January 2014 ORIGINAL ARTICLES

16. Haataja L, Mercuri E, Regev R, Cowan F, Rutherford M, Dubowitz V,

et al. Optimality score for the neurologic examination of the infant at

12 and 18 months of age. J Pediatr 1999;135:153-61.

17. Department for Communities and Local Government. English Indices of

Deprivation 2010. London; 2011. Available at: https://www.gov.uk/

government/publications/english-indices-of-deprivation-2010. [uploaded

March 24, 2011; cited February 16, 2013].

18. Cochran WG. Some methods for strengthening the common c2 tests.

Biometrics 1954;10:417-51.

19. van Noort-van der Spek IL, Franken MC, Weisglas-Kuperus N.

Language functions in preterm-born children: a systematic review and

meta-analysis. Pediatrics 2012;129:745-54.

20. Barre N, Morgan A, Doyle LW, Anderson PJ. Language abilities in

children who were very preterm and/or very low birth weight: a

meta-analysis. J Pediatr 2011;158:766-74.

21. Als H. A synactive model of neonatal behavioral organization: Frame-

work for the assessment and support of the neurobehavioral develop-

ment of the premature infant and his parents in the environment of

the neonatal intensive care unit. Phys Occupational Ther Pediatr 1986;

6:3-55.

Evaluation of Early Childhood Social-Communication DifficultiesChecklist for Autism in Toddlers

22. Bar-Shalita T, Vatine JJ, Parush S. Sensory modulation disorder: a risk

factor for participation in daily life activities. Dev Med Child Neurol

2008;50:932-7.

23. Bart O, Shayevits S, Gabis LV, Morag I. Prediction of participation and

sensory modulation of late preterm infants at 12 months: a prospective

study. Res Dev Disabil 2011;32:2732-8.

24. Bishop SL, Richler J, Lord C. Association between restricted and

repetitive behaviors and nonverbal IQ in children with autism spectrum

disorders. Child Neuropsychol 2006;12:247-67.

25. Ozonoff S, Macari S, Young GS, Goldring S, Thompson M, Rogers SJ.

Atypical object exploration at 12 months of age is associated with autism

in a prospective sample. Autism 2008;12:457-72.

26. Johnson S, Marlow N. Positive screening results on the modified

checklist for autism in toddlers: implications for very preterm popula-

tions. J Pediatr 2009;154:478-80.

27. Baron-Cohen S, Allen J, Gillberg C. Can autismbe detected at 18months?

The needle, the haystack, and the CHAT. Br J Psychiat 1992;161:839-43.

28. Angelidou A, Asadi S, Alysandratos KD, Karagkouni A, Kourembanas S,

Theoharides TC. Perinatal stress, brain inflammation, and risk of

autism—review and proposal. BMC Pediatr 2012;12:89.

50 Years Ago in THE JOURNAL OF PEDIATRICS

Central Nervous System Complications of Children with Acute Leukemia: AnEvaluation of Treatment MethodsEvans AE, D’Angio GJ, Mitus A. J Pediatr 1964;64:94-6

Fifty years ago in The Journal, Evans et al reported an historical cohort study of 53 children symptomatic from intra-cranial leukemia, treated by either lumbar puncture alone, cranial irradiation, or intrathecal methotrexate. Today

the results are not surprising; 98% of the irradiated patients became symptom-free for 2.8 months, and 88% of themethotrexate-treated patients were symptom-free 3.7 months (P = .07). Only 48% of the children undergoing simplelumbar puncture became asymptomatic and even then for only about 2 weeks. Whether this study’s small sample sizewould have survived today’s peer review process to merit publication is debatable.

Nonetheless, this paper presaged a landmark shift in the management and cure of childhood acute lymphoblasticleukemia (ALL). Indeed, the authors mention in their last paragraph the “prophylactic” use of monthly intrathecalmethotrexate in 12 patients whose central nervous system leukemia had already been eradicated and theirsymptom-free survival of 7 or more months. That success was unheralded! But, by the end of the 1960s, the “TotalTherapy” studies at St. Jude Children’s Research Hospital using prophylactic craniospinal irradiation and intrathecalmethotrexate reduced the rate of leukemia relapse into the central nervous system from more than 50% to approx-imately 10%, and afforded cures in greater than 50% of children in an era when ALL took the lives of 80% or more.1

The next 50 years of advancing cures in ALL and other childhood cancers will be more challenging. Now that manychildhood cancers have 5-year survival rates in excess of 80%, clinical trials will be cumbersome, as much larger sizeswill be necessary to demonstrate increasingly smaller increments of success. Accumulating the larger samples sizesrequired will be difficult because of cost as well as the increasing division of childhood cancers into smaller and smallerdiseases based upon molecular subtypes. Surely we will conceive new clinical trial designs to tackle these logisticalissues. However, we should never give short shrift to initial observations such as that of Evans et al, even when samplesize is small, if the findings are compelling and the impact potentially immense.

Paul Graham Fisher, MDDepartments of Neurology, Pediatrics, and Human Biology

Lucile Packard Children’s HospitalStanford UniversityPalo Alto, California

http://dx.doi.org/10.1016/j.jpeds.2013.08.003

Reference

1. Simone J, Aur RJA, Hustu HO, Pinkel D. “Total therapy” studies of acute lymphocytic leukemia in children: current results and prospects for

cure. Cancer 1972;30:1488-94.

in Children Born Preterm Using the Quantitative 33