Incidence of childhood brain tumour/leukaemia[edit source]
Childhood brain tumour and leukaemia are the leading forms of cancer in children in Australia and developed countries worldwide. Leukaemia is frequently reported as the most common cancer in children, representing approximately one-third of all diagnosed cancers (see Figure 3). This is closely followed by brain tumours, the most common of all solid tumours in children. Brain tumours are commonly reported to represent one- quarter of all cancers in children in Australia. In Australia, approximately 240 children are diagnosed with leukaemia every year, and 192 with brain tumour. Forty-five percent of new cases of childhood brain tumour are in young children aged 0–4 years. In the United States (US), brain and other central nervous system (CNS) cancers are more common than leukaemia in children in the 0–14 year age group. Presentation, histology, and diagnosis of a brain tumour or leukaemia in childhood provides important insight into the progression, incidence, location, accompanying symptoms and complications, malignancy, and the treatments required to halt, remove, or cure it. The most common brain tumour type in children is widely reported to be the astrocytoma with an incidence rate of 30–50%. The five-year survival rate for astrocytomas is reported to be 84%. Most prevalent is the juvenile pilocytic astrocytoma, which is a solid tumour currently with a ten-year survival rate of 96%. This brain tumour type commonly arises in the posterior fossa region in the brain, which includes the cerebellum, brain stem, and fourth ventricle. Sixty percent of all childhood brain tumours are located in the posterior fossa. Males are more likely to develop an astrocytoma compared to females. The next most frequently occurring brain tumour types in children are the medulloblastoma and the ependymoma; both malignant tumours with an incidence of 15–20% and 5–15% respectively.
 Five-year survival rates for medulloblastomas have been reported at 69%, and 72% for ependymomas. A slight male predominance is reported for both malignant types. Other common brain tumour types include craniopharyngiomas (4–7%), followed by supratentorial primitive neuroectodermal tumours (PNETs), visual pathway gliomas, choroid plexus tumours, pineal area tumours, and brainstem tumours.
Back to top
The most common leukaemia type in children is acute lymphoblastic leukaemia (ALL), accounting for more than 78% of diagnoses, followed by acute myeloid leukaemia (AML) at 16%. Children diagnosed with ALL have a higher five-year survival rate of 93%, with 76% for AML. Survival rates are similar across both genders.
The occurrence of childhood brain tumour or leukaemia (CBTL) in children shows wide diversity. For example, tissue origin for brain tumours, location within the central nervous system (CNS), and natural history in terms of growth rate and tumour dissemination. Resulting effects of CBTL are also greatly influenced by the age of the child at presentation. In particular, children aged less than 3 years of age at the time of CNS cancer treatment are considered to be at greatest risk for late effects due to the immature stage of their brain development. Inherently, a great challenge exists in the management of CBTL in regard to the developing brain, in addition to a need to respect the long-term function of the CNS.
Time to diagnosis rates are also one of the difficulties associated with paediatric diagnoses. This includes issues with early detection and accurate acknowledgement of early generalised, non-specific symptoms and insidious onset. Increased detection rates and more widely adopted and routinely administered diagnostic imaging practices have contributed to increases in incidence rates, particularly those seen in Australia and other developed countries worldwide.
However, continual improvements in imaging, neurosurgical techniques, radiobiographical knowledge of CNS radiation tolerance, and advances in chemotherapy and implementation of CNS prophylaxis, have resulted in improved treatment strategies and survival rates for brain tumours and ALL. 
Additionally, late sequelae that can occur as a result of treatment for CBTL is now routinely recognised, with effects on cognitive, neuroendocrine, and neuropsychological systems being evaluated critically and minimised where possible.
Back to top
Impact of childhood brain tumour/leukaemia on communication and swallowing[edit source]
While cancer treatment is essential for survival, the developing brain is extremely fragile and susceptible to the effects of treatment required to treat brain cancer and leukaemia. In fact, many effects resulting from CNS-targeted treatment are not realised until many years later, with persistent impact on subsequent development and communication skills in particular, due to late-occurring structural and functional changes in the brain. These changes are progressive and often irreversible and can appear any time up to 10–20 years post-treatment, interrupting normal development in children who face the largest proportion of their lives post-survival. Even though modern treatment protocols have changed over the decades to reduce negative effects from CNS targeted treatments, such as phasing out the use of cranial radiotherapy for ALL and adopting CNS-targeted chemotherapy, not all negative treatment effects have been avoided.
Children diagnosed with CBTL are at risk of a range of communication difficulties, from difficulties with producing clear speech, to understanding instructions, using vocabulary, producing sentences and grammar, and reading and writing.
 Children who are treated surgically for a brain tumour in the cerebellum are also at-risk of developing post-operative cerebellar mutism syndrome (pCMS), which involves a phase of mutism, or a total loss of speech, followed by speech and language difficulties.
The impact of these communication difficulties on a child/adolescent’s ability to participate in everyday life can be vast. They may find it harder to learn to talk as toddlers, tell stories, solve problems, make friends, understand jokes, succeed at school, get their first job or date. Survivors remain highly at-risk for developing communication difficulties well after cancer treatment is completed. Skills that are yet to develop are most vulnerable, with these children failing to develop skills at the expected rate over time after CNS cancer treatment. However, early intervention can minimise or prevent communication and swallowing difficulties if identified early.
Children diagnosed with CBTL also commonly experience swallowing difficulties. These difficulties may look like: trouble with chewing and biting, difficulty clearing food from the mouth effectively, difficulty with different food and fluid consistencies, fatiguing during eating, uncoordinated swallowing, or not coughing to bring up food. Swallowing difficulties frequently occur during oncology treatment, however, they may also exist into the longer-term. Swallowing difficulties can have life-threatening impacts related to choking and chest infections. Poor management of swallowing can lead to malnutrition and compromise development. Swallowing difficulties also have significant participation impacts for these children/adolescents such as the ability to engage in family mealtimes and eat out with friends.
While this guideline focuses on management in children, the impact of communication and swallowing difficulties on quality of life beyond childhood, adolescence, and into adulthood is also acknowledged for this population if they are not managed. Adult survivors of cancer may experience barriers to educational achievement as well as an impact to mental health, vocational independence and earning potential. The long-term burden of CBTL can weigh on families, communities, and the health system, including costs that are associated with primary and ongoing healthcare services.
Back to top
Evidence that informed the guideline[edit source]
The two main recommendations presented in this guideline are evidence-based. They have been informed by three sources of evidence as depicted in Figure 4:
- Systematic review of the literature: GRADE Certainty of Evidence ratings and narrative synthesis methods were employed
- Input from a Steering Committee comprised of research/ clinical experts and a consumer via the GRADE Evidence to Decision (EtD) Framework
- Input of a Health Professional and Consumer Group via a survey
Figure 4 Sources of evidence that were used to inform recommendations in this guideline
GRADE = Grading of Recommendations, Assessment, Development and Evaluation; EtD = Evidence to Decision
Back to top
- Australian Institute of Health and Welfare. Cancer in Australia 2019. Canberra, ACT: AIHW; 2019. Report No.: Cancer series no. 119. Cat. no. CAN 123. Available from: https://www.aihw.gov.au/reports/cancer/cancer-in-australia-2019/summary.
- Australian Institute of Health and Welfare. Australia’s children. Canberra, ACT: AIHW; 2020. Report No.: Cat. no. CWS 69.. Available from: https://www.aihw.gov.au/reports/children-youth/australias-children/contents/executive-summary.
- Ostrom QT, Gittleman H, Xu J, Kromer C, Wolinsky Y, Kruchko C, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009-2013. Neuro Oncol 2016 Oct 1;18(suppl_5):v1-v75 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28475809.
- Youlden DR, Baade PD, Green AC, Valery PC, Moore AS, Aitken JF. The incidence of childhood cancer in Australia, 1983-2015, and projections to 2035. Med J Aust 2020 Feb;212(3):113-120 Available from: http://www.ncbi.nlm.nih.gov/pubmed/31876953.
- Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 2012 Jul;62(4):220-41 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22700443.
- Youlden DR, Aitken JF. Childhood cancer in Australia, 1983-2015.; 2019 [cited 2020 Jun 6] Available from: https://cancerqld.blob.core.windows.net/content/ docs/Childhood-Cancer-in-Australia-1983-2015.pdf.
- Australian Institute of Health and Welfare. Cancer Data in Australia. Canberra, ACT: AIHW; 2020. Report No.: Cat No.: CAN 122.. Available from: https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/summary.
- Australian Institute of Health and Welfare. Brain and other central nervous system cancers. Canberra, ACT: AIHW; 2017. Report No.: Cat. no. CAN 106.. Available from: https://www.aihw.gov.au/reports/cancer/brain-other-central-nervous-system-cancers/contents/table-of-contents.
- Youlden DR, Baade PD, Ward L, et al. Childhood cancer survival in Australia, 1995-2004. Brisbane, Queensland: Viertel Centre for Research in Cancer Control, Cancer Council Queensland and the Australian Paediatric Cancer Registry; 2010 [cited 2020 Jun 6] Available from: https://cancerqld.org.au/wp-content/uploads/2015/11/childhood_cancer_survival_in_australia_1995-2004.pdf.
- Lanzkowsky P. Central nervous system malignancies. In: Lanzkowsky P, ed. Manual of Pediatric Hematology and Oncology London, UK: Academic Press; 2011. p. 647-670.
- Banerjee A, Nicolaides T. Low-grade gliomas. In: Gupta N, Banerjee A, Haas-Kogan D, eds. Pediatric CNS Tumors Berlin, Heidelberg: Springer; 2017. p. 1-35.
- Docking K, Paquier P, Morgan A. Childhood brain tumour. In: Cummings L, ed. Research in Clinical Pragmatics. Vol Perspectives in Pragmatics, Philosophy & Psychology. Cham, Switzerland: Springer-Verlag; 2017. p. 131-164.
- Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol 2012 Nov;14 Suppl 5:v1-49 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23095881.
- Fleming AJ, Chi SN. Brain tumors in children. Curr Probl Pediatr Adolesc Health Care 2012 Apr;42(4):80-103 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22433905.
- Imbach P. Brain tumors. In: Imbach P, Kühne T, Arceci RJ, eds. Pediatric Oncology: A Comprehensive Guide. Switzerland: Springer; 2014. p. 95-118.
- Keene DL, Johnston DL. Epidemiology of central nervous system tumors. In: Scheinemann K, Bouffet E, eds. Pediatric Neuro-Oncology. New York, NY: Springer; 2015. p. 9-12.
- Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol 2013 Nov;15 Suppl 2:ii1-56 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24137015.
- Diamandis P, Alkhotani A, Chan JA, Hawkins CE. Histopathological features of common pediatric brain tumors. In: Scheinemann K, Bouffet E, eds. Pediatric Neuro-Oncology. New York, NY: Springer; 2015. p. 41-58.
- Kline C, Forester C, Banerjee A. Ependymoma. In: Gupta N, Banerjee A, Haas-Kogan D, eds. Pediatric CNS Tumors Berlin, Heidelberg: Springer; 2017. p. 69-92.
- Smoll NR. Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs). Cancer 2012 Mar 1;118(5):1313-22 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21837678.
- Chang E, Goldsby R, Mueller S, Banerjee A. Late effects of treatment and palliative care. In: Gupta N, Banerjee A, Haas-Kogan D, eds. Pediatric CNS Tumors Berlin, Heidelberg: Springer; 2017. p. 365-387.
- Amid A, Keene DL, Johnston DL. Presentation of central nervous system tumors. In: Scheinemann K, Bouffet E, eds. Pediatric Neuro-oncology New York, NY: Springer; 2015. p. 3-8.
- Butler RW, Haser JK. Neurocognitive effects of treatment for childhood cancer. Ment Retard Dev Disabil Res Rev 2006;12(3):184-91 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17061287.
- Lewis FM, Murdoch BE, Docking KM. An investigation of general and high-level language skills in children treated with central nervous system-targeted chemotherapy for acute lymphoblastic leukemia. J Med Speech Lang Pathol [cited 2020 Jun 6];2011;19(2):27-36.
- Pieters R, Carroll WL. Biology and treatment of acute lymphoblastic leukemia. Pediatr Clin North Am 2008 Feb;55(1):1-20, ix Available from: http://www.ncbi.nlm.nih.gov/pubmed/18242313.
- Tait DM, Bailey CC, Cameron MM. Tumours of the central nervous system. In: Voute A, Barrett A, Lemerle J, eds. Cancer in Children: Clinical Management. Berlin, Germany: Springer-Verlag; 1992. p. 184-206.
- Auguste KI, Sun PP, Raffel C, Berger MS, Gupta N. Current surgical management. In: Gupta N, Banerjee A, Haas- Kogan D, eds. Pediatric CNS Tumors Berlin, Heidelberg: Springer; 2017. p. 301-315.
- Nicolaides T, Horn B, Banerjee A. Chemotherapy. In: Gupta N, Banerjee A, Haas-Kogan D, eds. Pediatric CNS Tumors Berlin, Heidelberg: Springer; 2017. p. 317-342.
- Bouffet E, Tabori U, Huang A, Bartels U. Possibilities of new therapeutic strategies in brain tumors. Cancer Treat Rev 2010 Jun;36(4):335-41 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20188479.
- Levy AS. Brain tumors in children: evaluation and management. Curr Probl Pediatr Adolesc Health Care 2005 Jul;35(6):230-45 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15956960.
- Molineus A, Boxberger N, Redlich A, Vorwerk P. Time to diagnosis of brain tumors in children: a single-centre experience. Pediatr Int 2013 Jun;55(3):305-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23480630.
- Janzen L, Mabbott D, Guger SL. Neuropsychological outcomes in pediatric brain tumor survivors. In: Scheinemann K, Bouffet E, eds. Pediatric Neuro-Oncology. New York, NY: Springer; 2015. p. 267-276.
- Plowman PN. Tumours of the central nervous system. In: Plowman PN, Pinkerton CR, eds. Paediatric Oncology: Clinical Practice and Controversies. London, UK: Chapman & Hall; 1992. p. 240-267.
- Walter AW, Hilden JM. Brain tumors in children. Curr Oncol Rep 2004 Nov;6(6):438-44 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15485612.
- Anderson V, Spencer-Smith M, Wood A. Do children really recover better? Neurobehavioural plasticity after early brain insult. Brain 2011 Aug;134(Pt 8):2197-221 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21784775.
- Rodgers SP, Trevino M, Zawaski JA, Gaber MW, Leasure JL. Neurogenesis, exercise, and cognitive late effects of pediatric radiotherapy. Neural Plast 2013;2013:698528 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23691370.
- Docking K, Munro N, Marshall T, Togher L. Narrative skills of children treated for brain tumours: The impact of tumour and treatment related variables on microstructure and macrostructure. Brain Inj 2016;30(8):1005-18 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27119976.
- Duffner PK. Risk factors for cognitive decline in children treated for brain tumors. Eur J Paediatr Neurol 2010 Mar;14(2):106-15 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19931477.
- Monje M, Fisher PG. Neurological complications following treatment of children with brain tumors. J Pediatr Rehabil Med 2011;4(1):31-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21757808.
- Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004 Jul;5(7):399-408 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15231246.
- O'Neil S, Ji L, Buranahirun C, Azoff J, Dhall G, Khatua S, et al. Neurocognitive outcomes in pediatric and adolescent patients with central nervous system germinoma treated with a strategy of chemotherapy followed by reduced-dose and volume irradiation. Pediatr Blood Cancer 2011 Oct;57(4):669-73 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21495164.
- Ris MD, Walsh K, Wallace D, Armstrong FD, Holmes E, Gajjar A, et al. Intellectual and academic outcome following two chemotherapy regimens and radiotherapy for average-risk medulloblastoma: COG A9961. Pediatr Blood Cancer 2013 Aug;60(8):1350-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23444345.
- Walsh KS, Paltin I. Neuropsychological effects of pediatric brain tumors and associated treatment. In: Mucci G, Torno L, eds. Handbook of Long Term Care of the Childhood Cancer Survivor. New York, NY: Springer; 2015. p. 249-262.
- von der Weid N, Mosimann I, Hirt A, Wacker P, Nenadov Beck M, Imbach P, et al. Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences. Eur J Cancer 2003 Feb;39(3):359-65 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12565989.
- Aarsen FK, Van Dongen HR, Paquier PF, Van Mourik M, Catsman-Berrevoets CE. Long-term sequelae in children after cerebellar astrocytoma surgery. Neurology 2004 Apr 27;62(8):1311-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15111667.
- Taylor OD, Ware RS, Weir KA. Speech pathology services to children with cancer and nonmalignant hematological disorders. J Pediatr Oncol Nurs 2012 Mar;29(2):98-108 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22472483.
- Chieffo D, Tamburrini G, Frassanito P, Arcangeli V, Caldarelli M, Di Rocco C. Preoperative neurocognitive evaluation as a predictor of brain tumor grading in pediatric patients with supratentorial hemispheric tumors. Childs Nerv Syst 2016 Oct;32(10):1931-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27659835.
- Docking KM, Murdoch BE, Ward EC. General language abilities following management of childhood supratentorial tumour: part I. Acta Neuropsych [cited 2020 Jun 6];2003;1(3):260-283 Available from: https://actaneuropsychologica.com/resources/html/article/details?id=18723.
- Docking KM, Murdoch BE, Ward EC. High-level language and phonological awareness abilities of children following management for supratentorial tumour: part II. Acta Neuropsych [cited 2020 Jun 6];2003;1(4):367-381 Available from: https://actaneuropsychologica.com/resources/html/article/details?id=18728.
- Mei C, Morgan AT. Incidence of mutism, dysarthria and dysphagia associated with childhood posterior fossa tumour. Childs Nerv Syst 2011 Jul;27(7):1129-36 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21442268.
- Morgan AT, Liégeois F, Liederkerke C, Vogel AP, Hayward R, Harkness W, et al. Role of cerebellum in fine speech control in childhood: persistent dysarthria after surgical treatment for posterior fossa tumour. Brain Lang 2011 May;117(2):69-76 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21334735.
- Catsman-Berrevoets CE, Patay Z. Cerebellar mutism syndrome. In: Manto M, Huisman TAGM, eds. Handbook of Clinical Neurology Amsterdam, Netherlands: Elsevier; 2018. p. 273- 288.
- Charalambides C, Dinopoulos A, Sgouros S. Neuropsychological sequelae and quality of life following treatment of posterior fossa ependymomas in children. Childs Nerv Syst 2009 Oct;25(10):1313-20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19554333.
- De Smet HJ, Baillieux H, Catsman-Berrevoets C, De Deyn PP, Mariën P, Paquier PF. Postoperative motor speech production in children with the syndrome of 'cerebellar' mutism and subsequent dysarthria: a critical review of the literature. Eur J Paediatr Neurol 2007 Jul;11(4):193-207 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17320435.
- Gudrunardottir T, Morgan AT, Lux AL, Walker DA, Walsh KS, Wells EM, et al. Consensus paper on post-operative pediatric cerebellar mutism syndrome: the Iceland Delphi results. Childs Nerv Syst 2016 Jul;32(7):1195-203 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27142103.
- Mariën P, De Smet H, Paquier P, De Deyn PP, Verhoeven J. Cerebellar mutism In: Manto M, Gruol DL, Schmahmann JD, Rossi F, Koibuchi N, eds. Handbook of the Cerebellum and Cerebellar Disorders Dordrecht: Springer; 2013. p. 1753-1769.
- Paquier PF, Walsh KS, Docking KM, Hartley H, Kumar R, Catsman-Berrevoets CE. Post-operative cerebellar mutism syndrome: rehabilitation issues. Childs Nerv Syst 2020 Jun;36(6):1215-1222 Available from: http://www.ncbi.nlm.nih.gov/pubmed/31222445.
- Morgan AT, Sell D, Ryan M, Raynsford E, Hayward R. Pre and post-surgical dysphagia outcome associated with posterior fossa tumour in children. J Neurooncol 2008 May;87(3):347-54 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18209951.
- Nagy P, Beckmann N, Cox S, Sheyn A. Management of Vocal Fold Paralysis and Dysphagia for Neurologic Malignancies in Children. Ann Otol Rhinol Laryngol 2019 Nov;128(11):1019-1022 Available from: http://www.ncbi.nlm.nih.gov/pubmed/31215235.
- Newman LA, Boop FA, Sanford RA, Thompson JW, Temple CK, Duntsch CD. Postoperative swallowing function after posterior fossa tumor resection in pediatric patients. Childs Nerv Syst 2006 Oct;22(10):1296-300 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16761160.
- Skinner R, Haupt R, Hjorth L, Kremer L. The European experience of establishing guidelines for surveillance of the childhood cancer survivor. In: Mucci G, Torno L, eds. Handbook of Long Term Care of the Childhood Cancer Survivor. New York, NY: Springer; 2015. p. 25-35.
- Lee WH, Oh BM, Seo HG, Kim SK, Phi JH, Chong S, et al. One-year outcome of postoperative swallowing impairment in pediatric patients with posterior fossa brain tumor. J Neurooncol 2016 Mar;127(1):73-81 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26619998.
- Bell J, Lingam R, Wakefield CE, Fardell JE, Zeltzer J, Hu N, et al. Prevalence, hospital admissions and costs of child chronic conditions: A population-based study. J Paediatr Child Health 2020 Sep;56(9):1365-1370 Available from: http://www.ncbi.nlm.nih.gov/pubmed/32502332.
- Cohen E, Berry JG, Camacho X, Anderson G, Wodchis W, Guttmann A. Patterns and costs of health care use of children with medical complexity. Pediatrics 2012 Dec;130(6):e1463-70 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23184117.
- Delaney L, Smith JP. Childhood health: trends and consequences over the life course. Future Child 2012;22(1):43-63 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22550685.