Chemobrain Research Articles

Repurposing of erythropoietin as a neuroprotective agent against methotrexate-induced neurotoxicity in rats.

Methotrexate (MTX) is a cytotoxic drug that can trigger neurotoxicity via enhancing oxidative stress, apoptosis, and inflammation. On the other hand, erythropoietin (EPO) functions as an antioxidant, anti-apoptotic, and anti-inflammatory agent, in addition to its hematopoietic effects. The present study was developed to examine the neuroprotective impact of EPO against MTX-provoked neurotoxicity in rats. Chemo fog was elicited in Wistar rats via injection of one dosage of MTX (20 mg/kg, i.p) on the sixth day of the study. EPO was injected at 500 IU/kg/day, i.p for 10 successive days. MTX triggered memory and learning impairment as evidenced by Morris water maze, passive avoidance, and Y-maze cognitive tests. In addition, MTX induced oxidative stress as evident from the decline in hippocampal Nrf2 and HO-1 levels. MTX brought about apoptosis, as demonstrated by the elevation in p53, caspase-3, and Bax levels, as well as the decrease in Bcl2 levels. MTX also decreased Beclin-1, an autophagy-related marker, and increased P62 expression. In addition, MTX downregulated Sirt-1/AKT/FoxO3a pathway and increased miRNA-34a gene expression. Moreover, MTX increased acetylcholinesterase activity and reduced neurogenesis. EPO administration remarkably counteracted MTX-induced molecular and behavioral disorders in rat hippocampi. Our findings impart preclinical indication for repurposing of EPO as a promising neuroprotective agent through modulating miRNA-34a, autophagy, and the Sirt-1/FoxO3a signaling pathway.

Aerobic exercise and CogniTIVe functioning in women with breAsT cancEr (ACTIVATE): A randomized controlled trial.

As the prevalence of chemotherapy-related cognitive impairment rises, investigation into treatment options is critical. The objectives of this study were to test the effects of an aerobic exercise intervention initiated during chemotherapy compared to usual care (wait list control condition) on (1) objectively measured cognitive function and self-reported cognitive function, as well as on (2) the impact of cognitive impairment on quality of life (QOL) postintervention (commensurate with chemotherapy completion). The Aerobic exercise and CogniTIVe functioning in women with breAsT cancEr (ACTIVATE) trial was a two-arm, two-center randomized controlled trial conducted in Ottawa and Vancouver (Canada). Fifty-seven women (Mage,48.8±10 years) diagnosed with stage I-III breast cancer and awaiting chemotherapy were randomized to aerobic exercise initiated with chemotherapy (nEX=28) or usual care during chemotherapy with aerobic exercise after chemotherapy completion (nUC=29). The intervention lasted 12-24 weeks and consisted of supervised aerobic training and at-home exercise. The primary outcome was objective cognitive function measured via 13 neuropsychological tests (standardized to M ± SD,0±1); secondary outcomes of self-reported cognitive function and its impact on QOL were assessed via questionnaires. Data collected pre- and postintervention (the primary end point) were analyzed. Although no significant differences between groups were found for objective cognitive function outcomes postintervention after accounting for multiple testing, four of six self-reported cognitive function outcomes showed significant differences favoring the aerobic exercise group. Among women initiating chemotherapy for breast cancer, aerobic exercise did not result in significant differences in objective cognitive function postintervention after chemotherapy completion; however, the results do support the use of this intervention for improving self-reported cognitive function and its impact on QOL.

Chemotherapy-induced cognitive impairment and its long-term development in patients with breast cancer: results from the observational CICARO study.

Chemotherapy-induced cognitive impairment (CICI) is a well-recognized side effect of breast cancer treatment. However, prospective long-term evaluations of CICI using standardized neuropsychological tests are scarce. This prospective longitudinal cohort study investigated cognitive dysfunction and its impact on quality of life and everyday functioning in patients with breast cancer receiving first-line chemotherapy compared to patients with breast cancer without chemotherapy. Assessment occurred prior to chemotherapy, postchemotherapy (median 6 months), and 2-3 years later. We used standardized neuropsychological tests, questionnaires, and scales to assess patients' quality of life and functioning. Additionally, serum analysis for neurodegenerative markers and autoantibodies was conducted. We included n = 53 patients. Overall cognitive function declined statistically significantly (P = .046) postchemotherapy compared to control patients, mostly driven by a reduced figural memory (P = .011). Patients who received chemotherapy showed a greater reduction in quality of life (increased fatigue symptoms, P = .023; reduced Karnofsky index, P<.001); however, without a statistically significant effect on cognitive decline. The neurodegenerative markers Neurofilament light chain (NfL) and phosphorylated Neurofilament heavy chain (pNfH) increased statistically significantly (P<.001) postchemotherapy and pNfH correlated with overall cognitive function. After 2-3 years, both cognitive performance and quality of life were comparable between chemotherapy-treated and control patients. Our findings suggest that chemotherapy statistically significantly contributes to overall cognitive dysfunction in patients with breast cancer, which disappears after 2-3 years, indicating a recovery in both objectively measurable cognitive function and subjective quality of life. Future research should examine larger sample sizes and explore screening indicators, particularly pNfH.

Melatonin mitigates doxorubicin induced chemo brain in a rat model in a NRF2/p53–SIRT1 dependent pathway

Cancer is a critical health problem, and chemotherapy administration is mandatory for its eradication. However, chemotherapy like doxorubicin (Dox) has serious side-effects including cognitive impairment or chemo brain. Melatonin is a neuroprotective agent that has antioxidant, and anti-inflammatory effects. We aimed to explore melatonin's effect on Dox-induced chemo brain to discover new mechanisms associated with Dox-induced neurotoxicity and try to prevent its occurrence. Thirty-two male albino rats had been equally divided into four groups; control, melatonin-administrated, Dox-induced chemo brain, and melatonin + Dox treated. On the 9th day, brain had been excised after scarification and had been assessed for reactive oxygen species measurement, histopathological analysis, immunohistochemical, gene and protein expressions for the nuclear factor erythroid 2-related factor 2 (Nrf2), p53 and Silent information regulator 2 homolog 1 (SIRT1). Our results show that melatonin coadministration diminished Dox induced hippocampal and prefrontal cortex (PFC) cellular degeneration. It alleviated Nitric Oxide (NO) level and reversed the decline of antioxidant enzyme activities. It also upregulated Nrf2, SIRT1 and downregulated p53 gene expression in rats receiving Dox. Moreover, melatonin elevated the protein expression level of Nrf2, SIRT1 and reduced p53 corresponding to immunohistochemical results. The data suggested that melatonin can mitigate Dox-induced neurotoxicity by aggravating the endogenous antioxidants and inducing neurogenesis through activation of Nrf2/p53–SIRT1signaling pathway in adult rats' PFC. These effects were associated with Nrf2, SIRT1 activation and p53 inhibition. This could be guidance to add melatonin as an adjuvant supplement to Dox regimens to limit its adverse effect on the brain function.

Insights into the Pathogenesis and Treatment of Chemotherapy-Induced Neuropathy: A Focus on Oxidative Stress and Neuroinflammation.

Cancer is a high-morbidity disease prevalent worldwide. Chemotherapy is the primarily used regimen for cancer treatment; however, it also brings severe side effects. Chemotherapy-induced Peripheral Neuropathy (CIPN) and Chemotherapy-induced Cognitive Impairment (CICI) are two main complications occurring in chemotherapy. They are both associated with nervous system injury and are therefore collectively referred to as Chemotherapy-induced Neuropathy (CIN). CIPN induces neuralgia and numbness in limbs, while CICI causes amnesia and cognitive dysfunction. Currently, there are no effective therapeutics to prevent or cure CIN, so research into new drugs to alleviate CIN becomes urgent. Oxidative stress and neuroinflammation are the common pathogenic mechanisms of CIPN and CICI. Excessive Reactive Oxygen Species (ROS) and pro-inflammatory cytokines cause peripheral nervous system damage and hence CIPN. Peripheral ROS and cytokines also change the permeability of the blood-brain barrier, thereby increasing oxidative stress and neuroinflammation in the central nervous system, ultimately leading to CICI. Several antidepressants have been used to treat CIN and exhibited good clinical effects. Their potential pharmacological mechanism has been reported to ameliorate oxidative stress and neuroinflammation, guiding a new feasible way for effective therapeutic development against CIN. This mini-review has summarized the latest advances in the research on CIN with respect to clinical status, pathogenesis, and treatment. It has also discussed the potential of repurposing antidepressants for CIN treatment and prospected the strategy of developing therapeutics by targeting oxidative stress and neuroinflammation against CIN.

High-dose chemotherapy for patients with stage III breast cancer with homologous recombination deficiency: a discrete choice experiment among healthcare providers.

High-dose chemotherapy with autologous stem cell rescue (HDCT) is currently under investigation as a potential therapy for patients with stage III HER2-negative breast cancer with homologous recombination deficiency (HRD). In addition to survival, the impact on short- and long-term side effects might influence the uptake of HDCT by healthcare professionals. As part of the SUBITO trial, we investigated healthcare professionals' treatment (outcome) preferences for patients with HRD stage III HER2-negative breast cancer and established how healthcare professionals make trade-offs between these treatment outcomes. We conducted a discrete choice experiment in which healthcare professionals were asked to choose repeatedly between scenarios with two treatment options (HDCT or standard of care (SOC)) that varied in outcome with respect to 10-year overall survival (OS), short-term toxicity, long-term cognitive impairment, and premature menopause. We analysed treatment preferences, relative importance, and trade-offs using a multinomial logistic model. Thirty-five of the 151 dedicated breast cancer professionals with extensive experience in treating breast cancer patients completed the survey. The 10-year OS and long-term cognitive impairment were the most important attributes. The results indicate a requirement of 10.4% and 25.1% absolute additional improvement in the 10-year survival rate to justify accepting moderate or severe long-term cognitive impairment as a trade-off, respectively. Therefore, we found in our dataset that healthcare professionals expected a large improvement in 10-year OS to accept moderate to severe cognitive impairment. This information calls for further research into chemotherapy-related cognitive impairment, shared decision-making, and treatment preferences for patients with stage III breast cancer.

Low sucrose diets protect long-term memory and EPA & DHA enriched diets alter insulin resistance in a mouse model of chemotherapy

Chemotherapy-related cognitive impairment (CRCI) and affective symptoms negatively impact quality of life in breast cancer survivors. The aim of this study was to determine the efficacy of high eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) and low sucrose diets to alleviate these symptoms in a mouse model of chemotherapy. Potential mechanisms involving insulin resistance were explored. We hypothesized that diets enriched in EPA+DHA and low amounts of sucrose would protect against the impact of chemotherapy on measures of CRCI. Female C57Bl/6 mice were randomized to 1 of 4 diets (2% kcal eicosapentaenoic acid + docosahexaenoic acid [EPA+DHA]/high or low sucrose, low omega-3/high or low sucrose) for 6 weeks and treated with two injections of doxorubicin-based chemotherapy or vehicle during week 2 and 4. Behavioral tests were performed 7 days after second injection. Chemotherapy increased serum insulin and decreased body weight, locomotion and exploratory behavior (all p < .05). Low sucrose consumption resulted in better long-term memory regardless of chemotherapy or vehicle injection (p < .05). 2% EPA+DHA consumption lessened insulin resistance (p < .05); however, controlling for body weight attenuated this effect (p = .08). There were no significant differences by diet or injection on liver lipid content; however, liver lipid content was positively correlated with insulin resistance scores (p < .05). Low sucrose diets may protect long-term memory during chemotherapy. The effect of EPA+DHA on insulin resistance and affective side effects during chemotherapy requires further investigation.

Cognitive Impairment from Breast Cancer Chemotherapy in the Perspective of Traditional Chinese Medicine

In recent years, the incidence of breast cancer has been on the rise globally and in China. The conventional treatment methods for breast cancer include surgery, radiotherapy, chemotherapy, endocrine therapy, targeted therapy, traditional Chinese medicine, and other biological immunotherapy. In the treatment of breast cancer, the status of chemotherapy drugs is unshakable, and the related toxic side effects have gradually attracted people's attention. Doxorubicin is an anthracycline drug, which is the cornerstone drug for adjuvant chemotherapy for breast cancer. It exerts anti-tumor effects by inserting DNA and inhibiting topoisomerase II, but it can also cause severe neurotoxicity by crossing the blood-brain barrier, clinically manifested as memory and executive function decline, etc., which has a huge impact on the patient's work and life. With the development of modern medicine, the advantages of traditional Chinese medicine in preventing and treating adverse reactions related to breast cancer and improving patients' quality of life are increasingly being recognized. Traditional Chinese medicine classifies chemotherapy-induced cognitive impairment into related diseases such as "dementia", "brain marrow depletion", and "forgetfulness" based on its main clinical symptoms, and achieves the therapeutic effect of improving chemotherapy-induced cognitive impairment through clinical differentiation and coordinating relevant therapies, providing a scientific basis for the treatment of adverse reactions related to malignant tumors by traditional Chinese medicine in radiotherapy and chemotherapy.

Coenzyme Q10 ameliorates chemotherapy-induced cognitive impairment in mice: a preclinical study.

Among the three most used anticancer drugs, cyclophosphamide, Adriamycin, and 5-Fluorouracil (CAF), the most significant outcome is chemobrain, caused by increased oxidative stress, inflammatory insult, and mitochondrial dysfunction. In this study, endogenous antioxidant coenzyme Q10 (CoQ10) was evaluated for its neuroprotective effects in CICI. The chemobrain was induced in Swiss albino female mice by administering CAF (40 + 4 + 25mg/kg) intraperitoneal (i.p.) in three cycles (single injection per week) followed by treatment with CoQ10 (40mg/kg; p.o.) for up to 3weeks followed by behavioral, biochemical, molecular and histopathological analysis. Treatment with CoQ10 significantly improved cognition by improving exploring time in novel objects recognition test followed by increasing the time spent in the target quadrant in MWM test as compared to CAF-treated animals. Moreover, CoQ10 demonstrated antioxidant properties by reducing the expression of LPO while increasing levels of GSH, SOD, and catalase as compared to CAF-treated animals. While the levels of AChEs were significantly reduced after CoQ10 treatment in CAF-treated animals. In terms of its mechanism, it effectively counteracted the pro-inflammatory substances (TNF-α and IL-1β) triggered by CAF while also enhancing the levels of anti-inflammatory markers (IL-10 and Nrf2). Moreover, CoQ10 showed mitochondrial enhancers and it improved the level of Complex (I, II, and IV). Besides that, mitochondrial morphological analysis was done by TEM, and neuronal morphology along with quantification analysis was performed by H&E staining using Image J software to confirm the neuroprotective effect of CoQ10 over CAF-induced cognitive impairment. This study suggests CoQ10 can protect the mitochondria by imposing antioxidant, and anti-inflammatory properties, which could be a potential therapy for CICI.

Dynamic changes in brain glymphatic function during preoperative chemotherapy in breast cancer patients.

The current study aimed to investigate the dynamic changes in brain glymphatic function during chemotherapy in breast cancer patients (BCP) and their correlation with cognitive function. A total of 40 healthy female participants (control group) and 80 female BCP were included. Various cognitive assessment tools were used to evaluate cognitive function. Diffusion tensor imaging along the perivascular space was employed to measure brain glymphatic function. Following chemotherapy, BCP exhibited a significant decline in various cognitive scores. After chemotherapy, the along the perivascular space index, a parameter indicating brain glymphatic function, was slightly higher than that at baseline and the control group levels and was correlated with cognitive scores. This study unveiled a close relationship between the dynamic changes in brain glymphatic function after chemotherapy and cognitive function in BCP. Our findings contribute to a deeper understanding of the brain mechanisms underlying chemotherapy-related cognitive impairment and provide a theoretical basis for future interventions and treatments. In addition, they offer a new perspective for exploring the relationship between brain function and cognitive states.

In-vitro and in-vivo studies of two-drug cocktail therapy targeting chemobrain via the Nrf2/NF-κB signaling pathway.

Today, we critically need alternative therapeutic options for chemotherapy-induced cognitive impairment (CICI), often known as chemo brain. Mitochondrial dysfunction and oxidative stress are two of the primary processes that contribute to the development of chemobrain. Therefore, the purpose of this study was to investigate how CoQ10 and berberine shield neurons from chemotherapy-induced damage in in-vitro studies and memory loss in vivo studies. For the in-vitro investigation, we employed SH-SY5Y cell lines, and for the in-vivo study, we used female Swiss albino mice divided into seven different groups. Data from in-vitro studies revealed that treatment with coenzyme Q10 (CoQ10) and berberine improved chemotherapy-induced toxicity by reducing mitochondrial and total cellular ROS, as well as apoptosis-elicited markers (caspase 3 and 9). CoQ10 and berberine therapy inhibited the nuclear translocation of NF-κB and, consequently, the subsequent expressions of NLRP3 and IL-1β, implying the prevention of inflammasome formation. Furthermore, CoQ10 and berberine therapy boosted Nrf2 levels. This is a regulator for cellular resistance to oxidants. The in vivo results showed that treatment with CoQ10 (40mg/kg) and berberine (200mg/kg) improved the behavioral alterations induced by CAF (40/4/25mg/kg) in both the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests. Furthermore, biochemical and molecular evidence revealed the antioxidant, mitochondrial restorative, and anti-inflammatory potential of CoQ10 (40mg/kg) and berberine (200mg/kg) against CAF (40/4/25mg/kg) subjected mice. In addition, the histological analysis using H&E staining and transmission electron microscopy (for mitochondrial morphology) showed that mice treated with the cocktails had an increased number of healthy neurons with intact mitochondria and a reduced presence of autophagic vacuoles in the hippocampal region of the brain. These findings back up our theory about this novel cocktail method for CAF-induced cognitive impairment.

Clinical study of chemotherapy-related cognitive impairment in patients with non-Hodgkin lymphoma.

Chemotherapy for malignant tumors can cause brain changes and cognitive impairment, leading to chemotherapy-induced cognitive impairment (CICI). Current research on CICI has focused on breast cancer and Hodgkin's lymphoma. Whether patients with non-Hodgkin's lymphoma (NHL) undergoing chemotherapy have cognitive impairment has not been fully investigated. To investigate whether NHL patients undergoing chemotherapy had cognitive impairments. The study included 100 NHL patients who were required to complete a comprehensive psychological scale including the Brief Psychiatric Examination Scale (MMSE) at two time points: before chemotherapy and within 2 wk of two chemotherapy courses. A language proficiency test (VFT), Symbol Number Pattern Test (SDMT), Clock Drawing Test (CDT), Abbreviated Daily Cognition Scale (ECog-12), Prospective and Retrospective Memory Questionnaire, and Karnofsky Performance Status were used to assess cognitive changes before and after chemotherapy. The VFT scores for before treatment (BT) and after treatment (AT) groups were 45.20 ± 15.62, and 42.30 ± 17.53, respectively (t -2.16, P < 0.05). The CDT scores were 8 (3.5-9.25) for BT and 7 (2.5-9) for AT groups (Z -2.1, P < 0.05). Retrospective memory scores were 13.5 (9-17) for BT and 15 (13-18) for AT (Z -3.7, P < 0.01). The prospective memory scores were 12.63 ± 3.61 for BT and 14.43 ± 4.32 for AT groups (t -4.97, P < 0.01). The ECog-12 scores were 1.71 (1.25-2.08) for BT and 1.79 (1.42-2.08) for AT groups (Z -2.84, P < 0.01). The SDMT and MMSE values did not show a significant difference between BT and AT groups. Compared to the AT group, the BT group showed impaired language, memory, and subjective cognition, but objective cognition and execution were not significantly affected.

Relationships Between Chemotherapy-Related Cognitive Impairment, Self-Care Ability, and Quality of Life in Breast Cancer Survivors: A Cross-Sectional Study

ObjectivesIt is not clear how chemotherapy-related cognitive impairment and self-care ability affect the quality of life of women with breast cancer. The purpose of this study was to explore the relationships between chemotherapy-related cognitive impairment, self-care ability, and quality of life in breast cancer patients, and test whether self-care ability plays a mediating role in the association between cognitive impairment and quality of life. MethodsThis study was a cross-sectional study, conducted in China in 2022. Self-reported scales were used to assess cognitive function, self-care ability, and quality of life. Data were analyzed using descriptive statistics, spearman correlation analysis and hierarchical multiple regression analyses, the SPSS Process program was used to explore the mediating effect of self-care ability. ResultsA total of 218 participants were investigated, and approximately 79.3% of patients experienced mild chemotherapy-related cognitive impairment, the mean quality of life score was 59.96 ± 14.15, and the mean self-care ability score was 107.4 ± 24.09. Significant correlations among cognitive impairment, self-care ability, and quality of life were observed (P < .05). Additionally, self-care ability played a partial mediating role between cognitive impairment and quality of life (P < .05), accounting for 24.3% and 22.3%, respectively. ConclusionsChemotherapy-related cognitive impairment and self-care ability are factors affecting the quality of life of breast cancer survivors. Self-care ability mediates the relationship between cognitive impairment and quality of life. Enhancing patients' self-care ability can improve the quality of life of patients with cognitive impairment. Implications for Nursing PracticeIn the future, oncology nurses should not only pay attention to the severity of cognitive impairment, but also assess the level of patients’ self-care ability, provide relevant medical and healthcare guidance, train self-management behavior and strengthen self-care ability by integrating multidisciplinary forces to improve the quality of life of breast cancer patients effectively.

Preoperative cognitive function as a risk factor of postoperative delirium in cancer surgeries: A systematic review and meta-analysis.

Postoperative delirium (POD) after cancer surgeries can be a result of chemo brain, anesthesia, surgery duration, and preoperative cognitive impairment. Although older age and preoperative cognitive dysfunction were reported to increase the risk of POD in noncardiac surgery, the role of preoperative cognitive function and age in the development of POD after all types of cancer surgeries is not clear. This study aimed to determine the relationship between preoperative cognitive function and likelihood of POD after cancer surgeries. This study used three main online databases and followed PRISMA guidelines. English language original articles that examined preoperative cognitive function before solid tumor cancer surgery and assessed patients for postoperative delirium were included. We employed the random effect meta-analysis method. The overall incidence of POD ranged from 8.7% to 50.9%. The confusion assessment method was the most common tool used to assess delirium. Mini-mental state evaluation (MMSE), Mini-cog, and Montreal cognitive assessment were the most common tools to assess cognitive function. The pooled (total observation = 4676) random effects SMD was estimated at -0.84 (95% confidence interval [CI]: -1.30 to -0.31), indicating that lower MMSE scores before surgery are associated with a higher risk of POD. The pooled (total observation = 2668) random effects OR was estimated at 5.17 (95% CI: 2.51 to -10.63), indicating preoperative cognitive dysfunction can significantly predict the occurrence of POD after cancer surgeries. In conclusion, preoperative cognitive function is an independent and significant predictor of POD after solid tumor cancer surgeries.

Systemic and targeted activation of Nrf2 reverses doxorubicin-induced cognitive impairments and sensorimotor deficits in mice.

While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug 1c which has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and 1c both reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by 1c has the potential to diminish unwanted effects of fumarates while retaining efficacy.

A prospective study to evaluate the prevelance of chemobrain (CB) in patients (pts) receiving adjuvant treatment.

e23174 Background: Although adjuvant chemotherapy (CT) significantly improves the clinical outcome of pts with early-stage (ES) cancer, it is also known to cause side-effects. CT-induced cognitive impairment or CB refers to a clinical condition characterized by lack of mental sharpness, memory and concentration impairment and difficulty in processing information and executing simple tasks. Prospective data regarding the emergence of CB are limited. We aimed to explore the prevalence and predictors for CB among pts receiving adjuvant CT and to evaluate its impact on their quality of life (QoL). Methods: This was a prospective cohort study conducted at the University Hospital of Larissa. Pts who were recently diagnosed with ES breast (BC) or colorectal (CRC) cancer and were about to receive adjuvant CT containing doxorubicin (D) or oxaliplatin (O), respectively, were eligible for this study (C1). The first control group (C2) consisted of ES cancer pts that were not eligible for adjuvant CT and the second group (C3) was recruited from a pool of healthy controls (HCs). All participants (pcs) met the following inclusion criteria: age &gt; 50 years old, ability to speak and write in Greek. Pts with pre-existing dementia/anxiety disorder and severe anemia were excluded from the study. Pts in C1 were assessed before receiving CT and 3 months after CT initiation. All subjects in C2 and C3 were assessed in 3 months intervals as well. After completion of the informed consent process, all pts and age-matched noncancer controls completed the Greek Version of Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) to specifically assess CB. QoL was measured using the EORTC QLQ-C30. Results: Overall, 82 pts (53 with BC and 29 with CRC) were included in C1, 36 pts (24 with BC and 12 with CRC) in C2 and 15 pcs in C3. At baseline, pts in C1 and C2 had significantly lower FACT-Cog scores than healthy controls in C3 (p: 0.028 and p:0.038, respectively), indicating a higher prevalence of self-reported cognitive impairment among pts with cancer after a curative surgery compared to age-matched HCs. However, after 3 months of CT the majority of pts in C1 (59/82, 72%) demonstrated a decline in their cognitive performance (35/53, 66% in BC pts receiving D and 24/29, 82% in CRC pts receiving O). Pts with CRC receiving O experienced more severe cognitive deficits. On the contrary, 55% of the pts in C2 (20/36, 16 with BC and 4 with CRC) demonstrated an improvement. The presence of CB (decline in cognitive functioning in the absence of severe anemia) was associated with decreased QoL (p = 0.004). Pts were mostly frustrated by the difficulty in executing simple tasks. Conclusions: As demonstrated in one of the largest cohorts of pts with ES cancer, CB is a common problem among pts receiving adjuvant CT and is associated with detrimental impact on daily life. Creating awareness is crucial to offer cancer survivors the best care directed at improving QoL.

Role of celecoxib in reducing cognitive impairment in patients receiving definitive chemoradiation for head and neck carcinoma: A phase II randomized placebo controlled trial (CELCI-HN study).

TPS12150 Background: Head and neck squamous cell carcinoma (HNSCC) is common in the Indian subcontinent and majority (65%) patients present in an advanced stage. Chemotherapy related cognitive impairment (CRCI) is a poorly defined and underestimated phenomenon in the HNSCC population. Through this study, we are attempting to establish evidence of activity of agents targeting neuro-inflammation in reducing or halting cognitive decline associated with definitive chemoradiotherapy for head and neck malignancies without adding to treatment-associated toxicity. This study can potentially aid in developing a cost effective approach with a readily available and cheap agent like celecoxib in improving the quality of life in this cohort of patients. Methods: This is a single center, double blinded placebo controlled phase 2 randomized trial. We intend to randomize 92 non metastatic HNSCC patients registered at a large tertiary cancer center of North India {Department of Medical Oncology (Head and Neck Cancer Clinic, All India Institute of Medical Sciences-National Cancer Institute, India)} planned for definitive chemoradiation (CTRT) with or without induction chemotherapy. Patients in the experimental arm will receive celecoxib 100 mg or matched placebo tablet orally twice a day starting with day 1 of initiation of definitive chemoradiotherapy/induction chemotherapy for a duration of 6 months or until unacceptable toxicity. Our primary objective is to determine the activity of celecoxib versus placebo in reducing cognitive decline in patients undergoing definitive CTRT with or without induction chemotherapy in HNSCC through patient reported outcome tools (FACT cog questionnaire). Secondary objectives include assessment of adverse event profile (measured using CTCAE v5.0), objective assessment of neurocognitive decline using neuropsychological battery of tests, to identify predictors of cognitive decline on the basis of site of malignancy, radiation dose to the base of skull and brainstem, age, comorbidities and educational status. Tertiary objective include evaluation of inflammatory biomarkers e.g serum COX-2, serum Interleukin and tumor necrosis factors-alpha levels at the end of therapy and on follow up. Clinical trial information: CTRI/2022/09/045579.

Quantifying chemotherapy-induced cognitive impairment in gastrointestinal cancer patients: A scoping review of methodological concerns in the literature.

Chemotherapy is one of the common treatments in cancer management. However, chemotherapy-induced cognitive impairment (CICI) is one notable side effect that can greatly impact a patient's quality of life. Literature on CICI in gastrointestinal (GI) cancers are few and inconsistent. This review aims to identify the methodological differences in such studies. A systematic search was performed in four electronic databases. All peer-reviewed primary literature published in English that evaluated cognitive-related functioning scores related to chemotherapy in GI cancer patients were included. Information about each study such as CICI findings, study limitations, methodology, and sample characteristics was extracted and synthesized. A total of 19 studies were included. Evidence of CICI was found in 50.0% (8 of 16) and 62.5% (5 of 8) studies that used objective and subjective measures, respectively. Methodological differences such as groups used for comparison, instruments used, and assessment from the length of time since chemotherapy were highlighted between studies that did and did not find evidence of CICI. This review suggests that the mixed findings can be attributed to the heterogeneous methodologies adopted in the evaluation of CICI in this field. Further studies are necessary to establish the presence and chronicity of CICI, and in which groups of patients to facilitate targeted interventions and treatments.

Nose-to-brain Drug Delivery System: An Emerging Approach to Chemotherapy-induced Cognitive Impairment.

The rise in global cancer burden, notably breast cancer, emphasizes the need to address chemotherapy-induced cognitive impairment, also known as chemobrain. Although chemotherapy drugs are effective against cancer, they can trigger cognitive deficits. This has triggered the exploration of preventive strategies and novel therapeutic approaches. Nanomedicine is evolving as a promising tool to be used for the mitigation of chemobrain by overcoming the blood-brain barrier (BBB) with innovative drug delivery systems. Polymer and lipid-based nanoparticles enable targeted drug release, enhancing therapeutic effectiveness. Utilizing the intranasal route of administration may facilitate drug delivery to the central nervous system (CNS) by circumventing first-pass metabolism. Therefore, knowledge of nasal anatomy is critical for optimizing drug delivery via various pathways. Despite challenges, nanoformulations exhibit the potential in enhancing brain drug delivery. Continuous research into formulation techniques and chemobrain mechanisms is vital for developing effective treatments. The intranasal administration of nanoformulations holds promise for improving therapeutic outcomes in chemobrain management. This review offers insights into potential future research directions, such as exploring novel drug combinations, investigating alternative delivery routes, or integrating emerging technologies to enhance the efficacy and safety of nanoformulations for chemobrain management.

CCR5 antagonist maraviroc alleviates doxorubicin-induced neuroinflammation and neurobehavioral deficiency by regulating NF-κB/NLRP3 signaling in a breast cancer mouse model

The chemotherapeutic agent Doxorubicin (DOX) is known to cause chemotherapy-induced cognitive impairment (CICI). Maraviroc, a potent C–C chemokine receptor 5 (CCR5) antagonist, shows neuroprotective properties, while its role in CICI remains unclear. This study determined the therapeutic potential of maraviroc on CICI. Adult C57BL/6J mice with implanted breast cancer cells received four weekly intraperitoneal injections of saline (Control group), 5 mg/kg DOX (DOX group), 10 mg/kg maraviroc (MVC group), or 5 mg/kg DOX with 10 mg/kg maraviroc (DOX + MVC group). The Morris Water Maze (MWM) was used for neurobehavioural test. Western blot analysis and immunofluorescence were used to evaluate the expressions of inflammatory markers, apoptosis-related proteins, and synaptic-related proteins. The volume and weight of tumor were also evaluated after treatments. DOX treatment significantly increased chemokines (CCL3, CCL4) and inflammatory cytokines (IL-1β, TNF-α) in tumor-bearing mice hippocampus. While maraviroc administration reduced hippocampal proinflammatory factors compared to the DOX group. Furthermore, it also lowered apoptosis markers, restored synaptic proteins levels, and inhibited the NF-κB/NLRP3 pathway. Accordingly, maraviroc treatment significantly improved DOX-induced neurobehavioural impairments as evidenced by an increased number of platform crossings and percentage of target quadrant time in the MWM test. Additionally, when combined with DOX, maraviroc had additional inhibitory effects on tumor growth. These findings suggest that maraviroc can mitigate DOX-induced CICI by suppressing elevated proinflammatory chemokines and cytokines through the NF-κB/NLRP3 pathway, potentially offering an anti-tumor benefit. This research presents a promising therapeutic approach for DOX-induced CICI, enhancing the safety and efficacy of cancer treatments.