Chemobrain Research Articles

A Retrospective Comparison of the Side Effect Prevalence and Severity of Multiple Myeloma Triplet Vs Quadruplet Induction Therapy

Background The treatment of multiple myeloma (MM) continues to evolve. New therapies provide the best responses and overall survival, however, the benefit may be counterbalanced by the appearance of side effects and their severity, such as gastrointestinal toxicities, musculoskeletal pain, and central and peripheral nervous system compromise (chemo brain and neuropathy). With more data supporting the efficacy and depth of response of quadruplet (quad) therapy in patients with MM (PMID: 30694857), this study investigated the increasingly important question: does quad induction therapy increase the prevalence or severity of side effects as compared to triplet (tri) therapy treatment regimens? Methods HealthTree® Cure Hub for Multiple Myeloma, a patient advocacy platform designed to allow patients to exchange personal experiences of disease and treatments, was used to analyze validated real-world-data concerning side effects and severity of patients receiving quad or tri therapy during induction. Patients who received fewer than tri or more than quad during induction therapy were excluded. A Pearson's Chi-squared test was performed to investigate differences between the proportions of each side-effect experienced and a two-sample t-test was used to evaluate the differences between side-effect severity (1 - hardly noticeable, 10 - unmanageable, stopped treatment). Results There were 1,204 total MM patients analyzed in this retrospective study. A majority of the patients analyzed receive tri therapy during induction (90.4%), while the remaining received quad therapy (9.6%). The three most common tri therapies in this analysis were lenalidomide, bortezomib, and dexamethasone (RVd, 69.7%); cyclophosphamide, bortezomib, and dexamethasone (CyborD, 13.2%); and carfilzomib, lenalidomide, and dexamethasone (KRd, 9.8%). The three most common quad therapies were daratumumab+RVd (28.7%), daratumumab & hyaluronidase+RVd (23.5%), and cyclophosphamide+RVd (CyRVd, 8.7%). The side effects and their severity were reported by 984 patients (82%). The analysis of side effects and severity included all tri and quad induction therapies received by patients in this study. There were 16 side effects that were reported by ≥15% of patients (Table 1). One third or more of patients reported fatigue/tired, neuropathy, constipation, diarrhea and low white blood cell count for both tri and quad therapies. The side effect of chemo brain was significantly greater (p = 0.006) in quad therapy patients (26%) than tri therapy patients (16%). Promisingly, the severity of side effects were not different between the two therapies. However, the most severe side effect reported by both therapies was musculoskeletal pain with an average score of 4.8 ± 1.6 (Quad) and 4.1 ± 2.4 (Tri). Conclusion Surprisingly, the addition of a fourth drug to a myeloma treatment regimen did not affect the severity or, on a whole, the prevalence of the side effects experienced by patients. Importantly, 12 reported side effects were on average uncomfortable but manageable or disruptive to my life in >15% of patients. Therefore, patients’ treatment strategies, regardless of the number of drugs used, should include plans to help address treatment disruption (intensity and duration) of these common side effects, while aggressively working to achieve durable disease control. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Functional changes of the prefrontal cortex, insula, caudate and associated cognitive impairment (chemobrain) in NSCLC patients receiving different chemotherapy regimen.

Chemotherapy-induced cognitive impairment (CICI), termed "chemobrain", is highly prevalent in cancer patients following the administration of chemotherapeutic agents. However, the potential pathophysiological mechanisms underlying CICI remain unknown. This study aimed to explore the functional changes of the brain and associated cognitive impairment in non-small cell lung cancer (NSCLC) patients receiving different chemotherapy regimen. A total of 49 NSCLC patients (25 patients receiving pemetrexed plus carboplatin chemotherapy (PeCC) and 24 patients receiving paclitaxel plus carboplatin chemotherapy (PaCC)) and 61 healthy controls (HCs) were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning, as well as cognitive function tests including Mini Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA), Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). Brain functional activities were measured by regional homogeneity (ReHo) values, which were calculated and compared between groups. In addition, the associations between ReHo values of changed brain regions and scores of cognitive scales were evaluated. NSCLC patients showed decreased scores of MMSE, MoCA and FACT-Cog and decreased ReHo values in the bilateral superior frontal gyrus (medial), middle frontal gyrus, left inferior frontal gyrus (orbital part) and increased ReHo values in the bilateral insula and caudate. Compared with HCs, patients receiving PeCC demonstrated decreased ReHo values in the right superior frontal gyrus (dorsolateral), left superior frontal gyrus (medial orbital), middle frontal gyrus, insula and rectus gyrus while patients receiving PaCC presented increased ReHo values in the right rolandic operculum, left insula and right caudate. Compared with patients receiving PaCC, patients receiving PeCC had decreased ReHo values in the left superior frontal gyrus (orbital part), middle frontal gyrus and increased ReHo values in the left inferior temporal gyrus, lingual gyrus. Moreover, positive relationships were found between ReHo values of the left and right superior frontal gyrus (medial) and the total scores of FACT-Cog in the patient group. The findings provided evidences that carboplatin-based chemotherapy could cause CICI accompanied by functional changes in the prefrontal cortex, insula, caudate. These might be the pathophysiological basis for CICI of NSCLC patients and were affected by the differences of chemotherapeutic agent administration through different biological mechanisms.

Levetiracetam Ameliorates Doxorubicin-Induced Chemobrain by Enhancing Cholinergic Transmission and Reducing Neuroinflammation Using an Experimental Rat Model and Molecular Docking Study.

Cancer chemotherapy-induced cognitive impairment (chemobrain) is a major complication that affects the prognosis of therapy. Our study evaluates the nootropic-like activity of levetiracetam (LEVE) against doxorubicin (DOX)-induced memory defects using in vivo and molecular modelling. Rats were treated with LEVE (100 and 200 mg/kg, 30 days) and chemobrain was induced by four doses of DOX (2 mg/kg, i.p.). Spatial memory parameters were evaluated using an elevated plus maze (EPM) and Y-maze. Additionally, acetylcholinesterase (AChE) and the neuroinflammatory biomarkers cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nuclear factor-κB (NF-κB), and tumor necrosis factor-alpha (TNF-α) were analyzed using brain homogenate. PharmMapper was used for inverse docking and AutoDock Vina was used for molecular docking. LEVE treatment significantly diminished the DOX-induced memory impairment parameters in both the EPM and Y-maze. In addition, the drug treatment significantly reduced AChE, COX-2, PGE2, NF-κB, and TNF-α levels compared to DOX-treated animals. The inverse docking procedures resulted in the identification of AChE as the potential target. Further molecular modelling studies displayed interactions with residues Gly118, Gly119, and Ser200, critical for the hydrolysis of ACh. Analysis of the results suggested that administration of LEVE improved memory-related parameters in DOX-induced animals. The 'nootropic-like' activity could be related to diminished AChE and neuroinflammatory mediator levels.

Aldehyde dehydrogenase 2 polymorphism is associated with chemotherapy-related cognitive impairment in patients with breast cancer who receive chemotherapy.

Chemotherapy-related cognitive impairment (CRCI) is a common but easily overlooked condition that markedly affects the quality of life (QOL) of patients with breast cancer. The rs671 is a common gene polymorphism of aldehyde dehydrogenase 2 (ALDH2) in Asia that is involved in aldehyde metabolism and may be closely related to CRCI. However, no study has yet summarised the association between ALDH2 and CRCI. This study enrolled one hundred and twenty-four patients diagnosed with breast cancer according to the pathology results, genotyped for ALDH2 single-nucleotide polymorphisms (SNP) to explore these. The mini-mental state exam (MMSE), verbal fluency test (VFT), and digit span test (DST) results were compared in these patients before and after chemotherapy (CT). We found that patients with ALDH2 gene genotypes of rs671_GG, rs886205_GG, rs4648328_CC, and rs4767944_TT polymorphisms were more likely to suffer from cognitive impairment during chemotherapy. A trend toward statistical significance was observed for rs671_GG of DST (z=2.769, p=0.006), VFT (t=4.624, P<0.001); rs886205_GG of DST (z=3.663, P<0.001); rs4648328_CC of DST (z=2.850, p=0.004), VFT (t=3.477, p=0.001); and rs4767944_TT of DST (z=2.967, p=0.003), VFT (t=2.776, p=0.008). The cognitive indicators of these patients significantly decreased after chemotherapy (p < 0.05). The difference in ALDH2 rs671 was most obvious. Our results showed what kinds of ALDH2 genotyped patients that are more likely to develop CRCI. In the future, it may be possible to infer the risk of CRCI by detecting the single-nucleotide locus of ALDH2 that is conducive to strengthening clinical interventions for these patients and improving their QOL. More importantly, this study has important implications for Asian women with breast cancer as ALDH2 rs671 is a common polymorphism in Asians.

The effect of doxorubicin or cyclophosphamide treatment on auditory brainstem response in mice.

Clinical studies suggest that chemotherapy is associated with long-term cognitive impairment in some patients. Several underlying mechanisms have been proposed; however, the etiology of chemotherapy-related cognitive dysfunction remains relatively unknown. There is evidence that oligodendrocytes and white matter tracts within the CNS may be particularly vulnerable to chemotherapy-related damage and dysfunction. Auditory brainstem responses (ABRs) have been used to detect and measure functional integrity of myelin in a variety of animal models of autoimmune disorders and demyelinating diseases. Limited evidence suggests that increases in interpeak latencies, associated with disrupted impulse conduction, can be detected in ABRs following 5-fluorouracil administration in mice. It is unknown if similar functional disruptions can be detected following treatment with other chemotherapeutic compounds and the extent to which alterations in ABR signals represent robust and long-lasting impairments associated with chemotherapy-related cognitive impairment. Thus, C57BL/6J mice were treated every 3rd day for a total of 3 injections with low or high dose cyclophosphamide, or doxorubicin. ABRs of mice were assessed on days 1, 7, 14, 56 and 6months following completion of chemotherapy administration. There were timing and amplitude differences in the ABRs of the doxorubicin and the high dose cyclophosphamide groups relative to the control animals. However, despite significant toxic effects as assessed by weight loss, the changes in the ABR were transient.

Induced pluripotent stem cell-derived brain organoids as potential human model system for chemotherapy induced CNS toxicity.

Neurotoxic phenomena are among the most common side effects of cytotoxic agents. The development of chemotherapy-induced polyneuropathy (CIPN) is a well-recognized adverse reaction in the peripheral nervous system, while changes of cognitive functions (post-chemotherapy cognitive impairment (PCCI)) are more diffuse and have only recently drawn scientific interest. PCCI in patients most often displays as short-term memory loss, reduced multitasking ability or deficits in language. Not least, due to a lack of preclinical human model systems, the underlying molecular mechanisms are poorly understood, and treatments are missing. We thus investigated whether induced pluripotent stem cell (iPSC)-derived brain organoids can serve as a human model system for the study of chemotherapy induced central nervous system toxicity. We robustly generated mature brain organoids from iPSC-derived neuronal precursor cells (NPC), which showed a typical composition with 1) dividing NPCs forming ventricle like structures 2) matured neurons and 3) supporting glial cells closer to the surface. Furthermore, upon stimulation the brain organoids showed functional signaling. When exposed to increasing concentrations of paclitaxel, a frequently used chemotherapy drug, we observed time dependent neurotoxicity with an EC50 of 153 nM, comparable to a published murine model system. Histological analysis after paclitaxel exposure demonstrated dose dependent apoptosis induction and reduced proliferation in the organoids with further Western blot analyses indicating the degradation of neuronal calcium sensor one protein (NCS-1) and activation of Caspase-3. We could also provide evidence that paclitaxel treatment negatively affects the pool of neuronal and astrocyte precursor cells as well as mature neurons. In summary our data suggests that human iPSC derived brain organoids are a promising preclinical model system to investigate molecular mechanisms underlying PCCI and to develop novel prevention and treatment strategies.

A Panax quinquefolius-Based Preparation Prevents the Impact of 5-FU on Activity/Exploration Behaviors and Not on Cognitive Functions Mitigating Gut Microbiota and Inflammation in Mice.

Simple SummaryChemotherapy-related cognitive impairment (CRCI) and fatigue worsen the quality of life (QoL) of cancer patients. Multicenter studies have shown that Panax quinquefolius and vitamin C, respectively, were effective in reducing the symptoms of fatigue in treated cancer patients. We developed a behavioral C57Bl/6j mouse model to study the impact of 5-Fluorouracil (5-FU) chemotherapy on activity/fatigue, emotional reactivity and cognitive functions. We used this model to evaluate the potentially beneficial role of a Panax quinquefolius-based solution containing vitamin C (Qiseng®) or vitamin C alone in these chemotherapy side effects. We established that Qiseng® prevents the reduction in activity/exploration and symptoms of fatigue induced by 5-FU and dampens chemotherapy-induced intestinal dysbiosis and systemic inflammation. We further showed that Qiseng® decreases macrophage infiltration in the intestinal compartment, thus preventing, at least in part, the systemic elevation of IL-6 and MCP-1 and further reducing the neuroinflammation likely responsible for the fatigue induced by chemotherapy, a major advance toward improving the QoL of patients.Chemotherapy-related cognitive impairment (CRCI) and fatigue constitute common complaints among cancer patient survivors. Panax quinquefolius has been shown to be effective against fatigue in treated cancer patients. We developed a behavioral C57Bl/6j mouse model to study the role of a Panax quinquefolius-based solution containing vitamin C (Qiseng®) or vitamin C alone in activity/fatigue, emotional reactivity and cognitive functions impacted by 5-Fluorouracil (5-FU) chemotherapy. 5-FU significantly reduces the locomotor/exploration activity potentially associated with fatigue, evokes spatial cognitive impairments and leads to a decreased neurogenesis within the hippocampus (Hp). Qiseng® fully prevents the impact of chemotherapy on activity/fatigue and on neurogenesis, specifically in the ventral Hp. We observed that the chemotherapy treatment induces intestinal damage and inflammation associated with increased levels of Lactobacilli in mouse gut microbiota and increased expression of plasma pro-inflammatory cytokines, notably IL-6 and MCP-1. We demonstrated that Qiseng® prevents the 5-FU-induced increase in Lactobacilli levels and further compensates the 5-FU-induced cytokine release. Concomitantly, in the brains of 5-FU-treated mice, Qiseng® partially attenuates the IL-6 receptor gp130 expression associated with a decreased proliferation of neural stem cells in the Hp. In conclusion, Qiseng® prevents the symptoms of fatigue, reduced chemotherapy-induced neuroinflammation and altered neurogenesis, while regulating the mouse gut microbiota composition, thus protecting against intestinal and systemic inflammation.

Choroid plexus-CSF-targeted antioxidant therapy protects the brain from toxicity of cancer chemotherapy

For many cancer patients, chemotherapy produces untreatable life-long neurologic effects termed chemotherapy-related cognitive impairment (CRCI). We discovered that the chemotherapy methotrexate (MTX) adversely affects oxidative metabolism of non-cancerous choroid plexus (ChP) cells and the cerebrospinal fluid (CSF). We used a ChP-targeted adeno-associated viral (AAV) vector approach in mice to augment CSF levels of the secreted antioxidant SOD3. AAV-SOD3 gene therapy increased oxidative defense capacity of the CSF and prevented MTX-induced lipid peroxidation in the hippocampus. Furthermore, this gene therapy prevented anxiety and deficits in short-term learning and memory caused by MTX. MTX-induced oxidative damage to cultured human cortical neurons and analyses of CSF samples from MTX-treated lymphoma patients demonstrated that MTX diminishes antioxidant capacity of patient CSF. Collectively, our findings motivate the advancement of ChP- and CSF-targeted anti-oxidative prophylactic measures to relieve CRCI.

The correlation between neutrophil-to-lymphocyte ratio, carcinoembryonic antigen, and carbohydrate antigen 153 levels with chemotherapy-related cognitive impairment in early-stage breast cancer patients.

BackgroundThe changes in inflammation and tumor biomarkers are associated with the anti-tumor immunological processes. Early detection and intervention are of great significance to the clinical management of cancer-related diseases. Peripheral blood biomarkers [e.g., neutrophil-to-lymphocyte ratio (NLR), carcinoembryonic antigen (CEA), and carbohydrate antigen 153 (CA153)] are obtained in real-timely, conveniently, and less invasively, and proved to availably predicted the disease states and prognosis of various cancers, including breast cancer (BC). Inflammation and poor disease management promote cognitive impairment. Chemotherapy-related cognitive impairment (CRCI) hazard long-term survival and quality of life (QOL) of BC patients, but its correlation with NLR, CEA, and CA153 is not clear.PurposeThis study aimed to investigate changes in NLR, CEA, and CA153 levels before and after chemotherapy and their correlation with CRCI in patients with early-stage BC.Materials and methodsThe 187 patients with BC who were measured for NLR, CEA, and CA153 values within the first 24 hours of admission, were assigned into two groups: the before/after chemotherapy group (BCG/ACG). The ACG was assigned into two subgroups based on the cognitive assessment results: the cognitive normal/impaired group (CNG/CIG). Patients’ self-perceived cognitive impairments were evaluated using a mini-mental state examination (MMSE), prospective and retrospective memory (PM and RM) questionnaire (PRMQ), and functional assessment of cancer therapy-cognitive function version 3 (FACT-Cog, version 3, including CogPCI, CogOth, CogPCA, and CogQOL). Their QOL was also evaluated.ResultsThe NLR and CA153 levels were elevated after chemotherapy (BCG vs ACG: Z = −1.996 and −1.615, P = 0.046 and 0.106, respectively), and significantly elevated in patients with CRCI (BCG vs CIG: Z = −2.444 and -2.293, P = 0.015 and 0.022; respectively). However, there was not reach significant difference in CEA levels between the four groups. In addition, there was a weak to moderate correlation between peripheral blood biomarkers (NLR, CEA, and CA153) levels and CRCI (r = −0.404, −0.205, −0.322; respectively; P < 0.001). Cognitive impairment scores (MMSE, PM, RM, and FACT-Cog) had a strong correlation with QOL in patients with early-stage BC (r = −0.786, 0.851, 0.849, and 0.938; respectively; P < 0.001).ConclusionNLR and CA153 m be valuable diagnostic adjuncts of CRCI, and CRCI has a strong correlation with QOL in patients with early-stage BC.

Rationale and design of the prevention of paclitaxel-related neurological side effects with lithium trial - Protocol of a multicenter, randomized, double-blind, placebo- controlled proof-of-concept phase-2 clinical trial.

IntroductionChemotherapy-induced polyneuropathy (CIPN) and post-chemotherapy cognitive impairment (PCCI) are frequent side effects of paclitaxel treatment. CIPN/PCCI are potentially irreversible, reduce quality of life and often lead to treatment limitations, which affect patients’ outcome. We previously demonstrated that paclitaxel enhances an interaction of the Neuronal calcium sensor-1 protein (NCS-1) with the Inositol-1,4,5-trisphosphate receptor (InsP3R), which disrupts calcium homeostasis and triggers neuronal cell death via the calcium-dependent protease calpain in dorsal root ganglia neurons and neuronal precursor cells. Prophylactic treatment of rodents with lithium inhibits the NCS1-InsP3R interaction and ameliorates paclitaxel-induced polyneuropathy and cognitive impairment, which is in part supported by limited retrospective clinical data in patients treated with lithium carbonate at the time of chemotherapy. Currently no data are available from a prospective clinical trial to demonstrate its efficacy.Methods and analysisThe PREPARE study will be conducted as a multicenter, randomized, double-blind, placebo-controlled phase-2 trial with parallel group design. N = 84 patients with breast cancer will be randomized 1:1 to either lithium carbonate treatment (targeted serum concentration 0.5–0.8 mmol/l) or placebo with sham dose adjustments as add-on to (nab-) paclitaxel. The primary endpoint is the validated Total Neuropathy Score reduced (TNSr) at 2 weeks after the last (nab-) paclitaxel infusion. The aim is to show that the lithium carbonate group is superior to the placebo group, meaning that the mean TNSr after (nab-) paclitaxel is lower in the lithium carbonate group than in the placebo group. Secondary endpoints include: (1) severity of CIPN, (2) amount and dose of pain medication, (3) cumulative dose of (nab-) paclitaxel, (4) patient-reported symptoms of CIPN, quality of life and symptoms of anxiety and depression, (5) severity of cognitive impairment, (6) hippocampal volume and changes in structural/functional connectivity and (7) serum Neurofilament light chain protein concentrations.Ethics and disseminationThe study protocol was approved by the Berlin ethics committee (reference: 21/232 – IV E 10) and the respective federal agency (Bundesinstitut für Arzneimittel und Medizinprodukte, reference: 61-3910-4044771). The results of the study will be published in peer-reviewed medical journals as well as presented at relevant (inter)national conferences.Clinical trial registration[https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00027165], identifier [DRKS00027165].

Activation of SIRT-1 Pathway by Nanoceria Sheds Light on Its Ameliorative Effect on Doxorubicin-Induced Cognitive Impairment (Chemobrain): Restraining Its Neuroinflammation, Synaptic Dysplasticity and Apoptosis.

Chemo fog is one of the most serious health concerns encountered by cancer survivors receiving doxorubicin (DOX)-based chemotherapy. Oxidative stress, neuroinflammation, apoptosis and impairment of synaptic plasticity are regarded as the key factors implicated in DOX-induced cognitive impairment. This research aimed to assess the possible neuroprotective effect of cerium oxide nanoparticles (CeNPs) against DOX-induced neurotoxicity. Forty-eight rats were divided into four groups (12 rats/group): control group, CeNPs group (received oral CeNPs solution (35 mg/kg) daily for 4 weeks), and DOX group (were administered DOX intraperitoneally (2 mg/kg, once/week for 4 weeks)) and DOX+ CeNPs group. The findings revealed that CeNPs mitigated behavioral alterations in DOX-induced cognitive deficit. Additionally, CeNPs alleviated the histopathological abnormalities in hippocampus and ameliorated DOX-induced neuroinflammation by downregulating the expression of NF-κB, TNF-α, IL-1β and IL6. In addition, CeNPs antagonized the apoptosis through reducing the protein expression of cytochrome c and caspase 3. In addition, it stimulated the antioxidant defense, as indicated by upregulating the expression of the Nrf2, HO-1 and PGC-1α genes. CeNPs improved synaptic plasticity via acting on the BDNF. These actions were related through the modification of SIRT-1 expression. Based on the aforementioned results, CeNPs antagonized the doxorubicin-induced neurodegeneration by its antioxidant, anti-inflammatory and antiapoptotic effects, alongside its SIRT-1 mediated mechanisms.

Chemotherapy-induced functional brain abnormality in colorectal cancer patients: a resting-state functional magnetic resonance imaging study.

IntroductionChemotherapy-induced cognitive impairment (i.e., “chemobrain”) is a common neurotoxic side-effect experienced by many cancer survivors who undergone chemotherapy. However, the central mechanism underlying chemotherapy-related cognitive impairment is still unclear. The purpose of this study was to investigate the changes of intrinsic brain activity and their associations with cognitive impairment in colorectal cancer (CRC) patients after chemotherapy.MethodsResting‐state functional magnetic resonance imaging data of 29 CRC patients following chemotherapy and 29 matched healthy controls (HCs) were collected in this study, as well as cognitive test data including Mini Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA) and Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). The measure of fractional amplitude of low-frequency fluctuation (fALFF) was calculated and compared between groups. The correlations between the fALFF of impaired brain region and cognitive performance were also analyzed.ResultsCompared with HCs, CRC patients following chemotherapy showed decreased fALFF values in the left anterior cingulate gyrus (ACG) and middle frontal gyrus, as well as increased fALFF values in the left superior frontal gyrus (orbital part) and middle occipital gyrus. Moreover, positive associations were identified between fALFF values of the left ACG and the total scores of MMSE, MoCA and FACT-Cog in the patient group.ConclusionThese findings indicated that CRC patients after chemotherapy had decreased intrinsic brain activity in the left ACG, which might be vulnerable to the neurotoxic side-effect of chemotherapeutic drugs and related to chemotherapy-induced cognitive impairment.

Alterations in degree centrality and cognitive function in breast cancer patients after chemotherapy.

The goal of this study was to determine the presence or absence of persistent functional impairments in specific brain regions in breast cancer patients during the recovery period after chemotherapy. We calculated degree centrality (DC) and explored the correlation between brain changes and cognitive scores in 29 female patients with breast cancer who had completed chemotherapy within 1-6 years (C + group) and in 28 age-matched patients with breast cancer who did not receive chemotherapy (C- group). All patients underwent rs-fMRI and cognitive testing. Differences in brain functional activity were explored using DC parameters. Correlations between brain features and cognitive scores were analyzed via correlation analysis. Compared with the C- group, the C + group obtained significantly lower motor and cognitive subscores on the Fatigue Scale for Motor and Cognitive Functions and four subscale scores of the Functional Assessment of Cancer Therapy-Cognitive Function (P < 0.05). Furthermore, the C + group exhibited a significantly higher DC z-score (zDC) in the right superior temporal gyrus and left postcentral gyrus (P < 0.01, FWE-corrected), and a lower zDC in the left caudate nucleus (P < 0.01, FWE-corrected). We found a positive correlation between digit symbol test (DST) scores and zDC values in the right superior temporal gyrus (r = 0.709, P < 0.001), and a negative correlation between DST scores and zDC values in the right angular gyrus (r = -0.784, P < 0.001) and left superior parietal gyrus (r = -0.739, P < 0.001). Chemotherapy can cause abnormal brain activity and cognitive decline in patients with breast cancer, and these effects are likely to persist. DC can be used as an imaging marker for chemotherapy-related cognitive impairment after chemotherapy in breast cancer patients.

Neuroimaging advances in chemotherapy-related cognitive impairment: from clinical to preclinical research

Neuroimaging advances in chemotherapy-related cognitive impairment: from clinical to preclinical research

Chemobrain in Breast Cancer: Mechanisms, Clinical Manifestations, and Potential Interventions.

Among the potential adverse effects of breast cancer treatment, chemotherapy-related cognitive impairment (CRCI) has gained increased attention in the past years. In this review, we provide an overview of the literature regarding CRCI in breast cancer, focusing on three main aspects. The first aspect relates to the molecular mechanisms linking individual drugs commonly used to treat breast cancer and CRCI, which include oxidative stress and inflammation, reduced neurogenesis, reduced levels of specific neurotransmitters, alterations in neuronal dendrites and spines, and impairment in myelin production. The second aspect is related to the clinical characteristics of CRCI in patients with breast cancer treated with different drug combinations. Data suggest the incidence rates of CRCI in breast cancer vary considerably, and may affect more than 50% of treated patients. Both chemotherapy regimens with or without anthracyclines have been associated with CRCI manifestations. While cross-sectional studies suggest the presence of symptoms up to 20 years after treatment, longitudinal studies confirm cognitive impairments lasting for at most 4 years after the end of chemotherapy. The third and final aspect is related to possible therapeutic interventions. Although there is still no standard of care to treat CRCI, several pharmacological and non-pharmacological approaches have shown interesting results. In summary, even if cognitive impairments derived from chemotherapy resolve with time, awareness of CRCI is crucial to provide patients with a better understanding of the syndrome and to offer them the best care directed at improving quality of life.

“Like Not Having an Arm”: Perspectives of Patients, Caregivers, and Practitioners on the Impact of Visitor Restrictions on Cancer Care During the COVID-19 Pandemic (RP405)

Outcomes1. Understand how caregiver absence affected the patient and caregiver dyadic relationship2. Understand how caregiver absence affected cancer and palliative care practitionersImportanceVisitor restriction policies to prevent the spread of COVID-19 between patients and practitioners have been widespread during the pandemic, resulting in the exclusion of caregivers at key points of cancer care and treatment decision making.Objective(s)Explore how visitor restrictions impacted cancer treatment decision making and care from patient, caregiver, and practitioner perspectives.Method(s)71 interviews, including 48 cancer patients, 4 family caregivers, and 19 cancer and palliative care practitioners from four academic cancer centers in the US between August 2020 and July 2021.ResultsVisitor restrictions that prevented caregivers from participating in clinic appointments and perioperative hospital stays were universally disliked by patients, caregivers, and practitioners. Patients felt deprived of an advocate to help ask questions and to process and retain medical information when patients felt overwhelmed or impaired with “chemo brain.” Caregivers discussed that visitor restrictions made them feel “out of the loop” and increased their anxiety about the patient's care. Cancer practitioners described how visitor restrictions impaired care because caregivers were not present to share valuable health information that the patient may have forgotten or neglected to mention, and clinicians had to spend extra time to call caregivers to relay information. Some surgical oncologists expressed moral distress because they perceived that the absence of caregivers negatively affected their patients’ health outcomes because caregivers were not there to provide emotional support during hospital stays.Conclusion(s)Our data indicate that the structure of the medical decision-making relationship is more tripartite than bilateral, with caregivers being a significant third actor within the medical decision-making process. Caregivers provided support in the decision-making and care process to both patients and practitioners, and their absence created additional burden on both.ImpactAs the pandemic continues into its second year with new surges and a return to visitor restrictions, health systems should reconsider visitor policies to ease the emotional and physical burden on patients, caregivers, and practitioners.

Rescuing Behavioral Impairment after Doxorubicin Chemotherapy in Rats

Chemotherapy regimens have been extensively used for the treatment of various types of cancers. Despite the effectiveness of this treatment, clinical use of chemotherapeutic agents often produces negative side effects like deficits in cognition and memory, delayed processing speed, and executive function. This condition is widely recognized as chemotherapy‐induced cognitive impairment or “Chemo brain.” Our study aimed to identify the neurobiological mechanisms possibly responsible for this cognitive impairment. We examined the effects of chronic treatment with the chemotherapeutic drug Doxorubicin on cognitive impairment. Doxorubicin is a reactive oxygen species‐producing antineoplastic Anthracycline agent that adversely affects hippocampal neurogenesis, causes neuro‐inflammation, and induces apoptosis. Baseline activity data were collected and then twelve young female Long Evans hooded rats were randomly assigned to receive either Doxorubicin (6mg/kg) or 0.9% saline given intraperitoneally, once weekly for four weeks. After treatment, rats were assessed on the string‐pulling task, the bar walk test, and open field test. Two individuals blind to the treatment calculated the average time duration, number of attempts to pull the string, number of misses, total number of mouth contacts before and after treatment for the string‐pulling task, number of deep slips, slight slips, and the total number of slips for the bar walk test. Similarly, the number of entries to the center, number of entries to the corners, time spent at the center vs corner, and latency to first enter and exit the center was calculated for the open field test and compared between two groups. No significant differences were detected between Dox‐treated and Control rats on any measure, which suggests that the Dox‐treatment produced little or no significant peripheral neuropathy that disrupted performance on the motor tasks we used and did not induce significant anxiety in our rats. Immuno‐histochemical analyses of brain tissues is ongoing to examine markers of neurogenesis and neuro‐inflammation.

Grape-Seed-Derived Procyanidin Attenuates Chemotherapy-Induced Cognitive Impairment by Suppressing MMP-9 Activity and Related Blood-Brain-Barrier Damage.

(1) Background: Chemotherapy-induced cognitive impairment (CICI) is often observed in cancer patients and impairs their life quality. Grape-seed-orientated procyanidin has been shown to have anti-inflammatory and neuroprotective effects, yet its effects in preventing CICI have not been investigated. (2) Method: Adult male mice received 2.3 mg/kg cisplatin or saline injections for three cycles consisting of five daily injections followed by 5 days of rest. Procyanidin or saline was administered 1 h prior to cisplatin treatment. Cognitive testing, gelatin zymography, and blood–brain-barrier (BBB) penetration tests were performed after treatment cessation. RAW264.7 cells were treated by stimulated supernatant of SHSY5Y cells. In addition, high-mobility group protein B1 (HMGB1) expression and MMP-9 activity were tested. (3) Results: Repeated cisplatin treatment increased BBB penetration, MMP-9 activity, impaired performance in contextual fear conditioning, and novel object recognition tasks. The knockout of MMP-9 rescues cognitive impairment and cisplatin-induced upregulation of HMGB1 in SHSY5Y cells. HMGB1/TLR4/IP3K/AKT signaling contributes to the increased MMP-9 activity in RAW264.7 cells. Procyanidin treatment attenuates MMP-9 activity, BBB damage, and CICI. (4) Conclusions: The results indicated that MMP-9 activation and BBB disruption is involved in CICI. Procyanidin may effectively alleviate the harmful effects of cisplatin.

Chemotherapy-induced cognitive impairment in breast cancer patients-risk factors and therapy

Chemotherapy-induced cognitive impairment in breast cancer patients-risk factors and therapy

Chemotherapy-Related Cognitive Impairment in Patients with Breast Cancer Based on Functional Assessment and NIRS Analysis.

Background: Chemotherapy-related cognitive impairment (CRCI), or “chemobrain,” isdefined as a phenomenon of cognitive deficits in cancer patients after chemotherapy and is characterized by deficits in areas of cognition, including memory, attention, speed of processing, and executive function, which seriously affect quality of life. The purpose of this study is to investigate the impact of CRCI in breast cancer (BC) patients in chemotherapy treatment (CT+) or not (CT−) and to analyze their relationship with detectable objective changes in cerebral activity during the execution of a phonological and semantic verbal fluency task (PVF and SVF). Methods: An observational, cross-sectional study was carried out at Badajoz University Hospital (Spain). A total of 180 women with BC were included. We used Cognitive Scale (FACT-Cog) for neuropsychological subjective assessment, obtaining scores of perceived cognitive impairment (PCI), and near-infrared spectroscopy system (NIRS) for neuropsychological objective assessment during a verbal fluency task (PVF and SVF), determining alterations in the prefrontal cortex (PFC) assessed as changes in regional saturation index (rSO2). Results: A total of 41.7% percent of the patients in the sample had PCI. CT+ was significantly associated with a worse impact in PCI ( = 50.60 ± 15.64 vs. = 55.01 ± 12.10; p = 0.005). Average rSO2 decreased significantly in CT+ ( = 63.30 ± 8.02 vs. = 67.98 ± 7.80; p < 0.001), and BC patients showed a significant decrease in PVF and SVF on average ( = 41.99 ± 9.52 vs. = 47.03 ± 9.31, = 33.43 ± 11.0 vs. = 36.14 ± 10.68, respectively; p < 0.001). Conclusions: Our findings suggest that cognitive impairments in the domain of executive functioning exist among patients with BC who received CT. The results corroborate the hypothesis that CT is an important factor in cognitive impairment in patients with BC, which has been demonstrated by both subjective (PCI) and objective (PVF, SVF, and rSO2) neuropsychological measures. The combination of doxorubicin, cyclophosphamide, and docetaxel induce cognitive impairment.