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This article provides an overview of the most recent literature on the cognitive adverse effects of chemotherapy in patients with breast cancer. The prevalence of cognitive dysfunction in patients treated with chemotherapy was variable in studies using a cross-sectional design. More recent prospective studies detected cognitive difficulties in subgroups of patients, mostly at short-term follow-ups, but other studies found no evidence of impairment. Studies using neuroimaging techniques and animal models have begun to examine structural and functional correlates of cognitive changes associated with chemotherapy. A review of the literature suggests that considerable progress has been made in the investigation of chemotherapy-related cognitive dysfunction in recent years, and highlights the importance of a multidisciplinary approach to further elucidate the mechanisms that may underlie treatment-related toxicity. [ABSTRACT FROM AUTHOR]

There is a paucity of research on treatment-related neurotoxicity in older adults with multiple myeloma (MM) treated with high-dose chemotherapy (HDC) and autologous SCT (HDC/ASCT), despite the increasing use of this regimen. We examined resting state functional connectivity (RSFC), gray matter (GM) volume, neurocognitive function (NF), and proinflammatory cytokines (PCy) in older patients with MM pre- and post-HDC/ASCT. Eighteen patients underwent MRI, NF tests, and serum PCy measurements prior to HDC/ASCT, and fifteen patients completed a follow up five-months post-HDC/ASCT. There were significant decreases in RSFC post-HDC/ASCT in (1) the central executive network (CEN) involving the left dorsolateral prefrontal cortex and right posterior parietal cortex ( p = 0.022) and (2) the CEN involving the right posterior parietal cortex and the salience network involving the right dorsal anterior cingulate cortex ( p = 0.029). There were no significant changes in GM or NF, except for improvements in attention (Digit Span Backward, p = 0.03). There were significant increases in several PCy post-HDC/ASCT ( p ≤ 0.05). In conclusion, RSFC decreased in frontal, parietal, and cingulate cortices post-HDC/ASCT, NF was relatively stable, and several PCy increased. These findings are congruent with other studies in cancer patients and provide supporting evidence for the vulnerability of frontoparietal regions to chemotherapy's adverse effects.

Language reorganization may represent an adaptive phenomenon to compensate tumor invasion of the dominant hemisphere. However, the functional changes over time underlying language plasticity remain unknown. We evaluated language function in patients with low-grade glioma (LGG), using task-based functional MRI (tb-fMRI), graph-theory and standardized language assessment. We hypothesized that functional networks obtained from tb-fMRI would show connectivity changes over time, with increased right-hemispheric participation. We recruited five right-handed patients (4M, mean age 47.6Y) with left-hemispheric LGG. Tb-fMRI and language assessment were conducted pre-operatively (pre-op), and post-operatively: post-op1 (4-8 months), post-op2 (10-14 months) and post-op3 (16-23 months). We computed the individual functional networks applying optimal percolation thresholding. Language dominance and hemispheric connectivity were quantified by laterality indices (LI) on fMRI maps and connectivity matrices. A fixed linear mixed model was used to assess the intra-patient correlation trend of LI values over time and their correlation with language performance. Individual networks showed increased inter-hemispheric and right-sided connectivity involving language areas homologues. Two patterns of language reorganization emerged: Three/five patients demonstrated a left-to-codominant shift from pre-op to post-op3 (type 1). Two/five patients started as atypical dominant at pre-op, and remained unchanged at post-op3 (type 2). LI obtained from tb-fMRI showed a significant left-to-right trend in all patients across timepoints. There were no significant changes in language performance over time. Type 1 language reorganization may be related to the treatment, while type 2 may be tumor-induced, since it was already present at pre-op. Increased inter-hemispheric and right-side connectivity may represent the initial step to develop functional plasticity.

Many patients treated with chemotherapy for non-central nervous system (CNS) cancers experience cognitive dysfunction. However, few studies have investigated treatment-related neurotoxicity in women with ovarian cancer. The goal of this study was to assess regional brain function in patients with ovarian cancer after first-line chemotherapy. Seventeen patients with ovarian cancer and seventeen healthy controls matched for gender, age and education participated in the study. The patients were evaluated 1-4 months after completion of first line taxane/platinum chemotherapy. All participants underwent resting state functional MRI (rsfMRI) and regional homogeneity (ReHo) indices were calculated. The results showed that patients had significantly decreased average ReHo values in the left middle frontal gyrus, medial prefrontal cortex, and right superior parietal lobule, compared to healthy controls. This is the first rsfMRI study showing ReHo alterations in frontal and parietal regions in patients with ovarian cancer treated with first-line chemotherapy. The findings are overall congruent with prior studies in non-CNS cancer populations and provide supporting evidence for the prevailing notion that frontal areas are particularly vulnerable to the adverse effects of chemotherapy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Patients with brain tumors treated with radiotherapy (RT) and chemotherapy (CT) often experience cognitive dysfunction. We reported that single nucleotide polymorphisms (SNPs) in the APOE, COMT, and BDNF genes may influence cognition in brain tumor patients. In this study, we assessed whether genes associated with late-onset Alzheimer's disease (LOAD), inflammation, cholesterol transport, dopamine and myelin regulation, and DNA repair may influence cognitive outcome in this population., Methods: One hundred and fifty brain tumor patients treated with RT ± CT or CT alone completed a neurocognitive assessment and provided a blood sample for genotyping. We genotyped genes/SNPs in these pathways: (i) LOAD risk/inflammation/cholesterol transport, (ii) dopamine regulation, (iii) myelin regulation, (iv) DNA repair, (v) blood-brain barrier disruption, (vi) cell cycle regulation, and (vii) response to oxidative stress. White matter (WM) abnormalities were rated on brain MRIs., Results: Multivariable linear regression analysis with Bayesian shrinkage estimation of SNP effects, adjusting for relevant demographic, disease, and treatment variables, indicated strong associations (posterior association summary [PAS] ≥ 0.95) among tests of attention, executive functions, and memory and 33 SNPs in genes involved in: LOAD/inflammation/cholesterol transport (eg, PDE7A, IL-6), dopamine regulation (eg, DRD1, COMT), myelin repair (eg, TCF4), DNA repair (eg, RAD51), cell cycle regulation (eg, SESN1), and response to oxidative stress (eg, GSTP1). The SNPs were not significantly associated with WM abnormalities., Conclusion: This novel study suggests that polymorphisms in genes involved in aging and inflammation, dopamine, myelin and cell cycle regulation, and DNA repair and response to oxidative stress may be associated with cognitive outcome in patients with brain tumors., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The standard treatment for primary central nervous system lymphoma (PCNSL) involves induction methotrexate-based chemotherapy with or without consolidation whole brain radiotherapy (WBRT). As WBRT carries a substantial risk for cognitive impairment, alternative consolidation treatments have been used to reduce neurotoxicity, including reduced-dose WBRT (rdWBRT) or high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT). In this study, we characterized cognitive functions in PCNSL patients achieving long-term remission following rdWBRT or HDC-ASCT., Methods: PCNSL patients completed cognitive evaluations at diagnosis, post-induction chemotherapy, and yearly up to 5 years following rdWBRT or HDC-ASCT. Quality of life (QoL), white matter (WM) disease, and cortical atrophy (CA) on MRI were assessed at similar intervals., Results: Performance was impaired on most cognitive tests at diagnosis. Linear mixed model analyses in each group showed statistically significant improvement from baseline up to year 3 in attention/executive functions, graphomotor speed, and memory; however, there was a decline in attention/executive functions and memory after year 3 in both groups. WM abnormalities increased over time in both groups, but more patients treated with rdWBRT developed CA and WM changes. There were no significant longitudinal group differences in cognitive performance or QoL., Conclusions: Results indicated improvement in cognitive function up to 3 years post-treatment, but a decline at later time points and an increase in brain structure abnormalities in both groups. The findings suggest that rdWBRT and HDC-ASCT may be associated with delayed neurotoxicity in progression-free patients and underscore the need for long-term follow-up to characterize cognitive dysfunction in PCNSL patients.

Brain tumor patients treated with radiotherapy (RT) often develop cognitive dysfunction, and recent studies suggest that the APOE ε-4 allele may influence cognitive outcome. The ε-4 allele is known to promote beta (β) amyloid deposition in the cortex, and preliminary evidence suggests that RT may be associated with this process. However, it is unknown whether β-amyloid accumulation contributes to treatment neurotoxicity. In this pilot study, we assessed neuropsychological functions and β-amyloid retention using 18 F-florbetaben (FBB) PET in a subset of brain tumor patients who participated in our study of APOE polymorphisms and cognitive functions. Twenty glioma patients treated with conformal RT ± chemotherapy participated in the study: 6 were APOE ε-4 carriers and 14 were non-ε-4 carriers. Patients completed a neuropsychological re-evaluation (mean time interval = 5 years, SD = 0.83) and brain MRI and FBB PET scans. Wilcoxon signed-rank test comparisons between prior and current neuropsychological assessments showed a significant decline in attention (Brief Test of Attention, p = 0.018), and a near significant decline in verbal learning (Hopkins Verbal learning Test-Learning, p = 0.07). Comparisons by APOE status showed significant differences over time in attention/working memory (WAIS-III digits forward, p = 0.028 and digits backward, p = 0.032), with a decline among APOE ε-4 carriers. There were no significant differences in any of the FBB PET analyses between APOE ε-4 carriers and non-ε-4 carriers. The findings suggest that glioma patients may experience worsening in attention and executive functions several years after treatment, and that the APOE ε-4 allele may modulate cognitive decline, but independent of increased β-amyloid deposition.

Women with ovarian cancer often undergo chemotherapy involving multiple agents. However, little is known about treatment-related central neurotoxicity in this population. The goal of this cross-sectional study was to assess brain structure and function and neurocognitive abilities in patients with ovarian cancer following first-line chemotherapy. Eighteen patients with ovarian, peritoneal and fallopian tube cancer and eighteen healthy controls matched for gender, age and education participated in the study. The patients were evaluated 1-4 months following completion of first-line taxane/platinum chemotherapy. All participants underwent structural and functional magnetic resonance imaging (MRI), and completed neuropsychological tests of attention, memory and executive functions. Neuroimaging assessments included voxel-based morphometry (VBM) for measuring gray matter (GM) volume, and functional MRI (fMRI) during the N-back working memory task. The results of VBM showed that patients had significantly reduced GM volume compared to healthy controls in the right middle/superior frontal gyrus, and in the left supramarginal gyrus and left inferior parietal lobule. fMRI results indicated significantly decreased activation in patients relative to healthy controls in the left middle frontal gyrus and left inferior parietal lobule during the N-back task (1/2/3-back >0-back). There were no statistically significant differences between the two groups on the neuropsychological tests. This is the first study showing structural and functional alterations involving frontal and parietal regions in patients with ovarian cancer treated with first-line chemotherapy. These findings are congruent with studies involving women with breast cancer, and provide additional supporting evidence for central neurotoxicity associated with taxane/platinum chemotherapy.

Background: Cognitive dysfunction is common among patients with brain tumors and can be associated with the disease and treatment with radiotherapy and chemotherapy. However, little is known about genetic risk factors that may moderate the vulnerability for developing cognitive dysfunction. In this study, we examined the association of single nucleotide polymorphisms (SNPs) in the catechol-O-methyl transferase (COMT), brain-derived neurotrophic factor (BDNF), and dystrobrevin-binding protein 1 (DTNBP1) genes with cognitive functions and neuroimaging outcomes in patients with brain tumors., Methods: One hundred and fifty patients with brain tumors completed neuropsychological tests of attention, executive functions, and memory and were genotyped for polymorphisms in the COMT, BDNF, and DTNBP1 genes. Ratings of white matter (WM) abnormalities on magnetic resonance imaging scans were performed., Results: Multivariate regression shrinkage analyses, adjusted for age, education, treatment type, time since treatment completion, and tumor location, indicated a significant association between the COMT SNP rs4680 (Val158Met) and memory with lower scores in delayed recall (P < .01) among homozygotes (valine/valine). Additional COMT, BDNF and DTNBP1 SNPs were significantly associated with attention, executive functions, and memory scores., Conclusion: This is the first study to suggest that known and newly described polymorphisms in genes associated with executive and memory functions in healthy individuals and other clinical populations may modulate cognitive outcome in patients with brain tumors., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hematopoietic stem cell transplantation (HSCT) is often used in the treatment of hematologic disorders. Although it can be curative, the pre-transplant conditioning regimen can be associated with neurotoxicity. In this prospective study, we examined white matter (WM) integrity with diffusion tensor imaging (DTI) and neuropsychological functioning before and one year after HSCT in twenty-two patients with hematologic disorders and ten healthy controls evaluated at similar intervals. Eighteen patients received conditioning treatment with high-dose (HD) chemotherapy, and four had full dose total body irradiation (fTBI) and HD chemotherapy prior to undergoing an allogeneic or autologous HSCT. The results showed a significant decrease in mean diffusivity (MD) and axial diffusivity (AD) in diffuse WM regions one year after HSCT (p-corrected <0.05) in the patient group compared to healthy controls. At baseline, patients treated with allogeneic HSCT had higher MD and AD in the left hemisphere WM than autologous HSCT patients (p-corrected <0.05). One year post-transplant, patients treated with allogeneic HSCT had lower fractional anisotropy (FA) and higher radial diffusivity (RD) in the right hemisphere and left frontal WM compared to patients treated with autologous HSCT (p-corrected <0.05).There were modest but significant correlations between MD values and cognitive test scores, and these were greatest for timed tests and in projection tracts. Patients showed a trend toward a decline in working memory, and had lower cognitive test scores than healthy controls at the one-year assessment. The findings suggest a relatively diffuse pattern of alterations in WM integrity in adult survivors of HSCT.

Cognitive dysfunction is prevalent among brain tumor patients treated with radiotherapy (RT) and chemotherapy. However, there are no approved pharmacological interventions for cognitive dysfunction in cancer patients. The goal of this pilot study was to examine the efficacy of donepezil, an acetylcholinesterase inhibitor used to treat Alzheimer's disease, in improving cognitive functions in brain tumor patients previously treated with RT + chemotherapy or chemotherapy alone. Fifteen patients with a brain tumor received a single daily dose of donepezil for 24 weeks (5 mg for 4 weeks, then 10 mg for 20 weeks). Patients completed cognitive evaluations prior to initiating therapy (baseline), and about 12 weeks (mid-study) and 24 weeks (end-of-study) subsequent to initiation of donepezil therapy. The results of linear mixed models analysis, controlling for each patient's baseline cognitive test score, showed a significant post-baseline improvement in attention (WAIS-III digit span forward; p = 0.037), graphomotor speed (WAIS-III digit symbol; p = 0.035) and visual memory (BVMT-R-delay; p = 0.025). There was also an improvement in self-reported quality of life (FACT-Br, social well-being subscale; p = 0.01). The findings of this pilot study suggest that treatment with donepezil may improve some aspects of cognitive functions and quality of life in brain tumor patients. Similar findings were reported in two prior trials of donepezil in brain tumor survivors.

High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an alternative to address chemoresistance and overcome the blood-brain barrier. In this single-center phase-2 study, newly diagnosed PCNSL patients received 5 to 7 cycles of chemotherapy with rituximab, methotrexate (3.5 g/m(2)), procarbazine, and vincristine (R-MPV). Those with a complete or partial response proceeded with consolidation HDC with thiotepa, cyclophosphamide, and busulfan, followed by ASCT and no radiotherapy. Primary end point was 1-year progression-free survival (PFS), N = 32. Median age was 57, and median Karnofsky performance status 80. Following R-MPV, objective response rate was 97%, and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median PFS and overall survival (OS) were not reached (median follow-up: 45 months). Two-year PFS was 79% (95% confidence interval [CI], 58-90), with no events observed beyond 2 years. Two-year OS was 81% (95% CI, 63-91). In transplanted patients, 2-year PFS and OS were 81%. There were 3 treatment-related deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions posttransplant. In conclusion, this treatment was associated with excellent disease control and survival, an acceptable toxicity profile, and no evidence of neurotoxicity thus far. This trial was registered at www.clinicaltrials.gov as NCT00596154., (© 2015 by The American Society of Hematology.)

Purpose: Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab., Experimental Design: Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1., Results: Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84-100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT., Conclusions: This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non-IDH-1-mutated glioblastoma., (©2014 American Association for Cancer Research.)

Objective: The goal of this study was to assess whether the APOE ε4 allele and other APOE single nucleotide polymorphisms (SNPs) influence neuropsychological and neuroimaging outcomes in patients with brain tumors., Methods: Two hundred eleven patients with brain tumors participated in the study. All patients completed standardized neuropsychological tests and provided a blood sample for APOE genotyping. Ratings of white matter abnormalities were performed on MRI scans. Patients were classified into 2 groups based on the presence (n = 50) or absence (n = 161) of at least one APOE ε4 allele. Additional APOE SNPs were genotyped in a subset of 150 patients., Results: Patients with at least one APOE ε4 allele had significantly lower scores in verbal learning and delayed recall, and marginally significant lower scores in executive function, in comparison to noncarriers of an ε4 allele. Patients with at least one ε4 allele and history of cigarette smoking had significantly higher scores in working memory and verbal learning than ε4 carriers who never smoked. Nine additional APOE SNPs were significantly associated with attention and executive and memory abilities. There were no significant differences between ε4 carriers and noncarriers on the extent of white matter abnormalities on MRI., Conclusions: The findings suggest that patients with brain tumors who are carriers of the APOE ε4 allele may have increased vulnerability to developing memory and executive dysfunction, and that additional SNPs in the APOE gene may be associated with cognitive outcome., (© 2014 American Academy of Neurology.)

Hematopoietic stem cell transplantation (HSCT) is an efficacious treatment for many hematologic malignancies. However, the conditioning regimen of high-dose (HD) chemotherapy with or without total body irradiation (TBI) can be associated with neurotoxicity. In this prospective study, we used quantitative neuroimaging techniques to examine regional gray matter and ventricular volumes, and standardized neuropsychological tests to assess cognitive function before and 1 year after HSCT in 28 patients with hematologic malignancies and in ten healthy controls evaluated at similar intervals. Nineteen patients received conditioning treatment with HD chemotherapy alone and nine had both TBI and HD chemotherapy. There was a significant reduction in gray matter volume in the middle frontal gyrus bilaterally and in the left caudate nucleus in the patient group (all patients combined) but not among healthy controls over the 1-year follow-up period. There was a significant increase in left lateral ventricle volume and in total ventricle volume in the patient group, relative to healthy controls. Similar brain structural changes were seen for patients treated with HD chemotherapy alone. The neuropsychological results showed that 21% of patients could be classified as impaired at baseline. The Reliable Change Index suggested no significantly different rates of cognitive decline between patients and healthy controls. The findings suggest that HSCT patients may be at an increased risk for developing regional brain volume loss, and that subgroups may experience cognitive dysfunction prior to and 1 year following the transplant.

Purpose: A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine in primary CNS lymphoma., Patients and Methods: Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor., Results: Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50 to 100). Thirty-one patients (60%) achieved a CR after R-MPV and received rdWBRT. The 2-year PFS for this group was 77%; median PFS was 7.7 years. Median overall survival (OS) was not reached (median follow-up for survivors, 5.9 years); 3-year OS was 87%. The overall (N = 52) median PFS was 3.3 years, and median OS was 6.6 years. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and follow-up scores remained relatively stable across the various domains (n = 12). All examined MRIs (n = 28) displayed a Fazekas score of ≤ 3, and no patient developed scores of 4 to 5; differences in ADC values did not predict response (P = .15), PFS (P = .27), or OS (P = .33)., Conclusion: R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.

Objectives: As advances in treatment have prolonged survival for many patients with ovarian cancer, there has been growing interest in assessing the adverse effects of disease and treatment. The aim of this study was to review the literature on cognitive function and quality of life (QOL) in this population., Methods: A review of published studies including formal assessment of neurocognitive functions and self-reported domains of quality of life, with an emphasis on cognitive function, was performed., Results: The small number of studies including formal evaluations of neurocognitive function suggests that many ovarian cancer patients experience cognitive difficulties associated with their disease and treatment. Several studies described declines in self-reported cognitive function that may impact QOL, but the results were not consistent across studies., Conclusions: Adequately powered longitudinal studies including formal neurocognitive and QOL assessments are needed to advance our understanding of the incidence of cognitive dysfunction and its impact on functional ability and QOL in ovarian cancer patients. These research efforts may ultimately contribute to treatment decision-making through the identification of vulnerable patients, and to the development of appropriate intervention strategies to improve cognitive function and QOL., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based chemotherapy (HD-MTX) alone or in combination with whole brain radiotherapy (WBRT). The combined modality regimen carries a substantial risk for cognitive impairment, and HD-MTX alone has been used more often recently in part to reduce neurotoxicity. In this study, we assessed cognitive functioning and quality of life in PCNSL survivors treated with WBRT + HD-MTX or HD-MTX alone. Fifty PCNSL patients in disease remission underwent a posttreatment baseline neuropsychological evaluation, and a subset of patients completed a follow-up evaluation. Quality of life and extent of white matter disease and atrophy on MRI were assessed. Comparisons according to treatment type after controlling for age and time since treatment completion showed that patients treated with HD-MTX alone had significantly higher scores on tests of selective attention and memory than patients treated with the combined modality regimen. Patients treated with WBRT + HD-MTX had impairments across most cognitive domains, and these were of sufficient severity to interfere with quality of life, as over 50% were not working due to their illness. Patients treated with HD-MTX alone did not meet criteria for cognitive impairment but scored within 1 SD below the normative sample on most tests. Patients with more extensive white matter disease had lower scores on tests of set-shifting and memory. Cognitive dysfunction was more prevalent in PCNSL survivors treated with WBRT + HD-MTX compared with patients treated with HD-MTX alone.

Objective: To ascertain the impact of prior antiplatelet and statin therapy on symptomatic embolic events in [corrected] infective endocarditis (IE)., Patients and Methods: We studied a retrospective cohort of adult patients with a diagnosis of IE who presented to Mayo Clinic (Rochester, MN) from January 1, 2003, to December 31, 2006. Patients were grouped into those who received treatment before infection or controls who did not receive treatment for both antiplatelet therapy and, separately, statin therapy. Because of the retrospective study design and thus the nonrandomized treatment groups, a propensity score approach was used to account for the confounding factors that may have influenced treatment allocation. Antiplatelet therapy included aspirin, dipyridamole, clopidogrel, ticlopidine or any combination of these agents. Statin therapy included atorvastatin, simvastatin, pravastatin, lovastatin, rosuvastatin, or fluvastatin. The primary end point was a symptomatic embolic event that occurred before or during hospitalization. Multivariable logistic regression was used to assess the propensity-adjusted effects of continuous daily therapy with antiplatelet and statin agents on risk of symptomatic emboli. Likewise, Cox proportional hazards regression was used to test for an independent association with 6-month mortality for each of the treatments., Results: The study cohort comprised 283 patients with [corrected] IE. Twenty-eight patients (24.1%) who received prior continuous antiplatelet therapy developed a symptomatic embolic event compared with 66 (39.5%) who did not receive such treatment. After adjusting for propensity to treat, the effect of antiplatelet therapy on embolic risk was not statistically significant (odds ratio, 0.71; 95% confidence interval [CI], 0.37-1.36; P=.30). Only 14 patients (18.2%) who received prior continuous statin therapy developed a symptomatic embolic event compared with 80 (39.4%) of the 203 patients who did not. After adjusting for propensity to treat with statin therapy, the benefit attributable to statins was significant (odds ratio, 0.30; 95% CI, 0.14-0.62; P=.001). The 6-month mortality rate of the entire cohort was 28% (95% CI, 23%-34%). No significant difference was found in the propensity-adjusted rate of 6-month mortality between patients who had and had not undergone prior antiplatelet therapy (P=.91) or those who had and had not undergone prior statin therapy (P=.87)., Conclusion: The rate of symptomatic emboli associated with IE was reduced in patients who received continuous daily statin therapy before onset of IE. Despite fewer embolic events observed in patients who received antiplatelet agents, a significant association was not found after adjusting for propensity factors. A continued evaluation of these drugs and their potential impact on subsequent embolism among IE patients is warranted.

Fatigue among students may harm their learning. This study evaluated the fatigue of nursing undergraduate students and its relations to their graduation year, participation in extracurricular activities, people with whom they lived, depression and their body mass index (BMI)). The study had the participation of 189 (60.2%) students from the EEUSP, from which 96.2% were women with the average age of 21.6 years old, 80.9% lived with their parents, 43.9% performed extracurricular activities, 24.8% had varied BMI and 22.2% presented dysphoria or depression (Beck Depression Inventory). Fatigue was moderate/intense for 83.5% of the students (Piper Fatigue Scale--Revised and Fatigue Pictogram) and 59.8% reported moderate/intense impairment in their habitual activities. Fatigue presented a positive correlation to the graduation year, to the BMI and to depression (p < 0.001). The academic activity was the main cause of fatigue, whereas sleep and leisure were the most frequent strategies to handle it. Fatigue was significant and intense, but there was an irregularity between its frequency, magnitude and impact in the daily life activities.

Background: Women diagnosed with ovarian cancer often undergo chemotherapy involving multiple agents. However, little is known about the incidence of cognitive adverse effects of chemotherapy in survivors of this disease. This cross-sectional study assessed neuropsychological functions in long-term survivors of ovarian cancer who were either in complete remission or with evidence of recurrent disease., Methods: Forty-eight women diagnosed with ovarian cancer 5 to 10 years prior to study enrollment underwent a brief neuropsychological evaluation; 22 patients were disease free and without history of recurrence (Group 1), and 26 patients had recurrent disease and were receiving treatment with chemotherapy or hormonal therapy (Group 2)., Results: There were no statistically significant differences between the two patient groups on tests of attention, memory, and executive functions. Group mean cognitive test scores were within the average range on all tests; however 28% of patients met criteria for cognitive impairment, a significantly higher frequency (p=0.03) than reported in healthy populations., Conclusions: In this study, neuropsychological test performance did not differ significantly between ovarian cancer survivors who were in remission and patients with recurrent disease and receiving treatment. Cognitive impairment was evident in a subset of patients, although group means test scores were within the average range. Additional research using prospective longitudinal designs is needed to clarify the contribution of disease, chemotherapy, hormonal therapy, and other risk factors to cognitive outcome in this clinical population., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Cognitive dysfunction associated with both the disease and the adverse effects of radiotherapy (RT) and chemotherapy is a significant problem among brain tumor patients. Currently, it is considered the most frequent complication among long-term survivors. A review of the literature indicates that whole-brain RT alone or in combination with chemotherapy results in cognitive dysfunction more pronounced than from either partial RT or chemotherapy alone. The cognitive domains sensitive to treatment adverse effects include attention, executive functions, memory, and graphomotor speed. An increasing number of studies and clinical trials have incorporated cognitive outcome measures and have provided relevant information about therapy-related neurotoxicity and the incidence of cognitive dysfunction. Recent studies have begun to elucidate the pathophysiologic mechanisms that may underlie RT and chemotherapy injury to the brain. Although there are no established preventive or therapeutic interventions for treatment-induced cognitive dysfunction, this is an area of growing interest, and several approaches are currently under investigation.

High-dose chemotherapy and whole brain radiotherapy (WBRT) can prolong survival in primary CNS lymphoma (PCNSL) patients, but is often associated with clinically significant cognitive decline. In this study we assessed neuropsychological functioning prospectively in newly diagnosed PCNSL patients treated with induction chemotherapy followed by reduced-dose WBRT. Twelve patients underwent neuropsychological evaluations at diagnosis, after induction chemotherapy, and 6 and 12 months after WBRT. Nine patients completed additional cognitive evaluations 18 and 24 months post-treatment. At diagnosis, patients had impairments in Executive Functions, Verbal Memory, and Motor Speed. There was a significant improvement in Executive Functions (P < 0.01) and Verbal Memory (P < 0.05) following induction chemotherapy, and scores remained relatively stable up to 12 months post-treatment. Among the nine patients who completed a 2-year follow-up, there was a significant improvement in the Executive domain (P < 0.05) and a trend toward a decline in the Verbal Memory domain. Executive and Verbal Memory functions improved following induction chemotherapy, likely due to decreased tumor burden and discontinuation of corticosteroid and anticonvulsant medications. There was no significant cognitive decline up to 24 months post-chemotherapy and reduced-dose WBRT in this group of PCNSL patients, however, difficulties in Verbal Memory and Motor speed persisted over the follow-up period.

Heart failure is a clinical syndrome associated with progressive cardiac, vascular, and renal dysfunction. Regardless of the initial injury, investigations have demonstrated that neurohormones play an important role in the complex multiorgan and cellular adaptations. Natriuretic peptides play a key role in this process, antagonizing the actions of the renin-angiotensin-aldosterone system, thus promoting vasodilatation and natriuresis. Other important physiologic properties of the natriuretic peptides are prolusitropic, sympathoinhibitory, antiproliferative, anti-ischemic, anti-inflammatory, and antioxidative. Administering exogenous natriuretic peptide is a US Food and Drug Administration-approved therapy for patients with advanced decompensated congestive heart failure. Also, measuring natriuretic peptide levels has diagnostic and prognostic value. More studies are needed to define the full potential of this unique family of endogenous peptides.

Background In patients with low-grade glioma (LGG), the tumor and its treatment with conformal radiation therapy (RT) and chemotherapy can disrupt cognitive function. However, the contribution of disease and treatment to long-term cognitive outcome remains to be elucidated. In this study, we performed longitudinal cognitive follow-up in a subgroup of patients who received RT, chemotherapy, or no treatment. Methods Twenty-five LGG patients underwent neuropsychological evaluations at study entry, and 6 and 12 months subsequently; 9 patients had RT +/- chemotherapy prior to enrollment and 16 had no treatment. Results At the initial evaluation, treated patients had impaired performance on motor speed only, but scored 1 standard deviation below normative values on tests of executive functions; untreated patients had no cognitive impairment. Repeated measures analyses of variance showed a significant variation over time (P = 0.03) in nonverbal memory (delayed recall); treated patients' performance improved at the 6-month follow-up to a level comparable to untreated patients, but both groups declined slightly by the 12-month evaluation. In a subset of patients (N = 16) available for an additional cognitive evaluation, significant changes between the 12-month and the long-term follow-up were seen in phonemic verbal fluency, mood and quality of life; untreated patients seen at short intervals improved slightly while treated patients seen at longer intervals declined. Conclusions Longitudinal follow-up showed that both disease duration and treatment with RT +/- chemotherapy contributed to a mild decrement in nonverbal recall and in some aspects of executive functions and quality of life in this group of LGG patients.

Background: Treatment-related neurotoxicity has been recognized as a significant problem in patients with primary central nervous system lymphoma (PCNSL) as effective treatment has increased survival rates. There is, however, a paucity of research on cognitive functions in this population., Design: In a review of the literature, a total of 17 articles that described cognitive outcome in adult PCNSL patients were identified., Results: The studies that assessed cognitive functions after whole-brain radiotherapy combined with chemotherapy reported cognitive impairment in most patients. Patients treated with chemotherapy alone had either stable or improved cognitive performance in most studies. Methodological problems, however, limited the ability to ascertain the specific contribution of disease and various treatment interventions to cognitive outcome. On the basis of the literature review, a battery of cognitive and quality-of-life (QoL) measures to be used in prospective clinical trials was proposed. The battery is composed of five standardized neuropsychological tests, covering four domains sensitive to disease and treatment effects (attention, executive functions, memory, psychomotor speed), and QoL questionnaires, and meets criteria for use in collaborative trials., Conclusion: The incorporation of formal and systematic cognitive evaluations in PCNSL studies will improve our understanding of treatment-related neurotoxicity in this population.

Purpose of Review: This article reviews the most recent literature on chemotherapy-associated cognitive changes in women with breast cancer., Recent Findings: Most cross-sectional studies reported neuropsychological impairment in patients treated with chemotherapy, but the prevalence was variable. Prospective studies documented cognitive dysfunction in subgroups of patients treated with chemotherapy, but other reports found no evidence of impairment. Studies using neuroimaging techniques and animal models have begun to examine structural and functional correlates of cognitive changes associated with chemotherapy., Summary: Significant advances have been made in the study of chemotherapy-related cognitive dysfunction over the past 10 years. The investigation of additional factors that may contribute to cognitive outcome, such as the effects of treatments other than chemotherapy and genetic susceptibility, is likely to further advance the field.

Background: The role of radiotherapy and chemotherapy in the treatment of low-grade gliomas (LGG) is controversial regarding their effect on survival and the development of neurotoxicity. The few published studies examining adverse treatment effects on cognition revealed conflicting results., Objective: To assess cognitive functioning in LGG patients who received conformal radiation therapy (RT), chemotherapy, or no treatment., Design: 40 LGG patients participated in the study; 16 patients had RT +/- chemotherapy, and 24 patients had no treatment. All patients underwent a neuropsychological evaluation. APOE genotype was obtained in 36 patients who were classified in two groups based on the presence or absence of at least one apolipoprotein E small je, Ukrainian-4 (APOE small je, Ukrainian-4) allele., Results: Treated LGG patients had lower scores than untreated patients on several cognitive domains; patients who completed treatment at intervals greater than 3 years and had long disease duration had significantly lower scores on the Non-Verbal Memory domain. Antiepileptic polytherapy, treatment history, and disease duration jointly contributed to low Psychomotor domain scores. 62% of treated patients showed white matter confluence on MRI, whereas only 9% of the untreated patients had such changes. Preliminary comparisons between APOE small je, Ukrainian-4 carriers (n = 9) and non-carriers (n = 27) on cognitive domain scores revealed no statistically significant differences, but APOE small je, Ukrainian-4 carriers had lower mean scores on the Verbal Memory domain than did non-small je, Ukrainian-4 carriers., Conclusions: RT +/- chemotherapy, disease duration, and antiepileptic treatment contributed to mild cognitive difficulties in LGG patients.

As effective treatment interventions have increased survival rates, there has been greater awareness that many brain tumor patients experience cognitive dysfunction despite adequate disease control. Cognitive difficulties often have an impact on quality of life and interfere with the patient's ability to function at premorbid levels; however, the incidence of cognitive dysfunction in brain tumor patients is unknown, because it has not been investigated systematically. Future prospective clinical trials in neuro-oncology should include cognitive outcome measures to increase understanding of the contribution of the tumor and the delayed effects of treatment to cognitive dysfunction.

Background: To determine the pathologic complete response rate of advanced ovarian cancer to weekly paclitaxel plus gemcitabine and carboplatin with filgrastim, and assess the longitudinal impact of this regimen on quality-of-life and cognitive functioning., Methods: Fourteen patients with advanced ovarian, peritoneal, or fallopian tube cancer were treated in the phase I portion of the study. Initial doses were paclitaxel: 60 mg/m(2) days 1, 8, and 15; gemcitabine: 800 mg/m(2) days 1 and 8; and carboplatin: area under the curve (AUC) 5 day 1, every 21 days for 6 cycles with filgrastim. Twenty-seven patients were treated at the phase II dose. Pathologic response was assessed by second-look laparoscopy in patients with complete response. Patients completed longitudinal assessments of quality-of-life and cognitive functioning., Results: Maximally tolerated doses were paclitaxel: 80 mg/m(2) days 1 and 8; gemcitabine: 800 mg/m(2) days 1 and 8; and carboplatin: AUC 5 day 1, every 21 days. Forty-eight percent of patients (13/27) experienced at least 1 grade 3 nonhematologic toxicity. Fifty percent (95% confidence interval [CI], 31-69%) of assessable patients achieved pathologic complete response. Median progression-free survival was 27.3 months (95% CI, 17.7 months to not reached), and overall survival 43.6 months (95% CI, 42 months to not reached). Cognitive functioning did not decline during or after chemotherapy. More highly educated women reported a perceived decline in concentration and memory while on chemotherapy. Quality-of-life scores were maintained during therapy., Conclusions: Fifty percent of patients with advanced-stage ovarian cancer achieved pathologic complete response to weekly paclitaxel plus gemcitabine and carboplatin. Cognitive functioning did not decline by objective measures, although highly educated women reported subjective impairment.

Background: Treatment for primary central nervous lymphoma (PCNSL) with chemotherapy and radiotherapy has resulted in improved survival, but some patients develop neurologic deterioration that represents a treatment-related toxic effect. This delayed neurotoxicity has been poorly defined in the literature, and the underlying mechanisms are unknown., Objective: To describe the clinical findings, time course, and pathophysiologic mechanisms associated with neurotoxicity in an attempt to generate hypotheses for future studies that address prevention and treatment of this complication of successful PCNSL therapy., Design: Retrospective review., Setting: Department of Neurology, Memorial Sloan-Kettering Cancer Center., Patients: One hundred eighty-five patients treated for PCNSL, including 43 who developed neurotoxicity., Main Outcome Measures: Potential risk factors, clinical course, and neuropsychological, neuroimaging, and histologic findings., Results: The 5-year cumulative incidence of neurotoxicity was 24%; this incidence increases over time. Neurotoxicity presented as a rapidly progressive subcortical dementia characterized by psychomotor slowing, executive and memory dysfunction, behavioral changes, gait ataxia, and incontinence. Imaging findings revealed diffuse white matter disease and cortical-subcortical atrophy. Available autopsy data showed white matter damage with gliosis, thickening of small vessels, and demyelination. Statistical analyses were performed, accounting for death as a competing risk. Older age (P = .01), mental status changes at diagnosis (P = .04), female sex (P = .05), and radiotherapy (P<.001) predicted neurotoxicity on univariate analysis, but only radiotherapy remained significant in the multivariate setting., Conclusion: These findings suggest that the core pathophysiologic mechanism is the interruption of frontal-subcortical circuits mediated by radiation damage, possibly caused by progressive microvascular alterations, loss of oligodendrocyte progenitors, or oxidative stress.

Object: The goal of this study was to investigate discordance between the location of speech arrest during awake cortical mapping, a common intraoperative indicator of hemispheric dominance, and silent speech functional magnetic resonance (fMR) imaging maps of frontal language function., Methods: Twenty-one cases were reviewed retrospectively. Images of silent speech fMR imaging activation were coregistered to anatomical MR images obtained for neuronavigation. These were compared with the intraoperative cortical photographs and the behavioral results of electrocorticography during awake craniotomy. An fMR imaging control study of three healthy volunteers was then conducted to characterize the differences between silent and vocalized speech fMR imaging protocols used for neurosurgical planning., Conclusions: Results of fMR imaging showed consistent and predominant activation of the inferior frontal gyrus (IFG) during silent speech tasks. During intraoperative mapping, however, 16 patients arrested in the precentral gyrus (PRG), well posterior to the fMR imaging activity. Of those 16, 14 arrested only in the PRG and not in the IFG as silent speech fMR imaging predicted. The control fMR imaging study showed that vocalized speech fMR imaging shifts the location of the fMR imaging prediction to include the motor strip and may be more appropriate for neurosurgical planning.

Two challenges need to be addressed to improve the outcome of patients with primary central nervous system lymphoma. The first challenge is to develop therapies that result in less toxicity and improved long-term outcome. The second challenge is to develop interventions to help those patients who develop treatment-related neurotoxicity; ongoing collaborative efforts are required to improve communication and understanding of this complication. Long-term follow up of prospective therapeutic studies should report on both disease control and the development of neurotoxicity. New protocols should include prospective longitudinal measures of neurocognitive function.

Purpose: To assess the safety and efficacy of intensive methotrexate-based chemotherapy followed by high-dose chemotherapy (HDT) with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma (PCNSL)., Patients and Methods: Twenty-eight patients received induction chemotherapy using high-dose systemic methotrexate (3.5 g/m2) and cytarabine (3 g/m2 daily for 2 days). Fourteen patients with chemosensitive disease evident on neuroimaging then received high-dose therapy using carmustine, etoposide, cytarabine, and melphalan with autologous stem-cell rescue., Results: The objective response rate to the induction-phase chemotherapy was 57%, and median overall survival is not yet assessable, with a median follow-up time of 28 months. The overall median event-free survival time is 5.6 months for all patients and 9.3 months for 14 patients who underwent transplantation. Six of these 14 patients (43%) remained disease-free at last follow-up. Treatment was well tolerated; there was one transplantation-related death. Prospective neuropsychologic evaluations have revealed no evidence of treatment-related neurotoxicity., Conclusion: This treatment approach is feasible in patients with newly diagnosed PCNSL without evidence of significant related neurotoxicity. Although the transplantation results are similar to those achieved in patients with aggressive or poor-prognosis systemic lymphoma, the low response rate to induction chemotherapy and the significant number of patients who experienced relapse soon after HDT suggest that more aggressive induction chemotherapy may be warranted.

Objective: To evaluate an integrated battery of preoperative functional magnetic resonance imaging (fMRI) tasks developed to identify cortical areas associated with tactile, motor, language, and visual functions., Methods: Sensitivity of each task was determined by the probability that a targeted region was activated for both healthy volunteers (n = 63) and surgical patients with lesions in these critical areas (n = 125). Accuracy of each task was determined by the correspondence between the fMRI maps and intraoperative electrophysiological measurements, including somatosensory evoked potentials (n = 16), direct cortical stimulation (n = 9), and language mapping (n = 5), and by preoperative Wada tests (n = 13) and visual field examinations (n = 6)., Results: For healthy volunteers, the overall sensitivity was 100% for identification of the central sulcus, visual cortex, and putative Wernicke's area, and 93% for the putative Broca's area (dominant hemisphere). For patients with tumors affecting these regions of interest, task sensitivity was 97% for identification of the central sulcus, 100% for the visual cortex, 91% for the putative Wernicke's area, and 77% for the putative Broca's area. These sensitivities were enhanced by the use of multiple tasks to target related functions. Concordance of the fMRI maps and intraoperative electrophysiological measurements was observed whenever both techniques yielded maps and Wada and visual field examinations were consistent with fMRI results., Conclusion: This integrated fMRI task battery offers standardized and noninvasive preoperative maps of multiple critical functions to facilitate assessment of surgical risk, planning of surgical routes, and direction of conventional, intraoperative electrophysiological procedures. Thus, a greater range of structural and functional relationships is brought to bear in the service of optimal outcomes for neurosurgery.

Although the correspondence between functional-magnetic resonance imaging (fMRI) representations of the sensorimotor cortex and intraoperative electrophysiology (including somatosensory evoked potential, SSEP, recordings and direct cortical stimulation) has been reported, a similar correspondence between fMRI and intraoperative localization of the language-sensitive cortex is not as well established. The aim of the present study was to evaluate the concordance between fMRI and intraoperative electrophysiology with respect to the localization of the language-sensitive and sensorimotor cortices. We present the results of 21 patients who underwent language and sensorimotor mapping by fMRI and intraoperative electrophysiology including SSEP recordings (n = 21), direct cortical stimulation of motor cortex (n = 15) and direct cortical stimulation of Broca's and Wernicke's area (n = 5). When responses were obtained with both methods, localization of function concurred in all cases. These observations suggest that fMRI represents a reliable preoperative tool for the identification of language-sensitive areas., (Copyright 2000 S. Karger AG, Basel)

Bismuth subsalicylate preparations are over-the-counter products for gastrointestinal complaints. Bismuth toxicity causes delirium, psychosis, ataxia, myoclonus, and seizures and is reversible over several weeks or months, when bismuth intake is stopped. We report a 54-year-old man with a 6-week history of progressive confusion and memory difficulty and a 2-3-week history of involuntary movements and gait impairment. His encephalopathy was further characterized by marked multifocal myoclonic jerks, coarse postural tremors, postural instability, and gait ataxia. He gradually improved. Extensive toxic, metabolic, and infectious workup demonstrated bismuth toxicity. Spinal tap and brain magnetic resonance scan were normal. Electroencephalography showed bihemispheric slowing. As his encephalopathy cleared, he reported using bismuth subsalicylate long term (daily intake of 8 oz). Bismuth levels 5 weeks after cessation of bismuth were elevated and normalized after 12 weeks. He followed a typical course for bismuth toxicity with subacute progressive encephalopathy and gradual recovery. Creutzfeldt-Jakob was strongly considered due to his rapidly progressive encephalopathy, multifocal myoclonus, and ataxia. Due to its rarity, bismuth toxicity is often overlooked. We hope this presentation will increase recognition of bismuth toxicity. We believe more detailed labeling of bismuth products is needed to avoid similar toxicity from this readily available product.