Posterior fossa syndrome is characterized by cerebellar dysfunction, oromotor/oculomotor apraxia, emotional lability and mutism in patients after infratentorial injury. The underlying neuroanatomical substrates of posterior fossa syndrome are unknown, but dentatothalamocortical tracts have been implicated. We used pre- and postoperative neuroimaging to investigate proximal dentatothalamocortical tract involvement in childhood embryonal brain tumour patients who developed posterior fossa syndrome following tumour resection. Diagnostic imaging from a cohort of 26 paediatric patients previously operated on for an embryonal brain tumour (13 patients prospectively diagnosed with posterior fossa syndrome, and 13 non-affected patients) were evaluated. Preoperative magnetic resonance imaging was used to define relevant tumour features, including two potentially predictive measures. Postoperative magnetic resonance and diffusion tensor imaging were used to characterize operative injury and tract-based differences in anisotropy of water diffusion. In patients who developed posterior fossa syndrome, initial tumour resided higher in the 4th ventricle (P = 0.035). Postoperative magnetic resonance signal abnormalities within the superior cerebellar peduncles and midbrain were observed more often in patients with posterior fossa syndrome (P = 0.030 and 0.003, respectively). The fractional anisotropy of water was lower in the bilateral superior cerebellar peduncles, in the bilateral fornices, white matter region proximate to the right angular gyrus (Tailerach coordinates 35, -71, 19) and white matter region proximate to the left superior frontal gyrus (Tailerach coordinates -24, 57, 20). Our findings suggest that multiple bilateral injuries to the proximal dentatothalamocortical pathways may predispose the development of posterior fossa syndrome, that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical underlying pathophysiological component of posterior fossa syndrome, and that decreased fractional anisotropy in the fornices and cerebral cortex may be related to the abnormal neurobehavioural symptoms of posterior fossa syndrome.
Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were ≥ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.
IMPORTANCE Limited studies have reported associations between anesthesia and neurocognitive and neuroimaging outcomes, particularly in pediatric patients who undergo multiple exposures to anesthesia as part of chronic disease management. OBJECTIVE To investigate whether general anesthesia is associated with neurocognitive impairment and neuroimaging abnormalities in long-term survivors of childhood acute lymphoblastic leukemia. DESIGN, SETTING, AND PARTICIPANTS A cohort study of 212 survivors of childhood acute lymphoblastic leukemia who received treatment between July 7, 2000, and November 3, 2010, and follow-up at a mean (SD) of 7.7 (1.7) years post diagnosis, was conducted at an academic medical center. Of 301 survivors who were alive and eligible for participation, 217 individuals (72.1%) agreed to participate in long-term follow-up. Data analysis was performed from August 23, 2017, to May 3, 2018. EXPOSURES For 5699 anesthesia procedures, data on duration and cumulative doses of all anesthetics, sedatives, analgesics, anxiolytics, and neuromuscular blockers were abstracted, along with cumulative doses of high-dose intravenous methotrexate and number of triple intrathecal chemotherapy treatments. MAIN OUTCOMES AND MEASURES Neurocognitive measures of attention, processing speed, executive function, and intelligence were examined. Brain volumes, cortical thickness, and diffusion tensor imaging of the whole brain, corpus callosum, frontal lobes, and parietal lobes were evaluated. RESULTS Of the 217 study participants, 212 were included in both neurocognitive and brain imaging analysis. Of these, 105 were female (49.5%); mean (SD) age at diagnosis was 14.36 (4.79) years; time since diagnosis was 7.7 (1.7) years. Adjusting for chemotherapy doses and age at diagnosis, neurocognitive impairment was associated with higher propofol cumulative dose (relative risk [RR], 1.40 per 100 mg/kg; 95% CI, 1.11-1.75), flurane exposure (RR, 1.10 per exposure; 95% CI, 1.01-1.21), and longer anesthesia duration (RR, 1.03 per cumulative hour; 95% CI, 1.00-1.06). Slower processing speed was associated with higher propofol dose (estimate [est], −0.30; P = .04), greater number of exposures to fluranes (est, −0.14; P = .01), and longer anesthesia duration (est, −0.04; P = .003). Higher corpus callosum white matter diffusivity was associated with dose of propofol (est, 2.55; P = .01) and duration of anesthesia (est, 2.40; P = .02). Processing speed was significantly correlated with corpus callosum diffusivity (r = −0.26, P < .001). CONCLUSIONS AND RELEVANCE Higher cumulative anesthesia exposure and duration may be associated with neurocognitive impairment and neuroimaging abnormalities in long-term survivors of childhood acute lymphoblastic leukemia, beyond the known outcomes associated with neurotoxic chemotherapies. Anesthesia exposures should be limited in pediatric populations with chronic health conditions who undergo multiple medical procedures.
Survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy only are at risk for neurocognitive impairment. Regions of interest were identified a priori based on glucocorticoid receptor distribution, and sex‐stratified multivariable linear regression models were used to test associations between brain MRI morphology and total number of intrathecal injections, and serum concentration of dexamethasone and methotrexate. Compared with controls, ALL survivors have persistently smaller volumes in the bilateral cerebellum (P < 0.005), hippocampal subregions (P < 0.03), temporal lobe regions (P < 0.03), frontal lobe regions (P < 0.04), and parietal lobe regions (precuneus; P < 0.002). Long‐term problems with learning may be related to residual posttreatment brain differences.
Chemotherapeutic agents used to treat acute lymphoblastic leukemia (ALL), the most common cancer affecting young children, have been associated with long-term cognitive impairments that reduce quality of life. Executive dysfunction is one of the most consistently observed deficits and can have substantial and pervasive effects on academic success, occupational achievement, psychosocial function, and psychiatric status. We examined the neural mechanisms of executive dysfunction by measuring structural and functional connectomes in 161 long-term survivors of pediatric ALL, age 8-21 years, who were treated on a single contemporary chemotherapy-only protocol for standard/high- or low-risk disease. Lower global efficiency, a measure of information exchange and network integration, of both structural and functional connectomes was found in survivors with executive dysfunction compared with those without dysfunction (p < 0.046). Patients with standard/high- versus low-risk disease and those who received greater number of intrathecal treatments containing methotrexate had the lowest network efficiencies. Patients with executive dysfunction also showed hyperconnectivity in sensorimotor, visual, and auditory-processing regions (p = 0.037) and poor separation between sensorimotor, executive/attention, salience, and default mode networks (p < 0.0001). Connectome disruption was consistent with a pattern of delayed neurodevelopment that may be associated with reduced resilience, adaptability, and flexibility of the brain network. These findings highlight the need for interventions that will prevent or manage cognitive impairment in survivors of pediatric acute lymphoblastic leukemia.
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