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Cited by 59Cancer-related cognitive impairment studiesAcute Lymphoblastic Leukemia researchChildhood Cancer Survivors' Quality of Life

Brain structure, working memory and response inhibition in childhood leukemia survivors

Open access
van der Plas, Ellen, Schachar, Russell J., Hitzler, Johann, Crosbie, Jennifer, Guger, Sharon L., Spiegler, Brenda J., Ito, Shinya, Nieman, Brian J.·2017·Brain and Behavior
DOI 10.1002/brb3.621PMC PMC5318374
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Abstract

Introduction: Survival rates for children with acute lymphoblastic leukemia (ALL) approach 95%. At the same time, there is growing concern that chemotherapy causes alterations in brain development and cognitive abilities. We performed MRI measurements of white and gray matter volume to explore how variation in brain structure may be related to cognitive abilities in ALL survivors and healthy controls. Methods: The sample included 24 male ALL survivors who had completed contemporary treatment 3–11 years prior, and 21 age‐ and sex‐matched controls. Participants were between 8 and 18 years old. Working memory and motor response inhibition were measured with the N‐Back and Stop Signal Tasks (SST), respectively. Participants underwent 3T structural MRI to assess white and gray matter volumes overall, lobe‐wise, and in cortical and atlas‐identified subcortical structures. Mental health was assessed with the Child Behavioral Checklist. Results: ALL survivors performed more poorly on measures of working memory and response inhibition than controls. Frontal and parietal white matter, temporal and occipital gray matter volume, and volumes of subcortical white and gray matter structures were significantly reduced in ALL survivors compared with controls. Significant structure‐function correlations were observed between working memory performance and volume of the amygdala, thalamus, striatum, and corpus callosum. Response inhibition was correlated with frontal white matter volume. No differences were found in psychopathology. Conclusions: Compared with controls, a reduction in volume across brain regions and tissue types, was detectable in ALL survivors years after completion of therapy. These structural alterations were correlated with neurocognitive performance, particularly in working memory. Confirming these observations in a larger, more representative sample of the population is necessary. Additionally, establishing the time course of these changes—and the treatment, genetic, and environmental factors that influence them—may provide opportunities to identify at‐risk patients, inform the design of treatment modifications, and minimize adverse cognitive outcomes.

AI snapshot

Written from the paper’s full text.

TL;DR

ALL survivors had poorer working memory and response inhibition and widespread lower regional gray/white matter volumes years after chemotherapy-only treatment compared with controls. Structural differences correlated with working memory, especially amygdala, thalamus, striatum, and corpus callosum volumes.

Key findings

  • Working memory was lower in survivors on the 1-back (84.3 vs 93.3, 9.6% lower, p = .0009) and 2-back (60.3 vs 74.2, 18.7% lower, p = .01), with no group difference on 0-back. Response inhibition was slower in survivors (SSRT 307.3 vs 244.0 ms, a 26.0% increase, p < .01).
  • MRI showed reduced frontal white matter (left −6.5%, right −6.4%), right parietal white matter (−5.8%), temporal/occipital gray matter (right −5.6% and −6.6%; left occipital −6.4%), 11 of 29 subcortical white matter structures lower by 5%–12%, and 4 of 10 subcortical gray matter structures lower: right amygdala −7.4%, right thalamus −4.8%, left globus pallidus −6.9%, left striatum −6.3%.
  • 1-back accuracy correlated with right amygdala volume (r = .51, q = 0.03), right/left thalamus (r = .39/.35, q = 0.09/0.1), left striatum (r = .34, q = 0.1), and total corpus callosum (r = .35, p = .02). Response inhibition correlated with right frontal white matter volume (r = −.31, p = .04, uncorrected).
  • No significant group differences were found in CBCL/YSR psychopathology, and no significant changes were observed in MT or DTI measurements.

Methods

  • Case-control study: final analyzed sample was 23 male ALL survivors and 21 age-, sex-, and ancestry-matched controls, ages 8–18, of European ancestry, treated with chemotherapy only and at least 2 years off treatment; the abstract reports 24 survivors. Mean age was 14.4 years (SD = 2.2) for survivors and 13.9 years (SD = 2.9) for controls; mean age at diagnosis was 4.4 years (SD = 1.8), and mean time since diagnosis was 10.0 years (SD = 2.5).
  • Measures included 3T structural MRI (T1, DTI, MT), N-back working memory, Stop Signal Task response inhibition, and CBCL/YSR mental health. Image analysis used CIVET/FSL, atlas-based subcortical segmentation, and deformation-based morphometry.
  • Analyses used generalized linear models or linear regression with age and group as predictors, age-corrected scores for visualization/correlations, Pearson correlations for structure–function relationships, and FDR q-values to account for multiple comparisons.

Limitations

  • Stated: the study included only males of European ancestry, so results may not represent females or other ancestries; the sample was not intended to distinguish high- versus standard-risk treatment protocols; only working memory and inhibition were assessed; a larger, more representative sample is needed.
  • Stated: most survivors were diagnosed between 2 and 6 years of age, so a larger targeted cohort is needed to assess older age at diagnosis; age at diagnosis, years since diagnosis, and treatment intensity were not correlated with age-adjusted total brain volume, white matter, or gray matter.
  • Evident from the text: the sample is small and cross-sectional, many anatomical comparisons use q < 0.1, some correlations are uncorrected, and the abstract/final analyzed survivor count differs (24 vs 23).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/brb3.621

Cites

115 of 115 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

32 of 74 cited sources checked · 11 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Detailed characterization of region-specific changes associated with chemotherapy treatment remains scant.

    “Thirdly, while global changes in tissue volumes have been reported (Krull et al., 2016; Reddick et al., 2014; Tamnes et al., 2015), detailed characterization of region‐specific changes associated with chemotherapy treatment remains scant (Genschaft et al., 2013).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Genschaft et al., 2013 source

      The Introduction says the authors examined selected brain regions, and the Results (Structural Brain Imaging; page unavailable) report region-specific volume differences. Neither passage assesses whether detailed characterization of chemotherapy-associated regional changes was scarce in the literature. The paper's own regional analysis does not, by itself, settle that broader claim. (LLM, conf=0.70)

      Experimental — accuracy not yet measured
  • Premisecitation

    Available studies often evaluate outcomes in adult survivors of childhood leukemia.

    “Firstly, available studies often evaluate outcomes in adult survivors of childhood leukemia (Blaauwbroek et al., 2007; Edelmann et al., 2014; Kanellopoulos et al., 2015; Tamnes et al., 2015; Zeller et al., 2013).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Blaauwbroek et al., 2007 source
    • cites Edelmann et al., 2014 source
    • cites Kanellopoulos et al., 2015 source
  • Premisecitation

    Transient white matter lesions do not show a clear relationship with functional abilities in ALL survivors.

    “however, these lesions do not show a clear relationship with functional abilities (Bhojwani et al., 2014; Pääkkö et al., 2000) and are therefore unlikely to account for the full range of deficits in ALL survivors.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Bhojwani et al., 2014 source

      The Discussion (page unavailable) says the clinical importance of leukoencephalopathy is unclear and calls for further study of whether it predicts later neurocognitive impairment. That supports the absence of an established relationship, but the paper does not assess functional abilities in survivors or show that transient lesions lack such a relationship. The Results also report that most MRI abnormalities in the followed subset persisted to week 120. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites Pääkkö et al., 2000

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Premisecitation

    Children with ALL require treatment at a time when the brain is undergoing major developmental changes.

    “Children with ALL require treatment at a time when the brain is undergoing major developmental changes (Dean et al., 2014; Giedd et al., 2010; O'Muircheartaigh et al., 2014).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Dean et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Giedd et al., 2010 source
    • cites O'Muircheartaigh et al., 2014 source
  • Premisecitation

    ALL survivors in late childhood or adolescence may face unique challenges associated with ongoing brain maturation processes.

    “Secondly, ALL survivors in late childhood or adolescence may be faced with unique challenges associated with ongoing brain maturation processes (Erus et al., 2015).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Erus et al., 2015 source

      The Introduction states that healthy brain maturation continues through childhood and adolescence, and the Discussion says cognitive processes continue to mature in adolescence. The Participants section describes a youth sample that excluded individuals with medical histories potentially affecting brain function; the paper does not establish that ALL survivors face unique challenges from these processes. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 20
  • The quote only partly states this claim. 3

  • May combine two claims.

    Premisecitation

    ALL treatment has changed dramatically since older survivors were diagnosed, with cranial radiation therapy almost entirely replaced by chemotherapy-only protocols.

    “ALL treatment has changed dramatically since these older survivors were diagnosed (Pui & Evans, 2013; Simone, 2006): due to concerns of significant neuropsychological effects (Janzen & Spiegler, 2008; Spiegler et al., 2006), cranial radiation therapy has almost entirely been replaced by chemotherapy‐only protocols (Pui & Evans, 2013; Pui et al., 2009).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Pui & Evans, 2013 source
    • cites Simone, 2006 source
    • cites Janzen & Spiegler, 2008 source

  • May combine two claims.

    Premisecitation

    ALL is more common in males, and males are given a more extended chemotherapy treatment due to increased risk for relapse.

    “ALL is more common in males (National Cancer Institute 2015) and males are given a more extended chemotherapy treatment due to increased risk for relapse (Brecher et al., 1986; Tiedemann, Chessells, & Sandland, 1982; Wofford et al., 1992).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites National Cancer Institute 2015

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Brecher et al., 1986 source
    • cites Tiedemann, Chessells, & Sandland, 1982 source

      The Introduction says boys with ALL fared worse than girls in some centres, partly because of testicular relapse. The Discussion suggests that more intensive chemotherapy might reduce this difference, and the Abstract describes two years of chemotherapy for boys after isolated testicular relapse. The paper does not say that males generally are given a longer course of chemotherapy than females because of relapse risk. The separately cited claim that ALL is more common in males is not attributed to this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Reductions in total white matter volume and increased fractional anisotropy have been reported in adult survivors of childhood ALL.

    “Reductions in total white matter volume and increased fractional anisotropy have been reported in adult survivors of childhood ALL (Aukema et al., 2009; Edelmann et al., 2014; Reddick et al., 2014),”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Aukema et al., 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Edelmann et al., 2014 source

      The Discussion reports higher fractional anisotropy in multiple fibre tracts of adult survivors than in controls. The Macrostructure section reports reduced white matter fraction in specific lobes, particularly the frontal and temporal lobes, but does not establish a reduction in total white matter volume across the brain. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Reddick et al., 2014 source

      The Results (Volumetric Assessment) report reduced white matter volume in cancer survivors, including those treated for ALL. But the Methods (Patients) specify participants aged 6–18, and the Discussion says this study did not measure fractional anisotropy; it reports that other studies found decreased, not increased, fractional anisotropy. Its volume assessment was also limited to a specific anatomical area, rather than the whole brain. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Neurocognitive and behavioral late effects of childhood ALL treatment include weaknesses in working memory, visual-spatial reasoning, motor coordination, processing speed, and attention.

    “Neurocognitive and behavioral late effects include weaknesses in working memory, visual‐spatial reasoning, motor coordination, processing speed, and attention (Campbell et al., 2009; Iyer, Balsamo, Bracken, & Kadan‐lottick, 2015; Jacola et al., 2016; Peterson et al., 2008).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Campbell et al., 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Iyer, Balsamo, Bracken, & Kadan‐lottick, 2015 source

      The Working memory, Information processing speed, and Fine motor functioning sections report weaknesses in childhood ALL survivors treated without cranial radiation. The Attention/concentration section reports mixed results and a nonsignificant pooled effect; the Visuoconstruction section does not establish a weakness in visual-spatial reasoning. The cited review therefore supports only part of the list. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Jacola et al., 2016 source

      The Introduction identifies attention and processing-speed deficits in survivors treated with chemotherapy only, and the Results report attention difficulties and elevated processing-speed risk with higher-intensity treatment. Working memory was assessed, but the paper does not establish the claimed visual-spatial reasoning or motor-coordination weaknesses; its Conclusion says function was largely age appropriate two years after treatment. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A previous lesion study of traumatic brain injury observed that response inhibition was correlated with frontal white matter volume.

    “Response inhibition was correlated with frontal white matter volume, consistent with previous observations in a lesion study of traumatic brain injury (Lipszyc et al., 2014).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Lipszyc et al., 2014 source

      The Abstract reports that children with frontal white matter lesions had poorer response inhibition, supporting the general connection to a TBI lesion study. But the paper does not report a correlation with frontal white matter volume; the Regression Analysis instead found no significant relationship between response inhibition and total lesion volume. Total lesion volume is not the same measure as frontal white matter volume. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The amygdala, thalamus, striatum, and corpus callosum have been implicated in performance on the N-Back previously.

    “These regions have been implicated in performance on the N‐Back previously (Dahlin, Neely, Larsson, Bäckman, & Nyberg, 2008; Kubat‐Silman, Dagenbach, & Absher, 2002; Schaefer et al., 2006; Takeuchi et al., 2010; Zou, Hong, Wang, Gao, & Yang, 2011).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Dahlin et al., 2008 source
    • cites Kubat-Silman et al., 2002 source
    • cites Schaefer et al., 2006 source

      Table 1 (Functional imaging and data analysis; page unavailable) lists both amygdalae among regions correlated with 3-back reaction time. It does not list the thalamus, striatum, or corpus callosum, and the Discussion’s account of other regions associated with performance does not identify them. This source therefore supports the amygdala portion, but not the other three regions attributed to it. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A recent study reported correlations between plasma MTX, cortical thickness in the dorsolateral prefrontal cortex and microstructure of the frontostriatal tract, suggesting that exposure to MTX is related to neuroanatomical changes.

    “A recent study reported correlations between plasma MTX, cortical thickness in the dorsolateral prefrontal cortex and microstructure of the frontostriatal tract (Krull et al., 2016), suggesting that exposure to MTX is related to neuroanatomical changes.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Krull et al., 2016 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Oligodendrocytes have a high metabolic rate and must produce large amounts of membranes and protein, particularly during myelination.

    “Oligodendrocytes have a high metabolic rate and must produce large amounts of membranes and protein, particularly during myelination (Bradl & Lassmann, 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Bradl & Lassmann, 2010 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The bulk (83%) of our survivors were diagnosed between 2 and 6 years of age.

    “However, the bulk (83%) of our survivors were diagnosed between 2 and 6 years of age, which corresponds to the age of peak ALL incidence (Inaba et al., 2013; National Cancer Institute 2015).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Inaba et al., 2013 source
    • cites National Cancer Institute 2015

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    Since MTX is delivered through all phases of ALL treatment, folate metabolism may be altered for an extended period, possibly resulting in build-up of homocysteine and/or secondary metabolic alterations.

    “Since MTX is delivered through all phases of ALL treatment, folate metabolism may be altered for an extended period, possibly resulting in build‐up of homocysteine (Fox & Stover, 2008; Krull et al., 2016; Li et al., 2010; Steinfeld et al., 2009), and/or secondary metabolic alterations (van der Plas et al., 2015; Steinfeld et al., 2009; Strain et al., 2013).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Fox & Stover, 2008 source
    • cites Krull et al., 2016 source

      The Appendix treatment schema lists methotrexate in multiple phases of ALL treatment, and the Discussion reports elevated homocysteine during therapy in association with high-dose methotrexate exposure. But the paper does not establish that folate metabolism remains altered for an extended period; the Discussion says treatment-related hyperhomocysteinemia is transient in most cases. The secondary-metabolic-alterations clause is cited to other sources, not Krull et al. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Li et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Incidence of ALL is higher in boys than in girls, and boys require longer treatment than girls due to sex-specific risk factors for ALL relapse.

    “Secondly, sex modulates disease‐ and treatment‐specific factors: incidence of ALL is higher in boys than in girls (Inaba et al., 2013; National Cancer Institute 2015; Pui & Evans, 2013; Pui et al., 1999; Sather, Miller, Nesbit, Heyn, & Hammond, 1981), and boys require longer treatment (~2.5 years) than girls (~2 years) due to sex‐specific risk factors for ALL relapse (Brecher et al., 1986; Tiedem”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Inaba et al., 2013 source
    • cites National Cancer Institute 2015

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Pui & Evans, 2013 source

      Pui and Evans (2013) is cited for the higher incidence of ALL in boys; the separate claim about treatment duration has different citations. The passages from Precise risk stratification and Host pharmacokinetics, pharmacodynamics and pharmacogenetics discuss prognosis and incidence by racial or ethnic group, but not incidence by sex. Searches for boys, girls, male, and male predominance found no passage addressing the cited comparison. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Ancestry is likely to also impact the risk and severity of late effects.

    “Similarly, ancestry, which is known to alter both pediatric ALL incidence and survival (Abrahão et al., 2015; Goggins & Lo, 2012; Linabery, Johnson, & Ross, 2012), is likely to also impact the risk and severity of late effects (Bhatia et al., 2002; Dores, Devesa, Curtis, Linet, & Morton, 2012; Lim, Bhatia, Robison, & Yang, 2014; Yang et al., 2010).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Bhatia et al., 2002 source

      The Discussion reports racial and ethnic differences in survival and speculates about differences in drug metabolism, but does not address the risk or severity of late effects. The Statistical analysis section defines the outcomes as overall and event-free survival, not late effects; searches for late effects, long-term complications, and treatment toxicity found no passage supporting the attributed point. Page numbers were not available in our copy. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites Dores et al., 2012

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Lim et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ancestry is known to alter both pediatric ALL incidence and survival.

    “Similarly, ancestry, which is known to alter both pediatric ALL incidence and survival (Abrahão et al., 2015; Goggins & Lo, 2012; Linabery, Johnson, & Ross, 2012), is likely to also impact the risk and severity of late effects (Bhatia et al., 2002; Dores, Devesa, Curtis, Linet, & Morton, 2012; Lim, Bhatia, Robison, & Yang, 2014; Yang et al., 2010).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Abrahão et al., 2015 source

      The Introduction says inherited genetic predisposition may differ across racial/ethnic groups, and the Results report differences in survival among those groups. But the paper does not establish that ancestry itself alters both overall pediatric ALL incidence and survival: its incidence discussion is hedged, and its survival analysis identifies associations rather than an ancestry-specific causal effect. No page numbers are available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Goggins & Lo, 2012 source
    • cites Linabery et al., 2012 source

      The Methods and Results report pediatric lymphoid leukemia incidence in relation to folic acid fortification, not ancestry. A passage under Figure 1 compares racial and ethnic distributions in SEER and the US population but does not link ancestry to ALL incidence or survival. Searches for ancestry, race, ethnicity, and survival found no passage addressing the attributed claim; pages were not provided in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • The quote only partly states this claim.

    Findingown data

    Among analyzed participants, ALL survivors had 18.7% lower 2-back accuracy than controls.

    “Subsequently, survivors scored on average of 18.7% lower (mean = 60.3; SD = 17.5) than controls (mean = 74.2; SD = 15.3), with the model showing significant age (t (39) = 3.7, p = .0007) and group (t (39) = −2.6, p = .01) coefficients”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    On the right side, temporal and occipital cortical volumes were smaller by 5.6% and 6.6%, respectively.

    “On the right side, volumes were smaller by 5.6% and 6.6%, respectively (t (41) = −2.3 and −2.4, q = 0.09).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither age at diagnosis nor years since diagnosis were predictive of age-adjusted SSRT.

    “Neither age at diagnosis nor years since diagnosis were predictive of age‐adjusted SSRT.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Age at diagnosis and years since diagnosis were not significantly associated with age-corrected target accuracy scores on the N-Back.

    “Age at diagnosis and years since diagnosis were not significantly associated with age‐corrected target accuracy scores on the N‐Back.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    ALL survivors had 9.6% lower 1-back accuracy than controls.

    “In the 1‐back condition, accuracy scores were 9.6% lower in survivors (mean = 84.3, SD = 9.1) than controls (mean = 93.3, SD = 5.5), which was highly significant between groups (t (41) = −3.6, p = .0009).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Subcortical white matter differences were present in 11 of 29 white matter structures tested, with 5% to 12% volume decreases.

    “Subcortical white matter differences were present in 11 of the 29 white matter structures tested, with 5% to 12% volume decreases”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Group and age significantly predicted SSRT.

    “The linear model indicated a significant effect of both group (t (40) = 2.8, p < .01) and age (−13 ms/yr, t (40) = −2.9, p < .01).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    ALL survivors had smaller volumes in the right amygdala, right thalamus, left globus pallidus, and left striatum.

    “Survivors exhibited smaller volumes in the amygdala (right, −7.4%), the thalamus (right, −4.8%), the globus pallidus (left, −6.9%), and the striatum (left, −6.3%).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    1-back accuracy was correlated with the genu and body of the corpus callosum, but not the splenium.

    “For the latter, tests showed significance independently for both the genu and the body of the corpus callosum (r = .37, t (40) = 2.6, q = 0.09), but not the splenium (q = 0.26).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In our sample, age at diagnosis and years since diagnosis had no significant impact on cognitive abilities or neuroanatomical outcomes.

    “In our sample, we found that age at diagnosis and years since diagnosis had no significant impact on cognitive abilities or neuroanatomical outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Survivors exhibited difficulties in working memory and response inhibition, and had lower regional gray and white matter volume compared with typically developing controls.

    “Survivors exhibited difficulties in working memory and response inhibition, and had lower regional gray and white matter volume compared with typically developing controls.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Control subjects were matched to ALL survivors on age, sex, and ancestry.

    “Control subjects were matched to ALL survivors on age, sex, and ancestry.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Control subjects were eligible only if they did not have a diagnosed learning disability or psychiatric disorder at the time of assessment.

    “Additionally, controls were eligible if they did not have a diagnosed learning disability or psychiatric disorder at the time of assessment.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Significance was reported using p-values or corrected p-values (q-values) computed with the false discovery rate to account for multiple comparisons.

    “We report significance using p‐values or corrected p‐values (q‐values), computed with the false discovery rate (FDR) (Benjamini & Hochberg, 1995) to account for multiple comparisons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Benjamini & Hochberg, 1995 source

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Participants were excluded from the N-back analysis if they did not achieve at least 30% target accuracy.

    “To ensure only those who performed above chance were considered, participants were excluded from the analysis if they did not achieve at least 30% target accuracy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    The study was restricted to males only to limit treatment-related variability and inherent sex differences in brain development while maximizing eligible participants.

    “To limit treatment‐related variability and inherent sex differences in brain development (De Bellis et al., 2001; Gur et al., 1999; Lange, Giedd, Castellanos, Vaituzis, & Rapoport, 1997; Kang, Herron, & Woods, 2011), while maximizing eligible participants, we restricted this study to males only.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites De Bellis et al., 2001 source
    • cites Gur et al., 1999 source
    • cites Lange, Giedd, Castellanos, Vaituzis, & Rapoport, 1997 source

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Individuals with fewer than 20% or greater than 80% successfully inhibited stop trials were excluded because this resulted in either too few correct stop trials or failed stop trials to calculate stable SSRTs.

    “Individuals with fewer than 20% or greater than 80% successfully inhibited stop trials were excluded because this resulted in either too few correct stop trials or failed stop trials to calculate stable SSRTs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is some evidence of associations between white matter morphology and motor processing speed in survivors of childhood ALL.

    “with some evidence of associations between white matter morphology and measures of attention and intelligence (Edelmann et al., 2014; Reddick et al., 2014) and motor processing speed (Aukema et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Aukema et al., 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    One ALL survivor did not meet the validity criteria for the Stop Signal Task.

    “One ALL survivor did not meet the validity criteria for the Stop Signal Task (total n = 43, 21 controls and 22 survivors [Figure 2]).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Deformation-based morphometry was restricted to a subcortical region-of-interest and served as a qualitative confirmation of atlas-based analyses.

    “Consequently, this analysis was restricted to a subcortical region‐of‐interest and served as a qualitative confirmation of atlas‐based analyses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Late effects of ALL treatment include cardiomyopathy, avascular necrosis of the joints, secondary cancers, and neurocognitive and behavioral challenges.

    “These late effects include cardiomyopathy, avascular necrosis of the joints, secondary cancers, and neurocognitive and behavioral challenges (Goldsby et al., 2010; Haddy, Mosher, & Reaman, 2009; Landier, Armenian, & Bhatia, 2015; Mariotto et al., 2009; Schultz et al., 2007a).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Goldsby et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Haddy, Mosher, & Reaman, 2009 source
    • cites Landier, Armenian, & Bhatia, 2015

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    The results did not show strong evidence for distinct 'affected' and 'not affected' groups among survivors, but suggested the distribution of ALL survivors was globally shifted relative to controls.

    “Our results did not show strong evidence among survivors for distinct “affected” and “not affected” groups, but rather suggested the distribution of ALL survivors was globally shifted relative to that of the controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Both neurocognitive and anatomical deficits were evident in childhood and adolescent ALL survivors even after nearly a decade had passed since ALL diagnosis.

    “The results indicate that both neurocognitive and anatomical deficits were evident in childhood and adolescent ALL survivors even after nearly a decade had passed since ALL diagnosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MTX targets folate synthesis.

    “One commonly suspected chemotherapy agent is MTX, which targets folate synthesis (Graham et al., 1992; Pak, Chan, & Mattson, 2003).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Graham et al., 1992 source
    • cites Pak, Chan, & Mattson, 2003 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Folate is a crucial constituent of one-carbon metabolism and is important for biosynthesis of purines and thymidylate, and remethylation of homocysteine to methionine.

    “Folate is a crucial constituent of one‐carbon metabolism (OCM) and is important for biosynthesis of purines and thymidylate, and remethylation of homocysteine to methionine (Fox & Stover, 2008; Li, Vijayanathan, Gulinello, & Cole, 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Fox & Stover, 2008 source
    • cites Li et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    Exposure to chemotherapy treatment results in brain development changes years after completion of treatment, with potential ramifications for quality of life in ALL survivors.

    “Our results do indicate that exposure to chemotherapy treatment results in brain development changes years after completion of treatment, with potential ramifications for quality of life in ALL survivors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The observed differences in brain structure and cognition between ALL survivors and controls are attributable to chemotherapy treatment rather than other factors.

  • May combine two claims.

    Interpretationown data

    Even patients treated with standard-risk, contemporary chemotherapy-only treatment protocols are at risk of alterations in brain development, and deficits in working memory and inhibitory control.

    “We conclude that even patients treated with standard‐risk, contemporary chemotherapy‐only treatment protocols are at risk of alterations in brain development, and deficits in working memory and inhibitory control.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The observed differences in brain structure and cognition between ALL survivors and controls are attributable to chemotherapy treatment rather than other factors.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A large majority of childhood ALL patients will become survivors.

    “As a large majority of childhood ALL patients will become survivors, late effects and their impact on quality of life are a crucial concern (Kunin‐Batson, Kadan‐Lottick, & Neglia, 2014; Mitchell et al., 2016), making the effort to identify targets for remediating cognitive, and behavioral deficits a pressing issue (Iyer et al., 2015; Kunin‐Batson et al., 2014; Olson & Sands, 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kunin-Batson et al., 2014 source
    • cites Mitchell et al., 2016

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    Structural changes are widespread and correlate with functional performance.

    “We have shown that structural changes are widespread and correlate with functional performance.”
    Quote in the paperSubstantial claim
42 of 42

  • The paper relies on this without support.

    Chemotherapy may disrupt or impair brain developmental processes and thereby lead to neurocognitive deficits.

    “Chemotherapy may disrupt or impair these processes and thereby lead to neurocognitive deficits.”

  • The paper relies on this without support.

    There is little understanding of the potential relationships between regional brain deficits and functional abilities in ALL survivors.

    “Finally, there is little understanding of the potential relationships between regional brain deficits and functional abilities in ALL survivors.”

  • The paper relies on this without support.

    The observed differences in brain structure and cognition between ALL survivors and controls are attributable to chemotherapy treatment rather than other factors.

    “Our results do indicate that exposure to chemotherapy treatment results in brain development changes years after completion of treatment”

  • The paper relies on this without support.

    The control participants are representative of typically developing children and free of conditions that would affect brain structure or cognition.

    “compared with typically developing controls”
4 of 4

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Consistentt(41) = 2.8reported p = .009 · recomputed p = .008

    “t (41) = 2.8, p = .009”

  • Consistentt(41) = 0.76reported p = .45 · recomputed p = .452

    “t (41) = 0.76, p = .45”

  • Consistentt(41) = -3.6reported p = .0009 · recomputed p < .001

    “t (41) = −3.6, p = .0009”

  • Consistentt(41) = 3reported p = .004 · recomputed p = .005

    “t (41)= 3.0, p = .004”

  • Consistentt(39) = 3.7reported p = .0007 · recomputed p < .001

    “t (39) = 3.7, p = .0007”

  • Consistentt(39) = -2.6reported p = .01 · recomputed p = .013

    “t (39) = −2.6, p = .01”

  • Consistentt(40) = 2.8reported p < .01 · recomputed p = .008

    “t (40) = 2.8, p < .01”

  • Consistentt(40) = -2.9reported p < .01 · recomputed p = .006

    “t (40) = −2.9, p < .01”

  • Consistentt(40) = 2.4reported p = .02 · recomputed p = .021

    “t (40) = 2.4, p = .02”

  • Consistentt(41) = -2.1reported p = .04 · recomputed p = .042

    “t (41) = −2.1, p = .04”

10 of 10

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Abstract and results give different survivor sample sizes

    Minor

    The abstract says the sample included 24 ALL survivors, but the results say the final analysis sample included 23 survivors.

1 of 1

Cites

Flagged first, then by citations

1 of the 116 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
van der Plas, E., Schachar, R. J., Hitzler, J., Crosbie, J., Guger, S. L., Spiegler, B. J., Ito, S., & Nieman, B. J.
Affiliations
  • Physiology and Experimental Medicine The Hospital for Sick Children Research Institute Toronto ON Canada
  • University of Toronto (CA)
  • Hospital for Sick Children (CA)
  • Ontario Institute for Cancer Research (CA)
ORCID
Hitzler, Johann
Venue
Brain and Behavior
Publisher
Wiley
Published
2016-12-29
Volume
7
Issue
2
Pages
e00621-e00621
ISSN
  • 2157-9032 (ISSN-L)
  • 2162-3279
DOI
10.1002/brb3.621
PMC
PMC5318374
OpenAlex
W2563015631
Semantic Scholar
57556fa276ee868ca33cd64631cda1a26599e87e
Cited by
59
References
116
Citations by year
2026: 1 · 2025: 7 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 10 · 2020: 8 · 2019: 9 · 2018: 5 · 2017: 2
FWCI
4.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain and Behavior (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • TSpace (University of Toronto) (submittedVersion, cc-by)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • Hospital for Sick Children
  • Ontario Mental Health Foundation
  • Canadian Cancer Society Research Institute
  • Canadian Institutes of Health Research
  • Pediatric Oncology Group of Ontario
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Childhood Cancer Survivors' Quality of Life
Keywords
childhood acute lymphoblastic leukemia, cancer survivors, chemotherapy-induced neurotoxicity, brain structure, white matter volume, gray matter volume, working memory, response inhibition, amygdala, thalamus, striatum, corpus callosum, frontal white matter, cognitive function, psychopathology
MeSH terms
Adolescent, Child, Humans, Inhibition, Psychological, Magnetic Resonance Imaging, Male, Memory, Short-Term, Survivors, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Cognitive Dysfunction, White Matter, Gray Matter

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-18.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-18.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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