patients (median age 6.0, range 0.2-15.0 years, 54% male). The most common cancer was Burkitt lymphoma (63/252, 25%). Fifteen percent of patients (37/252) died during the first 3 months of treatment. Of these 37 patients, 33 (89%) died of a treatment-related cause. Treatment-related mortality of all patients in the first 3 months of treatment was 13% (33/252). CONCLUSION: Fifteen percent of patients had an early death during treatment and 13% had a treatment-related death. This suggests the need to improve supportive care. Implementation of supportive care pathways adapted to local circumstances may be helpful.

Two decades of childhood cancer care in Cameroon: 2000-2020.

BACKGROUND: Before the year 2000, there was no dedicated childhood cancer service in Cameroon. The aim of this study was to investigate the progress made with pediatric oncology care in Cameroon from 2000 to 2020. METHOD: A literature search was conducted for published articles on childhood cancer in Cameroon and relevant documents, and conference abstracts were reviewed. The articles were analyzed under the themes: awareness, diagnosis, epidemiology, treatment, outcome, advocacy, partnerships, traditional and complementary medicine, palliative care, and capacity building. RESULTS: Low awareness on childhood cancer was addressed with education activities targeting the general population and health care professionals. Cancer diagnosis was achieved with cytology, histology, and simple imaging. Management for common and curable cancers was implemented with use of modified treatment regimens for low- and middle-income settings. Nutritional support was shown to mitigate the effects of malnutrition on treatment toxicity, and support was provided for transportation and accommodation. There was good collaboration between the pediatric oncology professionals nationally and twinning with international partners. Capacity building activities led to the availability of three pediatric oncologists and pediatric oncology-trained nurses. Advocacy nationally led to the support of the Ministry of Health with pediatric oncology-specific priority actions in the latest national cancer control plan. CONCLUSION: Childhood cancer should receive the necessary attention of health care policymakers in Cameroon. With continued commitment of government, nongovernmental organizations, charities, childhood cancer specialists, patient and parent groups, there should be an improved future for children with cancer in Cameroon.

The Evolution of a Hospital-Based Cancer Registry in Northwest Cameroon from 2004 to 2015.

Effective cancer registration is required for the development of cancer management policies, but is often deficient in the developing world. In 2008 cancer registration was set up Banso Baptist Hospital and Mbingo Baptist Hospital in the Northwest region of Cameroon, using the Pediatric Oncology Networked Database (POND). The objective of this study was to analyze the POND registry data for patients with cancer aged 0-15 years for the period 2004-15. A total of 1029 malignancies were recorded in children 0-15 years in the study period. The male-to-female ratio was 1.4:1. The median age at diagnosis was 7.22 years. The most common malignancies were lymphomas followed by nephroblastoma, retinoblastoma, rhabdomyosarcoma and Kaposi sarcoma. There were more Burkitt lymphomas cases between 2004 and 2009 than between 2010 and 2015, while the number of cases rose for other diagnoses like retinoblastoma and nephroblastoma. This report has demonstrated how pediatric oncology registration can be implemented, improved and sustained in a low- and middle-income country setting with limited resources. Using the data, these hospitals can improve their treatment planning and ensure the availability of essential chemotherapy for childhood cancers.

The outcome and cost of a capacity-building training programme on the early recognition and referral of childhood cancer for healthcare workers in North-West Cameroon.

Aim: Early cancer diagnosis is necessary to improve survival rates. The aim of this study was to assess the outcome and cost of the childhood cancer training programme amongst healthcare workers. Design: This was a prospective pre-post study design, using questionnaires for pre- and post-training testing. The warning signs of childhood cancer were used as the main teaching content to improve recognition and early diagnosis. Methods: Pre-training and post-training knowledge, as well as attitude questionnaires, was administered at the beginning and at the end of each training workshop. Paired samples t test and chi-square were used to compare the change in knowledge and differences between groups. Results: The overall percentage knowledge score increased from 51%-85% (p < .001). The doctors had a better knowledge score than the nurses in the pre-test (70% versus 50%, p = .008), but there was no significant difference in the post-test scores. The cost of training was €25.06 per healthcare worker. Conclusion: We recommend similar training programmes in public health to improve early diagnosis of childhood cancer.

Pediatric Oncology Clinical Trials and Collaborative Research in Africa: Current Landscape and Future Perspectives.

PURPOSE: Adequate clinical services have yet to be established in the majority of African countries, where childhood cancer survival rates vary from 8.1% to 30.3%. The aim of this review is to describe the landscape of pediatric oncology trials in Africa, identify challenges, and offer future opportunities for research collaborations. METHODS: The study includes data from the International Pediatric Oncology Society (SIOP) global mapping survey, meta-research identifying trials in Africa in ClinicalTrials.gov, and a literature overview of publications on the subject of pediatric oncology clinical research supported by expert opinions on the current situation and challenges. RESULTS: The SIOP global mapping survey received responses from 47 of 54 African countries, of which 23 have active clinical research programs. A preliminary search of ClinicalTrials.gov showed that only 105 (12.1%) of 868 African oncology studies included children and adolescents. Of these, 53 (50.5%) were interventional trials according to the registry's classification. The small number of African trials for children and adolescents included palliative care and leukemia trials. In African oncology journals and international pediatric oncology journals, < 1% of the pediatric oncology publications come from Africa. Services and research were strengthened by international collaboration. National studies focused on clinical needs, local challenges, or interventional priorities. Both the literature review and the expert opinions highlight the need to expand clinical research in Africa, despite ongoing regional instability and lack of resources. CONCLUSION: While a low number of pediatric clinical treatment trials are open to African children and adolescents, clinical research of high quality is being done in Africa. Several initiatives are stimulating the development of the research capacity across the continent, which should increase the publication output.

Improvement of overall survival in the Collaborative Wilms Tumour Africa Project.

INTRODUCTION: The Collaborative Wilms Tumour (WT) Africa Project implemented an adapted WT treatment guideline in six centres in sub-Saharan Africa. The primary objectives were to describe abandonment of treatment, death during treatment, event-free survival (EFS) and relapse following implementation. An exploratory objective was to compare outcomes with the baseline evaluation, a historical cohort preceding implementation. METHODS: The Collaborative WT Africa Project is a multi-centre prospective clinical trial that began in 2014. Funding was distributed to all participating centres and used to cover treatment, travel and other associated costs for patients. Patient characteristics, tumour characteristics and events were described. RESULTS: In total, 201 WT patients were included. Two-year EFS was 49.9 ± 3.8% when abandonment of treatment was considered an event. Relapse of disease occurred in 21% (42 of 201) of all included patients and in 26% (42 of 161) of those who had a nephrectomy. Programme implementation was associated with significantly higher survival without evidence of disease at the end of treatment (52% vs 68.5%, P = .002), significantly reduced abandonment of treatment (23% vs 12%, P = .009) and fewer deaths during treatment (21% vs 13%, P = .06). CONCLUSION: This collaborative implementation of an adapted WT treatment guideline, using relatively simple and low-cost interventions, was feasible. Two-year EFS was almost 50%. In addition, a significant decrease in treatment abandonment and an increase in survival at the end of treatment were observed compared to a pre-implementation cohort. Future work should focus on decreasing deaths during treatment and will include enhancing supportive care.

Destitution, treatment adherence and survival of children with Burkitt lymphoma in a twinning programme in Northwest Cameroon.

BACKGROUND: Burkitt lymphoma (BL) is a curable childhood cancer. Treatment adherence is crucial for a good outcome, but is potentially problematic in low- and middle-income countries owing to parental financial constraints. AIMS: To investigate the association of destitution with treatment adherence and its effect on the survival of patients with BL. METHODS: Patients received free medical treatment from a twinning programme at two Cameroon Baptist hospitals. A destitution assessment questionnaire, based on socioeconomic status, was completed at diagnosis. Medical records were reviewed for treatment adherence and survival. Chi-squared and Fisher's exact tests were used to compare groups. Kaplan-Meier plots were used to calculate overall survival, and log-rank chi-squared tests when comparing survival rates between patient subgroups. Significance was measured at P < .05. RESULTS: The 225 children with BL had a mean age of 8.2 years (median 8.0) and the overall survival was 52%. The mean family destitution score was 56% on a linear scale. Few (8%) patients delayed treatment appointments. A quarter (25%) experienced more than a 1-week follow-up delay and 9.8% absconded within 1 year. The destitution score was not significantly associated with delay of treatment, but with delay in follow-up (P < .001). Guardian relationship (single mother) and patient's age were significantly associated with overall survival (P = .025). CONCLUSIONS: Though linked to poor follow-up, destitution was not significantly associated with absconding patients, poor outcome or poor adherence to treatment, probably due to comprehensive financial support from the international twinning programme. However, additional support for single mothers should be considered.

Potentiation of antiseizure and neuroprotective efficacy of standard nerve agent treatment by addition of tariquidar.

Organophosphate (OP) induced seizures are commonly treated with anticholinergics, oximes and anticonvulsants. Inhibition of P-glycoprotein (PgP) has been shown to enhance the efficacy of nerve agent treatment in soman exposed rats. In the present study, the promising effects of the PgP inhibitor tariquidar were investigated in more detail in rats s.c. exposed to 150 µg/kg soman. Treatment with HI-6 and atropine sulfate (125 and 3 mg/kg i.m respectively) was administered 1 min after exposure. Diazepam (0.5 mg/kg i.m.) and/or tariquidar (7.5 mg/kg i.v.) were included either at 1 min or 40 min following onset of seizures. Animals that received tariquidar, in addition to HI-6 and atropine, at 1 min, displayed a rapid normalization of EEG activity and cessation of seizure-associated behaviour. This improvement by addition of tariquidar was even more substantial in animals that also received diazepam, either immediately or delayed. Animals exhibiting lower intensity seizures displayed less severe neuropathology (neuronal loss, microglia activation and astrogliosis), primarily in the piriform cortex, and to a lesser extent amygdala and entorhinal cortex. The present findings suggest that the interaction of tariquidar with atropine may be the decisive factor for enhanced treatment efficacy, given that atropine was previously found to be a PgP substrate. A more thorough understanding of the interactions of nerve agent antidotes, in particular the actions of central anticholinergics with benzodiazepines, could contribute to a future optimization of treatment combinations, particularly those aimed at later stage medical interventions.

Improved outcome at end of treatment in the collaborative Wilms tumour Africa project.

BACKGROUND: The Collaborative Wilms Tumour (WT) Africa Project has implemented an adapted WT treatment guideline in sub-Saharan Africa as a multi-centre prospective clinical trial. A retrospective, baseline evaluation of end-of-treatment outcome was performed for a 2-year period prior to the introduction of this guideline. The collaborative project aims to reduce both treatment abandonment and death during treatment to less than 10% for improving survival. PROCEDURE: All participating centres obtained local Institutional Research Board (IRB) approval and implemented the adapted WT treatment guideline. End-of-treatment outcome was documented for 2 years. It was divided into alive without evidence of disease, treatment abandonment, death during treatment and persistent disease. The outcome of children enroled in the first 2 years of the prospective clinical trial has been compared to the outcome before the start of the project. RESULTS: One hundred twenty-two patients were included in the baseline evaluation (2011-2012) and 133 in the first 2 years of the collaborative clinical trial (2014-2015). The percentage of patients alive without evidence of disease at the end of treatment increased from 52% (63/122) to 68% (90/133; P = 0.01). Treatment abandonment decreased from 23% (28/122) to 13% (17/133; P = 0.03). Death during treatment decreased from 21% (26/122) to 13% (17/133; P = 0.07). CONCLUSION: This collaboration, using relatively simple and low-cost interventions, led to a significant decrease in treatment abandonment and increase in survival without evidence of disease at the end of treatment.

Traditional and Complementary Medicine in Pediatric Oncology and Low-Middle Income Countries: Recommendations from the International Society of Pediatric Oncology (SIOP), T&CM Collaborative.

Significant strides have been made in the treatment of childhood cancer. Improvements in survival have led to increased attention toward supportive care indications; including the use of traditional and complementary medicine (T&CM). The use of T&CM among children and adolescents with cancer is well documented in both high-income countries (HICs) and low-middle income countries (LMICs). A higher incidence of the use of T&CM has been reported among children undergoing treatment in LMICs, which has elevated concerns related to drug interactions, adherence to therapy, and treatment-related toxicities. These observations have underscored the need for effective models of integrative care that are culturally sensitive yet sustainable in an LMIC setting. We present considerations inclusive of the clinical care, educational opportunities, governmental policy, and research priorities necessary for the development of models of integrative care for pediatric cancer units in an LMIC setting.

The role of traditional healers in the diagnosis and management of Burkitt lymphoma in Cameroon: understanding the challenges and moving forward.

BACKGROUND: Burkittlymphoma(BL) is the most common childhood cancer in Cameroon with a reported incidence of 3 per 100,000 children under 15 years in the Northwest region. Treatment at three Baptist mission hospitals has a recorded cure rate of over 50%. Traditional medicine(TM) is recognized by the national health system, but its scope is undefined and entraps children with BL. The aim of this study was to investigate the attitudes and practices of parents and traditional healers (TH) towards TM in children with BL in order to develop recommendations for an integrative approach and improved access to life-saving treatment for children with BL. METHODS: This is a descriptive case series of children diagnosed with BL treated at Banso, Mbingo, and Mutengene Baptist Hospitals between 2003 and 2014. A questionnaire was used to obtain the following information: demographic information, religion, the rate of use of TM, reasons why guardians chose to use TM, the diagnoses made by the TH, treatment offered, and the type of payment requested, based on the accounts of patient caregivers. Data was analyzed using Center for Disease Control Epi Info 7. RESULTS: Three hundred eighty-seven questionnaires were completed by parents/guardians. 55% had consulted a TH, of whom 76.1% consulted the TH as first choice. Common diagnoses provided by TH included liver problem, abscess, witchcraft, poison, hernia, side pain, mushroom in the belly and toothache. Methods of management included massage, cuts, concoctions, and incantations. The fee for these services included chickens, farm tools, and cash ranging from 200FCFA (0.4USD) to 100,000FCFA(200USD). The choice of TM was based on accessibility, failed clinic/hospital attendance, recommendation of relatives, and belief in TM. CONCLUSIONS: TH are involved in BL management in Cameroon. TH are ignorant about BL, resulting in non-referral, and thus delay in diagnosis and treatment. Collaboration with TH could reduce late diagnosis and improve cure rates of BL and other childhood cancers.

International incidence of childhood cancer, 2001-10: a population-based registry study.

BACKGROUND: Cancer is a major cause of death in children worldwide, and the recorded incidence tends to increase with time. Internationally comparable data on childhood cancer incidence in the past two decades are scarce. This study aimed to provide internationally comparable local data on the incidence of childhood cancer to promote research of causes and implementation of childhood cancer control. METHODS: This population-based registry study, devised by the International Agency for Research on Cancer in collaboration with the International Association of Cancer Registries, collected data on all malignancies and non-malignant neoplasms of the CNS diagnosed before age 20 years in populations covered by high-quality cancer registries with complete data for 2001-10. Incidence rates per million person-years for the 0-14 years and 0-19 years age groups were age-adjusted using the world standard population to provide age-standardised incidence rates (WSRs), using the age-specific incidence rates (ASR) for individual age groups (0-4 years, 5-9 years, 10-14 years, and 15-19 years). All rates were reported for 19 geographical areas or ethnicities by sex, age group, and cancer type. The regional WSRs for children aged 0-14 years were compared with comparable data obtained in the 1980s. FINDINGS: Of 532 invited cancer registries, 153 registries from 62 countries, departments, and territories met quality standards, and contributed data for the entire decade of 2001-10. 385 509 incident cases in children aged 0-19 years occurring in 2·64 billion person-years were included. The overall WSR was 140·6 per million person-years in children aged 0-14 years (based on 284 649 cases), and the most common cancers were leukaemia (WSR 46·4), followed by CNS tumours (WSR 28·2), and lymphomas (WSR 15·2). In children aged 15-19 years (based on 100 860 cases), the ASR was 185·3 per million person-years, the most common being lymphomas (ASR 41·8) and the group of epithelial tumours and melanoma (ASR 39·5). Incidence varied considerably between and within the described regions, and by cancer type, sex, age, and racial and ethnic group. Since the 1980s, the global WSR of registered cancers in children aged 0-14 years has increased from 124·0 (95% CI 123·3-124·7) to 140·6 (140·1-141·1) per million person-years. INTERPRETATION: This unique global source of childhood cancer incidence will be used for aetiological research and to inform public health policy, potentially contributing towards attaining several targets of the Sustainable Development Goals. The observed geographical, racial and ethnic, age, sex, and temporal variations require constant monitoring and research. FUNDING: International Agency for Research on Cancer and the Union for International Cancer Control.

Repeated dexamphetamine treatment alters the dopaminergic system and increases the phMRI response to methylphenidate.

Dexamphetamine (AMPH) is a psychostimulant drug that is used both recreationally and as medication for attention deficit hyperactivity disorder. Preclinical studies have demonstrated that repeated exposure to AMPH can induce damage to nerve terminals of dopamine (DA) neurons. We here assessed the underlying neurobiological changes in the DA system following repeated AMPH exposure and pre-treated rats with AMPH or saline (4 times 5 mg/kg s.c., 2 hours apart), followed by a 1-week washout period. We then used pharmacological MRI (phMRI) with a methylphenidate (MPH) challenge, as a sensitive and non-invasive in-vivo measure of DAergic function. We subsequently validated the DA-ergic changes post-mortem, using a.o. high-performance liquid chromatography (HPLC) and autoradiography. In the AMPH pre-treated group, we observed a significantly larger BOLD response to the MPH challenge, particularly in DA-ergic brain areas and their downstream projections. Subsequent autoradiography studies showed that AMPH pre-treatment significantly reduced DA transporter (DAT) density in the caudate-putamen (CPu) and nucleus accumbens, whereas HPLC analysis revealed increases in the DA metabolite homovanillic acid in the CPu. Our results suggest that AMPH pre-treatment alters DAergic responsivity, a change that can be detected with phMRI in rats. These phMRI changes likely reflect increased DA release together with reduced DAT binding. The ability to assess subtle synaptic changes using phMRI is promising for both preclinical studies of drug discovery, and for clinical studies where phMRI can be a useful tool to non-invasively investigate DA abnormalities, e.g. in neuropsychiatric disorders.

Dopaminergic neurotransmission in ventral and dorsal striatum differentially modulates alcohol reinforcement.

Dopaminergic neurotransmission in the striatum has been widely implicated in the reinforcing properties of substances of abuse. However, the striatum is functionally heterogeneous, and previous work has mostly focused on psychostimulant drugs. Therefore, we investigated how dopamine within striatal subregions modulates alcohol-directed behaviour in rats. We assessed the effects of infusion of the dopamine receptor antagonist alpha-flupenthixol into the shell and core of the nucleus accumbens (NAcc) and the dorsolateral striatum (DLS) on responding for alcohol under fixed ratio 1 (FR1) and progressive ratio (PR) schedules of reinforcement. Bilateral infusion of alpha-flupenthixol into the NAcc shell reduced responding for alcohol under both the FR1 (15 µg/side) and the PR schedule (3.75-15 µg/side) of reinforcement. Infusion of alpha-flupenthixol into the NAcc core (7.5-15 µg/side) also decreased responding for alcohol under both schedules. By contrast, alpha-flupenthixol infusion into the DLS did not affect FR1 responding, but reduced responding under the PR schedule (15 µg/side). The decreases in responding were related to earlier termination of responding during the session, whereas the onset and rate of responding remained largely unaffected. Together, these data suggest that dopamine in the NAcc shell is involved in the incentive motivation for alcohol, whereas DLS dopamine comes into play when obtaining alcohol requires high levels of effort. In contrast, NAcc core dopamine appears to play a more general role in alcohol reinforcement. In conclusion, dopaminergic neurotransmission acts in concert in subregions of the striatum to modulate different aspects of alcohol-directed behaviour.