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Children with cancer often endure a range of psychoneurological symptoms (PNS), including pain, fatigue, cognitive impairment, anxiety, depressive symptoms, and sleep disturbance. Despite their prevalence, the underlying pathophysiology of PNS remains unclear. Hypotheses suggest an interplay between the gut microbiome and the functional metabolome, given the immune, neurological, and inflammatory influences these processes exert. This mini-review aims to provide a synopsis of the literature that examines the relationship between microbiome-metabolome pathways and PNS in children with cancer, drawing insights from the adult population when applicable. While there is limited microbiome research in the pediatric population, promising results in adult cancer patients include an association between lower microbial diversity and compositional changes, including decreased abundance of the beneficial microbes Fusicatenibacter, Ruminococcus, and Odoribacter, and more PNS. In pediatric patients, associations between peptide, tryptophan, carnitine shuttle, and gut microbial metabolism pathways and PNS outcomes were found. Utilizing multi-omics methods that combine microbiome and metabolome analyses provide insights into the functional capacity of microbiomes and their associated microbial metabolites. In children with cancer receiving chemotherapy, increased abundances of Intestinibacter and Megasphaera correlated with six metabolic pathways, notably carnitine shuttle and tryptophan metabolism. Interventions that target the underlying microbiome-metabolome pathway may be effective in reducing PNS, including the use of pre- and probiotics, fecal microbiome transplantation, dietary modifications, and increased physical activity. Future multi-omics research is needed to corroborate the associations between the microbiome, metabolome, and PNS outcomes in the pediatric oncology population.

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INTRODUCTION: Colorectal cancer (CRC) survivors often experience neuropsychological symptoms, including anxiety and depression. Mounting evidence suggests a role for the kynurenine pathway in these symptoms due to potential neuroprotective and neurotoxic roles of involved metabolites. However, evidence remains inconclusive and insufficient in cancer survivors. Thus, we aimed to explore longitudinal associations of plasma tryptophan, kynurenines, and their established ratios with anxiety and depression in CRC survivors up to 12 months post-treatment. METHODS: In 249 stage I-III CRC survivors, blood samples were collected at 6 weeks, 6 months, and 12 months post-treatment to analyze plasma concentrations of tryptophan and kynurenines using liquid-chromatography tandem-mass spectrometry (LC/MS-MS). At the same timepoints, anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). Confounder-adjusted linear mixed models were used to analyze longitudinal associations. Sensitivity analyses with false discovery rate (FDR) correction were conducted to adjust for multiple testing. RESULTS: Higher plasma tryptophan concentrations were associated with lower depression scores (ß as change in depression score per 1 SD increase in the ln-transformed kynurenine concentration: -0.31; 95%CI: -0.56,-0.05), and higher plasma 3-hydroxyanthranilic acid concentrations with lower anxiety scores (-0.26; -0.52,-0.01). A higher 3-hydroxykynurenine ratio (HKr; the ratio of 3-hydroxykynurenine to the sum of kynurenic acid, xanthurenic acid, anthranilic acid, and 3-hydroxyanthranilic acid) was associated with higher depression scores (0.34; 0.04,0.63) and higher total anxiety and depression scores (0.53; 0.02,1.04). Overall associations appeared to be mainly driven by inter-individual associations, which were statistically significant for tryptophan with depression (-0.60; -1.12,-0.09), xanthurenic acid with total anxiety and depression (-1.04; -1.99,-0.10), anxiety (-0.51; -1.01,-0.01), and depression (-0.56; -1.08,-0.05), and kynurenic-acid-to-quinolinic-acid ratio with depression (-0.47; -0.93,-0.01). In sensitivity analyses, associations did not remain statistically significant after FDR adjustment. CONCLUSION: We observed that plasma concentrations of tryptophan, 3-hydroxyanthranilic acid, xanthurenic acid, 3-hydroxykynurenine ratio, and kynurenic-acid-to-quinolinic-acid ratio tended to be longitudinally associated with anxiety and depression in CRC survivors up to 12 months post-treatment. Future studies are warranted to further elucidate the association of plasma kynurenines with anxiety and depression.

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PURPOSE: Anxiety, depression, sleep disorder, fatigue, and pain develop as common psychoneurological symptoms in patients with glioma, and their occurrence and development are potentially related to inflammatory factors. However, this theory has not been proven within the context of glioma. This study aimed to estimate interconnections among psychoneurological symptoms and inflammatory biomarkers by a network analysis. PATIENTS AND METHODS: We selected 203 patients with stage I-IV glioma from a tertiary hospital in China using convenient sampling method. Patients completed the self-made questionnaires, Hamilton Anxiety Scale-14 (HAMA-14), Hamilton Depression Scale-24 (HAMD-24), Pittsburgh Sleep Quality Index (PSQI), Multidimensional Fatigue Inventory-20 (MFI-20), and pain Numerical Rating Scale (NRS). The plasma inflammatory cytokines were examined. Partial correlation network analysis was performed to illustrate interactions of symptoms and inflammatory biomarkers. RESULTS: Among the 203 included patients, all psychoneurological symptoms, except for depression and pain, exhibited significant connections with each other. Depression, anxiety, fatigue, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) with higher strength centrality indices were identified as the most central node within the symptom-biomarker network. CONCLUSIONS: Depression, anxiety, fatigue, IL-6, and TNF-α play a significant role in the symptom-biomarker network in patients with glioma. Medical staff should strengthen the dynamic evaluation of the involved symptoms and inflammatory cytokines and take effective measures to alleviate the burden of symptoms and improve the quality of life of patients.

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PURPOSE: In cancer patients, stress is associated with a psychoneurologic (PN) symptom cluster of depressed mood, anxiety, pain, fatigue, and sleep disturbance. The stress of caregiving may trigger similar symptoms among caregivers and warrants investigation. The purpose of this analysis was to characterize correlates of PN symptom burden in cancer caregivers. METHODS: Cancer patient-caregiver dyads (n = 29) provided eight weekly symptom reports using a web-based survey. Primary and secondary stressors of caregiving were also assessed. Mixed models accounting for repeated measurement were used to assess the between- and within-dyad predictors of caregiver PN symptom burden. The interaction of patient PN symptom burden and stress was tested. Exploratory cross-lagged Actor-Partner Interdependence Models were used to assess the week-to-week interdependence between patient and caregiver symptoms. RESULTS: Caregivers most frequently reported feeling anxious (44% on average across timepoints), sleep problems (31%), fatigue (25%), and depressed mood (24%). Mixed models indicated that within dyads, greater hours of care and more patient symptoms were associated with greater caregiver PN symptom burden. Greater baseline perceived stress was also associated with higher caregiver PN symptom burden and moderated the association between patient and caregiver PN symptom burden. Cross-lagged Actor-Partner Interdependence Models indicated longitudinal interdependence among survivor and caregiver symptom burden. CONCLUSIONS: The findings provide preliminary evidence of the interrelationship of PN symptom burden in caregivers and patients and the potential for stress to amplify this interrelationship, with implications for symptom management and supportive care practice.

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OBJECTIVE: Approximately 24-68% of breast cancer survivors report co-occurring psychoneurological symptoms of pain, fatigue, sleep disturbance, depression, and anxiety during and after cancer treatment. This study aimed to assess the feasibility and acceptability of acupuncture for the treatment of multiple psychoneurological symptoms among breast cancer survivors and explore metabolomic changes before and after acupuncture. METHODS: We conducted a single-arm, prospective pilot study of breast cancer survivors with at least two moderate to severe psychoneurological symptoms (>3 on a 0-10 scale). Acupuncture was administered twice weekly for 5 weeks, for 30 minutes per session. Along with Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires, a fasting serum comprehensive hydrophilic metabolites panel was analyzed at baseline and after acupuncture. RESULTS: Eight participants (mean age 52.5 ± 10.9 years; 62.5% Black) were enrolled. Feasibility was supported, with 67% recruitment, 87.5% retention, and 98% acceptability. Post intervention, PROMIS T-scores were reduced for all psychoneurological symptoms. Significant differences in serum metabolites before and after acupuncture were F-1,6/2,6-DP, glutathione disulfide, phosphorylcholine, 6-methylnicotinamide, glutathione, and putrescine (variable importance of projection values larger than 1.5 and p values <0.05). Pathway analysis indicated that glutathione metabolism (p = 0.002, q = 0.071), and arginine and proline metabolisms (p = 0.009, q = 0.166) were potentially involved in mechanisms of acupuncture. CONCLUSIONS: Acupuncture to reduce multiple psychoneurological symptoms among breast cancer survivors was feasible and acceptable. Study findings also shed light on the metabolic pathways involved in the acupuncture response and will be tested in future studies.

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BACKGROUND: Among breast cancer survivors, pain, fatigue, depression, anxiety, and sleep disturbance are common psychoneurological symptoms that cluster together. Inflammation-induced activation of the tryptophan-kynurenine metabolomic pathway may play an important role in these symptoms. AIMS: This study investigated the relationship between the metabolites involved in the tryptophan-kynurenine pathway and psychoneurological symptoms among breast cancer survivors. DESIGN: Cross-sectional study. SETTING: Participants were recruited at the oncology clinic at the University of Illinois Hospital & Health Sciences System. PARTICIPANTS/SUBJECTS: 79 breast cancer survivors after major cancer treatment. METHODS: We assessed psychoneurological symptoms with the PROMIS-29 and collected metabolites from fasting blood among breast cancer survivors after major cancer treatment, then analyzed four major metabolites involved in the tryptophankynurenine pathway (tryptophan, kynurenine, kynurenic acid, and quinolinic acid). Latent profile analysis identified subgroups based on the five psychoneurological symptoms. Mann-Whitney U tests and multivariable logistic regression compared targeted metabolites between subgroups. RESULTS: We identified two distinct symptom subgroups (low, 81%; high, 19%). Compared with participants in the low symptom subgroup, patients in the high symptom subgroup had higher BMI (p = .024) and were currently using antidepressants (p = .008). Using multivariable analysis, lower tryptophan levels (p = .019) and higher kynurenine/tryptophan ratio (p = .028) were associated with increased risk of being in the high symptom subgroup after adjusting for BMI and antidepressant status. CONCLUSION: The tryptophan-kynurenine pathway and impaired tryptophan availability may contribute to the development of psychoneurological symptoms.

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PURPOSE: The epigenetic clock has been acknowledged as an indicator for molecular aging, but few studies have examined possible associations of DNA methylation (DNAm) age or age acceleration (AA) with symptom burden in individuals who are treated for cancer. This study explored the association of DNAm age or AA with psychoneurological (PN) symptoms, including cognitive impairment, fatigue, sleep disturbances, pain, and depressive symptoms, in breast cancer survivors over a 2-year period. METHODS: We measured PN symptoms using reliable instruments and DNAm levels by Infinium HumanMethylation450K BeadChip (N = 72). DNAm age was calculated by the Horvath, Grim, and Hannum-based intrinsic and extrinsic age estimations. AA was defined by the residual regressing estimated epigenetic age on chronological age. Mixed regression models were fitted for AA and changes in AA to study the association over time. Separate linear regression models and a mixed-effects model were fitted for AA at each time point. RESULTS: Horvath-AA, Grim-AA, and extrinsic epigenetic AA were significantly changed over time, while intrinsic epigenetic AA did not exhibit any temporal changes. Increased AA was associated with greater anxiety and fatigue, as well as worse cognitive memory, adjusting for race, BMI, income, chemotherapy, radiation therapy, and chronological age. Increased DNAm age was associated with greater anxiety over 2 years. CONCLUSION: Our findings suggest DNAm age and AA may be associated with PN symptoms over the course of cancer treatment and survivorship. Some PN symptoms may be amenable to preventive interventions targeted to epigenetic clocks that influence aging-associated processes.

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INTRODUCTION: Emerging evidence highlights the roles the gut microbiome and the immune system, integral parts of the gut-brain axis, play in developing various symptoms in cancer patients. The purpose of this systematic review was to describe the roles of inflammatory markers and the gut microbiome, as well as to describe their associations with psychoneurological symptoms and gastrointestinal toxicities in women with gynecologic cancers. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Web of Science from January 2000 to February 2021. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were utilized to screen the found articles. The quality of the included studies was assessed using the Mixed Method Assessment Tool. In the included studies, various inflammatory markers and gut microbiome diversity and patterns were measured. RESULTS: Sixteen studies met the eligibility criteria and were included in this systematic review. While there were discrepancies in the associations between various inflammatory markers and symptoms, most of the studies showed positive correlations between interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) and cancer-related psychoneurological symptoms and gastrointestinal toxicities in gynecologic cancer patients. Although there was no consensus in alpha diversity, studies showed significant dissimilarity in the microbial communities (beta diversity) in patients with gastrointestinal toxicities compared with patients without symptoms or healthy controls. Studies also reported inconsistent findings in the abundance of bacteria at different taxonomic levels. Radiation enteritis-derived microbiota could stimulate TNF-α and interleukin 1 beta (IL-1ß) secretion. CONCLUSIONS: Alteration of inflammatory markers, the gut microbiome, and their associations show emerging evidence in the development of psychoneurological symptoms and gastrointestinal toxicities in women with gynecologic cancers. More studies on the interactions between the immune system and the gut microbiome, two integral parts of the gut-brain axis, are required to shed light on the roles they play in symptom development.

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CONTEXT: Children with cancer undergoing chemotherapy experience a cluster of psychoneurological symptoms (PNS), including pain, fatigue, anxiety, and depressive symptoms. Metabolomics is promising to differentiate metabolic pathways associated with the PNS cluster. OBJECTIVES: Identify metabolic pathways associated with the PNS cluster in children with cancer before and after chemotherapy. METHODS: Pain, fatigue, anxiety, and depressive symptoms were assessed using the Pediatric PROMIS scales. T-scores were computed and divided dichotomously by a cutoff point of 50; the PNS cluster was a sum of the four symptoms ranging from 0 (all T-scores <50) to 4 (all T-scores ≥50). Serum metabolites were processed using liquid chromatography mass-spectrometry untargeted metabolomics approach. Linear regression models examined metabolites associated with the PNS cluster. Metabolic pathway enrichment analysis was performed. RESULTS: Participant demographics (n = 40) were 55% female, 60% white, 62.5% aged 13-19 years, and 62.5% diagnoses of Hodgkin's lymphoma and B-cell acute lymphocytic leukemia. Among 9276 unique metabolic features, 454 were associated with pain, 281 with fatigue, 596 with anxiety, 551 with depressive symptoms, and 300 with the PNS cluster across one chemotherapy cycle. Fatty acids pathways were associated with pain: de novo fatty acid biosynthesis (p < .001), fatty acid metabolism (p = .001), fatty acid activation (p = .004), and omega-3 fatty acid metabolism (p = .009). Tryptophan amino acid pathway was associated with fatigue (p < .001), anxiety (p = .015), and the PNS cluster (p = .037). Carnitine shuttle was associated with the PNS cluster (p = .015). CONCLUSION: Fatty acids and amino acids pathways were associated with PNS in children undergoing chemotherapy. These findings require further investigation in a larger sample.

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Breast cancer is one of the most prevalent cancers in women. The improvement in breast cancer treatment has significantly increased the proportion of survival rate for women with breast cancer. Despite the advancement in breast cancer treatment, a great proportion of survivors suffer from co-occurring psychoneurological symptoms which impact their quality of life. The most frequently reported psychoneurological symptoms among women with breast cancer are depressive symptoms, anxiety, fatigue, sleep disturbances, and pain. These symptoms usually appear as a cluster. Inflammatory activation and serum metabolic alterations have been associated with the etiology of cancer and with various chronic neurocognitive disorders. However, to date, no studies considered the combined effects of inflammatory markers and metabolites in the development of psychoneurological symptoms in women with breast cancer especially those who were treated with chemotherapy. Further clarification of the relationships between the inflammatory markers, serum metabolic alterations, and psychoneurological symptoms in women with breast cancer should be pursued.

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PURPOSE: The microbiome-gut-brain (MGB) axis provides a dynamic model to understand associations between the gut microbiota and psychoneurological comorbidities. The role of the MGB axis in cancer treatment-related psychoneurological symptoms (PNS) remains unknown. The purpose of this study was to conduct a systematic review of the existing literature to identify the influence of the gut microbiota on cancer and cancer treatment-related PNS and toxicities mediated by the MGB axis. METHODS: We searched the databases of PubMed, Embase, and Web of Science from their earliest records to October 2019. All studies identified in the database searches were screened by title and abstract, followed by a review of the full texts. The Johns Hopkins Nursing Evidence-Based Practice Model was adopted to assess the evidence levels and qualities; the Joanna Briggs Institute critical appraisal tools were used to assess the methodological quality and the possibility of bias for each included study. All the study findings were combined, synthesized, and presented through narrative format. RESULTS: Six studies were included in this systematic review. These studies primarily focused on cancer survivorship while receiving chemotherapy, and they were conducted between 2016 and 2019. The gut microbiome was assessed via fecal samples, which were analyzed using 16S rRNA sequencing approaches. With small-scale studies, the gut microbiota was associated with cancer treatment-related PNS, including fatigue, anxiety, depression, sleep disturbance, cognitive impairment, and chemotherapy-induced peripheral neuropathy. A higher relative abundance of Bacteroides was associated with a higher level of fear of cancer recurrence but a higher relative abundance of Lachnospiraceae.g and Ruminococcus was associated with a lower level in fear of cancer recurrence. Changes in fatigue interference were associated with the frequency of genera Faecalibacterium and Prevotella, and changes in anxiety were associated with the frequency of genera Coprococcus and Bacteroides. CONCLUSIONS: The gut microbiota showed significant associations with cancer treatment-related PNS. Recent work regarding the MGB axis in cancer psychoneurological toxicities focused primarily on individual toxicity and symptoms in cancer survivors with chemotherapy exposure. Associations between the gut microbiota and PNS should be further studied in cancer populations across different ages, cancer types, and treatment modalities.

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Cancer patients experience a cluster of co-occurring psychoneurological symptoms (PNS) related to cancer treatments. The gut microbiome may affect severity of the PNS via neural, immune, and endocrine signaling pathways. However, the link between the gut microbiome and PNS has not been well investigated in cancer patients, including those with head and neck cancers (HNCs). This pilot study enrolled 13 patients with HNCs, who reported PNS using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (CTCAEs). Stool specimens were collected to analyze patients' gut microbiome. All data were collected pre- and post-radiation therapy (RT). Associations between the bacterial abundances and the PNS clusters were analyzed using the linear discriminant analysis effect size; functional pathway analyses of 16S rRNA V3-V4 bacterial communities were conducted using Tax4fun. The high PNS cluster had a greater decrease in microbial evenness than the low PNS cluster from pre- to post-RT. The high and low PNS clusters showed significant differences using weighted UniFrac distance. Those individuals with the high PNS cluster were more likely to have higher abundances in phylum Bacteroidetes, order Bacteroidales, class Bacteroidia, and four genera (Ruminiclostridium9, Tyzzerella, Eubacterium_fissicatena, and DTU089), while the low PNS cluster had higher abundances in family Acidaminococcaceae and three genera (Lactococcus, Phascolarctobacterium, and Desulfovibrio). Both glycan metabolism (Lipopolysaccharide biosynthesis) and vitamin metabolism (folate biosynthesis and lipoic acid metabolism) were significantly different between the high and low PNS clusters pre- and post-RT. Our preliminary data suggest that the diversity and abundance of the gut microbiome play a potential role in developing PNS among cancer patients.

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PURPOSE: Psychoneurological (PN) symptoms, such as anxiety, cognitive impairment, depression, fatigue, sleep disturbances, and pain, are highly prevalent in breast cancer patients undergoing cancer treatment. Emerging evidence suggests that genetic polymorphisms may contribute to differential symptom susceptibility. We aimed to systematically review associations between genetic polymorphisms and PN symptoms during or after cancer treatment for early-stage breast cancer. METHODS: Twenty-six eligible articles published until October 2017 were identified in PubMed, PsycINFO, Web of Science, and additional records. Information on study characteristics, genetic polymorphisms, and PN symptoms was extracted. Study quality was evaluated by the STrengthening the REporting of Genetic Association (STREGA) guideline. Genes included in the analysis were categorized by biological pathways based on the Reactome database. RESULTS: A total of 54 single nucleotide polymorphisms and haplotypes that are significantly associated with PN symptoms were identified; half of them were associated with increased severity of PN symptoms, while the other half contributed to the decrease of PN symptoms. Pain has the known highest number of associated genetic polymorphisms reported, followed by fatigue, cognitive impairment, depressive symptoms, sleep disturbances, and anxiety. The majority of genetic polymorphisms were involved in immune system and neuronal system pathways. Most studies were unsuccessful in meeting the STREGA guideline, which requires transparent reporting of methods and results. CONCLUSIONS: This review provides comprehensive evidence of genetic polymorphisms underlying PN symptoms, which may pave the way for the development of personalized therapeutics targeting these symptoms. More well-designed genome-wide association studies are required to validate and replicate these findings.

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PURPOSE: The gut microbiome plays a critical role in maintaining children's health and in preventing and treating children's disease. Current application of the gut microbiome in childhood cancer is still lacking. This study aimed to systematically review the following: (1) alternations in the gut microbiome throughout cancer treatment trajectories in children, (2) the associations between the gut microbiome and gastrointestinal (GI) symptoms and psychoneurological symptoms (PNS), and (3) the efficacy of therapeutic interventions in the gut microbiome in children with cancer. METHODS: PubMed, EMBASE, the Cochrane Library, and the American Society of Clinical Oncology abstract were searched. Eligible studies included all study types in which the gut microbiome was primarily reported in children with cancer. The Mixed Methods Assessment Tool was used to evaluate the methodology quality of included studies. Seven studies met our eligibility criteria, including two cohort studies, two case-control studies, and three randomized controlled trails. RESULTS: The findings showed that the diversity estimates of the gut microbiome in children with cancer were lower than those of healthy controls both pre- and post-treatment. Children with cancer showed a significantly lower relative abundance of healthy gut microbiome (e.g., Clostridium XIVa and Bifidobacterium) during and after cancer treatment. No adequate literature was identified to support the associations between dysbiosis of the gut microbiome and GI symptoms/PNS. The use of prebiotics (fructooligosaccharides) and probiotics (Bifidobacterium or Lactobacilli) appears to improve the microenvironment of the gut around 1 month (4-5 weeks) during chemotherapy rather than at the beginning of treatment. Data also suggest that both prebiotic and probiotic interventions decrease clinical side effects (e.g., infection and morbidity risk) in children with cancer. CONCLUSIONS: This study adds to the evidence that dysbiosis of the gut microbiome can be improved using prebiotic and probiotic supplementations in children with cancer. More well-designed experimental studies are needed to confirm this conclusion. Further studies are needed to examine the associations between the gut microbiome and GI symptoms/PNS in childhood cancer.

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PURPOSE: The aim of the present study was to explore clusters of psychoneurological symptoms and inflammation (levels of C-reactive protein) over time in a cohort of women with early-stage breast cancer. Specifically, we examined the relationships among affective symptoms (depression, anxiety, fatigue, sleep disturbances, pain, and perceived stress), domains of cognitive performance, and levels of peripheral C-reactive over a period of 2 years. METHODS: This was a prospective, longitudinal study of 77 women diagnosed with early-stage breast cancer. Data collection, including symptom questionnaires, performance-based cognitive testing, and blood draws, took place at 5 time points: prior to initiating adjuvant chemotherapy, prior to the fourth chemotherapy treatment, and at 6, 12, and 24 months after the initiation of chemotherapy. RESULTS: Exploratory factor analysis with varimax orthogonal rotation was used to examine the covariance among symptoms at each visit. Using the factor scores and weighted sums, three clusters were identified: global cognition, affective symptoms, and cognitive efficiency. Peripheral levels of C-reactive protein were inversely correlated with the cognitive efficiency factor across time. CONCLUSIONS: The findings suggest that objectively measured domains of cognitive function occur independently of other affective symptoms that are commonly reported by women with breast cancer in long-term survivorship. The cognitive efficiency symptom cluster may be amenable to interventions targeted to biological influences that reduce levels of C-reactive protein.

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Personalized medicine applies knowledge about the patient's individual characteristics in relation to health and intervention outcomes, including treatment response and adverse side-effects, to develop a tailored treatment plan. For women with breast cancer, personalized medicine has substantially improved the rate of survival, however, a high proportion of these women report multiple, co-occurring psychoneurological symptoms over the treatment trajectory that adversely affect their quality of life. In a subset of these women, co-occurring symptoms referred to as symptoms clusters, can persist long after treatment has ended. Over the past decade, research from the field of nursing and other health sciences has specifically examined the potential underlying mechanisms of the psychoneurological symptom cluster in women with breast cancer. Recent findings suggest that epigenetic and genomic factors contribute to inter-individual variability in the experience of psychoneurological symptoms during and after breast cancer treatment. While nursing research has been underrepresented in the field of personalized medicine, these studies represent a shared goal; that is, to improve patient outcomes by considering the individual's risk of short- and long-term adverse symptoms. The aim of this paper is to introduce a conceptual model of the individual variations that influence psychoneurological symptoms in women with breast cancer, including perceived stress, hypothalamic-pituitary adrenocortical axis dysfunction, inflammation, as well as epigenetic and genomic factors. The proposed concepts will help bring nursing research and personalized medicine together, in hopes that this hitherto neglected and understudied area of biomedical research convergence may ultimately lead to the development of more targeted clinical nursing strategies in breast cancer patients with psychoneurological symptoms.

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AIMS: To examine how symptom cluster subgroups defined by extreme discordant composite scores, cut-off scores, or a median split influence statistical associations with peripheral cytokine levels in women with breast cancer. BACKGROUND: Systemic cytokine dysregulation has been posited as a potential biological mechanism underlying symptom clusters in women with breast cancer. Symptom characteristics may play an important role in identifying cytokines of significant etiological importance, however, there is no consensus regarding the ideal subgrouping technique to use. DESIGN: A secondary analysis of data collected from a cross-sectional descriptive study of women with stage I-II breast cancer was used to examine and compare the relationships between peripheral cytokine levels and symptom subgroups defined by extreme discordant composite scores, cut-off scores, or a median split. METHODS: Participant symptom scores were transformed into a composite score to account for variability in symptom intensity, frequency and interference. Cytokine levels in subgroups defined by composite scores within the highest and lowest 20% were contrasted with those composed from cut-off scores and a median split. RESULTS: Subgroups defined by the composite score or cut-off scores resulted in similar statistical relationships with cytokine levels in contrast to the median split technique. The use of a median split for evaluating relationships between symptoms clusters and cytokine levels may increase the risk of a type I error. CONCLUSION: Composite and cut-off scores represent best techniques for defining symptom cluster subgroups in women with breast cancer. Using a consistent approach to defining symptom clusters across studies may assist in identifying relevant biological mechanisms.