Evaluating patient-reported symptoms and late adverse effects following completion of first-line chemotherapy for ovarian cancer using the MOST (Measure of Ovarian Symptoms and Treatment concerns).

OBJECTIVES: Knowledge on the course of symptoms patients with ovarian cancer experience is limited. We documented the prevalence and trajectories of symptoms after first-line chemotherapy using the Measure of Ovarian Symptoms and Treatment concerns (MOST). METHODS: A total of 726 patients who received platinum-based chemotherapy for ovarian cancer were asked to complete the MOST every 3 months, beginning 6 months post-diagnosis and continuing for up to 4 years. We used descriptive statistics to examine temporal changes in MOST-S26 index scores for disease or treatment-related (MOST-DorT), neurotoxicity (MOST-NTx), abdominal (MOST-Abdo), and psychological (MOST-Psych) symptoms, and wellbeing (MOST-Wellbeing) and selected individual symptoms. We used group-based trajectory models to identify groups with persistently poor symptoms. RESULTS: The median MOST-Abdo, MOST-DorT and MOST-Wellbeing score were worst at chemotherapy-end but improved and stabilised by 1, 3 and 12 months after treatment, respectively. The median MOST-NTx score peaked at 1 month after treatment before improving, while the median MOST-Psych score did not change substantially over time. Long-term moderate-to-severe fatigue (32%), trouble sleeping (31%), sore hands and feet (21%), pins and needles (20%) and anxiety (18%) were common. Trajectory models revealed groups of patients with persistent symptoms had MOST-DorT scores above 30 and MOST-NTx scores above 40 at treatment-end. CONCLUSIONS: Although many patients report improvements in symptoms by 3 months after first-line chemotherapy for ovarian cancer, patients who score > 30/100 on MOST-S26-DorT or > 40/100 on MOST-S26-NTx at the end of chemotherapy are likely to have persistent symptoms. The MOST could triage this at-risk subset for early intervention.

Oroxylum Indicum ameliorates chemotherapy induced cognitive impairment.

While chemotherapy is the most effective therapeutic approach for treating a variety of cancer patients, commonly used chemotherapeutic agents, often induce several adverse effects. Escalating evidence indicates that chemotherapeutics, particularly doxorubicin (DOX) and cyclophosphamide (CPS), induce cognitive impairment associated with central nervous system toxicity. This study was performed to determine neuroprotective effects of Oroxylum indicum extract (OIE) in regard to preventing chemotherapy induced cognitive impairment (CICI) occurring after 4 cycles of DOX (2mg/kg) and CPS (50mg/kg) combination chemotherapy in male C57BL/6J mice. OIE significantly prevented the chemotherapy impaired short-term cognitive performance, exploratory behavior associated with cognitive performance, cognitive performance, and spatial learning and memory in the Y-maze, Open-Field, Novel Object Recognition, and Morris Water Maze tests, respectively. These data suggest that OIE protects from the CICI. OIE decreased the reactive oxygen species and lipid peroxide generated by the chemotherapy treatment in the brain, while also blocking the chemotherapy-induced glutathione depletion. These results establish that OIE exhibits potent antioxidant activity in chemotherapy treated mice. Notably, OIE significantly increased the Complex-I and Complex-IV activities in the brain, indicating that OIE enhances mitochondrial function in the brain. In silico analysis of the major active chemical constituents (Oroxylin A, Baicalein and Chrysin) of OIE indicated that OIE has a favorable absorption, distribution, metabolism and excretion (ADME) profile. Taken together, our results are consistent with the conclusion that OIE prevents CICI by counteracting oxidative stress and perhaps by improving mitochondrial function.

Cognitive Dysfunction and Neurophysiologic Mechanism of Breast Cancer Patients Undergoing Chemotherapy Based on Resting State Functional Magnetic Resonance Imaging.

We studied chemotherapy-related cognitive impairment via resting state (RS)-functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) in 19 cases of patients with early breast cancer. White matter neuropsychological test treatment were carried out before and after chemotherapy, RS-fMRI, and DTI evaluation. In RS-fMRI with regional homogeneity (ReHo) reflects brain activity. In the DTI with fractional anisotropy (FA) reflect the integrity of the white matter. Determining the region of interest by image analysis, we calculated the neuropsychologic test score using the paired t-test and FA change ReHo values of regions of interest. Finally after the test treatment, in the chemotherapy group for pairing correlation analysis t-test scores change in meaningful inspection and change ReHo and FA. Chemotherapy after chemotherapy than before chemotherapy difference memory test and self-evaluation of cognitive (P < 0.05). ReHo value increases occurred in the right orbitofrontal region and the left dorsolateral prefrontal cortex. Declines in brain regions were the anterior inferior cerebellar lobe, cerebellar lobe, right middle temporal gyrus and the superior temporal gyrus, the lower right of the center area, and the central gyrus. This prospective study on resting state and RS-fMRI functional magnetic resonance DTI study DTI sequence combination chemotherapy for breast cancer-related cognitive disorders supports the "chemo brain" point of view. Chemotherapy can cause memory decline, accompanied by a partial area of the brain and white matter integrity in brain activity changes. Prompt clinical treatment RS-fMRI and DTI have potential applications in assessing chemotherapy-related cognitive impairment.

Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only.

Importance: Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). Objective: 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. Exposure: ALL treatment using chemotherapy-only protocols. Main Outcomes and Measures: 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. ß 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). Results: 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: ß = 55.54; SE = 25.55; P = .03; right cerebellum: ß = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: ß = 82.71; SE = 31.04; P = .009; right cerebellum: ß = 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 (ß = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (ß = -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. Conclusions and Relevance: 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.

Bexarotene normalizes chemotherapy-induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice.

Frequently reported neurotoxic sequelae of cancer treatment include cognitive deficits and sensorimotor abnormalities that have long-lasting negative effects on the quality of life of an increasing number of cancer survivors. The underlying mechanisms are not fully understood and there is no effective treatment. We show here that cisplatin treatment of mice not only caused cognitive dysfunction but also impaired sensorimotor function. These functional deficits are associated with reduced myelin density and complexity in the cingulate and sensorimotor cortex. At the ultrastructural level, myelin abnormalities were characterized by decompaction. We used this model to examine the effect of bexarotene, an agonist of the RXR-family of nuclear receptors. Administration of only five daily doses of bexarotene after completion of cisplatin treatment was sufficient to normalize myelin density and fiber coherency and to restore myelin compaction in cingulate and sensorimotor cortex. Functionally, bexarotene normalized performance of cisplatin-treated mice in tests for cognitive and sensorimotor function. RNAseq analysis identified the TR/RXR pathway as one of the top canonical pathways activated by administration of bexarotene to cisplatin-treated mice. Bexarotene also activated neuregulin and netrin pathways that are implicated in myelin formation/maintenance, synaptic function and axonal guidance. In conclusion, short term treatment with bexarotene is sufficient to reverse the adverse effects of cisplatin on white matter structure, cognitive function, and sensorimotor performance. These encouraging findings warrant further studies into potential clinical translation and the underlying mechanisms of bexarotene for chemobrain.

Post-chemotherapy cognitive impairment in hematological patients: current understanding of chemobrain in hematology.

Introduction: Cognitive impairment caused by chemotherapies, a condition known as chemobrain, is a possible side effect that affects alertness, learning, memory, and concentration.Areas covered: Chemobrain has been principally investigated as a possible side-effect among cancer patients. However, numerous drugs used to treat hematological malignancies can determine the appearance of chemobrain. In this review, we have examined some commonly used drugs for the treatment of hematological malignancies which are known to have a deleterious action on cognitive functions.Numerous mechanisms have been suggested, comprising the direct neurotoxicity of chemotherapeutic drugs, oxidative stress, genetic predisposition, cytokine-provoked damage, histone modifications, immune alteration, and the action of chemotherapeutic on trophic factors and structural proteins of brain cells.Expert commentary: Cognitive dysfunction provoked by the treatment of hematological diseases is an actual challenge in clinical practice. Actually, there are no totally efficient and innocuous treatments for this syndrome. It is important that further investigations specify the existence of predictors and gravity factors to pre- and post-therapy cognitive change and identify the influence of tumor treatments on the cognitive alterations in long-term, cancer survivors. Moreover, future studies are needed to analyze the interactions between genetic risk, amyloid accumulation, intrinsic brain networks, and chemotherapy.

An Overview on Chemotherapy-induced Cognitive Impairment and Potential Role of Antidepressants.

BACKGROUND: Cognitive impairment is an adverse reaction of cancer chemotherapy and is likely to affect up to 75% of patients during the treatment and 35% of patients experience it for several months after the chemotherapy. Patients manifest symptoms like alteration in working ability, awareness, concentration, visual-verbal memory, attention, executive functions, processing speed, fatigue and behavioural dysfunctions. Post-chemotherapy, cancer survivors have a reduced quality of life due to the symptoms of chemobrain. Apart from this, there are clinical reports which also associate mood disorders, vascular complications, and seizures in some cases. Therefore, the quality of lifestyle of cancer patients/ survivors is severely affected and only worsens due to the absence of any efficacious treatments. With the increase in survivorship, it's vital to identify effective strategies, until then only symptomatic relief for chemobrain can be provided. The depressive symptoms were causally linked to the pathophysiological imbalance between the pro and antiinflammatory cytokines. CONCLUSION: The common causative factor, cytokines can be targeted for the amelioration of an associated symptom of both depression and chemotherapy. Thus, antidepressants can have a beneficial effect on chemotherapy-induced inflammation and cognitive dysfunction via cytokine balance. Also, neurogenesis property of certain antidepressant drugs rationalises their evaluation against CICI. This review briefly glances upon chemotherapy-induced cognitive impairment (CICI), and the modulatory effect of antidepressants on CICI pathomechanisms.

A mouse model of chemotherapy-related cognitive impairments integrating the risk factors of aging and APOE4 genotype.

Some cancer survivors experience marked cognitive impairment, referred to as cancer-related cognitive impairment (CRCI). CRCI has been linked to the genetic factor APOE4, the strongest genetic risk factor for Alzheimer's disease (AD). We used APOE knock-in mice to test whether the relationship between APOE4 and CRCI can be demonstrated in a mouse model, to identify associations of chemotherapy with behavioural and structural correlates of cognition, and to test whether chemotherapy affects markers of AD. Twelve-month old C57BL/6 J female APOE3 (n = 30) and APOE4 (n = 31) knock-in mice were randomized to treatment with either doxorubicin (10 mg/kg) or saline. Behavioural assays at 2-21 weeks-post exposure included open field maze, elevated zero maze, pre-pulse inhibition, Barnes maze, and fear conditioning. Ex-vivo magnetic resonance imaging was used to determine regional volume differences at 31-35 weeks-post exposure, and tissue sections were analyzed for markers of AD pathogenesis. Minimal toxicities were observed in the aged mice after doxorubicin exposure. In the Barnes maze assay, APOE3 mice did not exhibit impairment in spatial learning after doxorubicin treatment, but APOE4 mice demonstrated significant impairments in both the initial identification of the escape hole and the latency to full escape at 6 weeks post-exposure. Both APOE3 and APOE4 mice treated with doxorubicin showed impairment of spatial memory. Grey matter volume in the frontal cortex decreased in APOE4 mice treated with doxorubicin vs. APOE3 mice. This study demonstrates cognitive impairments in aged APOE4 knock-in mice after doxorubicin treatment and establishes this system as a novel and powerful model of CRCI.