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Neurobiological Impacts of Cancer and Cancer Treatments: Mechanisms, Risk Factors, Biomarkers, and Prevention/Recovery

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Survivorship and Quality of Life".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 24650

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Special Issue Editor

Dr. Helene Castel

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Guest Editor

Astrocyte and Vascular Niche Research Team, DC2N Department, Inserm U1239, University of Rouen Normandie, Cancer and Cognition Platform, 76821 Mont-Saint-Aignan, France
Interests: neuro-oncology; brain tumors and microenvironment; ion channels
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Special Issue Information

Dear Colleagues,

Diagnostic and therapeutic advances in the field of cancer have considerably increased the chances of survival with improved prospects for better quality of life, even in metastatic situations. Consequently, toxicity of cancer treatments is also evolving. Among the deleterious effects of cancer treatments, neurological toxicities have recently been characterized, leading more or less to long-term cognitive disorders. Patients with non-central nervous system (CNS) cancer complain of several treatment-related side effects, including cognitive symptoms also called cancer-related cognitive impairment (CRCI). These cognitive deficits, often reported with chemotherapy, result in impairment of short-term and working memory, attention, executive functions, and/or processing speed in patients during and after the treatment period. Cognitive difficulties associated with chemotherapy and/or radiotherapy impact patient quality of life during cancer treatment but also in the post-cancer period. Brain imaging studies in this population have reported reductions in gray matter volume or density, reductions in white matter microstructure, and changes in brain activation and connectivity after chemotherapy exposure, suggestive of neurotoxicity. In addition, through preclinical research, there have been significant advances in our appreciation of lost and spared cognitive and emotional abilities, recovery over time, biological and integrated mechanisms, as well as associated non-cognitive abnormalities such as “fatigue” and emotional reactivity. From a neurobiological point of view, mechanisms linked to inflammation/neuroinflammation have been demonstrated as well as direct (through crossing of the blood–brain barrier) or indirect damage to neuronal precursors and/or cerebral vascularization, alteration of neurotransmitter systems, mitochondrial activity and oxidative stress, and changes in the brain structure such as seen in animal models after chemo- or radiotherapy. The long-term impact of treatment on neurological function is an important issue in terms of quality of life (QoL) and management during and after cancer. Depending on the patient’s age, these CRCIs pose major questions in terms of benefit/risk of treatment, return to work, social relations, and even autonomy.

The therapeutic field in oncology is expanding, with new medical approaches such as new generation hormone therapy, targeted therapy or immunotherapy as well as new radiotherapy strategies (stereotactic/proton/hadrontherapy radiotherapy, especially for slow-growing brain tumors) which allow improvements in terms of survival for cancer patients. Consequently, the toxicity of cancer treatments is currently evolving, and as patients can expect longer survival times, the impact of these new cancer treatments in association with chemotherapy and radiotherapy on quality of life and cognition is a major issue. Thus, a number of current challenges include (i) longitudinally evaluating, in standardized and clinical current practice, cognitive complaints and altered specific cognitive domains, emotional and mood behavior, and fatigue in cancer patients; (ii) identifying populations of patients at risk and biomarkers predictive of cerebral toxicities; and (iii) understanding the anatomical and physiopathological mechanisms induced. Preclinical research should markedly contribute to the identification of therapy-induced alteration of specific cognitive domains, their duration and recovery over time, biological mechanisms and, importantly, prevention/compensating strategies. These studies and actions aim to build and evaluate rehabilitation and interventional strategies for these patients, with the objective of better quality of life, return to work, and/or sustained autonomy.

Dr. Helene Castel
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

cancer treatment
cognitive function
fatigue
brain imaging
biomarker
neuroprotection
rehabilitation
management
animal behavior

Published Papers (9 papers)

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Research

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14 pages, 691 KiB

Open AccessArticle

Symptoms of Depression and Anxiety in Adults with High-Grade Glioma: A Literature Review and Findings in a Group of Patients before Chemoradiotherapy and One Year Later

by Monica Ribeiro, Mohamed Amine Benadjaoud, Laura Moisy, Julian Jacob, Loïc Feuvret, Alexander Balcerac, Marie-Odile Bernier, Dimitri Psimaras, Khê Hoang-Xuan, Georges Noel, Nathalie Jouniaux-Delbez and Damien Ricard

Cancers 2022, 14(21), 5192; https://doi.org/10.3390/cancers14215192 - 22 Oct 2022

Cited by 1 | Viewed by 1898

Abstract

High-grade glioma (HGG) is associated with several external and internal stressors that may induce mood alterations at all stages of the disease. Symptoms of depression and anxiety in persons with glioma have multifactorial etiology and require active follow-up. We reviewed the literature data on the prevalence, mechanisms likely involved in the etiology of mood alterations in persons with HGG and psychosocial interventions found beneficial in treating these symptoms. We also investigated the prevalence and clinical variables that could increase the risk of depression and anxiety symptoms in a group of patients with HGG at two disease time-points: after surgery, before and 1 year after chemoradiotherapy. Literature findings revealed complex mechanisms underlying these symptoms and highlighted the importance of providing early access to palliative care. Our results show a high rate of anxiety and depression symptoms in the first stage of the disease and increased concomitance of these symptoms at the 1-year follow-up. Depression and anxiety symptoms at 1 year after the end of chemoradiotherapy were associated with the presence of symptoms at the first stage of the disease and tumor progression. Antiepileptic drugs and corticosteroid intake did not increase the risk of depressive and anxious symptoms among patients. Active management of mood alterations is an essential part of the care and contributes to patients’ well-being and quality of life. Full article

(This article belongs to the Special Issue Neurobiological Impacts of Cancer and Cancer Treatments: Mechanisms, Risk Factors, Biomarkers, and Prevention/Recovery)

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38 pages, 5682 KiB

Open AccessArticle

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

by Renaud Parment, Martine Dubois, Laurence Desrues, Alexandre Mutel, Kléouforo-Paul Dembélé, Nicolas Belin, Laure Tron, Charlène Guérin, Moïse Coëffier, Vincent Compère, Céline Féger, Florence Joly, Pascal Hilber, David Ribet and Hélène Castel

Cancers 2022, 14(18), 4403; https://doi.org/10.3390/cancers14184403 - 10 Sep 2022

Cited by 3 | Viewed by 2774

Abstract

Chemotherapy-related cognitive impairment (CRCI) and fatigue constitute common complaints among cancer patient survivors. Panax quinquefolius has been shown to be effective against fatigue in treated cancer patients. We developed a behavioral C57Bl/6j mouse model to study the role of a Panax quinquefolius-based solution containing vitamin C (Qiseng^®) or vitamin C alone in activity/fatigue, emotional reactivity and cognitive functions impacted by 5-Fluorouracil (5-FU) chemotherapy. 5-FU significantly reduces the locomotor/exploration activity potentially associated with fatigue, evokes spatial cognitive impairments and leads to a decreased neurogenesis within the hippocampus (Hp). Qiseng^® fully prevents the impact of chemotherapy on activity/fatigue and on neurogenesis, specifically in the ventral Hp. We observed that the chemotherapy treatment induces intestinal damage and inflammation associated with increased levels of Lactobacilli in mouse gut microbiota and increased expression of plasma pro-inflammatory cytokines, notably IL-6 and MCP-1. We demonstrated that Qiseng^® prevents the 5-FU-induced increase in Lactobacilli levels and further compensates the 5-FU-induced cytokine release. Concomitantly, in the brains of 5-FU-treated mice, Qiseng^® partially attenuates the IL-6 receptor gp130 expression associated with a decreased proliferation of neural stem cells in the Hp. In conclusion, Qiseng^® prevents the symptoms of fatigue, reduced chemotherapy-induced neuroinflammation and altered neurogenesis, while regulating the mouse gut microbiota composition, thus protecting against intestinal and systemic inflammation. Full article

(This article belongs to the Special Issue Neurobiological Impacts of Cancer and Cancer Treatments: Mechanisms, Risk Factors, Biomarkers, and Prevention/Recovery)

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28 pages, 6003 KiB

Open AccessArticle

Multi-Targeting Approach in Glioblastoma Using Computer-Assisted Drug Discovery Tools to Overcome the Blood–Brain Barrier and Target EGFR/PI3Kp110β Signaling

by Catarina Franco, Samina Kausar, Margarida F. B. Silva, Rita C. Guedes, Andre O. Falcao and Maria Alexandra Brito

Cancers 2022, 14(14), 3506; https://doi.org/10.3390/cancers14143506 - 19 Jul 2022

Cited by 8 | Viewed by 2034

Abstract

The epidermal growth factor receptor (EGFR) is upregulated in glioblastoma, becoming an attractive therapeutic target. However, activation of compensatory pathways generates inputs to downstream PI3Kp110β signaling, leading to anti-EGFR therapeutic resistance. Moreover, the blood–brain barrier (BBB) limits drugs’ brain penetration. We aimed to discover EGFR/PI3Kp110β pathway inhibitors for a multi-targeting approach, with favorable ADMET and BBB-permeant properties. We used quantitative structure–activity relationship models and structure-based virtual screening, and assessed ADMET properties, to identify BBB-permeant drug candidates. Predictions were validated in in vitro models of the human BBB and BBB-glioma co-cultures. The results disclosed 27 molecules (18 EGFR, 6 PI3Kp110β, and 3 dual inhibitors) for biological validation, performed in two glioblastoma cell lines (U87MG and U87MG overexpressing EGFR). Six molecules (two EGFR, two PI3Kp110β, and two dual inhibitors) decreased cell viability by 40–99%, with the greatest effect observed for the dual inhibitors. The glioma cytotoxicity was confirmed by analysis of targets’ downregulation and increased apoptosis (15–85%). Safety to BBB endothelial cells was confirmed for three of those molecules (one EGFR and two PI3Kp110β inhibitors). These molecules crossed the endothelial monolayer in the BBB in vitro model and in the BBB-glioblastoma co-culture system. These results revealed novel drug candidates for glioblastoma treatment. Full article

(This article belongs to the Special Issue Neurobiological Impacts of Cancer and Cancer Treatments: Mechanisms, Risk Factors, Biomarkers, and Prevention/Recovery)

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23 pages, 1059 KiB

Open AccessArticle

Pre-Surgery Demographic, Clinical, and Symptom Characteristics Associated with Different Self-Reported Cognitive Processes in Patients with Breast Cancer

by Yu-Yin Allemann-Su, Marcus Vetter, Helen Koechlin, Steven M. Paul, Bruce A. Cooper, Kate Oppegaard, Michelle Melisko, Jon D. Levine, Yvette Conley, Christine Miaskowski and Maria C. Katapodi

Cancers 2022, 14(13), 3281; https://doi.org/10.3390/cancers14133281 - 5 Jul 2022

Cited by 5 | Viewed by 2045

Abstract

Cancer related cognitive impairment (CRCI) is a common and persistent symptom in breast cancer patients. The Attentional Function Index (AFI) is a self-report measure that assesses CRCI. AFI includes three subscales, namely effective action, attentional lapses, and interpersonal effectiveness, that are based on working memory, inhibitory control, and cognitive flexibility. Previously, we identified three classes of patients with distinct CRCI profiles using the AFI total scores. The purpose of this study was to expand our previous work using latent class growth analysis (LCGA), to identify distinct cognitive profiles for each of the AFI subscales in the same sample (i.e., 397 women who were assessed seven times from prior to through to 6 months following breast cancer surgery). For each subscale, parametric and non-parametric statistics were used to determine differences in demographic, clinical, and pre-surgical psychological and physical symptoms among the subgroups. Three-, four-, and two-classes were identified for the effective action, attentional lapses, and interpersonal effectiveness subscales, respectively. Across all three subscales, lower functional status, higher levels of anxiety, depression, fatigue, and sleep disturbance, and worse decrements in energy were associated with worse cognitive performance. These and other modifiable characteristics may be potential targets for personalized interventions for CRCI. Full article

(This article belongs to the Special Issue Neurobiological Impacts of Cancer and Cancer Treatments: Mechanisms, Risk Factors, Biomarkers, and Prevention/Recovery)

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12 pages, 1724 KiB

Open AccessArticle

The Extent of Necrosis in Brain Metastases May Predict Subtypes of Primary Cancer and Overall Survival in Patients Receiving Craniotomy

by Jihwan Yoo, Yoon Jin Cha, Hun Ho Park, Mina Park, Bio Joo, Sang Hyun Suh and Sung Jun Ahn

Cancers 2022, 14(7), 1694; https://doi.org/10.3390/cancers14071694 - 26 Mar 2022

Cited by 3 | Viewed by 1912

Abstract

Although necrosis is common in brain metastasis (BM), its biological and clinical significances remain unknown. We evaluated necrosis extent differences by primary cancer subtype and correlated BM necrosis to overall survival post-craniotomy. We analyzed 145 BMs of patients receiving craniotomy. Necrosis to tumor ratio (NTR) was measured. Patients were divided into two groups by NTR: BMs with sparse necrosis and with abundant necrosis. Clinical features were compared. To investigate factor relevance for BM necrosis, multivariate logistic regression, random forests, and gradient boosting machine analyses were performed. Kaplan–Meier analysis and log-rank tests were performed to evaluate the effect of BM necrosis on overall survival. Lung cancer was a more common origin for BMs with abundant necrosis (42/72, 58.33%) versus sparse necrosis (23/73, 31.51%, p < 0.01). Primary cancer subtype and tumor volume were the most relevant factors for BM necrosis (p < 0.01). BMs harboring moderately abundant necrosis showed longer survival, versus sparse or highly abundant necrosis (p = 0.04). Lung cancer BM may carry larger necrosis than BMs from other cancers. Further, moderately abundant necrosis in BM may predict a good prognosis post-craniotomy. Full article

(This article belongs to the Special Issue Neurobiological Impacts of Cancer and Cancer Treatments: Mechanisms, Risk Factors, Biomarkers, and Prevention/Recovery)

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15 pages, 1846 KiB

Open AccessArticle

Neuroinflammation and Its Association with Cognition, Neuronal Markers and Peripheral Inflammation after Chemotherapy for Breast Cancer

by Gwen Schroyen, Jeroen Blommaert, Donatienne van Weehaeghe, Charlotte Sleurs, Mathieu Vandenbulcke, Nina Dedoncker, Sigrid Hatse, An Goris, Michel Koole, Ann Smeets, Koen van Laere, Stefan Sunaert and Sabine Deprez

Cancers 2021, 13(16), 4198; https://doi.org/10.3390/cancers13164198 - 20 Aug 2021

Cited by 29 | Viewed by 4298 | Correction

Abstract

To uncover mechanisms underlying chemotherapy-induced cognitive impairment in breast cancer, we studied new biomarkers of neuroinflammation and neuronal survival. This cohort study included 74 women (47 ± 10 years) from 22 October 2017 until 20 August 2020. Nineteen chemotherapy-treated and 18 chemotherapy-naïve patients with breast cancer were assessed one month after the completion of surgery and/or chemotherapy, and 37 healthy controls were included. Assessments included neuropsychological testing, questionnaires, blood sampling for 17 inflammatory and two neuronal survival markers (neurofilament light-chain (NfL), and brain-derived neurotrophic factor (BDNF) and PET-MR neuroimaging. To investigate neuroinflammation, translocator protein (TSPO) [¹⁸F]DPA714-PET-MR was acquired for 15 participants per group, and evaluated by volume of distribution normalized to the cerebellum. Chemotherapy-treated patients showed higher TSPO expression, indicative for neuroinflammation, in the occipital and parietal lobe when compared to healthy controls or chemotherapy-naïve patients. After partial-volume correction, differences with healthy controls persisted (p_FWE < 0.05). Additionally, compared to healthy- or chemotherapy-naïve controls, cognitive impairment (17–22%) and altered levels in blood markers (F ≥ 3.7, p ≤ 0.031) were found in chemotherapy-treated patients. NfL, an axonal damage marker, was particularly sensitive in differentiating groups (F = 105, p = 4.2 × 10 ⁻²¹), with levels 20-fold higher in chemotherapy-treated patients. Lastly, in chemotherapy-treated patients alone, higher local TSPO expression was associated with worse cognitive performance, higher blood levels of BDNF/NfL, and decreased fiber cross-section in the corpus callosum (p_FWE < 0.05). These findings suggest that increased neuroinflammation is associated with chemotherapy-related cognitive impairment in breast cancer. Additionally, NfL could be a useful biomarker to assess neurotoxic effects of anticancer chemotherapies. Full article

(This article belongs to the Special Issue Neurobiological Impacts of Cancer and Cancer Treatments: Mechanisms, Risk Factors, Biomarkers, and Prevention/Recovery)

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27 pages, 79533 KiB

Open AccessArticle

The Prostate Cancer Therapy Enzalutamide Compared with Abiraterone Acetate/Prednisone Impacts Motivation for Exploration, Spatial Learning and Alters Dopaminergic Transmission in Aged Castrated Mice

by Celeste Nicola, Martine Dubois, Cynthia Campart, Tareq Al Sagheer, Laurence Desrues, Damien Schapman, Ludovic Galas, Marie Lange, Florence Joly and Hélène Castel

Cancers 2021, 13(14), 3518; https://doi.org/10.3390/cancers13143518 - 14 Jul 2021

Cited by 5 | Viewed by 3452

Abstract

Cognitive side effects after cancer treatment threatening quality of life (QoL) constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are examples of next-generation therapy (NGT) administered to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment were reported. We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ for 5 days per week for six consecutive weeks. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH⁺-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus highlighted ENZ-induced dopaminergic regulation within the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN⁺-neurons in the dorsal hippocampus. The consequences of the mCRPC treatment ENZ on aged castrated mouse motivation to exploration and cognition should make reconsider management strategy of elderly prostate cancer patients. Full article

(This article belongs to the Special Issue Neurobiological Impacts of Cancer and Cancer Treatments: Mechanisms, Risk Factors, Biomarkers, and Prevention/Recovery)

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14 pages, 8757 KiB

Open AccessArticle

Age- and Intravenous Methotrexate-Associated Leukoencephalopathy and Its Neurological Impact in Pediatric Patients with Lymphoblastic Leukemia

by Ilona Rijmenams, Daan Moechars, Anne Uyttebroeck, Ahmed Radwan, Jeroen Blommaert, Sabine Deprez, Stefan Sunaert, Heidi Segers, Céline R. Gillebert, Jurgen Lemiere and Charlotte Sleurs

Cancers 2021, 13(8), 1939; https://doi.org/10.3390/cancers13081939 - 16 Apr 2021

Cited by 8 | Viewed by 2952

Abstract

Methotrexate (MTX) is associated with leukoencephalopathy (LE) in children treated for lymphoblastic leukemia/lymphoma (ALL/LBL). However, large-scale studies with systematic MR acquisition and quantitative volumetric lesion information remain limited. Hence, the prevalence of lesion burdens and the potential risk factors of LE in this population are still inconclusive. FLAIR-MRI scans were acquired at the end of treatment in children who were treated for ALL/LBL, which were quantitatively analyzed for LE. Voxels were assigned to the lesion segmentation if indicated by two raters. Logistic and linear regression models were used to test whether lesion presence and size were predicted by risk factors such as age at diagnosis, gender, intrathecal (IT-) or intravenous (IV-)MTX dose, CNS invasion, and acute neurological events. Patients with a pre-existing neurological condition or low-quality MR scan were excluded from the analyses. Of the 129 patients, ten (8%) suffered from CNS invasion. Chemotherapy-associated neurological events were observed in 13 patients (10%) during therapy, and 68 patients (53%) showed LE post-treatment. LE was more frequent in cases of lower age and higher cumulative IV-MTX doses, while the extent of LE and neurological symptoms were associated only with IV-MTX doses. Neurological events were not significantly associated with LE, even though symptomatic patients demonstrated a higher ratio of LE (n = 9/13) than asymptomatic patients (n = 59/116). This study suggests leukoencephalopathy frequently occurs in both symptomatic and asymptomatic leukemia patients. Younger children and patients treated with higher cumulative IV-MTX doses might need more regular screening for early detection and follow-up of associated sequelae. Full article

(This article belongs to the Special Issue Neurobiological Impacts of Cancer and Cancer Treatments: Mechanisms, Risk Factors, Biomarkers, and Prevention/Recovery)

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Review

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27 pages, 2681 KiB

Open AccessReview

Episodic Memory and Recollection Network Disruptions Following Chemotherapy Treatment in Breast Cancer Survivors: A Review of Neuroimaging Findings

by Meenakshie Bradley-Garcia, Gordon Winocur and Melanie J. Sekeres

Cancers 2022, 14(19), 4752; https://doi.org/10.3390/cancers14194752 - 29 Sep 2022

Cited by 1 | Viewed by 2110

Abstract

Long-term memory disturbances are amongst the most common and disruptive cognitive symptoms experienced by breast cancer survivors following chemotherapy. To date, most clinical assessments of long-term memory dysfunction in breast cancer survivors have utilized basic verbal and visual memory tasks that do not capture the complexities of everyday event memories. Complex event memories, including episodic memory and autobiographical memory, critically rely on hippocampal processing for encoding and retrieval. Systemic chemotherapy treatments used in breast cancer commonly cause neurotoxicity within the hippocampus, thereby creating a vulnerability to memory impairment. We review structural and functional neuroimaging studies that have identified disruptions in the recollection network and related episodic memory impairments in chemotherapy-treated breast cancer survivors, and argue for the need to better characterize hippocampally mediated memory dysfunction following chemotherapy treatments. Given the importance of autobiographical memory for a person’s sense of identity, ability to plan for the future, and general functioning, under-appreciation of how this type of memory is impacted by cancer treatment can lead to overlooking or minimizing the negative experiences of breast cancer survivors, and neglecting a cognitive domain that may benefit from intervention strategies. Full article

(This article belongs to the Special Issue Neurobiological Impacts of Cancer and Cancer Treatments: Mechanisms, Risk Factors, Biomarkers, and Prevention/Recovery)

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