Processing speed, working memory, and IQ: a developmental model of cognitive deficits following cranial radiation therapy

IQ decrements following cranial radiation therapy (CRT) for acute lymphoblastic leukemia (ALL) are most apparent years after treatment. The authors examined a developmental model for delayed deficits by evaluating the relationship between processing speed, working memory, and IQ in long-term survivors of childhood ALL (n = 27) compared with demographically matched controls (n = 27). The ALL group treated with CRT showed deficits in IQ, working memory, and processing speed relative to controls. Differences in IQ between the CRT group and controls were mediated by differences in working memory. Processing speed did not fully account for the working memory deficit in the CRT group. Participants with ALL treated only with chemotherapy showed similar working memory and processing speed as matched controls. Data suggest that deficits in processing speed and working memory following CRT may underlie declines in IQ.     

Verbal cognitive functioning and learning in girls treated for acute lymphoblastic leukemia by chemotherapy with or without cranial irradiation

Neuropsychological problems have frequently been reported following treatment of Acute Lymphoblastic Leukemia (ALL), however, partly because of the heterogeneity of the previously studied samples, the specific nature of these deficits is still a matter of debate. These problems, however, appear to be related more to the combination of cranial radiation therapy (CRT) and intrathecal chemotherapy (ITC) than to ITC alone. In this study, we evaluated a homogenous group of l9 girls between the ages of 7 and 11 years, 30 months after the completion of treatment. Nine received cranial radiation and chemotherapy and 10 were treated with chemotherapy alone. The patients were compared to 10 normal healthy controls. Neuropsychological tests included the Wechsler Intelligence Scale for Children-Third Edition (WISC-III), the California Verbal Learning Test-Children's Version (CVLT-C), and the Calculation and Passage Comprehension subtests of the Woodcock-Johnson Psycho-Educational Battery-Revised. Results confirmed the presence of a verbal learning deficit in ALL girls treated with the combination of ITC and CRT. The ITC and CRT group scored significantly lower than the healthy controls on the Passage Comprehension subtest and on 5 of the 6 verbal subtests of the WISC-III. Furthermore, compared to nonirradiated patients and healthy normal controls, the ITC and CRT group was impaired on the Freedom from Distractibility index of the WISC-III, indicating an auditory-verbal attention deficit. On the CVLT-C, the ITC and CRT group was particularly impaired on the second half of the learning trials compared to the other two groups, showing a plateau in their performance. The ITC group was not different from the healthy control group, suggesting a less detrimental effect of the ITC alone on verbal abilities. Globally, these results indicate a deficit affecting auditory attention and verbal learning in girls who receive ITC and CRT, which may suggest the necessity for special educational assistance for these children.     

Motor and perceptual timing deficits among survivors of childhood leukemia

OBJECTIVE: There is growing evidence of cerebellar-frontal system change in children treated for leukemia with chemotherapy alone (Lesnik et al., 1998). METHODS: We compared 22 long-term survivors of acute lymphoblastic leukemia (ALL), aged 8-18, to 22 age- and gender-matched controls on tasks emphasizing cerebellar-frontal functioning including judgment of time duration and motor timing. Groups were also compared on a judgment of pitch task, used as a control measure. Children with ALL were at least 5 years from diagnosis, treated with intrathecal chemotherapy (methotrexate in all, hydrocortisone and cytarabine in 20/22), but not radiation therapy, and free from recurrence of disease. RESULTS: After controlling for IQ, the ALL group had poorer performance than controls on judgment of long duration and motor timing, but not judgment of pitch. CONCLUSIONS: Treatment with intrathecal and infusional chemotherapy for childhood ALL may be associated with skill deficits comparable to those seen in individuals with cerebellar-frontal abnormalities.     

DNA methylation and obesity in survivors of pediatric acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study

Because survivors of pediatric acute lymphoblastic leukemia (ALL) are more likely to be obese than unaffected contemporaries, we compared DNA methylation profiles between normal‐weight and obese survivors at adiposity‐associated CpG sites previously‐reported by epigenome‐wide association studies (EWAS) of body mass index (BMI) in the general population. We selected 96 ALL survivors from the Childhood Cancer Survivor Study: 48 obese and 48 normal weight. The Illumina HumanMethylation450 BeadChip was used to compare DNA methylation at 211 loci identified in EWAS of BMI in the general population. Thirty‐nine loci were associated (false discovery rate <0.05) with obesity among survivors who only received chemotherapy (n = 49). No loci were significantly associated with obesity among CRT‐exposed survivors (n = 47). Our results suggest that previously identified BMI‐DNA methylation loci are associated with obesity in ALL survivors who were spared CRT, while no loci were significantly associated with obesity in survivors who received CRT.     

A Genetic Investigation of the Covariation Among Inspection Time, Choice Reaction Time, and IQ Subtest Scores

Information processing speed, as measured by elementary cognitive tasks, is correlated with higher order cognitive ability so that increased speed relates to improved cognitive performance. The question of whether the genetic variation in Inspection Time (IT) and Choice Reaction Time (CRT) is associated with IQ through a unitary factor was addressed in this multivariate genetic study of IT, CRT, and IQ subtest scores. The sample included 184 MZ and 206 DZ twin pairs with a mean age of 16.2 years (range 15-18 years). They were administered a visual (pi-figure) IT task, a two-choice RT task, five computerized subtests of the Multidimensional Aptitude Battery, and the digit symbol substitution subtest from the WAIS-R. The data supported a factor model comprising a general, three group (verbal ability, visuospatial ability, broad speediness), and specific genetic factor structure, a shared environmental factor influencing all tests but IT, plus unique environmental factors that were largely specific to individual measures. The general genetic factor displayed factor loadings ranging between 0.35 and 0.66 for the IQ subtests, with IT and CRT loadings of -0.47 and -0.24, respectively. Results indicate that a unitary factor is insufficient to describe the entire relationship between cognitive speed measures and all IQ subtests, with independent genetic effects explaining further covariation between processing speed (especially CRT) and Digit Symbol.     

Visual and Verbal Short-Term Memory Deficits in Childhood Leukemia Survivors After Intrathecal Chemotheraphy

Assessed survivors of childhood lymphoblastic leukemia (ALL)treated with intrathecal chemotherapy, using the Wide RangeAssessment of Memory and Learning (WRAML), compared to controlswithout cancer, matched as closely as possible-in age, SES,and gender. Mild, but consistent, deficits were found in bothvisual-spatial and verbal single-trial memory tasks. In multitriallearning, only visual-spatial tasks resulted in deficient scores,while verbal learning was within the normal range. IQ resultsindicated scores 10–20 points lower in the ALL group.Memory results are related to deficits in strategic planningand attentional distractiveness. The WRAML may be a useful clinicaltool to evaluate differential memory deficits in children withALL.     

No association between the Catechol-O-Methyltransferase (COMT) val158met polymorphism and cognitive improvement following cognitive remediation therapy (CRT) in schizophrenia

Cognitive deficits are rate limiters on recovery in schizophrenia that respond poorly to pharmacotherapy. Cognitive remediation therapy (CRT), a novel psychological therapy, has produced promising outcomes for cognition. However, little is known about the biological mechanisms that might underlie individual differences in CRT response. Catechol-O-Methyltransferase (COMT) is associated specifically with prefrontal cognition. The COMT Val158Met polymorphism is known to have a functional effect on the rate of dopamine degradation, which may be related to cognitive treatment response. This study aimed to determine whether COMT genotype influences cognitive improvement following CRT in schizophrenia. Participants with schizophrenia were recruited from three randomised controlled trials of CRT compared to treatment as usual, and one CRT treatment only trial, each providing 40 CRT sessions. Eighty-seven participants (40%) agreed to participate in the genetic study, and provided DNA for COMT genotyping. Cognitive function and psychopathology were assessed at baseline, post-treatment and 3-6-month follow-up. People with the COMT Val/Met genotype performed more poorly on categories achieved at baseline on the Wisconsin Card Sorting Test (WCST) than those homozygous for the Val or Met allele. Cognitive function improved with CRT but there was no association between this cognitive improvement and COMT genotype, either in the CRT group or in the total sample. The COMT val158Met polymorphism does not appear to be a clinically useful biomarker of cognitive improvement following CRT in schizophrenia. A complex set of factors may influence cognitive change, however, such that the COMT genotype might still have a subtle effect on response to CRT or similar interventions.     

Behavioral Adkjustmnet and Social Functioning of Long-Term, Survivors of Childhood Leukemia: Parent and Teacher Reports

Obtained parent and teacher reports of behavior and social competencefor children who were survivors of acute lymphoblastic leukemia(ALL). At followup, children were 5–18 years of age, 48months postdiagnosis, in first continuous remission, and ofchemotherapy. Each child had been randomized to receive either1,800 cGY whole brain radiation therapy (WBRT) plus intrathecalmethotrexate (IT MTX), or IT MTX alone as central nervous systemprophylaxis, and one of four chemotherapy regimenss that variedin treatment intensity. Scores on standardized measures (CBCL-P/Tand PIC) were generally similar to instrument, norms. Parents,but not teachers, reported heightened child somatic concerns.There was no effect of WBRT or chemotherapy regimen on ratingsof behavioral adjustment. Results indicate minimal psychosocialmorbidity among long-term survivors of ALL and suggest thatthe stressful life envents associated with cancer and its treatmentdo not cause significant behavioral or emotional diffculties.     

Pathways Linking Treatment Intensity and Psychosocial Outcomes among Adult Survivors of Childhood Leukemia

To determine the pathways between treatment intensity (age at diagnosis, dosage of chemotherapy [intrathecal methotrexate; IT-MTX] and cranial radiation [CRT]) and various psychosocial outcomes, review of medical records and structured interviews were carried out in 510 adult survivors of childhood leukemia. Structural equation modeling revealed that higher treatment intensity during childhood (indicated by treatment with high-dose CRT, low-dose IT-MTX, and adjusted by younger age at diagnosis) predicted more health- compromising behaviors as adults through lower educational achievement. Additionally, higher childhood treatment intensity predicted current negative mood both directly and via changes in perceived limitations. The present study's findings suggest that higher treatment intensity during childhood may serve as a risk factor for adult survivors' health-compromising behaviors through neuropsychological deficits that arise from cancer treatment.     

MRI morphometry of mamillary bodies, caudate nuclei, and prefrontal cortices after chemotherapy for childhood leukemia: multivariate models of early and late developing memory subsystems.

Neurotoxic intrathecal chemotherapy for childhood acute lymphoblastic leukemia (ALL) affects developing structures and functions of memory and learning subsystems selectively. Results show significant reductions in magnetic resonance imaging morphometry of mamillary bodies, components of the corticolimbic-diencephalic subsystem subserving functionally later developing, single-trial memory, nonsignificant changes in bilateral heads of the caudate nuclei, components of the corticostriatal subsystem subserving functionally earlier developing, multitrial learning, significant reductions in prefrontal cortical volume, visual and verbal single-trial memory deficits, and visuospatial, but not verbal, multitrial learning deficits. Multiple regression models provide evidence for partial dissociation and connectivity between the subsystems, and suggest that greater involvement of caudate may compensate for inefficient corticolimbic-diencephalic components.     

Cognitive effects of childhood leukemia therapy: a case for four specific deficits

Prophylactic treatment of the central nervous system (CNS) with cranial irradiation and antineoplastic drugs has made childhood acute lymphoblastic leukemia (ALL) a survivable disease, but at the same time there have been many reports of iatrogenic effects, including deficits in cognitive functioning. Previous research suggests a particular effect on the Freedom from Distractibility factor of the WISC-R, memory, and attention. These particular abilities are tested in a group of 43 ALL survivors, with comparisons against solid tumor as well as sibling controls. The results indicate that four cognitive processes are affected by CNS prophylaxis for ALL: short-term memory, speed of processing, visuomotor coordination, and sequencing ability. Younger children have a more severe speed of processing deficit and children treated with a less rigorous protocol appear to be slightly less affected generally. The specific cognitive deficits found are related to neurological evidence on both theoretical and empirical grounds. Results suggest that children who have received CNS prophylaxis are able to learn, but may be slower to acquire new material and may benefit from bimodal presentation.     

Pre-Emptive Immunotherapy for Clearance of Molecular Disease in Childhood Acute Lymphoblastic Leukemia after Transplantation

Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) after transplantation. Patients with ALL who consecutively underwent transplantation in Frankfurt/Main, Germany between January 1, 2005 and July 1, 2014 were included in this retrospective study. Chimerism monitoring was performed in all, and MRD assessment was performed in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC). The 3-year probabilities of event-free survival (EFS) were .69?±?.06 for the cohort without IT and .69?±?.10 for IT patients. Incidences of relapse (CIR) and treatment-related mortality (CITRM) were equally distributed between both cohorts (without IT: 3-year CIR, .21?±?.05, 3-year CITRM, .10?±?.04; IT patients: 3-year CIR, .18?±?.09, 3-year CITRM .13?±?.07). Accordingly, 3-year EFS and 3-year CIR were similar in CC and MC patients with IT, whereas MC patients without IT experienced relapse. IT was neither associated with an enhanced immune recovery nor an increased risk for acute graft-versus-host disease. Relapse prevention by IT in patients at risk may lead to the same favorable outcome as found in CC and MRD-negative-patients. This underlines the importance of excellent MRD and chimerism monitoring after transplantation as the basis for IT to improve survival in childhood ALL.     

Prenatal alcohol exposure causes attention deficits in male rats

Children with fetal alcohol spectrum disorder (FASD) are often diagnosed with attention-deficit/ hyperactivity disorder (ADHD). These children show increases in reaction time (RT) variability and false alarms on choice reaction time (CRT) tasks. In this study, adult rats prenatally exposed to ethanol were trained to perform a CRT task. An analysis of the distribution of RTs obtained from the CRT task found that rats with a history of prenatal ethanol exposure had more variable RT distributions, possibly because of lapses of attention. In addition, it was found that, similar to children with FASD, the ethanol-exposed rats had more false alarms. Thus, rats with prenatal ethanol exposure show attention deficits that are similar to those of children with FASD and ADHD.     

Sex differences in cognitive processing in children treated with CNS prophylaxis for acute lymphoblastic leukemia

Evaluated cognitive processing in 51 children (27 female, 24 male) who had been treated for acute lymphoblastic leukemia (ALL) with CNS prophylaxis (cranial radiation in combination with intrathecal chemotherapy) and were continuously disease-free for 5 to 12 years. The control group comprised 15 children treated for Wilm's tumor. Functions assessed included visuoperceptual skills, generation of organizational strategies, sensitivity to organizational structure, and attention. The ALL group showed performance deficits relative to the solid tumor controls in appreciating the organization inherent in complex visuospatial material and alertness, with females more severely affected than males. Sex differences favoring males on IQ and academic achievement were related to these cognitive processes.     

Precursor T-cell acute lymphoblastic leukemia/lymphoma involving the uterine cervix,myometrium, endometrium,and appendix

This report presents a case of precursor T-cell acute lymphoblastic leukemia/lymphoma (ALL) involving the uterine cervix, myometrium, endometrium, and appendix. The patient was a 38-year-old woman with a history of ALL who had been in remission for 4 years following chemotherapy. The malignant lymphoid infiltrate was characterized by blasts, showing scant cytoplasm, irregular hyperchromatic nuclei, and occasional prominent nucleoli. They were immunoreactive for CD45RB, CD3, CD43, CD34, and focally for TdT. Curiously, the blasts replaced the endometrial stroma and spared the associated epithelium. The patient was again treated with chemotherapy but her disease did not respond. She succumbed to her disease approximately 10 months after her initial evaluation for symptoms related to ALL relapse. Precursor T-cell ALL most commonly presents as a mediastinal mass in adolescent males. Although any organ may be affected, involvement of the female reproductive organs is rare. This case shows some of the varied manifestations of precursor T-cell ALL and highlights the necessity of considering the female reproductive tract as a possible location of relapsing disease.     

Atypical haemolytic uraemic syndrome as a complication of induction chemotherapy for acute lymphoblastic leukaemia

This report describes a case of fatal haemolytic uraemic syndrome (HUS) developing in a child with acute lymphoblastic leukaemia (ALL) during induction chemotherapy. The aetiology in this case is uncertain but it may have resulted from treatment with L-asparaginase or vincristine. The possibility of HUS during induction chemotherapy for ALL should be considered early on in the treatment regimen, if clinical signs and symptoms suggest this diagnosis, so that appropriate treatment can be instituted.     

Changes in the hepatitis B surface antibody in childhood acute lymphocytic leukaemia survivors after treatment with the CCLG‐ALL 2008 protocol

Antibody levels after hepatitis B virus (HBV) vaccination may be affected by suppression of the immune system due to cancer therapy. As such, childhood acute lymphocytic leukaemia (ALL) survivors are at risk of HBV infection due to immunosuppression secondary to chemotherapy. However, the hepatitis B surface antibody (HBsAb)‐seropositive rate of childhood ALL survivors after chemotherapy is unknown, and the need to revaccinate HBsAb‐seronegative ALL survivors is not appreciated in China. To assess the changes in HBsAb before and after chemotherapy, we retrospectively analyzed clinical data from 547 patients treated with the Chinese Children Leukaemia Group (CCLG)‐ALL 2008 protocol from 1 April 2008 to 30 August 2019. The results revealed that 416 patients (76·1%) were HBsAb‐seropositive at diagnosis, and at the time of the cessation of chemotherapy, 177 patients (32·4%) were HBsAb‐seropositive and 370 patients (67·6%) were HBsAb‐seronegative. Interestingly, 11 patients who were HBsAb‐seronegative at diagnosis converted to seropositive at the time of the cessation of chemotherapy. HBsAb titres were decreased after chemotherapy (P < 0·0001). Further, patients with higher HBsAb titres at diagnosis were more likely to maintain protective antibody titres at the completion of chemotherapy (P < 0·0001). The loss of antibody was more remarkable in younger patients (≤ 10 years) both at diagnosis (P = 0·009) and at the completion of chemotherapy (P = 0·006). In summary, this study showed that 67·6% of patients were HBsAb‐seronegative at the time of the cessation of chemotherapy, which indicates that ALL survivors are at high risk of HBV. As a result, HBV revaccination after chemotherapy should be highly valued in ALL survivors.     

儿童急性淋巴细胞白血病化疗前后细胞免疫的变化及与人巨细胞病毒感染的关系

目的 探讨儿童急性淋巴细胞白血病(ALL)化疗前后细胞免疫的变化及与人巨细胞病毒(HCMV)感染的关系.方法 103例接受化疗的ALL患儿设为ALL组,34例健康儿童设为对照组,流式细胞术检测对照组、ALL组初治时、化疗结束时、化疗后3个月T细胞亚群.化疗结束时采用PCR检测HCMV病毒,并根据检测结果分为感染组和未感染组,对比分析两组T细胞亚群差异,多因素Logistic回归分析HCMV感染的影响因素.结果 ALL组(初治时)T细胞亚群CD3+、CD4+ 、CD8+、CD4 +/CD8+均低于对照组,差异有统计学意义(P ＜0.05);ALL组化疗前后CD3+、CD4+、CD4+/CD8+表现出先降低后升高的趋势,差异具有统计学意义(P＜0.05);化疗结束时共18例患者HCMV病毒检测为阳性,感染组化疗结束时CD3+、CD4+、CD4+/CD8+低于未感染组,差异有统计学意义(P＜0.05);多因素Logistic回归分析显示,疾病危险度是ALL患儿HCMV感染的危险因素(AOR=1.543,95％ CI:1.213～1.809,P=0.028),而CD3+、CD4+、CD4+/CD8+、最低PLT是HCMV感染的保护因素.结论 ALL自身以及化疗后细胞免疫功能降低,增加了HCMV感染风险,细胞免疫功能下降与HCMV感染可能互为因果.     

Histological differences between preoperative chemoradiotherapy and chemotherapy for rectal cancer: a clinicopathological study

Pathological studies on the different histological effects between neoadjuvant chemotherapy (NAC) and preoperative chemoradiation therapy (preoperative CRT) have not been performed. The purpose of this study is to elucidate the histological differences in tissue received from NAC and preoperative CRT for rectal cancer to evaluate whether a pathological assessment method used after CRT can be applied for NAC. One hundred and thirty‐eight patients were enrolled in this study; 88 patients underwent their operations after preoperative CRT or NAC, and 50 patients underwent surgery only. Residual tumor area was measured using morphometry software and we compared the stromal component of myofibroblasts, immune cells, and vasculature to elucidate the difference of therapeutic effect between them. The grade of reduction after preoperative CRT was more prominent than that seen in NAC. Also, ypT downstaging was more prominent in preoperative CRT than in NAC, and ypN downstaging was more frequent in NAC than in preoperative CRT. Preoperative CRT showed more marked myofibroblasts and fewer immune cells than did NAC, which indicates different effects on the cancer microenvironment. Our histological results suggest different effects between NAC and preoperative CRT on tumor tissue. The best assessment method available for a variable therapeutic protocol should be further investigated.     

Cognitive status of children treated with central nervous system prophylactic chemotherapy for acute lymphocytic leukemia.

Treatment-related cognitive impairments have been reported for survivors of childhood leukemia following prophylactic central nervous system (CNS) treatment with craniospinal radiation. We examined the neurocognitive status of 46 children with acute lymphocytic leukemia (ALL) to assess the impact of a regimen consisting of systemic chemotherapy and prophylactic CNS chemotherapy. By comparing three groups of ALL children (i.e., patients whose diagnosis was recent, patients 1 year postdiagnosis currently receiving CNS prophylactic chemotherapy, and off-therapy patients who had been treated with chemotherapy for 3 years) and their healthy siblings on measures of sequential and simultaneous processing, we were able to examine the effects of CNS prophylactic and systemic chemotherapy at various points during treatment. Results indicate that the children who had received a 3-year course of chemotherapy (off-therapy patients) were more impaired on tasks involving right-hemisphere simultaneous processing than were sibling controls or ALL children whose diagnosis was recent and whose treatment had just begun. Age at diagnosis did not interact with the effects of chemotherapy. These findings support the need for continued evaluation of cognitive functioning in ALL, children receiving CNS prophylactic chemotherapy to identify potential harmful neurocognitive sequelae of treatment.