Dilemmas in the Management of an Infant with Neuroblastoma Metastasized to the Muscles.

The risk stratification of infants with metastatic neuroblastoma (NB) has evolved over time from stage 4/M or IVs/4S/MS/Ms according to various staging systems. Despite these developments for some genetic aberrations, the prognostic value and the impact of soft tissue metastases in infants are not fully understood, nor well described in the different classification systems, hampering the definitions to uniformly treat patients and predict prognosis. A literature review on staging of infants with M/MS disease was performed at the occasion of the diagnosis of NB in an 8-month-old boy who presented with atypical metastatic sites in soft tissue and an aberrant tumor biology. The definitions of stage 4/4S/4s/M/MS/Ms were evaluated and compared to enable tumor risk stratification and inform management. International NB groups use different criteria for defining stage of infants with metastasized NB, resulting in differences in management. Limited literature is available on soft tissue metastases, especially muscular metastases, and is poorly incorporated into management guidelines mainly due to the lack of data. The uncertain prognosis of rare genetic aberrancies may add to the difficulties in treatment decisions. In some rare cases of NB in infants, the international treatment classification is not sufficient for staging and treatment decisions. Based on tumor progression, biology of unknown significance and a lack of evidence to classify a child under 12 months with NB and multiple muscular metastases, the patient was treated as stage 4/M and intermediate-risk protocols with a favorable outcome.

Erythrocytapheresis in Children and Young Adults with Hemoglobinopathies and Iron Overload in Need of Iron Chelation Therapy.

Limited data regarding erythrocytapheresis in children, adolescents, and young adults have been published. The aim of this study was to evaluate erythrocytapheresis, either as a standalone therapy or in combination with iron chelation therapy, in children and young adults with hemoglobinopathies in whom current iron chelation therapy is not sufficient in decreasing the iron overload during management. We retrospectively analysed erythrocytapheresis in 19 patients with hemoglobinopathies in need of iron chelation therapy diagnosed with sickle cell disease (SCD) or ß-thalassemia major. Patients were divided into (1) a case cohort who received erythrocytapheresis alone or in combination with iron chelation therapy and (2) a control cohort who received oral iron chelation therapy alone. Serum ferritin and haemoglobin levels were compared at five different time points over a one-year period. In the erythrocytapheresis cohort, there was a significant decrease in serum ferritin (p < 0.001). In the iron chelation therapy alone cohort, there was no significant decrease in serum ferritin over time (p = 0.156). Comparing the evolution of median serum ferritin between therapy with erythrocytapheresis and iron chelation therapy showed a statistically significant difference (p = 0.008). Patients with ß-thalassemia major receiving erythrocytapheresis showed a greater reduction in serum ferritin compared to patients without (p = 0.036). A difference could not be shown between the erythrocytapheresis and iron chelation single therapies (p = 0.100). This study showed an overall significant reduction in serum ferritin in patients with hemoglobinopathies treated with erythrocytapheresis in addition to iron chelation. A clinical, although not statistical, trend of higher haemoglobin levels was maintained. Erythrocytapheresis in paediatric patients with ß-thalassemia major was as effective in decreasing ferritin levels as in previously reported studies with SCD. Erythrocytapheresis is a promising therapy for treating and preventing transfusion-related iron overload.

Socioeconomic status significantly impacts childhood cancer survival in South Africa.

BACKGROUND AND AIMS: Significantly discrepant survival rates have been documented in single disease childhood cancer cohorts in South Africa; those from higher socioeconomic groups were shown to have a significantly lower risk of death than those from less affluent households. This study aimed to determine the impact of socioeconomic status (SES) on childhood cancer survival using pooled South African data. METHODS: Five databases spanning January 2000 to December 2021 were interrogated. SES status was assigned based on a public sector annual household income classification. H0 households (formally unemployed) received free healthcare. H1, H2 and H3 (annual income > United States Dollar [USD] 19,000) households paid for healthcare relative to their income. The Spearman test assessed correlations between SES and disease stage in patients with solid tumours. Hazard ratios were determined using Cox regression modelling. The Kaplan-Meier procedure estimated overall survival (OS). RESULTS: A total of 1598 children were eligible for analysis; 1269 had a solid tumour with a negative correlation between SES and stage (Spearman rho = -.178; p < .001). Patients with solid tumours and lower SES showed proportionately higher numbers of stage III and IV disease (p < .01). This proportion decreased with higher SES categories. In the multivariate analyses adjusted for sex, age, tumour type and stage, higher SES was associated with lower mortality risk (p < .001), indicating that the impact of SES on survival was in excess of any effect that could be explained by lower stage disease alone. There was a strong positive correlation between race and SES (Fisher's exact tests, p < .001) across all groups and all SES strata. Five-year OS was 85.3% in children from H3 households versus 46.3% in children from H0 households (p < .001). CONCLUSION: SES significantly impacts childhood cancer survival for children with solid tumours in South Africa. SES is a robust surrogate for race in South Africa as a prognostic metric of disease outcome in childhood cancer. Advocacy to increase social support for impoverished patients is essential to achieve equitable improvements in outcomes treated with standardised national treatment guidelines.

Evaluating the baseline survival outcomes of the "six Global Initiative for Childhood Cancer index cancers" in Africa.

Limited survival data for the six Global Initiative for Childhood Cancer (GICC) priority cancers are available in Africa. Management of pediatric malignancies in Africa is challenging due to lack of resources, setting-specific comorbidities, high rates of late presentation and treatment abandonment. Reporting of outcome data is problematic due to the lack of registries. With the aim of evaluating the feasibility of baseline outcomes for the six index cancers, we present a descriptive analysis of respective survival rates in Africa. The survival rates were between 18% (lower middle-income countries) to 82.3% (upper middle-income countries) for acute lymphoblastic leukemia, between 26.9% (low-income countries) to 77.9% (upper middle-income countries) for nephroblastoma, between 23% (low-income countries) to 100% (upper middle-income countries), for retinoblastoma, 45% (low-income countries) to 95% (upper middle-income countries) for Hodgkin lymphoma and 28% (low-income countries) to 76% (upper middle-income countries) for Burkitt lymphoma. Solutions to improve survival rates and reported outcomes include establishing and funding sustainable registries, training and to actively include all countries in consortia from different African regions.HighlightsContinental differences in childhood cancer management such lack of resources, setting-specific comorbidities, high rates of late presentation and treatment abandonment, present challenges to the achievement of Global Initiative for Childhood Cancer goals.The available data registries do not adequately inform on the true incidences and outcomes of childhood cancers in Africa.The pathophysiology of some childhood cancers in Africa are associated with high-risk prognostic factors.Outcomes can be improved by greater regional collaboration to manage childhood cancer based on local resources and tumor characteristics.Some individual countries have reached the Global Initiative for Childhood Cancer goals for single cancers and it should be possible for more African countries to follow suit.

A retrospective evaluation of the presentation, prognostic factors and outcomes of neuroblastoma in Ugandan children.

Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. The complete burden and outcomes in Uganda are unknown. The study was a multicenter retrospective chart review of children aged between 0 to 15 years diagnosed with NB from 2010 to 2020. Demographic, clinical and tumor-related characteristics were extracted for analysis. Kaplan-Meier survival curves and Cox regression models were used to determine the one-year overall survival (OS) and identify prognostic factors. Seventy-five patients were evaluated, with a median age at diagnosis of 48 months (IQR 26-108 months). Fever (74.7%), weight loss (74.7%), high blood pressure (70.3%) and abdominal swelling/mass (65.3%) were the most common features at diagnosis. Suprarenal tumors (52%) and stage 4 disease (70.7%) were also common. The one-year OS was 60.0% (95%CI 56.8%; 64.3%) with a median survival time of 12.6 months (95% CI: 8.1; 20.8). The one-year OS for non-metastatic and metastatic disease was 67.3% and 42.6% (p = 0.11) respectively. Leukocytosis (p < 0.001) at diagnosis was of prognostic significance while clinical remission after induction chemotherapy (p < 0.001) provided survival advantages. Children who received maintenance chemotherapy had a longer median survival time of 38.5 months (range 10.8-69.5). Age (p = 0.001), lung metastasis (p < 0.001), and leukocytosis (p < 0.001) remained significant on multivariate analysis. In this Ugandan study, leukocytosis was a clinical predictor of prognosis, metastatic disease had management challenges and maintenance chemotherapy prolonged the survival time but not OS.

Ugandan children diagnosed with neuroblastoma present with advanced disease.Surgery and radiotherapy are under-utilized in the management of neuroblastoma, but have prognostic value in neuroblastoma outcomes.Children under the age of 12 months are under-diagnosed in Uganda, but those that do present for treatment fare poorer than older age groups.The overall survival is poor but the survival time can be increased with maintenance chemotherapy.

The pre-surgical factors that determine the decision to proceed to resection in children diagnosed with high-risk neuroblastoma in a resource limited setting.

Surgical control has prognostic value in neuroblastoma (NB). Advanced NB is common at diagnosis in South Africa. We investigated the pre-surgery factors that influenced decisions to perform surgical resections. We included 204 patients with high-risk NB from a national retrospective study, who completed induction chemotherapy between 2000 and 2016.The median age was 32.4 months (IQR 15.1 - 53.5 months). Primary tumor resection was achieved in 76.9% of patients between 0-18 months of age, 51.8% between 18-60 months and 51.7% older than 60 months (p < 0.001). Only 43.2% of patients with distant metastatic disease had surgery done (p < 0.001). LDH was >750 U/L in 46.8% and ferritin >120 g/dL in 53.1% of those who had surgery (p = 0.005). The majority (80.4%), who had achieved post-induction metastatic complete remission (mCR), were operated, while 28.7% without mCR had surgery (p < 0.001). The long-term overall survival in patients with mCR and primary tumor resection was 36.5% compared to those with mCR without primary tumor resection (25.4%) and without mCR (≤3.0%)(p < 0.001). Age (p < 0.001), stage (p < 0.001), mCR (p < 0.001) and treatment setting (p < 0.001) were of prognostic significance. The tumor site and MYCN-amplification did not significantly predict resection rates. Post-induction mCR and stage were associated with surgical resection and five-year OS (p < 0.001) on multivariate analysis.Patients with high-risk NB who achieved mCR and had primary tumor resections are curable in limited resourced settings. Stage and post-induction mCR were significant variables that led to surgery. These variables should be included as indications in the management of metastatic NB in resource limited settings.

High-risk neuroblastoma that achieved post-induction chemotherapy metastatic remission and have undergone resection, is curable, even in limited resource settings.Achieving metastatic complete remission was the only factor that significantly predicated if surgery was done.The age at diagnosis, stage and hospitals with expertise in neuroblastoma surgery were of prognostic significance in South Africa.If a patient with high-risk neuroblastoma achieves metastatic complete remission in a resource limited setting, it should be an indication for resection of the primary tumor.

Current status of African pediatric oncology education efforts aligned with the Global Initiative for Childhood Cancer.

Education of the pediatric oncology workforce is an important pillar of the World Health Organization CureAll technical package. This is not only limited to healthcare workers, but all stakeholders in the childhood cancer management process. It includes governmental structures, academic institutions, parents and communities. This review evaluated the current educational and advocacy training resources available to the childhood cancer community, the contribution of SIOP Africa in the continental educational needs and evaluated future needs to improve the management of pediatric malignancies in reaching the Global Initiative for Childhood Cancer goals. Childhood cancer, unlike adult cancers, has not been prioritized in African cancer control plans nor the teaching and advocacy surrounding pediatric oncology. The availability of formal training programs for pediatric oncologists, pediatric surgeons and radiotherapy specialists are limited to particular countries. In pharmacy and nutritional services, the exposure to pediatric oncology is limited while training in advocacy doesn't exist. Many nonacademic stakeholders are creating the opportunities in Africa to gain experience and train in these various fields, but formal training programs should still be advocated for. LEARNING POINTSThe African continent has various resources to increase the capacity of childhood cancer care stakeholders to increase their knowledge.African pediatric oncology teams rely on a multitude of international sources for training while developing their own.There is a greater need for formal, standardized cancer training especially for pediatric surgeons, radio-oncologists and nurses.Greater inclusion of pathologists, pediatric oncology pharmacists and dieticians into multidisciplinary care and childhood cancer training should be facilitated and resourced.Successful advocacy programs and tool kits exist in parts of Africa, but the training in advocacy is still underdeveloped.

The clinicopathological profile and value of multidisciplinary management of pediatric brain tumors in a low-income setting.

Brain tumors are the most common solid tumors in children and a leading cause of cancer-related mortality in children worldwide. Data on the epidemiology and management of pediatric brain tumors in Uganda are limited. We aimed to assess the clinicopathological profile and management of pediatric brain tumors at the national oncology center in Uganda since the inception of weekly multidisciplinary meetings. Records of children younger than19 years diagnosed with primary brain tumors at Uganda Cancer Institute between 2017 and 2021 were retrospectively reviewed. Patient and tumor characteristics were collected with multidisciplinary team management treatment plans for analysis. There were 35 patients evaluated, most of whom were males (57.1%). Craniopharyngioma (n = 9, 25.7%) was the most common brain tumor, followed by astrocytoma (n = 5, 14.2%) and medulloblastoma (n = 4, 11.4%). Management included surgical resection in 28.5% of patients, chemotherapy (28.6%), radiotherapy (17.1%) and palliative care (20.0%). Over the last five years, there were increasing trends in the number of cases discussed in the multidisciplinary team and the number for whom the multidisciplinary management decisions were implemented. The majority (n = 18, 51.4%) of the children with brain tumors were alive and active in care, 34.2% abandoned treatment/lost to follow-up, and 8.6% died. The relative distribution of pediatric brain tumors types in Uganda Cancer Institute differs slightly from international reports, and there has been a notable increase in the number of cases over the years. Implementing multidisciplinary management decisions benefited patients and decreased abandonment and patient loss to follow-up.

Multidisciplinary team management for pediatric neuro-oncology is a sustainable resource for improved patient care and outcome in resource-limited settings.Pediatric neuro-oncology patients have lower rates of treatment abandonment and loss to follow-up when managed according to multidisciplinary team meetings.

Conference report on the 14th International Society of Paediatric Oncology African Continental Meeting, 16-18 March 2022, Kampala, Uganda.

Together with the Africa Continental Branch of the International Society of Paediatric Oncology (SIOP Africa), the Uganda Cancer Institute, a tertiary governmental institution for specialised cancer care services, research and training, hosted the 14th continental meeting of SIOP Africa from the 16-18 March 2022. Under the conference theme, 'Innovate for Africa', the hybrid conference brought together close to 400 international delegates to discuss innovations and experiences, as well as share the latest research in the field of paediatric oncology. The World Health Organisation 2030 Global Initiative for Childhood Cancer provided the main starting point for the conference with a comprehensive pre-conference workshop programme, from multiple stakeholders and organisations and the themes for the plenaries towards improving survival to the main breakout sessions. Delegates discussed various ways of improving outcomes in Africa, despite the challenges faced individually and collectively ranging from education, management systems and treatment guidelines to future governmental and NGO involvement in African cancer care. The main achievements of the conference were various commitments for collaboration, investing in junior investigators, development of registries and systems for improved childhood care on the African continent, while working towards greater access to advanced management options such as targeted therapies and bone marrow transplant services.

If prophylactic HPV vaccination is considered in a woman with CIN2+, what is the value and should it be given before or after the surgical treatment?

Since the introduction of human papilloma virus (HPV) vaccination, the number of precancerous lesions has decreased in countries with a high HPV vaccination coverage. Currently women who present with a precancerous cervical lesions (CIN2 + ), are often not vaccinated or not vaccinated with the latest vaccine. Although resection of the precancerous lesion is the standard approach, the guidelines regarding vaccination are not clear. Vaccination will be valuable in reducing the risk of recurrence. Therefore, it is beneficial to understand the importance of vaccination or revaccination with the nonavalent vaccine in these cases. Furthermore, the timing of vaccination, either before or after surgery, should be determined. To answer these questions, twelve studies regarding vaccination and conization were reviewed. The inconsistency of study designs and inclusion criteria between the different studies introduced a considerable risk of bias. Nevertheless, the analysis showed that 43 women needed to be vaccinated and treated for CIN2 + lesions to prevent a recurrence. The ideal timing could not be established, but theoretically vaccination before the start of treatment was most logic. Although the data is not level 1 evidence, these recommendations should be used during counseling in the clinical setting until results of ongoing randomized controlled trials become available.

Malignant extracranial germ cell tumours: A first national report by the South African Children's Cancer Study Group.

OBJECTIVE: To determine the overall survival (OS) and prognostic factors influencing outcomes in children and adolescents with malignant extracranial germ cell tumours (MEGCTs) in preparation for the development of a harmonised national treatment protocol. METHODS: A retrospective folder review was undertaken at nine South African paediatric oncology units to document patient profiles, tumour and treatment-related data and outcomes for all children with biopsy-proven MEGCTs from birth up to and including 16 years of age. RESULTS: Between 1 January 2000 and 31 December 2015, 218 patients were diagnosed with MEGCTs. Female sex (hazard ratio [HR] 0.284, p = .037) and higher socio-economic status (SES) (HR 0.071, p = .039) were associated with a significantly lower risk of death. Advanced clinical stage at diagnosis significantly affected 5-year OS: stage I: 96%; stage II: 94.3%; stage III: 75.5% (p = .017) and stage IV (60.1%; p < .001). There was a significant association between earlier stage at presentation and higher SES (p = .03). Patients with a serum alpha-fetoprotein (AFP) level of more than 33,000 ng/ml at diagnosis had significantly poorer outcomes (p = .002). The use of chemotherapy significantly improved survival, irrespective of the regimen used (p < .001). CONCLUSIONS: The cohort demonstrated a 5-year OS of 80.3% with an event-free survival (EFS) of 75.3%. Stage, the use of chemotherapy and an elevated serum AFP level of more than 33,000 ng/ml were independently predictive of outcome. The relationship between SES and outcome is important as the implementation of the new national protocol hopes to standardise care across the socio-economic divide.

The scope of childhood cancer in South Africa: A response to 'Childhood cancers in a section of the South African private health sector - Analysis of medicines claims data'.

Childhood cancer is an under resourced medical field that is emerging as a great healthcare concern in low- and middle-income countries such as South Africa. Therefore, reporting data in this field that may inform policymakers should be representative of the subject matter. This article aims to discuss why medicines claims as an indicator for incidence, as per an article published in 2020, is not representative of childhood malignancies in the South African setting. Literature to support the commentary were sourced using Pubmed, Google scholar, and data presented by members of the South African Children's Cancer Study Group (SACCSG). Private medical aid coverage in South Africa between 2002 and 2018 varied between 15.5% and 18.2%. Of these, 9.5% were children under 18 years and 3.5% were under the age of six. Only 13.5% of children were treated in private paediatric oncology units during 2015. The limitations in the study were the variable medical aid coverage, the disproportionate age representation, and lack of reliable indicators for measurement and calculation of incidence. Utilising one medicines claims data base to evaluate the incidence of childhood cancer in South Africa is not representative and cannot inform policy. CONTRIBUTION: This article highlights the importance of accurate registration of childhood cancer diagnoses, especially when data and conclusions based on these results inform policy. The study highlights the limitations of extrapolating general conclusions based on data representing only a small sector of the childhood cancer landscape in South Africa.

Thrombocytopenia in severe iron deficiency anemia in children.

AIM: Iron deficiency anemia (IDA) is common in the pediatric population and often accompanied by mild thrombocytosis, but rarely profound thrombocytopenia is seen. We describe the data of children with IDA and thrombocytopenia in two centers and discuss the published data in the literature. METHODS: In this retrospective case series, the medical records of patients under the age of 19 years old diagnosed with IDA in two tertiary medical centers over the last 10 years, were reviewed. The data were collected and compared to the data published in the medical literature. RESULTS: All the patients presented with severe IDA and thrombocytopenia improved with iron treatment. Although none of the patients had signs of major bleeding, the thrombocytopenia could mostly be classified as severe (platelet count <50×10E9/L). Due to the severity of the anemia, in about half of the cases, a red blood cell transfusion was given. The peak of the platelet count was seen in the first month after the start of iron treatment. In eight cases of children with IDA, the thrombocytopenia appeared after the supplementation of iron was started. CONCLUSION: Clinically stable children with severe IDA and thrombocytopenia, where other causes are very unlikely, warrant an empiric monotherapy with iron to prevent unnecessary investigations and treatments.

The Challenges of Crizotinib Treatment in a Child With Anaplastic Large Cell Lymphoma.

Survival in cases involving childhood malignancy is reaching nearly 80% in high-income countries, yet cancer remains one of the leading disease-related causes of death in children. In adult oncology the role of targeted therapies is established, but information regarding the use of these therapies in children is limited, largely because targeted therapies were developed in the context of adult pathologies. The few pediatric reports regarding crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, seem promising. This case of an 8-year-old male with an ALK-positive anaplastic large cell lymphoma highlights the challenges of treating children with crizotinib. Our experience with crizotinib was more challenging than described in the limited pediatric reports. Not only was the tumor response poorer than described in the reports, but a substantial amount of side-effects and practical difficulties, such as the method of administration and dosing, made management challenging. Many challenges for the use of targeted therapy in pediatric care currently persist. The limited research in pediatric populations leaves uncertainty regarding efficacy and short- and long-term side effects as well as practical difficulties. Despite a clear underlying biological rationale for certain targeted therapies, their contribution toward improving the outcome of childhood cancer remains largely unclear.

Reporting Incidences of Neuroblastoma in Various Resource Settings.

PURPOSE: The incidences of neuroblastoma (NB) differ significantly between various resource settings because of varying quality of cancer registries and underdiagnoses. This study aimed to evaluate current regional variations as reported by international cancer registries and the theoretical and reported differences in international NB incidences and to evaluate South Africa (SA) as a case for variable reporting. METHODS: A comprehensive literature review on registries reporting on NB was performed to construct incidence tables. The SEER Program incidence of 10.5/million children was used to calculate the expected number of NB cases for each country. Registry data of NB cases between 2000 and 2016 were requested from The South African National Cancer registry (SA-NCR) and the South African Children's Tumour Registry (SACTR) for comparison and to perform a probabilistic linkage study. RESULTS: Internationally, incidences varied between -97.1% and +80% compared with the SEER program. SA under-reported NB cases by an estimated 74.2%. Between 2000 and 2016, the SA-NCR reported between 23 and 51 cases/year, whereas the SACTR reported between 18 and 57 cases/year for the same period. The incidence reported by the SA-NCR varied between 1.5 and 2.8/million children under 15-year per year, whereas the SACTR reported 1.74-2.6 cases/million children. Both registries reported incidences less than high-income country. A probabilistic record linkage of the two registries resulted in a combined incidence of 2.9 cases/million children. CONCLUSION: As with most low- and middle-income countries, SA has either a lower incidence or underdiagnoses of NB cases. The reasons for under-reporting are not clear, but can be due to undiagnosed NB cases with spontaneous regression, missed possible cases because of lack of autopsies, and diagnosed cases not recorded in registries.