Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.
JAMA Netw Open. 2020 Nov 2;3(11):e2025839. doi: 10.1001/jamanetworkopen.2020.25839.
Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL).
To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network.
DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020.
ALL treatment using chemotherapy-only protocols.
This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. β values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count).
Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm3 vs 75 134 [6780] mm3; P < .001; male: 77 335 [6210] mm3 vs 79 020 [7420] mm3; P < .001). In female survivors, decreased cerebellar volume was associated with worse performance in Rey-Osterrieth complex figure test (left cerebellum: β = 55.54; SE = 25.55; P = .03; right cerebellum: β = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: β = 82.71; SE = 31.04; P = .009; right cerebellum: β = 91.06; SE = 30.72; P = .004). In female survivors, increased number of intrathecal treatments (ie, number of separate injections) was also associated with Worse Rey-Osterrieth test performance (β = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (β = -0.0014; SE = 0.0005; P = .01). Executive dysfunction was correlated with increased global efficiency between smaller brain regions (Pearson r = -0.24; P = .01) compared with individuals without dysfunction. Anatomical connectivity showed differences between impaired and nonimpaired survivors. Analysis of variance of effective-connectivity weights identified a significant interaction association (F = 3.99; P = .02) among the direction and strength of connectivity between the cerebellum and DLPFC, female sex, and executive dysfunction. Finally, no effective connectivity was found between the precuneus and DLPFC in female survivors with executive dysfunction.
These findings suggest that dexamethasone exposure was associated with smaller cerebello-thalamo-cortical regions in survivors of ALL and that disruption of effective connectivity was associated with impairment of executive function in female survivors.
采用现代单纯化疗方案治疗与儿童急性淋巴细胞白血病（ALL）幸存者的神经认知障碍风险相关。
确定甲氨蝶呤和糖皮质激素的联合使用是否与大脑抗氧化系统的干扰以及小脑-丘脑-皮质网络中糖皮质激素敏感区域的损伤和破坏有关。
设计、地点和参与者：本横断面研究于 2016 年 12 月至 2019 年 7 月在一家儿科癌症三级护理中心进行。参与者包括 ALL 幸存者，他们距癌症诊断超过 5 年，年龄在 8 岁或以上，并且接受机构的单纯化疗方案治疗。招募年龄匹配的社区成员作为对照组。数据分析于 2017 年 8 月至 2020 年 8 月进行。
使用单纯化疗方案治疗 ALL。
本研究比较了幸存者和社区对照组个体之间的脑容量，并检查了甲氨蝶呤和地塞米松暴露与幸存者认知结果之间的关联。比较了认知障碍幸存者和无认知障碍幸存者之间的功能和有效连接测量值。根据发表的指南， Rey-Osterrieth 复杂图形测试（一种要求个体复制图形然后根据记忆绘制图形的认知评估）的分数根据全国代表性参考数据进行了转换，以衡量组织和计划缺陷。小脑体积或化疗暴露的神经认知测试β值代表 z 分数（小脑的 1 SD 变化的 mm3/1 SD，地塞米松和甲氨蝶呤 AUC 的 mm3/[g×hr/L]，总鞘内计数的 mm3/鞘内计数）的神经认知结果的变化量。
在 302 名合格的参与者中，218 名（72%）参加了研究，其中 176 名（58%）有可用的磁共振成像（MRI）结果。在这些参与者中，89 名（51%）为女性，诊断时的平均（范围）年龄为 6.8（1-18）岁，评估时的平均（范围）年龄为 14.5（8-27）岁。在招募的 100 名社区个体作为对照组中，有 82 名有可用的 MRI 结果；其中，35 名（43%）为女性，评估时的平均（范围）年龄为 13.8（8-26）岁。幸存者和对照组个体的总脑容量没有显著差异。与对照组人群相比，两性幸存者的平均（SD）小脑体积均较小（女性：70568[6465]mm3与 75134[6780]mm3；P<0.001；男性：77335[6210]mm3与 79020[7420]mm3；P<0.001）。在女性幸存者中，小脑体积的减少与 Rey-Osterrieth 复杂图形测试的表现较差有关（左小脑：β=55.54；SE=25.55；P=0.03；右小脑：β=52.57；SE=25.50；P=0.04）和占主导地位的手运动加工速度（即滚柱钉板测试）较差（左小脑：β=82.71；SE=31.04；P=0.009；右小脑：β=91.06；SE=30.72；P=0.004）。在女性幸存者中，鞘内治疗次数（即单独注射次数）的增加也与 Rey-Osterrieth 测试表现较差有关（β=-0.154；SE=0.063；P=0.02），地塞米松暴露的增加也与该表现有关（β=-0.0014；SE=0.0005；P=0.01）。执行功能障碍与较小脑区之间的全局效率增加呈负相关（Pearson r=-0.24；P=0.01），与无功能障碍的个体相比。有效连接的方差分析确定了方向和强度之间的相互作用关联（F=3.99；P=0.02），小脑和 DLPFC 之间的连接、女性性别和执行功能障碍。最后，在有执行功能障碍的女性幸存者中，没有发现小脑前扣带回和 DLPFC 之间的有效连接。
这些发现表明，地塞米松暴露与 ALL 幸存者的小脑-丘脑-皮质区域较小有关，而有效连接的破坏与女性幸存者的执行功能障碍有关。
