The international scandal of defective asparaginase: A blight on children with cancer.

Acute lymphoblastic leukemia is the commonest form of cancer in children and adolescents worldwide, and asparaginase is an essential component of successful chemotherapy for this disease associated with long-term survival rates often exceeding 90% in high-income countries. Demonstrably defective preparations of asparaginase, distributed from China and India, increase the burden of morbidity and mortality, reducing attainable survival rates. This adverse outcome is enabled by inadequate regulation and oversight, especially in resource-poor settings in low- and middle-income countries where the great majority of children and adolescents with cancer live. The pediatric oncology community must rise to the challenge.

The UK's contribution to cancer control in low-income and middle-income countries.

Cancer mortality rates in low-income and middle-income countries (LMICs) are unacceptably high, requiring both collaborative global effort and in-country solutions. Experience has shown that working together in policy, clinical practice, education, training, and research leads to bidirectional benefit for LMICs and high-income countries. For over 60 years, the UK National Health Service has benefited from recruitment from LMICs, providing the UK with a rich diaspora of trained health-care professionals with links to LMICs. A grassroots drive to engage with partners in LMICs within the UK has grown from the National Health Service, UK academia, and other organisations. This drive has generated a model that rests on two structures: London Global Cancer Week and the UK Global Cancer Network, providing a high-value foundation for international discussion and collaboration. Starting with a historical perspective, this Series paper describes the UK landscape and offers a potential plan for the future UK's contribution to global cancer control. We also discuss the opportunities and challenges facing UK partnerships with LMICs in cancer control. The UK should harness the skills, insights, and political will from all partners to make real progress.

The role of twinning in sustainable care for children with cancer: A TIPPing point? SIOP PODC Working Group on Twinning, Collaboration, and Support.

With the World Health Organization (WHO) Global Initiative for Childhood Cancer, there is renewed interest in sustainable interventions to improve childhood cancer care in low-/middle-income countries (LMICs). Practitioners in LMICs have traditionally practiced "twinning," i.e., targeted international pediatric oncology partnerships (TIPPs) between one or more institutions in a high-income country (HIC) and an LMIC, to improve care for children with cancer in the latter. The International Society of Paediatric Oncology Committee for Paediatric Oncology in Developing Countries Working Group on Twinning, Collaboration, and Support reviewed guidelines from https://cancerpointe.com and the current literature, gathered input from practitioners in LMICs, and in this article discuss the role of TIPPs in the WHO initiative.

Developing institutions for cancer care in low-income and middle-income countries: from cancer units to comprehensive cancer centres.

Global cancer centres operate across different sizes, scales, and ecosystems. Understanding the essential aspects of the creation, organisation, accreditation, and activities within these settings is crucial for developing an affordable, equitable, and quality cancer care, research, and education system. Robust guidelines are scarce for cancer units, cancer centres, and comprehensive cancer centres in low-income and middle-income countries. However, some robust examples of the delivery of complex cancer care in centres in emerging economies are available. Although it is impossible to create an optimal system to fit the unique needs of all countries for the delivery of cancer care, we summarise what has been published about the development and management of cancer centres in low-income and middle-income countries so far and highlight the need for clinical and political leadership.

Comparing doctors' and nurses' accounts of how they provide emotional care for parents of children with acute lymphoblastic leukaemia.

OBJECTIVE: Despite the emphasis that communication skills training (CST) programmes place on attending to the emotional care of patients, evidence suggests that practitioners neglect this aspect of patient care. We describe and compare doctors' and nurses' accounts of managing the emotional care of parents of children with leukaemia, with the overall objective of examining how their accounts might inform training and policy. METHODS: Audio-recorded qualitative interviews with 30 doctors and nurses working in six UK paediatric oncology and haematology treatment centres were analysed interpretatively, drawing on the constant comparative method. RESULTS: Doctors' and nurses' descriptions of managing emotional care differed markedly. Doctors described reassuring parents through their ongoing clinical care of the child and by explaining the potentially curative nature of treatment. Doctors did not think they could reassure parents by eliciting and explicitly discussing parents' fears. In contrast, nurses relied on psychological skills and explicit discussion of parents' emotions to provide reassurance. Both doctors and nurses relied on each other to ensure that parents' emotional needs were met by the multidisciplinary team rather than by individual practitioners. CONCLUSION: Nurses' accounts of providing emotional care resembled the emphasis on explicit emotional talk in CST. However, doctors' accounts indicated that they provided emotional care in ways that diverged markedly from expectations in CST but that were more consistent with their biomedical and authoritative role in patient care. These findings may have implications for CST in future revisions of guidelines, but work is first needed to explore parents' perspectives on emotional care.

Young people describe their prediagnosis cancer experience.

OBJECTIVE: Young people often report a protracted journey to diagnosis and frequently report perceived delays. This study was undertaken to increase understanding of the self-reported prediagnosis experiences in young people with a non-haematological cancer, as close as possible to the time of diagnosis. METHODS: Narrative interviews were conducted with 24 young people aged 16-24, 2-4 months from the diagnosis of a solid tumour. Data were analysed to identify whether prediagnosis narratives could be classified according to shared characteristics (typologies) to identify broader contextual issues concerning cancer, and cancer risk perceptions, in this age group. Case notes were also accessed to contextualize and confirm accounts. RESULTS: The main themes, which included a group narrative concerning perspectives of delay, included the impact on an individual's everyday life by symptoms; the role that significant others in young peoples' lives played in the interpretation of symptom significance; the negotiation of entry into, and experiences of, generalist health care; entry into specialist care; and the threshold points that exemplified when events shifted and a diagnosis was eventually obtained. CONCLUSIONS: The narratives reveal complex, and multidimensional explanations for delay with individual and contextual factors contributing. Insights were gained into preventable diagnostic delay; including investigations having been instigated, but not followed up. Each narrative also offered significant insights into how cancer symptoms should be considered within the context of young peoples' lives. This would help prevent signs and symptoms in this age group failing to trigger suspicion and not being treated seriously.

The contrasting age-incidence patterns of bone tumours in teenagers and young adults: Implications for aetiology.

Bone tumours comprise 0.2% of cancers overall but 5.7% in 15-24 year olds. To explore the relationship with adolescence we have analysed age-incidence patterns of bone tumours in a large national dataset. Data on incident cases of bone tumours in 0-84 year olds in England, 1979-2003, were extracted from national cancer registration data. Incidence rates per million person-years by 5-year age-group, sex, morphology and primary site were calculated and adjusted to the world standard population. Nine thousand one hundred forty-six cases were identified giving an overall age-standardized rate of 7.19 per million person-years. The distribution by morphology was: osteosarcoma, 34.2%; chondrosarcoma, 27.2%; Ewing sarcoma, 19.3%; other, 19.4%. The distribution varied by age. Ewing sarcoma was most common in 0-9 year olds, osteosarcoma in 10-29 year olds and chondrosarcoma in 30-84 year olds. 29.2% of all tumours occurred in 0-24 year olds. Highest incidence of osteosarcoma and Ewing sarcoma in females was in 10-14 year olds. In males, peak incidence occurred at 15-19 years and exceeded that in females. Chondrosarcoma incidence steadily increased with age. The proportions of Ewing sarcomas occurring in respective bones were consistent with those of the adult skeleton by weight. In osteosarcoma tumours of long bones of lower limb were markedly over-represented in the adolescent peak, being six times more than at any other site. Variation in incidence patterns with age and site suggests pubertal bone growth to be a key factor in osteosarcoma while different biological pathways could be relevant for Ewing sarcoma.

Comparative incidence patterns and trends of gonadal and extragonadal germ cell tumors in England, 1979 to 2003.

BACKGROUND: It is believed that gonadal and extragonadal germ cell tumors (GCTs) arise from primordial germ cells and may have similar etiopathogenesis. Unlike testicular GCTs, there has been limited comprehensive population-based analysis of ovarian and extragonadal GCTs. METHODS: All malignant GCTs and all central nervous system (CNS) GCTs with benign and uncertain behavior that were registered in England in the age group 0 to 84 years from 1979 to 2003 were included in the current study. Incidence rates were calculated and adjusted to the world standard population. RESULTS: There were 33,364 GCTs (92.5% testes, 3.9% ovary, 3.2% extragonadal) in individuals aged 0 to 84 years. The CNS was the most common extragonadal site. An initial peak in incidence at ages 0 to 4 years of nongerminomas was observed at all sites except ovary. Second incidence peaks between ages 10 to 39 years that were more marked among males also were observed at all sites. The ages at these incidence peaks varied by site and were 10 to 14 years (CNS), 15 to 19 years (ovary), 25 to 29 years (other extragonadal sites), and 30 to 34 years (testes). A statistically significant increase in incidence over time was observed in germinomas (testes, CNS) and nongerminomas (testes, ovary). CONCLUSIONS: The age-incidence patterns observed suggested a common initiation of GCTs in embryonic/fetal life with variable rates of tumor progression as a result of subsequent events that may be site specific. The authors concluded that future genetic studies should consider GCTs from all sites to enable a better understanding of their etiology.

Faith and protection: the construction of hope by parents of children with leukemia and their oncologists.

BACKGROUND: Oncologists are criticized for fostering unrealistic hope in patients and families, but criticisms reflect a perspective that is oversimplified and "expert" guidance that is ambiguous or impractical. Our aim was to understand how pediatric oncologists manage parents' hope in practice and to evaluate how they address parents' needs. METHODS: Participants were 53 parents and 12 oncologists whom they consulted across six U.K. centers. We audio recorded consultations approximately 1-2, 6, and 12 months after diagnosis. Parents were interviewed after each consultation to elicit their perspectives on the consultation and clinical relationship. Transcripts of consultations and interviews were analyzed qualitatively. RESULTS: Parents needed hope in order to function effectively in the face of despair, and all wanted the oncologists to help them be hopeful. Most parents focused hope on the short term. They therefore needed oncologists to be authoritative in taking responsibility for the child's long-term survival while cushioning parents from information about longer-term uncertainties and being positive in providing information about short-term progress. A few parents who could not fully trust their oncologist were unable to hope. CONCLUSION: Oncologists' pivotal role in sustaining hope was one that parents gave them. Most parents' "faith" in the oncologist allowed them to set aside, rather than deny, their fears about survival while investing their hopes in short-term milestones. Oncologists' behavior generally matched parents' needs, contradicting common criticisms of oncologists. Nevertheless, oncologists need to identify and address the difficulty that some parents have in fully trusting the oncologist and, consequently, being hopeful.

Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia.

Chimeric fusion genes are highly prevalent in childhood acute lymphoblastic leukemia (ALL) and are mostly prenatal, early genetic events in the evolutionary trajectory of this cancer. ETV6-RUNX1-positive ALL also has multiple ( approximately 6 per case) copy number alterations (CNAs) as revealed by genome-wide single-nucleotide polymorphism arrays. Recurrent CNAs are probably "driver" events contributing critically to clonal diversification and selection, but at diagnosis, their developmental timing is "buried" in the leukemia's covert natural history. This conundrum can be resolved with twin pairs. We identified and compared CNAs in 5 pairs of monozygotic twins with concordant ETV6-RUNX1-positive ALL and 1 pair discordant for ETV6-RUNX1 positive ALL. We compared, within each pair, CNAs classified as potential "driver" or "passenger" mutations based upon recurrency and, where known, gene function. An average of 5.1 (range 3-11) CNAs (excluding immunoglobulin/T-cell receptor alterations) were identified per case. All "driver" CNAs (total of 32) were distinct within each of the 5 twin pairs with concordant ALL. "Driver" CNAs in another twin with ALL were all absent in the shared ETV6-RUNX1-positive preleukemic clone of her healthy co-twin. These data place all "driver" CNAs secondary to the prenatal gene fusion event and most probably postnatal in the sequential, molecular pathogenesis of ALL.

Subsequent publication rate of studies from India presented at the annual congresses of SIOP.

Subsequent publication as a complete manuscript is a desirable end-point for studies presented at scientific meetings. Between 2001 and 2005, 191 studies from India were presented at annual congresses of the International Society of Paediatric Oncology. Of these 24 (12.6%) were published with a median time to publication of 20 months. This subsequent publication rate is lower than previous reports of SPR for either paediatric or oncological meetings. A lower proportion of oral presentations and randomised clinical trials (RCTs) could partly explain our findings. Further research is needed to understand barriers to subsequent publication of presented data from India.

Cancer at ages 15-29 years: the contrasting incidence in India and England.

BACKGROUND: There has been a steady increase in published research from Europe and North America on the epidemiology of cancers in young people. There are limited data from the developing world. We contrast the incidence of cancer at ages 15-29 years in India and England. PROCEDURE: Malignant neoplasms in those aged 15-29 years registered during 2001-2003 in five urban population-based cancer registries (PBCRs) of India and in eight PBCRs in England were included. Site-based classification was used. Age-standardized incidence rates were expressed per 100,000 person years. RESULTS: In India, 4,864 (5.8%) of 84,450 cases and in England, 8,137 (1.2%) of 65,6752 cancer cases occurred in those aged 15-29 years. For this age group, the incidence rate for males and females in India were 12.91 and 14.19, and in England were 27.75 and 28.88, respectively. In males aged 15-29 years, the three most common cancers in India were leukemia, lymphoma, and central nervous system tumors and in England were cancers of male genital organs, lymphoma, and leukemia. Cancers of female genital organs, breast, and leukemia were most common in females in India and cancers of female genital organs, lymphoma, and melanoma in England. For cancers of mouth, stomach, and gall bladder, the incidence was higher in India. CONCLUSION: Incidence of cancer at ages 15-29 years in England is higher at most sites than in India. Variation in environmental exposures between the two countries might be an explanation. Under-ascertainment of cases and gender bias in seeking healthcare may also influence reported incidence rates in India.

Treatment non-adherence in teenage and young adult patients with cancer.

Adhering to treatment can be a significant issue for many patients diagnosed with chronic health conditions and this has been reported to be greater during the adolescent years. However, little is known about treatment adherence in teenage and young adult (TYA) patients with cancer. To increase awareness of the adherence challenges faced by these patients, we have reviewed the published work. The available evidence suggests that a substantial proportion of TYA patients with cancer do have difficulties, with reports that up to 63% of patients do not adhere to their treatment regimens. However, with inconsistent findings across studies, the true extent of non-adherence for these young patients is still unclear. Furthermore, it is apparent that there are many components of the cancer treatment regimen that have yet to be assessed in relation to patient adherence. Factors that have been shown to affect treatment adherence in TYA patients include patient emotional functioning (depression and self-esteem), patient health beliefs (perceived illness severity and vulnerability), and family environment (parental support and parent-child concordance). Strategies that foster greater patient adherence are also identified. These strategies are multifactorial, targeting not only the patient, but the health professional, family, and treatment regimen. This review highlights the lack of interventional studies addressing treatment adherence in TYA patients with cancer, with only one such intervention being identified: a video game intervention focusing on behavioural issues related to cancer treatment and care. Methodological issues in measuring adherence are addressed and suggestions for improving the design of future adherence studies highlighted, of which there is a great need.

Relationship between height at diagnosis and bone tumours in young people: a meta-analysis.

OBJECTIVE: Some evidence exists that patients with osteosarcoma and Ewing sarcoma are taller than the general population. However, previous studies are under-powered, lack comprehensive data and show inconsistencies. METHODS: Relevant studies linking osteosarcoma and Ewing sarcoma with height at diagnosis were identified in two major online databases, Medline (1950 to 2009) and Embase (1980 to 2009). Outcomes in individual studies were reported as standard deviation (SD) scores or percentages of study population with height at diagnosis above the median of the reference population. We performed separate random-effects meta-analyses for each outcome and tumour type. RESULTS: 14 studies examined the height of patients with osteosarcoma or Ewing sarcoma. Meta-analyses on SD scores found patients with osteosarcoma were 0.260 SD (95% CI: 0.088-0.432) taller than the reference population (five studies). A meta-analysis on percentages found 62% (95% CI: 57%-67%) of patients were estimated to have a height above the median (six studies). Patients with Ewing sarcoma were 0.096 SD (95% CI 0.004-0.188) taller (four studies). Only one study reported the percentage of Ewing sarcoma patients with height above the median. CONCLUSION: The average height of patients with osteosarcoma, but not Ewing sarcoma, was significantly above the average height of the reference population by 2-3 centimetres. The observed differences indicate the involvement of pubertal longitudinal bone growth in osteosarcoma development while different biological pathways could be relevant for Ewing sarcoma.

Assessing the impact of paediatric oncology publications using three citation databases.

Despite some reported limitations, Web of Science has been the standard source to assess the impact of individual articles, and consequently journals. By analysing the citations to articles published in the field of paediatric oncology, we demonstrate that Scopus and Google Scholar, the two new citation databases, retrieve more citations than Web of Science. The strength of Scopus lies in identifying non-English literature from Western and Eastern Europe, while Google Scholar is proficient at identifying English and non-English literature from Africa, Asia and Central and South America. These findings have implications for researchers, journals and health libraries.

Balancing high accrual and ethical recruitment in paediatric oncology: a qualitative study of the 'look and feel' of clinical trial discussions.

BACKGROUND: High accrual to clinical trials enables new treatment strategies to be tested rapidly, accurately and with generalisability. Ethical standards also must be high so that participation is voluntary and informed. However, this can be difficult to achieve in trials with complex designs and in those which are closely embedded in clinical practice. Optimal recruitment requires a balance of both ethical and accrual considerations. In the context of a trial of stratified treatments for children with acute lymphoblastic leukaemia (UKALL2003) we examined how recruitment looked to an observer and how it felt to the parents, to identify how doctors' communication could promote or inhibit optimal recruitment. METHODS: We audio-recorded, transcribed and analysed routine doctor-patient consultations (n = 20) and interviews between researchers and parents (n = 30 parents) across six UK treatment centres. Analysis was informed by the constant comparative method. For consultation transcripts, analysis focussed on how doctors presented the trial. We compared this with analysis of the interview transcripts which focussed on parents' perceptions and understanding of the trial. RESULTS: Parents and doctors discussed the trial in most consultations, even those that did not involve a decision about randomisation. Doctors used language allying them both with the trial and with the parent, indicating that they were both an 'investigator' and a 'clinician'. They presented the trial both as an empirical study with a scientific imperative and also as offering personalisation of treatment for the child. Parents appeared to understand that trial involvement was voluntary, that it was different from routine care and that they could withdraw from the trial at any time. Some were confused about the significance of the MRD test and the personalisation of treatment. CONCLUSIONS: Doctors communicated in ways that generally promoted optimal recruitment, indicating that trials can be embedded into clinical practice. However, parents were unclear about some details of the trial's rationale, suggesting that recruitment to trials with complicated designs, such as those involving stratified treatments, might need enhanced explanation.

Interventions other than anticoagulants and systemic antibiotics for prevention of central venous catheter-related infections in children with cancer.

BACKGROUND: Use of central venous catheters (CVC) in treatment of children with cancer is associated with infective complications. Current evidence-based guidelines to prevent catheter-related infections are mainly relevant to the adult population. They are not cancer (especially not childhood cancer) specific. Two existing Cochrane reviews have looked at prophylactic antibiotics and anticoagulants to prevent CVC-related infections. OBJECTIVES: The primary objective was to find which interventions, if any, were effective in preventing CVC-related infections in children with cancer. Further objectives were to examine the effectiveness of each intervention in the following subgroups: implanted versus external catheters, haematological versus non-haematological malignancies, and in those receiving haematopoietic stem cell transplants (HSCT) versus no HSCT. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2008, Issue 4), MEDLINE (January 1950 to January 2009), EMBASE (January 1980 to January 2009) and CINAHL(R) (January 1982 to March 2009). We also searched reference lists of relevant articles and proceedings of relevant international conferences (2004 to 2008). SELECTION CRITERIA: Randomised and quasi-randomised studies comparing any intervention (other than anticoagulants, systemic antibiotics and antibiotic lock techniques) versus no intervention, placebo or any other intervention to prevent CVC-related infections in children with cancer. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed trial quality and extracted data. Where necessary, we contacted study authors for further data and clarification of methods. MAIN RESULTS: Three trials involving two different interventions were included. Two trials involving 680 children compared flushing CVC with urokinase (with or without heparin) versus heparin alone. Neither of these trials reported on the primary outcome of catheter-related blood stream infection (CRBSI). There was a non-significantly decreased rate of catheter-associated infection (CAI) (Rate Ratio 0.72, 95% confidence interval 0.12 to 4.41) in the urokinase (with or without heparin) arm compared with the heparin arm.One trial involving 113 children compared frequency of catheter dressing change every 15 days versus every 4 days. It did not report on CRBSI or CAI. There were no premature catheter removals for infection in either of the trial arms. AUTHORS' CONCLUSIONS: Three RCTs for only two types of interventions to prevent CVC-related infections in children with cancer have been identified. Flushing CVC with urokinase (with or without heparin) compared to heparin alone possibly leads to decrease in CAI rates. Changing catheter dressings every 15 days versus every 4 days does not lead to more premature catheter removals due to infection although data were insufficient to assess if catheter-related infection rates were changed.