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Fowler CG, Tarantino MI, Gillett AE, Muñiz V, Anderson MA, Bonner RL, Vichaya EG. Using a murine model to explore the impact of sex and APOE4 on cisplatin-induced cognitive impairment. Brain Behav Immun 2025; 129:1-14. [PMID: 40374126 DOI: 10.1016/j.bbi.2025.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 04/22/2025] [Accepted: 05/12/2025] [Indexed: 05/17/2025] Open
Abstract
Chemotherapy-induced cognitive impairment (CICI) is reported in over 35% of cancer survivors. Understanding risk factors for the development of CICI may provide insight into mechanisms and treatment. Being female and carrying the E4 allele of the APOE gene are risk factors for late-onset Alzheimer's disease, and there is emerging evidence that they may also confer risk for CICI. We sought to investigate these factors in a middle-aged (8-9 months) murine model of CICI. We used a 2 (+/- cisplatin) x 2 (male/female) x 2 (wild-type/APOE4 transgenic) factorial design in which cisplatin, or an equal volume of saline vehicle, was administered at 2.3 mg/kg/day for 5 days for 2 rounds separated by a 5-day rest. Behavioral tests of cognition and activity were evaluated one month after treatment completion followed by tissue collection. Male mice exhibited more severe weight loss following cisplatin, irrespective of genotype. Cisplatin was also associated with reduced open-field and nest building activity for both sexes and genotypes. In the puzzle box task, cisplatin treatment reduced performance in the task with indication that sex and genotype trial dependently modulated performance. In the novel object task, male mice of both genotypes showed cisplatin-induced deficits. In analyzing tissue, we did not note significant cisplatin-induced neuroinflammatory processes. We did observe an effect of cisplatin on brain Bdnf mRNA expression that varied by brain region, sex, and genotype. Within the hippocampus, cisplatin reduced Bdnf in male mice but mildly elevated it within female mice; within the frontal cortex, Bdnf expression was reduced by cisplatin in both sexes but more severely in APOE4 mice. Overall, our data provide evidence that both sex and genotype may modulate the effect of cisplatin on the brain and on cognitive performance.
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Affiliation(s)
- Caroline G Fowler
- Department of Psychology & Neuroscience, Baylor University, One Bear Place 97334, Waco, TX 76798. USA
| | - Mia I Tarantino
- Department of Psychology & Neuroscience, Baylor University, One Bear Place 97334, Waco, TX 76798. USA
| | - Avery E Gillett
- Department of Psychology & Neuroscience, Baylor University, One Bear Place 97334, Waco, TX 76798. USA
| | - Valeria Muñiz
- Department of Psychology & Neuroscience, Baylor University, One Bear Place 97334, Waco, TX 76798. USA
| | - Marlee A Anderson
- Department of Psychology & Neuroscience, Baylor University, One Bear Place 97334, Waco, TX 76798. USA
| | - Reece L Bonner
- Department of Psychology & Neuroscience, Baylor University, One Bear Place 97334, Waco, TX 76798. USA
| | - Elisabeth G Vichaya
- Department of Psychology & Neuroscience, Baylor University, One Bear Place 97334, Waco, TX 76798. USA.
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Park JY, Lengacher CA, Rodriguez CS, Meng H, Kip KE, Morgan S, Joshi A, Hueluer G, Wang JR, Tinsley S, Cox C, Kiluk J, Donovan KA, Moscoso M, Bornstein E, Lucas JM, Fonseca T, Krothapalli M, Padgett LS, Nidamanur S, Hornback E, Patel D, Chamkeri R, Reich RR. The Moderating Role of Genetics on the Effectiveness of the Mindfulness-Based Stress Reduction for Breast Cancer (MBSR(BC)) Program on Cognitive Impairment. Biol Res Nurs 2025; 27:216-228. [PMID: 39413359 DOI: 10.1177/10998004241289629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2024]
Abstract
BACKGROUND Genetics may influence symptoms experienced by breast cancer survivors (BCS) by moderating the effects of stress-reducing interventions, including the Mindfulness-Based Stress Reduction (MBSR(BC)) program, to reduce symptom severity. As part of a larger clinical trial, the aim of this study was to evaluate genetic variants as moderators of MBSR(BC) on improvements among BCS in cognitive functioning and symptoms. METHODS BCS (n = 128) were randomized to MBSR(BC) or the Breast Cancer Education Support Program. Objective neuropsychological and subjective measures of cognitive performance, and psychological and physical symptoms were collected at baseline, 6, 12, and 26 weeks. Linear mixed models were implemented to identify MBSR(BC)'s effects over time. A total of 22 single nucleotide polymorphisms (SNPs) from 20 genes known to be related to these symptoms were investigated using genomic DNA. These SNPs were tested as moderators of MBSR(BC) program effects. RESULTS Results showed MBSR(BC) participants experienced significantly greater benefits in cognitive functioning, however, the level of benefit varied based on one's genetic profile. Effects sizes, consistency across similar measures were investigated. Among 22 candidate SNPs, rs4680 in COMT, rs1800497 in ANKK1, and rs6277 in DRD2 demonstrated the strongest, most consistent positive effects in moderating MBSR(BC)'s impact on cognitive outcomes. CONCLUSIONS Although the effects were small, this translational research may potentially identify BCS with genotypes that would be most influenced by the MBSR(BC) program. These results may be used to develop personalized intervention programs tailored to the genetic profile of each breast cancer survivor who received chemotherapy or chemotherapy and radiation. TRIAL REGISTRATION ClinicalTrials.gov, https://www.ClinicalTrials.gov Registration Number: NCT02786797.
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Affiliation(s)
| | | | | | - Hongdao Meng
- College of Behavioral and Community Sciences, University of South Florida, Tampa, FL, USA
| | - Kevin E Kip
- UPMC Health Services Division, Pittsburgh, PA, USA
| | - Sandra Morgan
- University of South Florida College of Nursing, Tampa, FL, USA
| | | | | | - Julia R Wang
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | | | - Charles Cox
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | | | | | | | | | - Jean M Lucas
- Sarasota Memorial Health Care System, Sarasota, FL, USA
| | | | | | - Lynne S Padgett
- Veteran Affairs Office of Research & Development, Washington, DC, USA
| | | | | | - Diya Patel
- College of Arts and Sciences, University of South Florida, Tampa, FL, USA
| | - Ramya Chamkeri
- College of Arts and Sciences, University of South Florida, Tampa, FL, USA
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Torre M, Zanella CA, Feany MB. The Biological Intersection Between Chemotherapy-Related Cognitive Impairment and Alzheimer Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00026-4. [PMID: 39863251 DOI: 10.1016/j.ajpath.2024.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/27/2024] [Accepted: 12/23/2024] [Indexed: 01/27/2025]
Abstract
Alzheimer disease (AD) is the most common type of dementia and one of the leading causes of death in elderly patients. The number of patients with AD in the United States is projected to double by 2060. Thus, understanding modifiable risk factors for AD is an urgent public health priority. In parallel with the number of patients with AD, the number of cancer survivors is estimated to increase significantly, and up to 80% of cancer patients treated with chemotherapy will develop cognitive deficits, termed chemotherapy-related cognitive impairment. This review discusses biologically plausible pathways underlying both disorders, with the goal of understanding why a proportion of chemotherapy patients may be at higher risk of developing AD. Highlighted are the E4 allele of the apolipoprotein E gene, neuroinflammation, oxidative stress, DNA damage, mitochondrial dysfunction, neuronal and synaptic loss, cellular senescence, brain-derived neurotrophic factor signaling, white matter damage, blood-brain barrier/vascular dysfunction, tau pathology, and transposable element reactivation.
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Affiliation(s)
- Matthew Torre
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas; Center for Alzheimer's and Neurodegenerative Diseases, Baylor College of Medicine, Houston, Texas.
| | - Camila A Zanella
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Mel B Feany
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Chan A, Chan D, Ng DQ, Zheng HF, Tan QM, Tan CJ, Toh JHM, Yap NY, Toh YL, Ke Y, Wang ECA, Lim QPN, Ho HK, Chew L, Tan TJ. HEalth-Related Quality of Life-Intervention in Survivors of Breast and Other Cancers Experiencing Cancer-Related Fatigue and Associated Cognitive Symptoms Using TraditionAL Chinese Medicine: The 'HERBAL' Trial. Integr Cancer Ther 2025; 24:15347354251314514. [PMID: 39840742 PMCID: PMC11755541 DOI: 10.1177/15347354251314514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/10/2024] [Accepted: 01/06/2025] [Indexed: 01/23/2025] Open
Abstract
INTRODUCTION As pharmacological strategies remain limited for relieving fatigue and associated cognitive symptoms, integrative modalities such as traditional Chinese medicine (TCM) could be explored as therapeutic strategies in cancer survivors. Here, we evaluate and report the efficacy and safety of a TCM concoction, modified Xiang Bei Yang Rong Tang (XBYRT), on quality of life (QOL), cancer-related fatigue (CRF), and cognitive symptoms, compared to placebo. METHODS In a single-centered, randomized, double-blinded, placebo-controlled pilot trial conducted from 2019 to 2022, fatigued cancer survivors ≥21 years old were recruited to receive the XBYRT intervention or placebo (5% diluted) once daily for the duration of 8 weeks. Patient-reported outcomes for QOL, CRF, cognition, blood samples for biomarker testing, and adverse events were collected at baseline (T0), 4 weeks (T1), 8 weeks (T2), and 10 weeks (T3) after baseline. Linear regression was performed to evaluate differences between groups at T2 and T3. RESULTS A total of 1502 patients were screened, with 672 patients considered eligible. Of the eligible, 15 XBYRT and 13 placebo subjects with similar mean ages (58.5 vs 58.4) were recruited. Both groups were predominantly Chinese (93% vs 62%), breast cancer patients (87% vs 62%), and diagnosed with stage 2 cancer (60% vs 46%). Although no significant difference was found in QOL between groups, the XBYRT group exhibited improved emotional fatigue at T3 (P = .045) and higher BDNF levels at T2 (P = .047) and T3 (P = .029). After baseline adjustment, XBYRT was associated with better perceived cognitive impairment at T2 (P = .011) and T3 (P = .017), as well as overall perceived cognitive function at T3 (P = .028). XBYRT is well tolerated, with grade 3 adverse events reported in three XBYRT (20%) and two placebo (15%) subjects. CONCLUSION In this pilot study, XBYRT as an integrative therapy is safe and generates encouraging improvements in cognitive and fatigue symptoms. Difficulties with recruitment limited the generalizability of trial findings, thus findings should be verified through a larger, multi-centered trial.
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Affiliation(s)
| | | | - Ding Quan Ng
- University of California Irvine, Irvine, CA, USA
| | | | - Quan Ming Tan
- Singapore Thong Chai Medical Institution, Singapore, Singapore
| | | | | | - Ning Yi Yap
- Subang Jaya Medical Centre, Subang Jaya, Malaysia
| | - Yi Long Toh
- National University of Singapore, Singapore, Singapore
| | - Yu Ke
- National Cancer Centre Singapore, Singapore
| | | | | | - Han Kiat Ho
- National University of Singapore, Singapore, Singapore
| | - Lita Chew
- National University of Singapore, Singapore, Singapore
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Sheppard DP, Noll KR, Wefel JS, Bradshaw ME. Neuropsychological Evaluation for Oncology. Neurol Clin 2024; 42:875-887. [PMID: 39343481 PMCID: PMC11443061 DOI: 10.1016/j.ncl.2024.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Cognitive dysfunction is common in cancers and their treatments. Factors that can contribute to cognitive dysfunction include direct and indirect effects of cancer, surgery, radiation, systemic therapy, as well as comorbidities, fatigue, and mood disturbance. Using objective, validated measures, a neuropsychological evaluation can provide information regarding patterns of cognitive function. Emphasis of cognitive domains assessed may vary depending on disease and treatment history. Cognitive interventions can minimize the effects of cancer-related cognitive dysfunction on daily life.
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Affiliation(s)
- David P Sheppard
- Department of Rehabilitation Medicine, University of Washington, 1959 Northeast Pacific Street Box 356490, Seattle, WA 98195, USA
| | - Kyle R Noll
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 431, Houston, TX 77030, USA
| | - Jeffrey S Wefel
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 431, Houston, TX 77030, USA
| | - Mariana E Bradshaw
- Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 431, Houston, TX 77030, USA.
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Hsiao CP, Goto T, Von Ah D, Saligan LN. Cancer-Related Cognitive Impairment Associated with APOE rs7412 and BDNF rs6265 in Breast Cancer Survivors. Semin Oncol Nurs 2024; 40:151721. [PMID: 39198096 DOI: 10.1016/j.soncn.2024.151721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 09/01/2024]
Abstract
OBJECTIVES Cancer-related cognitive impairment (CRCI) is a highly prevalent and debilitating symptom reported by breast cancer survivors (BCS). The etiology of CRCI remains unclear, leading to poor symptom management. Building from prior studies, BCS with the C/C genotype of apolipoprotein E (APOE) rs7412 and the T/T genotype of brain-derived neurotrophic factor (BDNF) rs6265 were hypothesized to experience more severe CRCI. Therefore, we investigated the relationships between the severity of CRCI and polymorphisms of APOE and BDNF among BCS. METHODS This was a subanalysis of data from a larger descriptive, correlational, and cross-sectional study. Subjective and objective CRCI were measured using the Patient-Reported Outcomes Measurement Information System and CANTAB Cambridge Cognitive assessment, respectively. Buccal swab samples were collected to evaluate the single nucleotide polymorphisms. Multivariable generalized linear regression models were used to analyze data. RESULTS APOE rs7412 and BDNF rs6265 were significantly associated with lower self-reported cognitive abilities in a total of 353 BCS. Age was positively associated with self-reported cognitive scores, indicating that younger BCS perceived lower cognitive abilities. Individuals carrying genotype of C/T for APOE with the C/C or C/T for BDNF showed positive associations with cognitive abilities. CONCLUSIONS Younger BCS with the C/C genotype for APOE rs7412 and the T/T genotype for BDNF rs6265 may be at risk for CRCI. Knowledge regarding predictive markers for CRCI symptoms is essential for precision symptom management. Further investigation with a longitudinal and translational design is necessary to explore the etiologies for CRCI. IMPLICATIONS FOR NURSING PRACTICE Integrating genetic phenotyping into routine clinical practice will provide nurses with unique opportunities to understand individual susceptibilities, and how symptoms may trigger other symptoms. Further, findings from these innovative investigations will provide symptom interventionists and implementation scientists with critical data to optimize individualized strategies for symptom prevention, detection, and management.
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Affiliation(s)
- Chao-Pin Hsiao
- Case Western Reserve University School of Nursing, Cleveland, Ohio
| | - Taichi Goto
- Symptoms Biology Unit, Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland
| | - Diane Von Ah
- The Ohio State University College of Nursing, Columbus, Ohio
| | - Leorey N Saligan
- Symptoms Biology Unit, Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland.
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Lavoie Smith EM, Von Ah D. Neurotoxicity in Cancer Survivorship: The Significance of Cancer-Related Cognitive Impairment and Chemotherapy-Induced Peripheral Neuropathy. Semin Oncol Nurs 2024; 40:151724. [PMID: 39183088 DOI: 10.1016/j.soncn.2024.151724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 07/27/2024] [Accepted: 07/31/2024] [Indexed: 08/27/2024]
Affiliation(s)
- Ellen M Lavoie Smith
- Professor and Marie O'Koren Endowed Chair, Assistant Dean of Research and Scholarship, University of Alabama at Birmingham School of Nursing, Department of Acute, Chronic & Continuing Care, Birmingham, AL
| | - Diane Von Ah
- Mildred E. Newton Endowed Professor, Distinguished Professor of Cancer Research, The Ohio State University, College of Nursing, Columbus, OH.
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8
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Liu Y, Yin S, Lu G, Du Y. The intersection of the nervous system and breast cancer. Cancer Lett 2024; 598:217132. [PMID: 39059572 DOI: 10.1016/j.canlet.2024.217132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 07/15/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024]
Abstract
Breast cancer (BC) represents a paradigm of heterogeneity, manifesting as a spectrum of molecular subtypes with divergent clinical trajectories. It is fundamentally characterized by the aberrant proliferation of malignant cells within breast tissue, a process modulated by a myriad of factors that govern its progression. Recent endeavors outline the interplay between BC and the nervous system, illuminate the complex symbiosis between neural structures and neoplastic cells, and elucidate nerve dependence as a cornerstone of BC progression. This includes the neural modulations on immune response, neurovascular formation, and multisystem interactions. Such insights have unveiled the critical impact of neural elements on tumor dynamics and patient prognosis. This revelation beckons a deeper exploration into the neuro-oncological interface, potentially unlocking novel therapeutic vistas. This review endeavors to delineate the intricate mechanisms between the nervous system and BC, aiming to accentuate the implications and therapeutic strategies of this intersection for tumor evolution and the formulation of innovative therapeutic approaches.
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Affiliation(s)
- Yutong Liu
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, No.71Xinmin Street, Changchun, Jilin, China
| | - Shiqi Yin
- Anhui University of Science and Technology Affiliated Fengxian Hospital, 6600 Nanfeng Road, Shanghai, China
| | - Guanyu Lu
- Cancer Center, The First Hospital of Jilin University, No.71Xinmin Street, Changchun, Jilin, China
| | - Ye Du
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, No.71Xinmin Street, Changchun, Jilin, China.
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Rufino KA, Goli P, Patriquin MA, Kosten TR, Nielsen DA, Salas R. Val/Met BDNF as a genetic risk for a false sense of security in post-discharge suicide risk. J Affect Disord 2024; 354:98-103. [PMID: 38447916 DOI: 10.1016/j.jad.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 02/14/2024] [Accepted: 03/03/2024] [Indexed: 03/08/2024]
Abstract
BACKGROUND The time after discharge from psychiatric inpatient care is one of the most dangerous periods in terms of suicide risk. Predicting who is at higher risk could help with resource allocation to assure patients at high risk of suicide attempts are most closely followed. We previously showed that inpatients who improve their suicide ideation levels faster while in inpatient treatment are the ones with highest rates of post-discharge suicide. Here, we studied the possible genetic underpinnings associated with such risk. METHOD We recorded the slope of suicide ideation recovery of 710 psychiatric inpatients from which we studied two genetic variants likely associated with suicide risk: The serotonin transporter variant 5-HTTLPR, and the BDNF gene variant Val66Met. RESULTS We found that inpatients carrying the BDNF Met variant (hypothesized as conferring higher suicide risk) improved their suicide ideation scores faster than Val/Val carrying inpatients. No significant association was found for 5-HTTLPR. LIMITATIONS The present sample was genetically homogenous, and future research should replicate these findings on a more diverse sample. CONCLUSIONS In conclusion, we found a paradoxical result: Carrying the BDNF Met variant allows inpatients to improve faster, which was shown to confer higher risk at the post-discharge period. This may explain some inconsistencies in the literature in terms of the role of BDNF in suicide ideation and attempts.
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Affiliation(s)
- K A Rufino
- The Menninger Clinic, Houston, TX, USA; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, USA; Department of Social Sciences, The University of Houston Downtown, Houston, TX, USA
| | - P Goli
- Rice University, Houston, TX, USA
| | - M A Patriquin
- The Menninger Clinic, Houston, TX, USA; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, USA; Michael E DeBakey VA Medical Center, Houston, TX, USA
| | - T R Kosten
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, USA; Michael E DeBakey VA Medical Center, Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - D A Nielsen
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, USA; Michael E DeBakey VA Medical Center, Houston, TX, USA
| | - R Salas
- The Menninger Clinic, Houston, TX, USA; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; Center for Translational Research on Inflammatory Diseases, Michael E DeBakey VA Medical Center, Houston, TX, USA.
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Hariharan R, Hood L, Price ND. A data-driven approach to improve wellness and reduce recurrence in cancer survivors. Front Oncol 2024; 14:1397008. [PMID: 38665952 PMCID: PMC11044254 DOI: 10.3389/fonc.2024.1397008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
For many cancer survivors, toxic side effects of treatment, lingering effects of the aftermath of disease and cancer recurrence adversely affect quality of life (QoL) and reduce healthspan. Data-driven approaches for quantifying and improving wellness in healthy individuals hold great promise for improving the lives of cancer survivors. The data-driven strategy will also guide personalized nutrition and exercise recommendations that may help prevent cancer recurrence and secondary malignancies in survivors.
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Affiliation(s)
- Ramkumar Hariharan
- College of Engineering, Northeastern University, Seattle, WA, United States
- Institute for Experiential Artificial Intelligence, Northeastern University, Boston, MA, United States
| | - Leroy Hood
- Institute for Systems Biology, Seattle, WA, United States
- Buck Institute for Research on Aging, Novato, CA, United States
- Phenome Health, Seattle, WA, United States
| | - Nathan D. Price
- Institute for Systems Biology, Seattle, WA, United States
- Thorne HealthTech, New York, NY, United States
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Rick O, Gerhardt A, Schilling G. Cancer-Related Cognitive Dysfunction: A Narrative Review for Clinical Practice. Oncol Res Treat 2024; 47:218-223. [PMID: 38471462 DOI: 10.1159/000538277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 03/06/2024] [Indexed: 03/14/2024]
Abstract
BACKGROUND Cancer-related cognitive dysfunction (CRCD) is a major functional disorder in patients with cancer. This central nervous dysfunction is found in up to 60% of patients after tumour therapy, often significantly limits the quality of life, and significantly impedes participation in working life. For this reason, diagnosis and treatment of CRCD are of central importance. This narrative review is intended to provide an overview and support for practical clinical care with regard to diagnostics and therapeutic options. SUMMARY In Germany, CRCD has received insufficient attention in clinical practice due to the lack of guidelines for diagnosis and therapy. The pathophysiology is complex and cannot be explained by chemotherapeutic treatment alone. In addition to the tumour disease as such and the tumour therapy, psychological factors such as anxiety and depression as well as sleep disorders also play a significant role. Today, it is known that in addition to age, molecular genetic changes also have an effect on cognitive function. Morphologically, CRCD can be located in the frontal cortex and hippocampus. In addition to easy-to-use screening instruments such as the visual analogue scale, validated questionnaires such as the Questionnaire of Subjectively Experienced Deficits in Attention (FEDA) developed in Germany are also available. These allow the suspected diagnosis to be substantiated and the patient to be referred to further neurological, neuropsychological, or psycho-oncological diagnostics. Within the framework of further neuropsychological diagnostics, the International Cognition and Cancer Task Force (ICCTF) recommends testing learning, memory, processing speed, and executive functions. From the authors' point of view, a step-by-step diagnosis is recommended in order to avoid overdiagnosis. In clinical practice, graduation according to the "Common Terminology Criteria for Adversity Events" (CTCAE Version 5.0) is suitable for assessing the degree of severity. Cognitive training should be behaviourally oriented and include regular practice of cognitive skills to restore attention, psychomotor speed, memory, and executive functions. The best evidence is currently found for web-based training programmes that can be used by the patient at home. There is also evidence for mindfulness training and physical exercises. In particular, the combination of these three therapeutic elements currently seems to be the optimal treatment strategy for CRCD. KEY MESSAGES Cognitive dysfunction should be given much more attention in the clinical care of cancer patients. Diagnostic tools for this purpose and evidence-based therapeutic interventions are available. In the future, networks should be created that allow for better care of patients with CRCD.
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Affiliation(s)
- Oliver Rick
- Klinik Reinhardshöhe, Bad Wildungen, Germany
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12
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Zhou X, Zhang X, Zhong T, Zhou M, Gao L, Chen L. Prevalence and associated factors of chemotherapy-related cognitive impairment in older breast cancer survivors. J Adv Nurs 2024; 80:484-499. [PMID: 37675947 DOI: 10.1111/jan.15842] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 08/11/2023] [Accepted: 08/23/2023] [Indexed: 09/08/2023]
Abstract
AIMS To examine the prevalence and associated factors of chemotherapy-related cognitive impairment (CRCI) in older breast cancer survivors (BCS). DESIGN Systematic review. DATA SOURCES We searched EMBASE, PubMed, PsychInfo, CINAHL, Cochrance Library, Web of Science, CNKI and SinoMed, without language restrictions, for studies published from the establishment of the database to September 2022. REVIEW METHODS Two researchers independently examined the full texts, data extraction and quality assessment, and any discrepancies were resolved through discussion with a third reviewer. Quality of evidence was assessed using the Newcastle-Ottawa Scale and the Agency for Healthcare Research and Quality Scale. RESULTS The seven included studies showed that the estimated prevalence of CRCI in older BCS ranged from 18.6% to 27% on objective neuropsychological tests and from 7.6% to 49% on subjective cognitive assessments. The areas most affected were attention, memory, executive functioning and processing speed. CRCI was associated with 10 factors in six categories, including sociodemographic (e.g. age, education level), physiological (e.g. sleep disorders, fatigue and comorbidities), psychological (e.g. anxiety, depression), treatment modalities (e.g. chemotherapy cycles, chemotherapy regimens), genetic (e.g. APOE2, APOE4) and lifestyle factor (e.g. physical inactivity). CONCLUSION CRCI is multifactorial and has a relatively high prevalence. However, the results of subjective and objective cognitive examinations were inconsistent, possibly due to variations in tools used to evaluate different definitions of CRCI. Nevertheless, as there are few published studies of older BCS, this conclusion still require verification by well-designed studies in the future. IMPACT We found that the prevalence of CRCI in older adults is relatively high and multifactorial, providing evidence for further health care for this population. NO PATIENT OR PUBLIC CONTRIBUTION There was no patient or public involvement.
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Affiliation(s)
- Xuan Zhou
- Jilin University School of Nursing, Changchun, China
| | - Xueyan Zhang
- Jilin University School of Nursing, Changchun, China
| | | | - Meng Zhou
- Jilin University School of Nursing, Changchun, China
| | - Lan Gao
- The First Hospital of Jilin University, Changchun, China
| | - Li Chen
- Jilin University School of Nursing, Changchun, China
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Goto T, Saligan LN, Li X, Xiang L, Kwiat C, Nguyen C, Crouch A, Von Ah D. Associations of brain-derived neurotrophic factor rs6265 polymorphism and cognitive function in breast cancer survivors from a cross-sectional study. Cancer Med 2024; 13:e6975. [PMID: 38379321 PMCID: PMC10839126 DOI: 10.1002/cam4.6975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 12/28/2023] [Accepted: 01/18/2024] [Indexed: 02/22/2024] Open
Abstract
BACKGROUND Breast cancer survivors (BCS) often complain of cancer-related cognitive impairment (CRCI) during and even months after completing primary cancer treatments, particularly chemotherapy. The etiology of CRCI is unknown, but associations of CRCI with germline genetic polymorphisms have been reported, including Brain-Derived Neurotrophic Factor (BDNF) rs6265 polymorphism. The current study investigated the associations of specific BDNF rs6265 with CRCI. METHODS Cancer-related cognitive impairment was assessed using subjective reports of cognitive symptoms (the version 1.0, 8-item short-forms of the Patient-Reported Outcomes Measurement Information System®) and computerized objective cognitive function scores (CANTAB®). BDNF rs6265 genotypes were determined from buccal swabs. The associations of specific BDNF rs6265 with CRCI were examined by either one-way analysis of variance or the Kruskal-Wallis test followed by post hoc tests and rank-based regression analysis. RESULTS We examined 356 female BCS. The mean (SD) age was 55.6 (9.8) years old, the median (IQR) years since cancer diagnosis were 4.0 (6.0), and 331 (92.7%) were self-described as White. BCS carrying the Met/Met genotype showed poorer results on 'visual episodic memory and new learning' and 'spatial working memory and executive function.' This relationship was observed regardless of prior chemotherapy. CONCLUSION Our findings suggest that carrying the BDNF rs6265 Met/Met genotype increases the risk for CRCI in BCS. These results are foundational in nature and provide important information to identify mechanisms underpinning CRCI.
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Affiliation(s)
- Taichi Goto
- Symptoms Biology Unit, Division of Intramural ResearchNational Institute of Nursing Research, National Institutes of HealthBethesdaMarylandUSA
| | - Leorey N. Saligan
- Symptoms Biology Unit, Division of Intramural ResearchNational Institute of Nursing Research, National Institutes of HealthBethesdaMarylandUSA
| | - Xiaobai Li
- Department of BiostatisticsNational Institutes of Health Clinical CenterBethesdaMarylandUSA
| | - Lichen Xiang
- Symptoms Biology Unit, Division of Intramural ResearchNational Institute of Nursing Research, National Institutes of HealthBethesdaMarylandUSA
| | - Catherine Kwiat
- Symptoms Biology Unit, Division of Intramural ResearchNational Institute of Nursing Research, National Institutes of HealthBethesdaMarylandUSA
| | - Christopher Nguyen
- Symptoms Biology Unit, Division of Intramural ResearchNational Institute of Nursing Research, National Institutes of HealthBethesdaMarylandUSA
| | - Adele Crouch
- Indiana University School of NursingIndianapolisIndianaUSA
| | - Diane Von Ah
- The Ohio State University College of NursingColumbusOhioUSA
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Vaiana AM, Chen Y, Gelfond J, Johnson-Pais TL, Leach RJ, Ramamurthy C, Thompson IM, Morilak DA. Effects of vortioxetine on hippocampal-related cognitive impairment induced in rats by androgen deprivation as a model of prostate cancer treatment. Transl Psychiatry 2023; 13:307. [PMID: 37788996 PMCID: PMC10547695 DOI: 10.1038/s41398-023-02600-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 09/15/2023] [Accepted: 09/20/2023] [Indexed: 10/05/2023] Open
Abstract
Advances in prostate cancer treatment have significantly improved survival, but quality of life for survivors remains an under-studied area of research. Androgen deprivation therapy (ADT) is a foundational treatment for advanced prostate cancer and is used as an adjuvant for prolonged periods in many high-risk, localized tumors. More than half of patients treated with ADT experience debilitating cognitive impairments in domains such as spatial learning and working memory. In this study, we investigated the effects of androgen deprivation on hippocampal-mediated cognition in rats. Vortioxetine, a multimodal antidepressant, has been shown to improve cognition in depressed patients. Thus, we also tested the potential efficacy of vortioxetine in restoring impaired cognition after ADT. We further investigated mechanisms that might contribute to these effects, measuring changes in the circuitry and gene expression within the dorsal hippocampus. ADT via surgical castration induced impairments in visuospatial cognition on the novel object location test and attenuated afferent-evoked local field potentials recorded in the CA1 region of the dorsal hippocampus. Chronic dietary administration of vortioxetine effectively reversed these deficits. Castration significantly altered gene expression in the hippocampus, whereas vortioxetine had little effect. Pathway analysis revealed that androgen depletion altered pathways related to synaptic plasticity. These results suggest that the hippocampus may be vulnerable to ADT, contributing to cognitive impairment in prostate cancer patients. Further, vortioxetine may be a candidate to improve cognition in patients who experience cognitive decline after androgen deprivation therapy for prostate cancer and may do so by restoring molecular and circuit-level plasticity-related mechanisms compromised by ADT.
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Affiliation(s)
- Alexandra M Vaiana
- Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, 78229, USA
- Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, 78229, USA
- Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Yidong Chen
- Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, 78229, USA
- Department of Population Health Sciences, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Jonathan Gelfond
- Department of Population Health Sciences, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Teresa L Johnson-Pais
- Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, 78229, USA
- Department of Urology, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Robin J Leach
- Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, 78229, USA
- Department of Cell Systems & Anatomy, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Chethan Ramamurthy
- Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, 78229, USA
- Department of Medicine, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Ian M Thompson
- Department of Urology, University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - David A Morilak
- Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
- Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
- Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX, 78229, USA.
- South Texas Veterans Health Care System, San Antonio, TX, 78229, USA.
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Franco-Rocha OY, Lewis KA, Longoria KD, De La Torre Schutz A, Wright ML, Kesler SR. Cancer-related cognitive impairment in racial and ethnic minority groups: a scoping review. J Cancer Res Clin Oncol 2023; 149:12561-12587. [PMID: 37432455 DOI: 10.1007/s00432-023-05088-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 06/30/2023] [Indexed: 07/12/2023]
Abstract
PURPOSE Disparities in cognitive function among racial and ethnic groups have been reported in non-cancer conditions, but cancer-related cognitive impairment (CRCI) in racial and ethnic minority groups is poorly understood. We aimed to synthesize and characterize the available literature about CRCI in racial and ethnic minority populations. METHODS We conducted a scoping review in the PubMed, PsycInfo, and Cumulative Index to Nursing and Allied Health Literature databases. Articles were included if they were published in English or Spanish, reported cognitive functioning in adults diagnosed with cancer, and characterized the race or ethnicity of the participants. Literature reviews, commentaries, letters to the editor, and gray literature were excluded. RESULTS Seventy-four articles met the inclusion criteria, but only 33.8% differentiated the CRCI findings by racial or ethnic subgroups. There were associations between cognitive outcomes and the participants' race or ethnicity. Additionally, some studies found that Black and non-white individuals with cancer were more likely to experience CRCI than their white counterparts. Biological, sociocultural, and instrumentation factors were associated with CRCI differences between racial and ethnic groups. CONCLUSIONS Our findings indicate that racial and ethnic minoritized individuals may be disparately affected by CRCI. Future research should use standardized guidelines for measuring and reporting the self-identified racial and ethnic composition of the sample; differentiate CRCI findings by racial and ethnic subgroups; consider the influence of structural racism in health outcomes; and develop strategies to promote the participation of members of racial and ethnic minority groups.
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Affiliation(s)
- Oscar Y Franco-Rocha
- School of Nursing, University of Texas at Austin, 1710 Red River St, Austin, TX, USA.
| | - Kimberly A Lewis
- School of Nursing, University of Texas at Austin, 1710 Red River St, Austin, TX, USA
- Department of Physiological Nursing, School of Nursing, University of California, San Francisco, San Francisco, CA, USA
| | - Kayla D Longoria
- School of Nursing, University of Texas at Austin, 1710 Red River St, Austin, TX, USA
| | - Alexa De La Torre Schutz
- Brain Health Neuroscience Lab, School of Nursing, The University of Texas at Austin, 1710 Red River St, Austin, TX, USA
| | - Michelle L Wright
- School of Nursing, University of Texas at Austin, 1710 Red River St, Austin, TX, USA
| | - Shelli R Kesler
- School of Nursing, University of Texas at Austin, 1710 Red River St, Austin, TX, USA
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Ng DQ, Cheng I, Wang C, Tan CJ, Toh YL, Koh YQ, Ke Y, Foo KM, Chan RJ, Ho HK, Chew L, Bin Harunal Rashid MF, Chan A. Brain-derived neurotrophic factor as a biomarker in cancer-related cognitive impairment among adolescent and young adult cancer patients. Sci Rep 2023; 13:16298. [PMID: 37770565 PMCID: PMC10539508 DOI: 10.1038/s41598-023-43581-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 09/26/2023] [Indexed: 09/30/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) improves cognitive function by stimulating neurogenesis and neuroplasticity. We hypothesize that higher plasma BDNF levels are protective against cognitive toxicity among adolescent and young adult cancer patients (15-39 years old). In a prospective, longitudinal study, we recruited 74 newly diagnosed cancer and 118 age-matched non-cancer controls who completed the Cambridge Neuropsychological Test Automated Battery (CANTAB), Functional Assessment of Cancer Therapy-Cognitive Function questionnaire (FACT-Cog) and blood draws. Plasma BDNF was quantified using an enzyme-linked immunosorbent assay. Genomic DNA from buffy coat was genotyped for BDNF Val66Met. Most cancer participants were diagnosed with breast (24%) and head/neck (22%) cancers. After adjusting for sociodemographic variables (age, gender, race, marital status, education years), cancer participants had lower BDNF levels (ng/mL) at baseline (median: 10.7 vs 21.6, p < 0.001) and 6-months post-baseline (median: 8.2 vs 15.3, p = 0.001) compared to non-cancer controls. Through linear mixed modelling adjusted for sociodemographic variables, baseline cognition, fatigue, psychological distress, and time, we observed that among cancer participants, lower baseline BDNF levels were associated with worse attention (p = 0.029), memory (p = 0.018) and self-perceived cognitive abilities (p = 0.020) during cancer treatment. Met/Met was associated with enhanced executive function compared to Val/Val (p = 0.012). Plasma BDNF may serve as a predictive biomarker of cancer-related cognitive impairment.
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Affiliation(s)
- Ding Quan Ng
- Department of Clinical Pharmacy Practice, University of California Irvine, 802 W Peltason Dr, Irvine, CA, 92697-4625, USA
| | - Ivy Cheng
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Claire Wang
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Chia Jie Tan
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Yi Long Toh
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Yong Qin Koh
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Yu Ke
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Koon Mian Foo
- Department of Pharmacy, KK Women and Children's Hospital, Singapore, Singapore
| | - Raymond J Chan
- Caring Futures Institutes, College of Nursing and Health Sciences, Flinders University, Adelaide, Australia
| | - Han Kiat Ho
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Lita Chew
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
- Department of Pharmacy, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Alexandre Chan
- Department of Clinical Pharmacy Practice, University of California Irvine, 802 W Peltason Dr, Irvine, CA, 92697-4625, USA.
- Department of Pharmacy, National Cancer Centre Singapore, Singapore, Singapore.
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Iranzo P, Callejo A, Arbej J, Menao S, Isla D, Andrés R. [Risk factors for cancer-related cognitive impairment in breast and colorectal cancer patients who undergo chemotherapy]. An Sist Sanit Navar 2023; 46:e1040. [PMID: 37594060 PMCID: PMC10498134 DOI: 10.23938/assn.1040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 03/28/2023] [Accepted: 06/08/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND Our study aims to evaluate the impact of different factors on cancer-related cognitive impairment in patients who undergo chemotherapy. METHODOLOGY Prospective longitudinal single-centre study that included patients with breast and colon carcinoma who underwent chemotherapy as part of their treatment. Clinical and genetic characteristics of the patients (single nucleotide polymorphisms, SNPs) were collected. Patients' neurocognitive status was assessed using eleven validated tests at three time points: before chemotherapy (M0 - baseline), between one and four weeks after completing chemotherapy (M1), and between 24-30 weeks after completing chemotherapy (M2). RESULTS Sixty-two patients were included in this study; 82% were female, median age was 56 years (range 30-74), and 64.5% had been diagnosed with breast cancer. Overall, better cognitive results at M0 were associated with age < 55 years, higher educational level, absence of comorbidities, and the CC variant rs471692 (TOP2A). Significant decline was found between M0 to M1 in the Rey Auditory Verbal Learning Test and the Letter and Number test, with evidence of recovery in M2 compared to M0 regarding the following test: Visual Memory, Functioning Assessment Short Test (FAST), Digit Symbol Substitution and Cube. In the multivariate analysis, being =55 years of age, adjuvant chemotherapy, presence of comorbidities, tobacco and alcohol use, and GT variant rs1800795 were associated with cognitive decline between M0 and M1. CONCLUSION Being =55 years of age, female, presence of comorbidities and basic education level are related to a higher risk of cognitive impairment after chemotherapy.
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Affiliation(s)
| | | | - Julio Arbej
- Servicio de Psiquiatría. Hospital Clínico Universitario Lozano Blesa. Zaragoza. España..
| | - Sebastian Menao
- Servicio de Bioquímica. Hospital Clínico Universitario Lozano Blesa. Zaragoza. España..
| | - Dolores Isla
- Servicio de Bioquímica. Hospital Clínico Universitario Lozano Blesa. Zaragoza. España..
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Mao J, Chao K, Jiang FL, Ye XP, Yang T, Li P, Zhu X, Hu PJ, Zhou BJ, Huang M, Gao X, Wang XD. Comparison and development of machine learning for thalidomide-induced peripheral neuropathy prediction of refractory Crohn’s disease in Chinese population. World J Gastroenterol 2023; 29:3855-3870. [PMID: 37426324 PMCID: PMC10324537 DOI: 10.3748/wjg.v29.i24.3855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/07/2023] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Thalidomide is an effective treatment for refractory Crohn’s disease (CD). However, thalidomide-induced peripheral neuropathy (TiPN), which has a large individual variation, is a major cause of treatment failure. TiPN is rarely predictable and recognized, especially in CD. It is necessary to develop a risk model to predict TiPN occurrence.
AIM To develop and compare a predictive model of TiPN using machine learning based on comprehensive clinical and genetic variables.
METHODS A retrospective cohort of 164 CD patients from January 2016 to June 2022 was used to establish the model. The National Cancer Institute Common Toxicity Criteria Sensory Scale (version 4.0) was used to assess TiPN. With 18 clinical features and 150 genetic variables, five predictive models were established and evaluated by the confusion matrix receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), specificity, sensitivity (recall rate), precision, accuracy, and F1 score.
RESULTS The top-ranking five risk variables associated with TiPN were interleukin-12 rs1353248 [P = 0.0004, odds ratio (OR): 8.983, 95% confidence interval (CI): 2.497-30.90], dose (mg/d, P = 0.002), brain-derived neurotrophic factor (BDNF) rs2030324 (P = 0.001, OR: 3.164, 95%CI: 1.561-6.434), BDNF rs6265 (P = 0.001, OR: 3.150, 95%CI: 1.546-6.073) and BDNF rs11030104 (P = 0.001, OR: 3.091, 95%CI: 1.525-5.960). In the training set, gradient boosting decision tree (GBDT), extremely random trees (ET), random forest, logistic regression and extreme gradient boosting (XGBoost) obtained AUROC values > 0.90 and AUPRC > 0.87. Among these models, XGBoost and GBDT obtained the first two highest AUROC (0.90 and 1), AUPRC (0.98 and 1), accuracy (0.96 and 0.98), precision (0.90 and 0.95), F1 score (0.95 and 0.98), specificity (0.94 and 0.97), and sensitivity (1). In the validation set, XGBoost algorithm exhibited the best predictive performance with the highest specificity (0.857), accuracy (0.818), AUPRC (0.86) and AUROC (0.89). ET and GBDT obtained the highest sensitivity (1) and F1 score (0.8). Overall, compared with other state-of-the-art classifiers such as ET, GBDT and RF, XGBoost algorithm not only showed a more stable performance, but also yielded higher ROC-AUC and PRC-AUC scores, demonstrating its high accuracy in prediction of TiPN occurrence.
CONCLUSION The powerful XGBoost algorithm accurately predicts TiPN using 18 clinical features and 14 genetic variables. With the ability to identify high-risk patients using single nucleotide polymorphisms, it offers a feasible option for improving thalidomide efficacy in CD patients.
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Affiliation(s)
- Jing Mao
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Kang Chao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Fu-Lin Jiang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Xiao-Ping Ye
- Department of Pharmacy, Guangdong Women and Children Hospital, Guangzhou 510000, Guangdong Province, China
| | - Ting Yang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Pan Li
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Xia Zhu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Pin-Jin Hu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Bai-Jun Zhou
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Min Huang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Xue-Ding Wang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
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Fleming B, Edison P, Kenny L. Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management. BMJ 2023; 380:e071726. [PMID: 36921926 DOI: 10.1136/bmj-2022-071726] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
Cognitive impairment is a debilitating side effect experienced by patients with cancer treated with systemically administered anticancer therapies. With around 19.3 million new cases of cancer worldwide in 2020 and the five year survival rate growing from 50% in 1970 to 67% in 2013, an urgent need exists to understand enduring side effects with severe implications for quality of life. Whereas cognitive impairment associated with chemotherapy is recognized in patients with breast cancer, researchers have started to identify cognitive impairment associated with other treatments such as immune, endocrine, and targeted therapies only recently. The underlying mechanisms are diverse and therapy specific, so further evaluation is needed to develop effective therapeutic interventions. Drug and non-drug management strategies are emerging that target mechanistic pathways or the cognitive deficits themselves, but they need to be rigorously evaluated. Clinically, consistent use of objective diagnostic tools is necessary for accurate diagnosis and clinical characterization of cognitive impairment in patients treated with anticancer therapies. This should be supplemented with clinical guidelines that could be implemented in daily practice. This review summarizes the recent advances in the mechanisms, clinical characterization, and novel management strategies of cognitive impairment associated with treatment of non-central nervous system cancers.
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Affiliation(s)
- Ben Fleming
- Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Paul Edison
- Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK
- College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK
| | - Laura Kenny
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
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Saita K, Amano S, Kaneko F, Okamura H. A scoping review of cognitive assessment tools and domains for chemotherapy-induced cognitive impairments in cancer survivors. Front Hum Neurosci 2023; 17:1063674. [PMID: 36891148 PMCID: PMC9987518 DOI: 10.3389/fnhum.2023.1063674] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 01/30/2023] [Indexed: 02/22/2023] Open
Abstract
Backgrounds Cancer survivors suffer from specific symptoms known as chemotherapy-induced cognitive impairments (CICIs). CICIs are difficult to capture with existing assessments such as the brief screening test for dementia. Although recommended neuropsychological tests (NPTs) exist, international consensus and shared cognitive domains of assessment tools are unknown. The aim of this scoping review was as follows: (1) to identify studies that assess CICIs in cancer survivors; (2) to identify shared cognitive assessment tools and domains by mapping the domains reported in studies using the International Classification of Functioning, Disability and Health (ICF) framework. Methods The study followed the recommendations made by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. We searched the following three databases through October 2021: PubMed, CINAHL, and Web of Science. Prospective longitudinal or cross-sectional studies were selected to determine CICI-specific assessment tools for adult cancer survivors. Results Sixty-four prospective studies (36 longitudinal studies and 28 cross-sectional studies) were included after checking for eligibility. The NPTs were divided into seven main cognitive domains. The specific mental functions were often used in the order of memory, attention, higher-level cognitive functions, and psychomotor functions. Perceptual functions were used less frequently. In some ICF domains, shared NPTs were not clearly identified. In some different domains, the same NPTs were used, such as the trail making test and the verbal fluency test. When the association between the publishing year and the amount of NPT use was examined, it was found that the amount of tool use tended to decline over the publication years. The Functional Assessment of Cancer Therapy-Cognitive function (FACT-Cog) was a shared consensus tool among the patient-reported outcomes (PROs). Conclusion Chemotherapy-induced cognitive impairments are currently gaining interest. Shared ICF domains such as memory and attention were identified for NPTs. There was a gap between the publicly recommended tools and the tools actually used in the studies. For PROs, a clearly shared tool, FACT-Cog, was identified. Mapping the domains reported in studies using the ICF can help in the process of reviewing consensus on which NPTs may be used to target cognitive domains. Systematic review registration https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000053710, identifier UMIN000047104.
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Affiliation(s)
- Kazuya Saita
- Department of Psychosocial Rehabilitation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Satoru Amano
- Department of Rehabilitation, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
| | - Fumiko Kaneko
- Department of Psychosocial Rehabilitation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hitoshi Okamura
- Department of Psychosocial Rehabilitation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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21
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Oppegaard KR, Armstrong TS, Anguera JA, Kober KM, Kelly DL, Laister RC, Saligan LN, Ayala AP, Kuruvilla J, Alm MW, Byker WH, Miaskowski C, Mayo SJ. Blood-based biomarkers of cancer-related cognitive impairment in non-central nervous system cancer: A scoping review. Crit Rev Oncol Hematol 2022; 180:103822. [PMID: 36152911 DOI: 10.1016/j.critrevonc.2022.103822] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/17/2022] [Accepted: 09/19/2022] [Indexed: 11/24/2022] Open
Abstract
This scoping review was designed to synthesize the extant literature on associations between subjective and/or objective measures of cancer-related cognitive impairment (CRCI) and blood-based biomarkers in adults with non-central nervous system cancers. The literature search was done for studies published from the start of each database searched (i.e., MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, grey literature) through to October 20, 2021. A total of 95 studies are included in this review. Of note, a wide variety of biomarkers were evaluated. Most studies evaluated patients with breast cancer. A variety of cognitive assessment measures were used. The most consistent significant findings were with various subjective and objective measures of CRCI and levels of interleukin-6 and tumor necrosis factor. Overall, biomarker research is in an exploratory phase. However, this review synthesizes findings and proposes directions for future research.
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Affiliation(s)
- Kate R Oppegaard
- University of California San Francisco, School of Nursing, Department of Physiological Nursing, USA
| | - Terri S Armstrong
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, USA
| | - Joaquin A Anguera
- University of California San Francisco, Department of Neurology and Psychiatry, USA
| | - Kord M Kober
- University of California San Francisco, School of Nursing, Department of Physiological Nursing, USA
| | - Debra Lynch Kelly
- University of Florida, College of Nursing, USA; University of Florida Health Cancer Center, USA
| | - Rob C Laister
- Princess Margaret Cancer Centre, University Health Network, Canada
| | - Leorey N Saligan
- Symptoms Biology Unit, Division of Intramural Research, National Institutes of Health, USA
| | | | - John Kuruvilla
- Princess Margaret Cancer Centre, University Health Network, Canada
| | - Mark W Alm
- Toronto General Hospital, University Health Network, Canada
| | - William H Byker
- Vancouver General Hospital, Vancouver Coastal Health, Canada
| | - Christine Miaskowski
- University of California San Francisco, School of Nursing, Department of Physiological Nursing, USA; University of California San Francisco, School of Medicine, Department of Anesthesia and Perioperative Care, USA
| | - Samantha J Mayo
- Princess Margaret Cancer Centre, University Health Network, Canada; Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Canada.
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22
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Park JY, Lengacher CA, Reich RR, Park HY, Whiting J, Nguyen AT, Rodríguez C, Meng H, Tinsley S, Chauca K, Gordillo-Casero L, Wittenberg T, Joshi A, Lin K, Ismail-Khan R, Kiluk JV, Kip KE. Translational Genomic Research: The Association between Genetic Profiles and Cognitive Functioning or Cardiac Function Among Breast Cancer Survivors Completing Chemotherapy. Biol Res Nurs 2022; 24:433-447. [PMID: 35499926 PMCID: PMC9630728 DOI: 10.1177/10998004221094386] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Introduction: Emerging evidence suggests that Chemotherapy (CT) treated breast cancer survivors (BCS) who have "risk variants" in genes may be more susceptible to cognitive impairment (CI) and/or poor cardiac phenotypes. The objective of this preliminary study was to examine whether there is a relationship between genetic variants and objective/subjective cognitive or cardiac phenotypes. Methods and Analysis: BCS were recruited from Moffitt Cancer Center, Morsani College of Medicine, AdventHealth Tampa and Sarasota Memorial Hospital. Genomic DNA were collected at baseline for genotyping analysis. A total of 16 single nucleotide polymorphisms (SNPs) from 14 genes involved in cognitive or cardiac function were evaluated. Three genetic models (additive, dominant, and recessive) were used to test correlation coefficients between genetic variants and objective/subjective measures of cognitive functioning and cardiac outcomes (heart rate, diastolic blood pressure, systolic blood pressure, respiration rate, and oxygen saturation). Results: BCS (207 participants) with a mean age of 56 enrolled in this study. The majority were non-Hispanic white (73.7%), married (63.1%), and received both CT and radiation treatment (77.3%). Three SNPs in genes related to cognitive functioning (rs429358 in APOE, rs1800497 in ANKK1, rs10119 in TOMM40) emerged with the most consistent significant relationship with cognitive outcomes. Among five candidate SNPs related to cardiac functioning, rs8055236 in CDH13 and rs1801133 in MTHER emerged with potential significant relationships with cardiac phenotype. Conclusions: These preliminary results provide initial targets to further examine whether BCS with specific genetic profiles may preferentially benefit from interventions designed to improve cognitive and cardiac functioning following CT.
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Affiliation(s)
- Jong Y. Park
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Richard R. Reich
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Hyun Y. Park
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Junmin Whiting
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Anh Thy Nguyen
- Department of Epidemiology and
Biostatistics, USF College of Public Health, University of South
Florida, Tampa, FL, USA
| | | | - Hongdao Meng
- School of Aging Studies, College of
Behavioral and Community Sciences, University of South
Floridaa, Tampa, FL, USA
| | - Sara Tinsley
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
| | | | | | | | - Anisha Joshi
- University of South Florida College
of Nursing, Tampa, FL, USA
| | - Katherine Lin
- University of South Florida College
of Nursing, Tampa, FL, USA
| | - Roohi Ismail-Khan
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
| | - John V. Kiluk
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Kevin E. Kip
- UPMC Health Services
Division, Pittsburgh, PA, USA
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23
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Guijosa A, Freyria A, Espinosa‐Fernandez JR, Estrada‐Mena FJ, Armenta‐Quiroga AS, Ortega‐Treviño MF, Catalán R, Antonio‐Aguirre B, Villarreal‐Garza C, Perez‐Ortiz AC. Pharmacogenetics of taxane-induced neurotoxicity in breast cancer: Systematic review and meta-analysis. Clin Transl Sci 2022; 15:2403-2436. [PMID: 35892315 PMCID: PMC9579387 DOI: 10.1111/cts.13370] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 05/09/2022] [Accepted: 06/20/2022] [Indexed: 01/25/2023] Open
Abstract
Taxane-based chemotherapy regimens are used as first-line treatment for breast cancer. Neurotoxicity, mainly taxane-induced peripheral neuropathy (TIPN), remains the most important dose-limiting adverse event. Multiple genes may be associated with TIPN; however, the strength and direction of the association remain unclear. For this reason, we systematically reviewed observational studies of TIPN pharmacogenetic markers in breast cancer treatment. We conducted a systematic search of terms alluding to breast cancer, genetic markers, taxanes, and neurotoxicity in Ovid, ProQuest, PubMed, Scopus, Virtual Health, and Web of Science. We assessed the quality of evidence and bias profile. We extracted relevant variables and effect measures. Whenever possible, we performed random-effects gene meta-analyses and examined interstudy heterogeneity with meta-regression models and subgroup analyses. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and STrengthening the REporting of Genetic Association Studies (STREGA) reporting guidance. A total of 42 studies with 19,431 participants were included. These evaluated 262 single-nucleotide polymorphisms (SNPs) across 121 genes. We conducted meta-analyses on 23 genes with 60 SNPs (19 studies and 6246 participants). Thirteen individual SNPs (ABCB1-rs2032582, ABCB1-rs3213619, BCL6/-rs1903216, /CAND1-rs17781082, CYP1B1-rs1056836, CYP2C8-rs10509681, CYP2C8-rs11572080, EPHA5-rs7349683, EPHA6-rs301927, FZD3-rs7001034, GSTP1-rs1138272, TUBB2A-rs9501929, and XKR4-rs4737264) and the overall SNPs' effect in four genes (CYP3A4, EphA5, GSTP1, and SLCO1B1) were statistically significantly associated with TIPN through meta-analysis. In conclusion, through systematic review and meta-analysis, we found that polymorphisms, and particularly 13 SNPs, are associated with TIPN, suggesting that genetics does play a role in interindividual predisposition. Further studies could potentially use these findings to develop individual risk profiles and guide decision making.
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Affiliation(s)
| | - Ana Freyria
- School of MedicineUniversidad PanamericanaMexico CityMexico
| | | | | | | | | | - Rodrigo Catalán
- School of MedicineUniversidad PanamericanaMexico CityMexico,Thoracic Oncology UnitInstituto Nacional de CancerologíaMexico CityMexico
| | | | - Cynthia Villarreal‐Garza
- Breast Cancer Center, Hospital Zambrano Hellion TecSalud, Tecnologico de MonterreySan Pedro Garza GarcíaNuevo LeónMexico
| | - Andric C. Perez‐Ortiz
- School of MedicineUniversidad PanamericanaMexico CityMexico,Transplant CenterMassachusetts General HospitalBostonMassachusettsUSA
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24
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Hajj A, Khoury R, Hachem R, Awad A, Hallit S, Sacre H, Nasr F, Karak FE, Chahine G, Kattan J, Khabbaz LR. Clinical and genetic factors associated with self-reported cognitive deficits in women with breast cancer: the "CAGE-Cog" study. BMC Cancer 2022; 22:996. [PMID: 36123640 PMCID: PMC9487123 DOI: 10.1186/s12885-022-10077-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 09/06/2022] [Indexed: 11/27/2022] Open
Abstract
Background Breast cancer patients undergoing chemotherapy treatment are at particular risk of experiencing acute cognitive impairment leading to daily challenges in decision-making and reduced quality of life and functional autonomy. The aim was to assess the relationship between clinical and genetic factors and cognitive function in a sample of patients with breast cancer undergoing chemotherapy. Methods A cross-sectional study was carried out between November 2017 and June 2019 on women (N = 112) treated for breast cancer by intravenous chemotherapy at the oncology outpatient unit of Hôtel-Dieu de France Hospital, Beirut. Patients were evaluated with the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog). Other validated scales were also used to assess depression, anxiety, sleep disorders, pain, and fatigue. DNA was obtained by a buccal swab (FTA®technology) for genotyping of different genes (ABCB1, COMT, DRD2, OPRM1, CLOCK, CRY2, and PER2) using the Lightcycler®(Roche). Results The mean age of participants was 56.04 years. Multivariable analysis, taking the four FACT-Cog subscores as the dependent variables, showed that the mean cognitive score decreased with higher depression, anxiety, and insomnia scores. Patients with university education levels had better perceived cognitive abilities than those with primary education. Moreover, carrying the G allele for the OPRM1 polymorphism (c.118A > G;rs197791) was significantly associated with a better cognitive function compared to AA patients (B = 2.05; p = 0.038). Conclusions A comprehensive oncological care plan should include a personalized assessment of all factors related to cognitive functioning in cancer patients, particularly anxiety and depression, to achieve an optimal patient outcome. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10077-6.
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Affiliation(s)
- Aline Hajj
- Faculty of Pharmacy, Saint-Joseph University of Beirut, Beirut, Lebanon. .,Laboratoire de Pharmacologie, Pharmacie Clinique Et Contrôle de Qualité Des Médicaments, Saint-Joseph University of Beirut, Beirut, Lebanon. .,Faculty of Pharmacy, Université Laval, Québec, Canada.
| | - Rita Khoury
- Faculty of Pharmacy, Saint-Joseph University of Beirut, Beirut, Lebanon.,Laboratoire de Pharmacologie, Pharmacie Clinique Et Contrôle de Qualité Des Médicaments, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Roula Hachem
- Faculty of Pharmacy, Saint-Joseph University of Beirut, Beirut, Lebanon.,Laboratoire de Pharmacologie, Pharmacie Clinique Et Contrôle de Qualité Des Médicaments, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Aya Awad
- Faculty of Pharmacy, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Souheil Hallit
- School of Medicine and Medical Sciences, Holy Spirit University of Kaslik, P.O. Box 446, Jounieh, Lebanon.,Research Department, Psychiatric Hospital of the Cross, Jal Eddib, Lebanon.,Psychology Department, College of Humanities, Effat University, Jeddah, 21478, Saudi Arabia
| | - Hala Sacre
- INSPECT-LB (Institut National de Santé Publique, d'Épidémiologie Clinique Et de Toxicologie-Liban), Beirut, Lebanon
| | - Fady Nasr
- Department of Hemato-Oncology, Faculty of Medicine, Hôtel-Dieu de France Hospital, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Fadi El Karak
- Department of Hemato-Oncology, Faculty of Medicine, Hôtel-Dieu de France Hospital, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Georges Chahine
- Department of Hemato-Oncology, Faculty of Medicine, Hôtel-Dieu de France Hospital, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Joseph Kattan
- Department of Hemato-Oncology, Faculty of Medicine, Hôtel-Dieu de France Hospital, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Lydia Rabbaa Khabbaz
- Faculty of Pharmacy, Saint-Joseph University of Beirut, Beirut, Lebanon.,Laboratoire de Pharmacologie, Pharmacie Clinique Et Contrôle de Qualité Des Médicaments, Saint-Joseph University of Beirut, Beirut, Lebanon
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25
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Lan B, Lv D, Sun X, Yang M, Zhang L, Ma F. Genetic Variations in IFNGR1, BDNF and IL-10 May Predict the Susceptibility to Depression and Anxiety in Chinese Women With Breast Cancer. Clin Breast Cancer 2022; 22:674-680. [DOI: 10.1016/j.clbc.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 06/29/2022] [Accepted: 07/01/2022] [Indexed: 11/03/2022]
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26
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Wolff BS, Allen HR, Feng LR, Saligan LN. BDNF Val66Met Polymorphism Reduces the Fatigue-Like Effects of 5-Fluorouracil on Voluntary Wheel-Running Activity in Mice. Front Behav Neurosci 2022; 16:880969. [PMID: 35558437 PMCID: PMC9087735 DOI: 10.3389/fnbeh.2022.880969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
Fatigue is a persistent and debilitating symptom following cancer treatments such as chemotherapy. Recent clinical studies have suggested a common single-nucleotide polymorphism of brain-derived neurotrophic factor (BDNF), Val66Met (rs6265), may be related to the severity of fatigue following cancer treatment. In this study, we tested transgenic mice homozygous for the human Val66Met BDNF gene and wild-type controls. We injected three doses of 5-fluorouracil (5FU) as a model of chemotherapy treatment, and we used changes in voluntary wheel running activity (VWRA) as a measure of fatigue-like behavior. Prior to 5FU injection, we found that during the baseline wheel-running period, the Val66Met mice lost more weight than WT controls. We next administered 5FU and saw a robust fatigue-like phenotype that lasted about 2 weeks. During the first week, the fatigue-like phenotype was less severe in the Val66Met mice and unrelated to the age of the mice. In contrast, during the second week after 5FU treatment, the fatigue-like phenotype was unrelated to the BDNF genotype but was more severe in middle aged mice compared to young mice. We conclude that the BDNF polymorphism may play a direct, protective role against chemotherapy-induced fatigue.
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27
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Was H, Borkowska A, Bagues A, Tu L, Liu JYH, Lu Z, Rudd JA, Nurgali K, Abalo R. Mechanisms of Chemotherapy-Induced Neurotoxicity. Front Pharmacol 2022; 13:750507. [PMID: 35418856 PMCID: PMC8996259 DOI: 10.3389/fphar.2022.750507] [Citation(s) in RCA: 103] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 03/02/2022] [Indexed: 12/15/2022] Open
Abstract
Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in the clinic as the main cancer treatment either alone or as an adjuvant therapy before and after surgery. Although the use of chemotherapeutic drugs improved the survival of cancer patients, these drugs are notorious for causing many severe side effects that significantly reduce the efficacy of anti-cancer treatment and patients’ quality of life. Many widely used chemotherapy drugs including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, and thalidomide analogs may cause direct and indirect neurotoxicity. In this review we discuss the main effects of chemotherapy on the peripheral and central nervous systems, including neuropathic pain, chemobrain, enteric neuropathy, as well as nausea and emesis. Understanding mechanisms involved in chemotherapy-induced neurotoxicity is crucial for the development of drugs that can protect the nervous system, reduce symptoms experienced by millions of patients, and improve the outcome of the treatment and patients’ quality of life.
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Affiliation(s)
- Halina Was
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland
| | - Agata Borkowska
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine, Warsaw, Poland.,Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Ana Bagues
- Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain.,High Performance Research Group in Experimental Pharmacology (PHARMAKOM-URJC), URJC, Alcorcón, Spain.,Unidad Asociada I+D+i del Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Longlong Tu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Julia Y H Liu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Zengbing Lu
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - John A Rudd
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.,The Laboratory Animal Services Centre, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.,Department of Medicine Western Health, University of Melbourne, Melbourne, VIC, Australia.,Regenerative Medicine and Stem Cells Program, Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia
| | - Raquel Abalo
- Área de Farmacología y Nutrición, Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos (URJC), Alcorcón, Spain.,Unidad Asociada I+D+i del Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.,High Performance Research Group in Physiopathology and Pharmacology of the Digestive System (NeuGut-URJC), URJC, Alcorcón, Spain.,Grupo de Trabajo de Ciencias Básicas en Dolor y Analgesia de la Sociedad Española del Dolor, Madrid, Spain
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28
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Porter GA, O’Connor JC. Brain-derived neurotrophic factor and inflammation in depression: Pathogenic partners in crime? World J Psychiatry 2022; 12:77-97. [PMID: 35111580 PMCID: PMC8783167 DOI: 10.5498/wjp.v12.i1.77] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/21/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Major depressive disorder is a debilitating disorder affecting millions of people each year. Brain-derived neurotrophic factor (BDNF) and inflammation are two prominent biologic risk factors in the pathogenesis of depression that have received considerable attention. Many clinical and animal studies have highlighted associations between low levels of BDNF or high levels of inflammatory markers and the development of behavioral symptoms of depression. However, less is known about potential interaction between BDNF and inflammation, particularly within the central nervous system. Emerging evidence suggests that there is bidirectional regulation between these factors with important implications for the development of depressive symptoms and anti-depressant response. Elevated levels of inflammatory mediators have been shown to reduce expression of BDNF, and BDNF may play an important negative regulatory role on inflammation within the brain. Understanding this interaction more fully within the context of neuropsychiatric disease is important for both developing a fuller understanding of biological pathogenesis of depression and for identifying novel therapeutic opportunities. Here we review these two prominent risk factors for depression with a particular focus on pathogenic implications of their interaction.
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Affiliation(s)
- Grace A Porter
- Department of Pharmacology, UT Health San Antonio, San Antonio, TX 78229, United States
| | - Jason C O’Connor
- Department of Pharmacology, University of Texas Health San Antonio, San Antonio, TX 78229, United States
- Audie L. Murphy VA Hospital, South Texas Veterans Health System, San Antonio, TX 78229, United States
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29
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Dias-Carvalho A, Ferreira M, Ferreira R, Bastos MDL, Sá SI, Capela JP, Carvalho F, Costa VM. Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events. Arch Toxicol 2022; 96:11-78. [PMID: 34725718 DOI: 10.1007/s00204-021-03171-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 09/23/2021] [Indexed: 01/22/2023]
Abstract
Cognitive dysfunction has been one of the most reported and studied adverse effects of cancer treatment, but, for many years, it was overlooked by the medical community. Nevertheless, the medical and scientific communities have now recognized that the cognitive deficits caused by chemotherapy have a strong impact on the morbidity of cancer treated patients. In fact, chemotherapy-induced cognitive dysfunction or 'chemobrain' (also named also chemofog) is at present a well-recognized effect of chemotherapy that could affect up to 78% of treated patients. Nonetheless, its underlying neurotoxic mechanism is still not fully elucidated. Therefore, this work aimed to provide a comprehensive review using PubMed as a database to assess the studies published on the field and, therefore, highlight the clinical manifestations of chemobrain and the putative neurotoxicity mechanisms.In the last two decades, a great number of papers was published on the topic, mainly with clinical observations. Chemotherapy-treated patients showed that the cognitive domains most often impaired were verbal memory, psychomotor function, visual memory, visuospatial and verbal learning, memory function and attention. Chemotherapy alters the brain's metabolism, white and grey matter and functional connectivity of brain areas. Several mechanisms have been proposed to cause chemobrain but increase of proinflammatory cytokines with oxidative stress seem more relevant, not excluding the action on neurotransmission and cellular death or impaired hippocampal neurogenesis. The interplay between these mechanisms and susceptible factors makes the clinical management of chemobrain even more difficult. New studies, mainly referring to the underlying mechanisms of chemobrain and protective measures, are important in the future, as it is expected that chemobrain will have more clinical impact in the coming years, since the number of cancer survivors is steadily increasing.
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Affiliation(s)
- Ana Dias-Carvalho
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
| | - Mariana Ferreira
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Rita Ferreira
- LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Maria de Lourdes Bastos
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Susana Isabel Sá
- Unit of Anatomy, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
- Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine, University of Porto, Porto, Portugal
| | - João Paulo Capela
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, Porto, Portugal
| | - Félix Carvalho
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Vera Marisa Costa
- Associate Laboratory i4HB-Institute for Health and Bioeconomy, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
- UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
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30
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Lyu YR, Lee HY, Park HJ, Kwon OJ, Kim AR, Jung IC, Park YC, Cho JH, Kim JE, Kim M, Lee JH, Kim JH. Electroacupuncture for Cancer-Related Cognitive Impairment: A Clinical Feasibility Study. Integr Cancer Ther 2022; 21:15347354221098983. [PMID: 35608027 PMCID: PMC9134458 DOI: 10.1177/15347354221098983] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/20/2022] [Accepted: 04/20/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Cancer-related cognitive impairment (CRCI) is a significant problem for cancer patients, as the number of cancer survivors experiencing cognitive impairments is increasing in the absence of standard treatment. There have been attempts to improve the cognitive function of patients with cancer using acupuncture; however, no studies have been conducted using electroacupuncture. Thus, we designed a preliminary study to investigate the feasibility of a clinical trial using electroacupuncture in CRCI patients. METHODS We conducted a single-arm, pilot, clinical trial to investigate the feasibility of a study protocol for further large-scale clinical trials of electroacupuncture in CRCI patients. All participants were treated with electroacupuncture twice a week for 30 minutes at a time, for 8 weeks on acupoints GV20, GV24, EX-HN1, and GB20, HT7, PC6, and KI3. Both subjective and objective outcomes of cognitive function, quality of life (QoL), and psychological factors were measured in all participants at baseline, week 4, 8, and 12. For safety assessment, vital signs, laboratory examinations, and adverse events (AEs) were observed throughout the trial. RESULTS A total of 12 participants were enrolled at Daejeon and Dunsan Korean Medicine Hospital of Daejeon University from 21 April 2017 to 31 January 2018. After 8 weeks of treatment, electroacupuncture significantly improved both subjective and objective cognitive outcomes, including the perceived cognitive impairments scale of the Functional Assessment of Cancer Therapy-Cognitive Function, QoL scale of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-C30, Korean version of Montreal Cognitive Assessment, Boston Naming Test, Seoul Verbal Learning Test, and Rey Complex Figure Test. During the entire trial period, 19 AEs were observed, with no serious AEs. Additionally, it was found that all feasibility outcomes, including recruitment, completion, and adherence rates, achieved successful results as the ratio exceeded 0.8. CONCLUSION Our study results revealed that electroacupuncture improved cognitive complaints in cancer patients, and we expect electroacupuncture to be a safe and effective management therapy for CRCI patients. These feasibility trial results will be used as preliminary data for future randomized controlled clinical trials. TRIAL REGISTRATION NUMBER Korean Clinical Trial Registry (KCT0002168).
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Affiliation(s)
- Yee Ran Lyu
- Korea Institute of Oriental Medicine,
Daejeon, Republic of Korea
| | - Hye-Yoon Lee
- Pusan National University, Yangsan,
Republic of Korea
| | - Hyo-Ju Park
- Korea Institute of Oriental Medicine,
Daejeon, Republic of Korea
| | - O-jin Kwon
- Korea Institute of Oriental Medicine,
Daejeon, Republic of Korea
| | - Ae-Ran Kim
- Korea Institute of Oriental Medicine,
Daejeon, Republic of Korea
| | | | | | | | - Jung-Eun Kim
- Pusan National University Hospital,
Busan, Republic of Korea
| | - Mikyung Kim
- Sangji University, Wonju, Gangwon-do,
Republic of Korea
| | - Jun-Hwan Lee
- Korea Institute of Oriental Medicine,
Daejeon, Republic of Korea
- University of Science & Technology
(UST) Daejeon, Republic of Korea
| | - Joo-Hee Kim
- Sangji University, Wonju, Gangwon-do,
Republic of Korea
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31
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Országhová Z, Mego M, Chovanec M. Long-Term Cognitive Dysfunction in Cancer Survivors. Front Mol Biosci 2022; 8:770413. [PMID: 34970595 PMCID: PMC8713760 DOI: 10.3389/fmolb.2021.770413] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 11/17/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer-related cognitive impairment (CRCI) is a frequent side effect experienced by an increasing number of cancer survivors with a significant impact on their quality of life. Different definitions and means of evaluation have been used in available literature; hence the exact incidence of CRCI remains unknown. CRCI can be described as cognitive symptoms reported by cancer patients in self-reported questionnaires or as cognitive changes evaluated by formal neuropsychological tests. Nevertheless, association between cognitive symptoms and objectively assessed cognitive changes is relatively weak or absent. Studies have focused especially on breast cancer patients, but CRCI has been reported in multiple types of cancer, including colorectal, lung, ovarian, prostate, testicular cancer and hematological malignancies. While CRCI has been associated with various treatment modalities, including radiotherapy, chemotherapy, hormone therapy and novel systemic therapies, it has been also detected prior to cancer treatment. Therefore, the effects of cancer itself with or without the psychological distress may be involved in the pathogenesis of CRCI as a result of altered coping mechanisms after cancer diagnosis. The development of CRCI is probably multifactorial and the exact mechanisms are currently not completely understood. Possible risk factors include administered treatment, genetic predisposition, age and psychological factors such as anxiety, depression or fatigue. Multiple mechanisms are suggested to be responsible for CRCI, including direct neurotoxic injury of systemic treatment and radiation while other indirect contributing mechanisms are hypothesized. Chronic neuroinflammation mediated by active innate immune system, DNA-damage or endothelial dysfunction is hypothesized to be a central mechanism of CRCI pathogenesis. There is increasing evidence of potential plasma (e.g., damage associated molecular patterns, inflammatory components, circulating microRNAs, exosomes, short-chain fatty acids, and others), cerebrospinal fluid and radiological biomarkers of cognitive dysfunction in cancer patients. Discovery of biomarkers of cognitive impairment is crucial for early identification of cancer patients at increased risk for the development of CRCI or development of treatment strategies to lower the burden of CRCI on long-term quality of life. This review summarizes current literature on CRCI with a focus on long-term effects of different cancer treatments, possible risk factors, mechanisms and promising biomarkers.
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Affiliation(s)
- Zuzana Országhová
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Michal Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
| | - Michal Chovanec
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia
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Li L, Zhou R, Lv H, Song L, Xue X, Wu L. Inhibitive Effect of Luteolin on Sevoflurane-Induced Neurotoxicity through Activation of the Autophagy Pathway by HMOX1. ACS Chem Neurosci 2021; 12:3314-3322. [PMID: 34445868 DOI: 10.1021/acschemneuro.1c00157] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Luteolin is a flavone compound occurring in a variety of medicinal plants, which is reported to have neuroprotective properties. In this study, we aimed to explore the effects of luteolin in alleviating sevoflurane-induced neurotoxicity. GeneCards and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform were employed to screen luteolin, sevoflurane, and neurotoxicity-related genes. Subsequently, we isolated primary neurons from the hippocampus of 1-day-old C57BL/6J mice and tested for cytotoxicity after treatment of different concentrations of luteolin. Next, we measured the expression of apoptosis by flow cytometry and assessed inflammation-related factors, including heme oxygenase-1 expression detected by immunohistochemical staining and neuronal apoptosis. Finally, water maze, open field, and fear conditioning tests were conducted to observe the interaction between luteolin and sevoflurane in cognitive impairment of mice. Luteolin had the lowest cytotoxicity at concentrations of 30 or 60 μg/mL; we selected 30 μg/mL for drug administration experiments in vitro. Luteolin inhibited sevoflurane-induced neuronal apoptosis and inflammatory responses through the autophagic pathway and thus ameliorated sevoflurane-induced cognitive impairment in mice. Mechanistically, luteolin up-regulated heme oxygenase-1 expression, which activated the autophagy pathway in vitro. This was confirmed by subsequent histological experiments in mice and behavioral results showing rescue cognitive impairment. Our findings uncovered an inhibitory role of luteolin in sevoflurane-induced neuronal apoptosis and inflammatory response through activation of autophagy arising from up-regulation of heme oxygenase-1, thereby alleviating sevoflurane-induced cognitive impairment in mice.
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Affiliation(s)
- Lu Li
- Department of Anesthesiology, Honghui Hospital, Xi’an Jiaotong University, No. 555, Youyi East Road, Nanshaomen, Xi’an, Shaanxi 710054, P. R. China
| | - Rongsheng Zhou
- Department of Anesthesiology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P. R. China
| | - Haigang Lv
- Department of Anesthesiology, Honghui Hospital, Xi’an Jiaotong University, No. 555, Youyi East Road, Nanshaomen, Xi’an, Shaanxi 710054, P. R. China
| | - Lei Song
- Department of Anesthesiology, Honghui Hospital, Xi’an Jiaotong University, No. 555, Youyi East Road, Nanshaomen, Xi’an, Shaanxi 710054, P. R. China
| | - Xiaohong Xue
- Department of Blood Purification, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P. R. China
| | - Li Wu
- Department of Anesthesiology, Honghui Hospital, Xi’an Jiaotong University, No. 555, Youyi East Road, Nanshaomen, Xi’an, Shaanxi 710054, P. R. China
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Buskbjerg CR, Amidi A, Agerbaek M, Gravholt CH, Hosseini SMH, Zachariae R. Cognitive changes and brain connectomes, endocrine status, and risk genotypes in testicular cancer patients-A prospective controlled study. Cancer Med 2021; 10:6249-6260. [PMID: 34390226 PMCID: PMC8446403 DOI: 10.1002/cam4.4165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/12/2021] [Accepted: 07/15/2021] [Indexed: 11/07/2022] Open
Abstract
OBJECTIVE Previous research has indicated cognitive decline (CD) among testicular cancer patients (TCPs), even in the absence of chemotherapy, but little is known about the underlying pathophysiology. The present study assessed changes in cognitive functions and structural brain connectomes in TCPs and explored the associations between cognitive changes and endocrine status and hypothesized risk genotypes. METHODS Thirty-eight newly orchiectomized TCPs and 21 healthy controls (HCs) comparable to TCPs in terms of age and years of education underwent neuropsychological testing, structural MRI, and a biological assessment at baseline and 6 months later. Cognitive change was assessed with a neuropsychological test battery and determined using a standardized regression-based approach, with substantial change defined as z-scores ≤-1.64 or ≥1.64. MRI scans and graph theory were used to evaluate changes in structural brain connectomes. The associations of cognitive changes with testosterone levels, androgen receptor gene (AR) CAG repeat length, and genotypes (APOE, COMT, and BDNF) were explored. RESULTS Compared with HCs, TCPs showed higher rates of substantial decline on processing speed and visuospatial ability and higher rates of substantial improvement on verbal recall and visuospatial learning (p < 0.05; OR = 8.15-15.84). Brain network analysis indicated bilateral thalamic changes in node degree in HCs, but not in TCPs (p < 0.01). In TCPs, higher baseline testosterone levels predicted decline in verbal memory (p < 0.05). No effects were found for AR CAG repeat length, APOE, COMT, or BDNF. CONCLUSIONS The present study confirms previous findings of domain-specific CD in TCPs following orchiectomy, but also points to domain-specific improvements. The results do not indicate changes in brain connectomes or endocrine status to be the main drivers of CD. Further studies evaluating the mechanisms underlying CD in TCPs, including the possible role of the dynamics of the hypothalamic-pituitary-gonadal axis, are warranted.
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Affiliation(s)
- Cecilie R. Buskbjerg
- Unit for Psychooncology and Health PsychologyDepartment of Psychology and Behavioral SciencesAarhus UniversityAarhusDenmark
| | - Ali Amidi
- Unit for Psychooncology and Health PsychologyDepartment of Psychology and Behavioral SciencesAarhus UniversityAarhusDenmark
| | - Mads Agerbaek
- Department of OncologyAarhus University HospitalAarhusDenmark
| | - Claus H. Gravholt
- Department of EndocrinologyAarhus University HospitalAarhusDenmark
- Department of Molecular MedicineAarhus University HospitalAarhusDenmark
| | - SM Hadi Hosseini
- Department of Psychiatry and Behavioral SciencesSchool of MedicineStanford UniversityStanfordCaliforniaUSA
| | - Robert Zachariae
- Unit for Psychooncology and Health PsychologyDepartment of Psychology and Behavioral SciencesAarhus UniversityAarhusDenmark
- Department of OncologyAarhus University HospitalAarhusDenmark
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Bury-Kamińska M, Szudy-Szczyrek A, Nowaczyńska A, Jankowska-Łęcka O, Hus M, Kot K. Chemotherapy-Related Differences in Cognitive Functioning and Their Biological Predictors in Patients with Multiple Myeloma. Brain Sci 2021; 11:1166. [PMID: 34573187 PMCID: PMC8466339 DOI: 10.3390/brainsci11091166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/10/2021] [Accepted: 08/29/2021] [Indexed: 11/21/2022] Open
Abstract
The paper presents a study on the changes in cognitive functioning in patients undergoing chemotherapy with diagnosed multiple myeloma (MM). The aim of the study was to answer the following two main research questions: Does the treatment stage differentiate the functioning of cognitive processes in patients with diagnosed MM and to what extent? Is it possible to treat biological factors (TNF-α, IL-6, IL-10, and BDNF) as predictors of patients' cognitive functioning? The patients were examined twice, before the treatment and after 4-6 cycles of chemotherapy. Selected neuropsychological research methods as well as experimental and clinical trials were employed to diagnose the patients' general cognitive state, attention, memory, and executive functions. The level of biological factors was assessed with the ELISA test. The results show that the patients' cognitive functioning was worse before the treatment than during the cytostatic therapy. It was also possible to predict the cognitive state of patients suffering from multiple myeloma based on a selected biological parameter (neurotrophin BDNF).
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Affiliation(s)
- Magdalena Bury-Kamińska
- Department of Clinical Psychology and Neuropsychology, Institute of Psychology, Maria Curie-Skłodowska University in Lublin, 45 Głęboka, 20-612 Lublin, Poland
| | - Aneta Szudy-Szczyrek
- Department of Hemato-Oncology and Bone Marrow Transplantation, Medical University of Lublin, 2 Karmelicka, 20-400 Lublin, Poland; (A.S.-S.); (A.N.); (O.J.-Ł.); (M.H.); (K.K.)
| | - Aleksandra Nowaczyńska
- Department of Hemato-Oncology and Bone Marrow Transplantation, Medical University of Lublin, 2 Karmelicka, 20-400 Lublin, Poland; (A.S.-S.); (A.N.); (O.J.-Ł.); (M.H.); (K.K.)
| | - Olga Jankowska-Łęcka
- Department of Hemato-Oncology and Bone Marrow Transplantation, Medical University of Lublin, 2 Karmelicka, 20-400 Lublin, Poland; (A.S.-S.); (A.N.); (O.J.-Ł.); (M.H.); (K.K.)
| | - Marek Hus
- Department of Hemato-Oncology and Bone Marrow Transplantation, Medical University of Lublin, 2 Karmelicka, 20-400 Lublin, Poland; (A.S.-S.); (A.N.); (O.J.-Ł.); (M.H.); (K.K.)
| | - Klaudia Kot
- Department of Hemato-Oncology and Bone Marrow Transplantation, Medical University of Lublin, 2 Karmelicka, 20-400 Lublin, Poland; (A.S.-S.); (A.N.); (O.J.-Ł.); (M.H.); (K.K.)
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Magnuson A, Ahles T, Chen BT, Mandelblatt J, Janelsins MC. Cognitive Function in Older Adults With Cancer: Assessment, Management, and Research Opportunities. J Clin Oncol 2021; 39:2138-2149. [PMID: 34043437 PMCID: PMC8260910 DOI: 10.1200/jco.21.00239] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/11/2021] [Accepted: 03/25/2021] [Indexed: 12/12/2022] Open
Affiliation(s)
- Allison Magnuson
- Department of Medicine, University of Rochester Medical Center, Wilmot Cancer Institute, Rochester, NY
| | - Tim Ahles
- Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Bihong T. Chen
- Department of Diagnostic Radiology, City of Hope National Medical Center, Duarte, CA
| | - Jeanne Mandelblatt
- Georgetown-Lombardi Comprehensive Cancer Center, Cancer Control Program, Georgetown University Medical Center, Washington, DC
| | - Michelle C. Janelsins
- Department of Surgery, Cancer Control, University of Rochester Medical Center, Wilmot Cancer Institute, Rochester, NY
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Van Dyk K, Zhou X, Small BJ, Ahn J, Zhai W, Ahles T, Graham D, Jacobsen PB, Jim H, McDonald BC, Nudelman Holohan K, Patel SK, Rebeck GW, Root JC, Saykin AJ, Cohen HJ, Mandelblatt JS, Carroll JE. Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study. JNCI Cancer Spectr 2021; 5:pkab013. [PMID: 33748669 PMCID: PMC7962698 DOI: 10.1093/jncics/pkab013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/21/2021] [Indexed: 11/14/2022] Open
Abstract
Background Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene ε4 polymorphisms. APOE ε4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas ε2 polymorphisms protect against AD. However, the effects of ε2 polymorphisms on CRCD have not been evaluated. Methods We evaluated nonmetastatic breast cancer survivors (n = 427) and matched noncancer controls (n = 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an ε2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with ε2/ε4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any ε4 positivity. Results There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta = 0.32, 95% confidence interval = 0.00 to 0.65); the chemotherapy group with an ε2 allele had higher scores at baseline and maintained higher scores over time compared with those without an ε2 allele, and this protective effect was not seen for other groups. There was no effect of ε2 on learning and memory domain scores. Conclusions APOE ε2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.
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Affiliation(s)
- Kathleen Van Dyk
- UCLA Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, David Geffen School of Medicine, Jane and Terry Semel Institute for Neuroscience and Human Behavior, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Xingtao Zhou
- Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Brent J Small
- School of Aging Studies, University of South Florida, and Senior Member, Health Outcome and Behavior Program and Biostatistics Resource Core, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA
| | - Jaeil Ahn
- Department of Biostatistics, Bioinformatics, and Biomathematics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Wanting Zhai
- Department of Biostatistics, Bioinformatics, and Biomathematics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Tim Ahles
- Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | | | - Paul B Jacobsen
- Division of Cancer Control and Population Sciences, Healthcare Delivery Research Program, National Cancer Institute, Bethesda, MD, USA
| | - Heather Jim
- Department of Health Outcomes and Behavior, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA
| | - Brenna C McDonald
- Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kelly Nudelman Holohan
- Department of Medical and Molecular Genetics, Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sunita K Patel
- Departments of Population Sciences and Supportive Care Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - G William Rebeck
- Department of Neurosciences, Georgetown University School of Medicine, Georgetown University, Washington, DC, USA
| | - James C Root
- Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- Departments of Psychiatry and Anesthesiology, Weill Medical College of Cornell University, New York, NY, USA
| | - Andrew J Saykin
- Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana Alzheimer’s Disease Research Center, and the Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Harvey Jay Cohen
- Center for the Study of Aging and Human Development, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Jeanne S Mandelblatt
- Department of Oncology, Cancer Prevention and Control Program, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Judith E Carroll
- UCLA Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, David Geffen School of Medicine, Jane and Terry Semel Institute for Neuroscience and Human Behavior, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
- Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, Los Angeles, CA, USA
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ADHD: Reviewing the Causes and Evaluating Solutions. J Pers Med 2021; 11:jpm11030166. [PMID: 33804365 PMCID: PMC7999417 DOI: 10.3390/jpm11030166] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/05/2021] [Accepted: 02/23/2021] [Indexed: 12/11/2022] Open
Abstract
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder in which patients present inattention, hyperactivity, and impulsivity. The etiology of this condition is diverse, including environmental factors and the presence of variants of some genes. However, a great diversity exists among patients regarding the presence of these ADHD-associated factors. Moreover, there are variations in the reported neurophysiological correlates of ADHD. ADHD is often treated pharmacologically, producing an improvement in symptomatology, albeit there are patients who are refractory to the main pharmacological treatments or present side effects to these drugs, highlighting the importance of developing other therapeutic options. Different non-pharmacological treatments are in this review addressed, finding diverse results regarding efficacy. Altogether, ADHD is associated with different etiologies, all of them producing changes in brain development, leading to the characteristic symptomatology of this condition. Given the heterogeneous etiology of ADHD, discussion is presented about the convenience of personalizing ADHD treatment, whether pharmacological or non-pharmacological, to reach an optimum effect in the majority of patients. Approaches to personalizing both pharmacological therapy and neurofeedback are presented.
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Marton G, Bailo L, Pravettoni G. Exploring the possible application of implementation intention on prospective memory of cancer patients. COGENT PSYCHOLOGY 2021. [DOI: 10.1080/23311908.2021.1880303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Affiliation(s)
- Giulia Marton
- Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
- Applied Research Division for Cognitive and Psychological Science, European Institute of Oncology IRCCS, Milan, Italy
| | - Luca Bailo
- Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
- Applied Research Division for Cognitive and Psychological Science, European Institute of Oncology IRCCS, Milan, Italy
| | - Gabriella Pravettoni
- Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
- Applied Research Division for Cognitive and Psychological Science, European Institute of Oncology IRCCS, Milan, Italy
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39
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Bai L, Yu E. A narrative review of risk factors and interventions for cancer-related cognitive impairment. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:72. [PMID: 33553365 PMCID: PMC7859819 DOI: 10.21037/atm-20-6443] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Cancer-related cognitive impairment (CRCI) refers to a series of cognitive impairment symptoms associated with alternations in brain structure and function, caused by a non-central nervous system malignant tumor and its related treatment. CRCI may present as memory loss, impaired concentration, difficulty in multitasking and word retrieval, and reduced comprehension speed. CRCI has become one of the prevalent factors that compromise the quality of life for cancer survivors. Different treatments, including surgery, chemotherapy, radiotherapy, endocrine therapy, and targeted drugs, may contribute to CRCI. Meanwhile, patients’ factors, including emotional challenges and genetic makeup, also contribute to the development of CRCI. The condition can be treated with using stimulants methylphenidate and modafinil, metabolites of nicotine: cotinine, antidepressants of fluoxetine and fluvoxamine, dementia drug of donepezil, and antioxidants ZnSO4, n-acetyl cysteine, propofol, and Chinese herbal of silver leaf medicine. Psychotherapies, including meditation and relaxation, cognitive rehabilitation training, along with physical therapies, including aerobic exercise, resistance training, balance training, yoga, qigong, tai chi electroencephalogram biofeedback, and acupuncture, are also beneficial in alleviating cancer-related cognitive impairment symptoms. In recent years, researchers have focused on factors related to the condition and on the available interventions. However, most research was conducted independently, and no review has yet summarized the latest findings. This review details and discusses the status of related factors and potential treatments for CRCI. We also supply specific recommendations to facilitate future research and integration in this field.
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Affiliation(s)
- Lu Bai
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Beijing, China
| | - Enyan Yu
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Beijing, China
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40
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Mayo SJ, Lustberg M, M Dhillon H, Nakamura ZM, Allen DH, Von Ah D, C Janelsins M, Chan A, Olson K, Tan CJ, Toh YL, Oh J, Grech L, Cheung YT, Subbiah IM, Petranovic D, D'Olimpio J, Gobbo M, Koeppen S, Loprinzi CL, Pang L, Shinde S, Ntukidem O, Peters KB. Cancer-related cognitive impairment in patients with non-central nervous system malignancies: an overview for oncology providers from the MASCC Neurological Complications Study Group. Support Care Cancer 2020; 29:2821-2840. [PMID: 33231809 DOI: 10.1007/s00520-020-05860-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/26/2020] [Indexed: 02/07/2023]
Abstract
Cancer-related cognitive impairment (CRCI) is commonly experienced by individuals with non-central nervous system cancers throughout the disease and treatment trajectory. CRCI can have a substantial impact on the functional ability and quality of life of patients and their families. To mitigate the impact, oncology providers must know how to identify, assess, and educate patients and caregivers. The objective of this review is to provide oncology clinicians with an overview of CRCI in the context of adults with non-central nervous system cancers, with a particular focus on current approaches in its identification, assessment, and management.
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Affiliation(s)
- Samantha J Mayo
- Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Canada. .,Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
| | - Maryam Lustberg
- The Ohio State Comprehensive Cancer Center, Columbus, OH, USA
| | | | - Zev M Nakamura
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Diane Von Ah
- Indiana University School of Nursing, Indianapolis, IN, USA
| | - Michelle C Janelsins
- Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA.,Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA.,Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | | | - Karin Olson
- Faculty of Nursing, University of Alberta, Edmonton, Alberta, Canada
| | - Chia Jie Tan
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yi Long Toh
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeong Oh
- Peter MacCallum Cancer Centre, Parkville, Australia
| | - Lisa Grech
- National University of Singapore, Singapore, Singapore.,Swinburne University, Hawthorn, Australia.,University of Melbourne, Parkville, Australia.,Monash University, Clayton, Australia
| | - Yin Ting Cheung
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR
| | | | - Duska Petranovic
- Clinical Hospital Center Rijeka, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - James D'Olimpio
- Monter Cancer Center, Northwell Cancer Institute, Lake Success, NY, USA
| | - Margherita Gobbo
- Division of Oral Medicine and Pathology, Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.,Unit of Oral and Maxillofacial Surgery, Ca Foncello Hospital, Treviso, Italy
| | - Susanne Koeppen
- LVR-Klinikum Essen, University of Duisburg-Essen, Essen, Germany
| | | | | | | | | | - Katherine B Peters
- The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA
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Li W, Zhao J, Ding K, Chao HH, Li CSR, Cheng H, Shen L. Catechol-O-Methyltransferase Gene Polymorphisms and the Risk of Chemotherapy-Induced Prospective Memory Impairment in Breast Cancer Patients with Varying Tumor Hormonal Receptor Expression. Med Sci Monit 2020; 26:e923567. [PMID: 32985495 PMCID: PMC7531203 DOI: 10.12659/msm.923567] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Existing research evidence indicates that breast cancer patients have different degrees of cognitive dysfunction after chemotherapy, and polymorphisms in 3 genes (catechol-O-methyltransferase, COMT; apolipoprotein E, APOE; and brain-derived neurotrophic factor, BDNF) have been associated with cognitive impairment. However, the role of these 3 gene polymorphisms in modulating cognitive impairment in breast cancer survivors with varying hormonal receptor expression is not clear at present. To explore the effects of genetic polymorphisms in BDNF, APOE, and COMT on the regulation of prospective memory impairments induced by chemotherapy in breast cancer patients with various expression levels of estrogen receptor (ER) and progesterone receptor (PR). Material/Methods A total of 232 patients with breast cancer (113 with ER−/PR− and 119 with ER+/PR+) were evaluated before and after chemotherapy for cognitive function, including prospective memory. Following previously published sequencing procedures, we assessed 6 single-nucleotide polymorphisms (SNPs), including BDNF (rs6265), APOE (rs429358, rs7412), and COMT (rs165599, rs4680, rs737865). Results The patients showed poorer prospective memory scores after chemotherapy than before chemotherapy. Furthermore, the ER−/PR− group showed poorer event-based prospective memory (EBPM) scores than the ER+/PR+ group (z=−7.831, p<0.01) after chemotherapy. The patients with the COMT rs737865G/G genotype, compared with those with the A/A and A/G genotypes, showed a linear EBPM performance (β=1.499, 95% confidence interval (CI)=1.017~2.211) and were less likely to have memory impairment. In contrast, APOE and BDNF polymorphisms did not influence cognitive performance. Conclusions The patterns of hormonal receptor expression may be related to prospective memory impairments induced by chemotherapy in breast cancer patients. Furthermore, the COMT polymorphism (rs737865) was linearly related to the extent of deficits in EBPM and may represent a potential genetic marker of risk for cognitive deficits triggered by chemotherapy in patients with breast cancer.
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Affiliation(s)
- Wen Li
- Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China (mainland)
| | - Jingjing Zhao
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Ke Ding
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Herta H Chao
- Cancer Center, VA Connecticut Healthcare System, New Haven, CT, USA
| | - Chiang-Shan R Li
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Huaidong Cheng
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Li Shen
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
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Brain-derived neurotrophic factor polymorphism Val66Met protects against cancer-related fatigue. Transl Psychiatry 2020; 10:302. [PMID: 32848137 PMCID: PMC7450091 DOI: 10.1038/s41398-020-00990-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 12/26/2022] Open
Abstract
Cancer-related fatigue is an extremely common and debilitating psychiatric symptom that affects up to 80% of cancer patients. Despite its negative impact on the patient's quality of life, there is no well-established biomarker or mechanisms associated with this debilitating condition. The functional brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism (SNP) has been associated with a variety of psychiatric illnesses. We hypothesized that Val66Met may influence the risk for developing cancer-related fatigue. BDNF Val66Met was analyzed by polymerase chain reaction in 180 patients with confirmed cancer diagnoses. Fatigue was measured using the Functional Assessment of Cancer Therapy-Fatigue (FACIT-Fatigue) questionnaire. Depression was measured using the Hamilton Depression Scale (HAM-D). Data were transformed when necessary and regression models were constructed to access the association between genotype and symptom severity. Participants carrying the Met allele reported significantly less fatigue compared to the Val/Val genotype group. The presence of the Met allele did not influence depression levels. The results suggest that the BDNF Val66Met polymorphism confers protective advantage against cancer-related fatigue; whereas having the Val/Val genotype may be a genetic risk factor. Findings from this study not only provide clues to the neural basis of cancer-related fatigue, but also allow for symptom severity prediction and patient education with the goal to improve symptom management.
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Associations of plasma brain-derived neurotrophic factor (BDNF) and Val66Met polymorphism (rs6265) with long-term cancer-related cognitive impairment in survivors of breast cancer. Breast Cancer Res Treat 2020; 183:683-696. [DOI: 10.1007/s10549-020-05807-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 07/11/2020] [Indexed: 12/26/2022]
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Tan CJ, Mah JJJ, Goh WL, Poon E, Harunal Rashid MF, Chan A. Self-reported cognitive outcomes among adolescent and young adult patients with noncentral nervous system cancers. Psychooncology 2020; 29:1355-1362. [PMID: 32597001 PMCID: PMC7497100 DOI: 10.1002/pon.5456] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 05/19/2020] [Accepted: 06/22/2020] [Indexed: 01/06/2023]
Abstract
Objective Cancer‐related cognitive impairment (CRCI) among adolescent and young adult (AYA) cancer patients with noncentral nervous system (CNS) cancers has not been well studied. In this study, we aimed to describe CRCI‐associated trends and characteristics among AYA cancer patients. Methods In a longitudinal cohort of AYA cancer patients without CNS disease, CRCI was evaluated over 1 year using the Functional Assessment of Cancer Therapy‐Cognitive Function Instrument, a self‐reported cognitive outcome measure. CRCI prevalence was quantified using the previously established minimal clinically important difference. CRCI‐associated longitudinal trends and factors were evaluated with mixed‐effects model analysis. Results Ninety‐one patients (mean age = 28.4 ± 6.7 years) were included. Approximately one‐third (34.1%) experienced CRCI at least once during the study follow‐up. Female gender (P = .02), Indian ethnicity (P < .01), current smokers (P < .01), anxiety/depressive symptoms (P < .01) and fatigue (P < .01) were found to be associated with poorer cognitive function among AYAs. Conclusions Although AYA cancer patients were relatively young and without CNS disease involvement, a significant proportion of them experienced clinically important decline in cognitive function. With improved understanding of this subject, effective strategies can be formulated to promote awareness of CRCI and mitigate its negative effects among AYA cancer patients.
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Affiliation(s)
- Chia Jie Tan
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Jaclyn Jia Jun Mah
- Department of Pharmacy, National Cancer Centre Singapore, Singapore, Singapore
| | - Wei Lin Goh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Eileen Poon
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Alexandre Chan
- Department of Pharmacy, National Cancer Centre Singapore, Singapore, Singapore.,Duke-NUS Medical School, Singapore, Singapore.,Department of Clinical Pharmacy Practice, University of California, Irvine, California, USA
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Pathogenesis, Assessments, and Management of Chemotherapy-Related Cognitive Impairment (CRCI): An Updated Literature Review. JOURNAL OF ONCOLOGY 2020; 2020:3942439. [PMID: 32684930 PMCID: PMC7333028 DOI: 10.1155/2020/3942439] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/10/2020] [Accepted: 06/08/2020] [Indexed: 02/06/2023]
Abstract
There are various cancer treatments at present, and chemotherapy is one of the main methods. Chemotherapy-related cognitive impairment (CRCI), as one of the side effects of chemotherapy, has gradually attracted the attention of more and more researchers. CRCI has been verified by subjective reports and objective neuropsychological tests so far. But oncologists' understanding of it and its treatments are still incomplete. In this review, we mainly give a comprehensive overview of the mechanism of CRCI, then describe a variety of evaluation methods, and finally summarize the treatment approaches under current medical conditions and compare it with an excellent article published in 2015 with the aim of providing directions for future research and better understanding of CRCI for clinicians.
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46
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Allegra A, Innao V, Basile G, Pugliese M, Allegra AG, Pulvirenti N, Musolino C. Post-chemotherapy cognitive impairment in hematological patients: current understanding of chemobrain in hematology. Expert Rev Hematol 2020; 13:393-404. [PMID: 32129131 DOI: 10.1080/17474086.2020.1738213] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
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.
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Affiliation(s)
- Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 90100, Messina, Italy
| | - Vanessa Innao
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 90100, Messina, Italy
| | - Giorgio Basile
- Unit and School of Geriatrics, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Marta Pugliese
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 90100, Messina, Italy
| | - Andrea Gaetano Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 90100, Messina, Italy
| | - Nicolina Pulvirenti
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 90100, Messina, Italy
| | - Caterina Musolino
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 90100, Messina, Italy
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Kim HJ, Jung SO, Kim H, Abraham I. Systematic review of longitudinal studies on chemotherapy-associated subjective cognitive impairment in cancer patients. Psychooncology 2020; 29:617-631. [PMID: 32017297 DOI: 10.1002/pon.5339] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 12/12/2019] [Accepted: 01/13/2020] [Indexed: 12/22/2022]
Abstract
OBJECTIVES This systematic review of longitudinal studies, assessing subjective cognitive impairment (SCI) reported by adult cancer patients, aimed to summarize evidence on the impact of chemotherapy on SCI, identify moderators of SCI, and evaluate methodological issues. METHODS Data accrued from Pubmed, EMBASE, CINAHL, PsychInfo, and the Cochrane library. Inclusion criteria were original studies, an exclusively adult sample, valid and reliable subjective cognitive measures, and at least one baseline data point prior to and another after the initiation of chemotherapy. Data were collected on the sample composition, data-collection time points, outcome measures, statistical analysis, and major findings (ie, longitudinal changes in prevalence, severity, and associated factors). RESULTS Forty articles published between 2004 and 2019 were retained: 21 examined chemotherapy-treated patients only, and 19 employed control groups. Findings were mixed, with slightly more studies supporting the impact of chemotherapy on SCI. SCI tended to be more prevalent and severe after initiating chemotherapy, compared with patients' own baseline and controls not treated with chemotherapy. Impact appeared to be acute and more likely limited to subsamples. Most studies examining non-breast-cancer samples reported the lack or limited impact of chemotherapy on SCI. The most consistent moderators were depression and fatigue. Methodological issues regarding sampling design, measurement, and statistical analysis were discussed. CONCLUSION More rigorously designed longitudinal studies would clarify direct and indirect effects of chemotherapy on SCI.
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Affiliation(s)
- Hee-Ju Kim
- College of Nursing, The Catholic University of Korea, Seoul, South Korea
| | - Sun-Ok Jung
- College of Nursing, The Catholic University of Korea, Seoul, South Korea
| | - Hyang Kim
- College of Nursing, Seoul National University, Seoul, South Korea
| | - Ivo Abraham
- Department of Pharmacy Practice and Science, College of Pharmacy; Department of Family and Community Medicine, College of Medicine; Center for Health Outcomes and PharmacoEconomic Research, University of Arizona, Tucson, Arizona
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Smith L, Grabovac I, Yang L, López-Sánchez GF, Firth J, Pizzol D, McDermott D, Veronese N, Jackson SE. Sexual activity and cognitive decline in older age: a prospective cohort study. Aging Clin Exp Res 2020; 32:85-91. [PMID: 31494914 DOI: 10.1007/s40520-019-01334-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 08/19/2019] [Indexed: 01/09/2023]
Abstract
BACKGROUND To explore the association between sexual activity and change in cognitive function over 4 years in a representative sample of older adults in England. METHODS Data were from 1963 men and 2513 women participating in Wave 6 (2012/2013) and Wave 8 (2016/2017) of the English Longitudinal Study of Ageing. Participants reported whether or not they had engaged in any sexual activity in the last year. Cognitive function was assessed with tests of immediate and delayed recall. Adjusted general linear models were used to test associations between sexual activity and changes in cognitive function. RESULTS Men who were sexually active at baseline had better preservation in immediate (0.18 points, 95% CI 0.07-0.29, p = 0.002) and delayed recall (0.19 points, 95% CI 0.08-0.29, p = 0.001) over 4-year follow-up. No significant associations were observed for women. DISCUSSION Strengths of this study include large, representative sample, longitudinal design and adjustment for a wide range of potential confounders. The observational nature of our study means we cannot deduce the exact direction of effect of our findings. In addition, cognitive ability test scores in older people may reflect not only a possible decline, but also their peak prior cognitive ability; but we did not have any information regarding the trajectories of their cognitive function during the lifespan. CONCLUSION Health practitioners should be encouraged to screen older men relating to their sexual activity to identify those who may be at risk of cognitive decline. Older men will be heartened to know that sexual activity may aid in the prevention of age-related decline in cognition.
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Affiliation(s)
- Lee Smith
- The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, CB1 1PT, UK.
| | - Igor Grabovac
- Department of Social and Preventive Medicine, Centre for Public Health, Medical University of Vienna, Vienna, Austria
| | - Lin Yang
- Department of Epidemiology, Center for Public Health, Medical University of Vienna, Vienna, Austria
| | | | - Joe Firth
- NICM Health Research Institute, University of Western Sydney, Sydney, Australia
| | - Damiano Pizzol
- Italian Agency for Development Cooperation, 9135400, Jerusalem, Israel
| | - Daragh McDermott
- Division of Psychology, School of Psychology and Sports Sciences, Anglia Ruskin University, Cambridge, UK
| | - Nicola Veronese
- National Research Council, Neuroscience Institute, Aging Branch, Padua, Italy
| | - Sarah E Jackson
- Department of Behavioural Science and Health, UCL, London, UK
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Lange M, Joly F, Vardy J, Ahles T, Dubois M, Tron L, Winocur G, De Ruiter M, Castel H. Cancer-related cognitive impairment: an update on state of the art, detection, and management strategies in cancer survivors. Ann Oncol 2019; 30:1925-1940. [PMID: 31617564 PMCID: PMC8109411 DOI: 10.1093/annonc/mdz410] [Citation(s) in RCA: 380] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Advances in diagnostic and therapeutic strategies in oncology have significantly increased the chance of survival of cancer patients, even those with metastatic disease. However, cancer-related cognitive impairment (CRCI) is frequently reported in patients treated for non-central nervous system cancers, particularly during and after chemotherapy. DESIGN This review provides an update of the state of the art based on PubMed searches between 2012 and March 2019 on 'cognition', 'cancer', 'antineoplastic agents' or 'chemotherapy'. It includes the most recent clinical, imaging and pre-clinical data and reports management strategies of CRCI. RESULTS Evidence obtained primarily from studies on breast cancer patients highlight memory, processing speed, attention and executive functions as the most cognitive domains impaired post-chemotherapy. Recent investigations established that other cancer treatments, such as hormone therapies and targeted therapies, can also induce cognitive deficits. Knowledge regarding predisposing factors, biological markers or brain functions associated with CRCI has improved. Factors such as age and genetic polymorphisms of apolipoprotein E, catechol-O-methyltransferase and BDNF may predispose individuals to a higher risk of cognitive impairment. Poor performance on neuropsychological tests were associated with volume reduction in grey matter, less connectivity and activation after chemotherapy. In animals, hippocampus-based memory and executive functions, mediated by the frontal lobes, were shown to be particularly susceptible to the effects of chemotherapy. It involves altered neurogenesis, mitochondrial dysfunction or brain cytokine response. An important next step is to identify strategies for managing cognitive difficulties, with primary studies to assess cognitive training and physical exercise regimens. CONCLUSIONS CRCI is not limited to chemotherapy. A multidisciplinary approach has improved our knowledge of the complex mechanisms involved. Nowadays, studies evaluating cognitive rehabilitation programmes are encouraged to help patients cope with cognitive difficulties and improve quality of life during and after cancer.
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Affiliation(s)
- M. Lange
- INSERM, U1086, ANTICIPE, 14000 Caen,Clinical Research Department, Centre François Baclesse, 14000 Caen,Cancer and Cognition Platform, Ligue Nationale Contre le Cancer, 14000 Caen
| | - F. Joly
- INSERM, U1086, ANTICIPE, 14000 Caen,Clinical Research Department, Centre François Baclesse, 14000 Caen,Cancer and Cognition Platform, Ligue Nationale Contre le Cancer, 14000 Caen,Medical Oncology Department, CHU de Caen, 14000 Caen, France,Correspondence to: Prof. Florence Joly, Medical Oncology Department, Inserm U1086 Anticipe, Centre François Baclesse, 3 avenue Général Harris, Caen 14000, France. Tel: +33-2-3145-5002;
| | - J Vardy
- Concord Cancer Centre, Concord Repatriation General Hospital, Sydney, New South Wales,Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - T. Ahles
- Neurocognitive Research Lab, Memorial Sloan Kettering Cancer Center, New York, USA
| | - M. Dubois
- Cancer and Cognition Platform, Ligue Nationale Contre le Cancer, 14000 Caen,Normandie University, UNIROUEN, INSERM, DC2N, 76000 Rouen,Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen
| | - L. Tron
- INSERM, U1086, ANTICIPE, 14000 Caen,Cancer and Cognition Platform, Ligue Nationale Contre le Cancer, 14000 Caen,CHU de Caen, 14000 Caen, France
| | - G. Winocur
- Baycrest Centre, Rotman Research Institute, Toronto,Department of Psychology, Trent University, Peterborough,Department of Psychology and Psychiatry, University of Toronto, Toronto, Canada
| | - M.B. De Ruiter
- Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - H. Castel
- Cancer and Cognition Platform, Ligue Nationale Contre le Cancer, 14000 Caen,Normandie University, UNIROUEN, INSERM, DC2N, 76000 Rouen,Institute for Research and Innovation in Biomedicine (IRIB), 76000 Rouen
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Joly F, Lange M, Dos Santos M, Vaz-Luis I, Di Meglio A. Long-Term Fatigue and Cognitive Disorders in Breast Cancer Survivors. Cancers (Basel) 2019; 11:E1896. [PMID: 31795208 PMCID: PMC6966680 DOI: 10.3390/cancers11121896] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 11/25/2019] [Accepted: 11/26/2019] [Indexed: 01/20/2023] Open
Abstract
Survivors of early-stage breast cancer may report treatment-related side effects that persist for several years after the end of primary treatment. Among these, fatigue and cognitive disorders are frequent complaints and can negatively impact quality of life. Cancer-related fatigue is a very prevalent and distressing long-term side effect among breast cancer survivors that typically improves after completion of treatment, although many patients report severe fatigue several years post-treatment. Cognitive disorders are also common among survivors of breast cancer, especially if treated with chemotherapy. These symptoms are usually mild-to-moderate and often transient. Cognitive recovery is frequently observed within months or a few years after completion of chemotherapy or endocrine therapy. However, some breast cancer survivors may have persistent cognitive difficulties. Several types of interventions have proved to be beneficial in reducing cancer-related fatigue and cognitive difficulties. Most of these interventions for cancer-related fatigue are thought to be effective by reducing inflammation or disrupting pro-inflammatory circuits. Further studies are needed on cognitive management that has showed promising results. This narrative review summarizes the state of the art regarding long-term fatigue and cognitive disorders in patients with early breast cancer, describing prevalence, impact, pathophysiology, and risk factors, and focusing on available interventions.
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Affiliation(s)
- Florence Joly
- Clinical Research Department, Centre François Baclesse, 14000 Caen, France; (M.L.); (M.D.S.)
- INSERM U1086, ANTICIPE, Normandie Univ, UNICAEN, 14000 Caen, France
- Cancer and Cognition Platform, Ligue Nationale Contre le Cancer, 14000 Caen, France
- University Hospital of Caen, 14000 Caen, France
| | - Marie Lange
- Clinical Research Department, Centre François Baclesse, 14000 Caen, France; (M.L.); (M.D.S.)
- INSERM U1086, ANTICIPE, Normandie Univ, UNICAEN, 14000 Caen, France
- Cancer and Cognition Platform, Ligue Nationale Contre le Cancer, 14000 Caen, France
| | - Melanie Dos Santos
- Clinical Research Department, Centre François Baclesse, 14000 Caen, France; (M.L.); (M.D.S.)
- INSERM U1086, ANTICIPE, Normandie Univ, UNICAEN, 14000 Caen, France
- Cancer and Cognition Platform, Ligue Nationale Contre le Cancer, 14000 Caen, France
- University Hospital of Caen, 14000 Caen, France
- INSERM Unit 981, Gustave Roussy, 94800 Villejuif, France; (I.V.-L.); (A.D.M.)
| | - Ines Vaz-Luis
- INSERM Unit 981, Gustave Roussy, 94800 Villejuif, France; (I.V.-L.); (A.D.M.)
| | - Antonio Di Meglio
- INSERM Unit 981, Gustave Roussy, 94800 Villejuif, France; (I.V.-L.); (A.D.M.)
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