Association of plasma leptin, pro-inflammatory adipokines and cancer-related fatigue in early-stage breast cancer patients: A prospective cohort study.

Cancer-related fatigue (CRF) is subjective and has wide inter-individual variability. Given that leptin is commonly associated with fatigue syndrome, its use as a potential biomarker for CRF is being investigated. The primary objective of this study was to evaluate the association between leptin and CRF in early-stage breast cancer patients receiving chemotherapy. In a prospective cohort study, patients completed assessments at baseline (T1), during chemotherapy (T2) and after chemotherapy (T3). Levels of plasma leptin and adipokines were measured using a Luminex bead-immunoassay and CRF was measured using the Multi-Dimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). Data were analysed longitudinally using a generalised estimating equation incorporating clinically relevant parameters and pro-inflammatory adipokines. The analysis included 136 patients (mean age ± SD = 51.5 ± 8.8 years; 69.1% receiving anthracycline-based chemotherapy). More patients experienced CRF at T3 (23.8%) than at T2 (13.8%) compared to baseline. An increase was observed in the median plasma leptin level at T2, followed by a decrease at T3 (T1: 4.07 ng/mL, T2: 4.95 ng/mL and T3: 3.96 ng/mL). In the multivariate model, the change in leptin levels over time was significantly associated with the total MFSI-SF score (ß = -0.15, P = 0.003) after adjusting for the tumour necrosis factor-α (TNF-α) level, anxiety, depression, insomnia, age, menopausal status and type of chemotherapy. This is the first study to report leptin as a biomarker that predicts the onset of CRF over time. Future studies are required to validate the findings.

Association of mitochondrial DNA content in peripheral blood with cancer-related fatigue and chemotherapy-related cognitive impairment in early-stage breast cancer patients: a prospective cohort study.

PURPOSE: Cancer-related fatigue (CRF) and chemotherapy-related cognitive impairment (CRCI) are reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF and CRCI. This study aims to evaluate the association between peripheral blood mtDNA content reduction and severity of CRF and CRCI in patients receiving chemotherapy. METHODS: This was a prospective cohort study. Early-stage breast cancer patients receiving anthracycline- or taxane-based chemotherapy were recruited. CRF was assessed using MFSI-SF, and CRCI was assessed using FACT-Cog and CANTAB at two timepoints: baseline (T1; prior to treatment) and 6 weeks after initiation of treatment (T2). mtDNA content was measured at both timepoints using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluate the association between mtDNA reduction and worsening of CRF and CRCI, adjusting for age, anxiety, insomnia, plasma cytokines concentrations, and other clinically important covariates. RESULTS: A total of 108 patients (age 52.0 ± 9.2 years; 82.4% Chinese; 64.8% receiving anthracycline-based chemotherapy) were recruited. Proportions of patients with worsening of CRF increased from the lower to the upper quartiles of mtDNA reduction (22.2, 33.3, 55.6, and 63.0% in quartiles 1, 2, 3, and 4, respectively, p = 0.001 for trend). Reduction of mtDNA content was significantly greater among those with worsening of CRF and CRCI compared to those without CRF [mean reduction (± SD): 36.5 (46.1) vs. 9.4 (34.5), p < 0.001]. After adjusting for covariates, every 1-unit reduction of the mtDNA content was associated with a 4% increased risk for worsening of CRF (95% CI, 1-6%; p = 0.009). CONCLUSIONS: This is the first study to show that the reduction of mtDNA content in peripheral blood is associated with the onset of CRF in patients receiving chemotherapy. Further validation studies are required to confirm the findings.

Evaluation of plasma brain-derived neurotrophic factor levels and self-perceived cognitive impairment post-chemotherapy: a longitudinal study.

BACKGROUND: Preliminary evidence suggests that changes in plasma brain-derived neurotrophic factor (BDNF) levels may contribute to the occurrence of chemotherapy-associated cognitive impairment (CACI), and a previous study suggested that carriers of the BDNF Met homozygous genotype are protected from CACI. METHODS: This multicenter, prospective cohort study involved chemotherapy-receiving early-stage breast cancer (ESBC) patients. Self-perceived cognitive function was longitudinally assessed using the validated FACT-Cog (ver. 3) across three time points: Prior to chemotherapy (T1), during chemotherapy (T2), and at the end of chemotherapy (T3). Plasma BDNF levels were quantified using enzyme-linked immunosorbent assay. Genotyping was performed using Sanger Sequencing. RESULTS: A total of 51 chemotherapy-receiving ESBC patients (mean age: 52.6 ± 9.5 years) were recruited, and 11 patients (21.6%) reported subjective cognitive impairment post-chemotherapy. Overall, there was a reduction in median plasma BDNF levels over time (T1: 5423.0 pg/ml; T2: 5313.6 pg/ml; T3: 4050.3 pg/ml; p < 0.01). After adjusting for confounding factors, longitudinal analysis revealed that BDNF levels were associated with self-reported concentration deficit (p = 0.032). Carriers of Val/Val (p = 0.011) and Val/Met (p = 0.003) BDNF genotypes demonstrated a significant reduction in plasma BDNF levels over time; however, plasma BDNF levels were similar across all time points among Met homozygous carriers (p = 0.107). CONCLUSION: There was a statistically significant change in BDNF levels post-chemotherapy in ESBC patients, and plasma BDNF levels were associated with self-perceived concentration deficit in patients receiving chemotherapy.

Reporting adherence, validity and physical activity measures of wearable activity trackers in medical research: A systematic review.

BACKGROUND: Wearable activity trackers are gaining traction in medical research, providing both real-time and remote monitoring of physical fitness. Activity trackers offer an excellent source of personalized physical activity data from patients, as well as healthy individuals, that would provide insights into healthcare analytics and user-feedback on health status. In addition, these activity trackers would also allow researchers to monitor symptom severity and assist clinicians in providing their patients a more holistic care. Despite the promise of wearable device technology, there is still a lack of standardization in the medical literature regarding the analysis and reporting of adherence, validity and physical activity data generated by these activity trackers. OBJECTIVE: We performed a systematic review to identify the activity tracker-derived measures and evaluate the relations of reported adherence, validity, and physical activity types across currently available literature. METHODS: The searches were performed using Pubmed and Embase databases. Studies enrolling at least 1,000 human subjects regardless of health or disease status, using activity trackers of any brand used to track step count, distance, heart rate, energy expenditure or activity intensity, were included. Studies have been published between 2009 to March 2021, with editorials, systematic reviews, meta-analysis, grey literature, validation studies, study protocols and studies using smartphone trackers being excluded. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: A total of 27 studies met the eligibility criteria and were included in the review, with a total of 514,418 and 1,186,530 subjects recruited in observational and interventional studies, respectively. Apart from ActiGraph (n = 11, 41%), Fitbit (n = 4, 15%) and Axivity (n = 3, 11%) were found to be the most commonly used activity trackers in both types of studies. The wear duration of activity trackers ranged from 1 day to 59 months, with 1 week being the most common length (n = 16, 59%). The most frequently collected physical activity measure was activity intensity (n = 21, 78%), followed by step count (n = 9, 33%) and energy expenditure (n = 2, 7%). Most studies defined a valid day as wear-time of at least 10 h within 1 day (n = 10, 37%), and a valid interval as a week with at least 3 valid days (n = 8, 30%). CONCLUSIONS: This systematic review reveals the diverse analysis and reporting of activity tracker data in the medical literature. Future studies will need to evaluate the feasibility on adopting minimum reporting thresholds of data generated by wearable activity trackers.

Association of mitochondrial DNA content and displacement loop region sequence variations with cancer-related fatigue in breast cancer survivors receiving chemotherapy.

Cancer-related fatigue (CRF) is characterized by a lack of energy, and mitochondrial dysfunction is postulated to contribute to its etiology. This prospective cohort study assesses the self-reported fatigue levels of early-stage breast cancer patients using the validated Multi-Dimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) and blood samples drawn at three time points: before treatment, approximately 6 weeks, and 12 weeks after the initiation of chemotherapy. The aim of this study is to evaluate mitochondrial measures with CRF, over the course of chemotherapy using mitochondrial DNA (mtDNA content) and displacement loop (D-loop) region sequence variations at nucleotide positions 303, 489 and 514. The relative mtDNA copy number was determined via real-time quantitative polymerase chain reaction and compared between study time points and D-loop sequence variants. The association of mtDNA content with MFSI-SF total and sub-domain scores was analyzed in a sample of 155 patients (mean age ± SD: 51.7 ± 8.8 years). The median mtDNA content decreased over 12 weeks after the initiation of chemotherapy (p < 0.001). Baseline mtDNA content was lower for nucleotide position 303 in sequence variations than for the reference sequence (67.2 copies vs 79.1 copies, p = 0.03). Physical fatigue negatively correlated with mtDNA content in both unadjusted (ß = -0.0075, p = 0.048) and adjusted models (ß = -0.0062, p = 0.042), accounting for age, anxiety, insomnia, haemoglobin levels and body mass index. Our findings add to the literature indicating that mitochondrial function serves as an important target for mitigating CRF.

Prevalence of KRAS, BRAF, PI3K and EGFR mutations among Asian patients with metastatic colorectal cancer.

Mutations in oncogenes along the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the resistance to cetuximab in patients with metastatic colorectal cancer (mCRC). However, the relative significance of these mutations based on their frequencies of occurrence in the Singaporean population remains unclear. In the present study, the prevalence of Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), phosphoinositide 3-kinase (PI3K) and EGFR somatic mutations were determined among Singaporean patients with mCRC. DNA extracted from 45 pairs of surgically resected tumor and normal mucosa samples was subjected to direct sequencing or restriction fragment length polymorphism. Associations of the genetic mutations with various clinicopathological parameters were further explored. Mutations in either codon 12 or 13 of KRAS were confirmed as prominent phenomena among the included Singaporean mCRC patients, at a prevalence comparable with that of Caucasian and patients of other Asian ethnicities [33.3% (90% confidence interval, 21.8-44.9%)]. KRAS mutation was not associated with clinicopathological features, including age, gender and ethnicity of patients, or the tumor site, differentiation and mucinous status. Conversely, the prevalence of BRAF (0%), PI3K (2.2%) and EGFR (0%) mutations were low. The results of the present study indicate that KRAS mutations are prevalent among the studied population, and confirm the low prevalence of BRAF, PI3K and EGFR mutations. KRAS should be prioritized as an investigational gene for future studies of predictive biomarkers of cetuximab response among Singaporean patients with mCRC.

Current strategies for inhibiting FGFR activities in clinical applications: opportunities, challenges and toxicological considerations.

Aberrations in fibroblast growth factor receptor (FGFR) signaling are instrumental to the pathophysiology of several malignancies and disorders. Hence, FGFR inhibitors are explored in therapeutics with early candidates developed as competitors for the ATP-binding pocket in the kinase domain. More recent programs yielded compounds of diverse scaffolds with alternative binding modes. Concurrently, monoclonal antibodies and peptide-based agents provide independent options for clinical development. Notwithstanding this rapid progress, we contemplate the toxicological impact of FGFR inhibition based on the defined role of FGFR family members in physiology and homeostasis. The high homology among FGFR1-4 and also with other kinase subfamilies creates an additional challenge in developing selective inhibitors. It orchestrates an ongoing conundrum of moderating a balance between synergism through multitargeting kinase inhibition and minimizing off-target toxicities.