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.

Distinct and heterogeneous trajectories of self-perceived cognitive impairment among Asian breast cancer survivors.

OBJECTIVES: Currently, there are no studies that have established the self-perceived cognitive trajectories experienced by breast cancer patients (BCPs) post-chemotherapy. Therefore, we characterized the long-term trajectory of self-perceived cognitive function among Asian early-stage BCPs using the minimal clinically important difference of a subjective measure of cognitive function. METHODS: Early-stage BCPs who received chemotherapy were recruited and assessed at 4 time points: Before chemotherapy initiation (T1), 6 weeks post-chemotherapy initiation (T2), 12 weeks post-chemotherapy initiation (T3), and 15-months post-chemotherapy initiation (T4). All assessments were performed approximately within 2 weeks post-chemotherapy. Subjective and objective cognitive function were assessed using Functional Assessment of Cancer Therapy-Cognitive (version 3) and Headminder™. RESULTS: A total of 166 BCPs were recruited, of whom 131 completed assessment at all time points. Using the minimal clinically important difference of Functional Assessment of Cancer Therapy-Cognitive, 5 distinct cognitive trajectories were established. Of the 131 patients, 70 (53.4%) did not report any clinically significant cognitive impairment. Twenty-one (16.0%) patients reported acute cognitive changes during chemotherapy (T2 and/or T3) but not at T4. Forty patients (30.5%) reported clinically significant cognitive impairment at T4, of whom 18 did not report any cognitive impairment at earlier time points. Fifteen (11.5%) patients reported persistent cognitive impairment throughout all time points, while 7 (5.3%) patients reported intermittent cognitive impairment at T2 and T4 but not at T3. CONCLUSION: This is the first study to establish the existence of heterogeneous cognitive trajectories based on clinically significant thresholds of self-perceived cognitive impairment. The findings have important implications on the window for screening and management of post-chemotherapy cognitive impairment.

Development of a pharmacy educational environment questionnaire.

INTRODUCTION: A robust instrument for measuring the educational environment in a pharmacy patient care setting is currently lacking. The authors aimed to develop a person-reported outcome measure to gauge trainee pharmacists' perceptions of their clinical workplace-based educational environment. This paper reports the various sources of validity evidence. METHODS: A preliminary, three-domain (system, relationship, and personal), 36-item measurement instrument was developed by incorporating results from literature review, focus group interviews, iterative discussions among educators, and cognitive interviews. The preliminary instrument, together with the Dundee Ready Educational Environment Measure (DREEM) and Orientation to Happiness Scale (OHS), were administered to trainee pharmacists recruited from one pharmacy school and one healthcare cluster in Singapore. Rasch analysis was conducted on the overall instrument as well as three domains: System, Relationship, and Personal. RESULTS: The 36-item instrument was administered to 145 learners, of which 66 were trainee pharmacists and 79 undergraduate interns. Upon removal of the middle "neutral" category to resolve poorly functioning categories and removal of five poorly functioning items, the overall instrument and its domains generally showed good fit with the Rasch model. Moreover, the overall 31-item Singapore Pharmacy Educational Environment Questionnaire (SPEEQ) and its three domains showed moderate to high convergent correlation with all the five DREEM domains and low to non-significant divergent correlation with the OHS Pleasure of Life subscale. CONCLUSIONS: Among one sample of pharmacy trainees, the 31-item SPEEQ and its three component domains demonstrated notable validity evidence to gauge trainees' perceptions of their learning environment.

Brain-derived neurotrophic factor as a biomarker in cancer-related cognitive impairment among adolescent and young adult cancer patients.

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.

Cognitive impairment in adolescent and young adult cancer patients: Pre-treatment findings of a longitudinal study.

BACKGROUND: There is little information about cancer-related cognitive impairment (CRCI) in adolescent and young adults (AYA, 15-39 years old) due to its rare incidence. Here, we present the pre-treatment (before chemotherapy or radiotherapy) evaluation of cognitive function and ability of AYA with cancer (AYAC) in a multicentered cohort study. METHODS: Newly diagnosed AYAC and age-matched healthy controls (HC) were recruited between 2018 and 2021. The primary outcome was the comparison of pre-treatment cognitive impairment defined as 2 standard deviations (SDs) below the HC on ≥1 cognitive test, or >1.5 SDs below on ≥2 tests using CANTAB® between AYAC and HC. Secondary outcomes included self-perceived cognitive ability assessed by FACT-Cog v3 and biomarkers (inflammatory cytokines and brain-derived neurotrophic factor [BDNF]). RESULTS: We recruited 74 AYAC (median age = 34) and 118 HC (median age = 32). On objective cognitive testing, we observed three times more AYAC patients performed poorly on at least 2 cognitive tests compared to HC (40.5% vs. 13.6%, p < 0.001). AYAC self-perceived less degree of cognitive impairment than HC (p < 0.001). However, AYAC perceived a greater impact of cognitive changes on their quality of life compared to HC (p = 0.039). Elevated baseline inflammatory markers (IL-2, IL-4, IL-6, IL-8, IL-10 and IFN-γ) were observed among AYAC compared to HC, and baseline BDNF was lower in AYAC compared to HC. Interaction effects between cancer diagnosis and biomarkers were observed in predicting cognitive function. CONCLUSION: With the pre-existence of CRCI and risk factors of neuroinflammation even prior to systemic therapy, AYAC should receive early rehabilitation to prevent further deterioration of cognitive function after initiation of systemic therapies. (ClinicalTrials.gov Identifier: NCT03476070).

Anthracycline-Free Protocol for Favorable-Risk Childhood ALL: A Noninferiority Comparison Between Malaysia-Singapore ALL 2003 and ALL 2010 Studies.

PURPOSE: To investigate whether, for children with favorable-risk B-cell precursor ALL (BCP-ALL), an anthracycline-free protocol is noninferior to a modified Berlin-Frankfurt-Muenster ALL-IC2002 protocol, which includes 120 mg/m2 of anthracyclines. PATIENTS AND METHODS: Three hundred sixty-nine children with favorable-risk BCP-ALL (age 1-9 years, no extramedullary disease, and no high-risk genetics) who cleared minimal residual disease (≤0.01%) at the end of remission induction were enrolled into Ma-Spore (MS) ALL trials. One hundred sixty-seven standard-risk (SR) patients (34% of Malaysia-Singapore ALL 2003 study [MS2003]) were treated with the MS2003-SR protocol and received 120 mg/m2 of anthracyclines during delayed intensification while 202 patients (42% of MS2010) received an anthracycline-free successor protocol. The primary outcome was a noninferiority margin of 1.15 in 6-year event-free survival (EFS) between the MS2003-SR and MS2010-SR cohorts. RESULTS: The 6-year EFS of MS2003-SR and MS2010-SR (anthracycline-free) cohorts was 95.2% ± 1.7% and 96.5% ± 1.5%, respectively (P = .46). The corresponding 6-year overall survival was 97.6% and 99.0% ± 0.7% (P = .81), respectively. The cumulative incidence of relapse was 3.6% and 2.6%, respectively (P = .42). After adjustment for race, sex, age, presenting WBC, day 8 prednisolone response, and favorable genetic subgroups, the hazard ratio for MS2010-SR EFS was 0.98 (95% CI, 0.84 to 1.14; P = .79), confirming noninferiority. Compared with MS2003-SR, MS2010-SR had significantly lower episodes of bacteremia (30% v 45.6%; P = .04) and intensive care unit admissions (1.5% v 9.5%; P = .004). CONCLUSION: In comparison with MS2003-SR, the anthracycline-free MS2010-SR protocol is not inferior and was less toxic as treatment for favorable-risk childhood BCP-ALL.

Life-threatening infections during treatment for acute lymphoblastic leukemia on the Malaysia-Singapore 2003 and 2010 clinical trials: A risk prediction model.

AIM: Life-threatening infections significantly impact the care of children undergoing therapy for acute lymphoblastic leukemia (ALL) who are at risk of severe sepsis due to both host and treatment factors. Our aim was to develop a life-threatening infection risk prediction model that would allow remote rapid triage of patients to reduce time to first dose of antibiotics and sepsis-related mortality. METHODS: A retrospective analysis of 2068 fever episodes during ALL therapy was used for model building and subsequent internal validation. RESULTS: Three hundred and seventy-seven patients were treated for ALL in two institutions with comparable critical and supportive care resources. A total of 55 patients accounted for 71 admissions to the critical care unit for sepsis that led to eight septic deaths during a 16-year study period. A retrospective analysis of risk factors for sepsis enabled us to build a model focused on 13 variables that discriminated admissions requiring critical care well: area under the receiver operating characteristic curve of .82; 95% CI .76-.87, p<.001, and Brier score of .033. Significant univariate predictors included neutropenia, presence of symptoms of abdominal pain, diarrhea, fever during induction or steroid-based phases, and the lack of any localizing source of infection at time of presentation. CONCLUSION: We have developed a risk prediction model that can reliably identify ALL patients undergoing treatment who are at a higher risk of life-threatening sepsis. Clinical applicability can potentially be extended to low-middle income settings, and its utility should be further studied in real-world settings.

An Evaluation of DNA Methyltransferase 1 (DNMT1) Single Nucleotide Polymorphisms and Chemotherapy-Associated Cognitive Impairment: A Prospective, Longitudinal Study.

Strong evidence suggests that genetic variations in DNA methyltransferases (DNMTs) may alter the downstream expression and DNA methylation patterns of neuronal genes and influence cognition. This study investigates the association between a DNMT1 polymorphism, rs2162560, and chemotherapy-associated cognitive impairment (CACI) in a cohort of breast cancer patients. This is a prospective, longitudinal cohort study. From 2011 to 2017, 351 early-stage breast cancer patients receiving chemotherapy were assessed at baseline, the midpoint, and the end of chemotherapy. DNA was extracted from whole blood, and genotyping was performed using Sanger sequencing. Patients' self-perceived cognitive function and cognitive performance were assessed at three different time points using FACT-Cog (v.3) and a neuropsychological battery, respectively. The association between DNMT1 rs2162560 and cognitive function was evaluated using logistic regression analyses. Overall, 33.3% of the patients reported impairment relative to baseline in one or more cognitive domains. Cognitive impairment was observed in various objective cognitive domains, with incidences ranging from 7.2% to 36.9%. The DNMT1 rs2162560 A allele was observed in 21.8% of patients and this was associated with lower odds of self-reported cognitive decline in the concentration (OR = 0.45, 95% CI: 0.25-0.82, P = 0.01) and functional interference (OR = 0.48, 95% CI: 0.24-0.95, P = 0.03) domains. No significant association was observed between DNMT1 rs2162560 and objective cognitive impairment. This is the first study to show a significant association between the DNMT1 rs2162560 polymorphism and CACI. Our data suggest that epigenetic processes could contribute to CACI, and further studies are needed to validate these findings.

Replication and Meta-analysis of the Association between BDNF Val66Met Polymorphism and Cognitive Impairment in Patients Receiving Chemotherapy.

Cancer-related cognitive impairment (CRCI) adversely affects cancer patients. We had previously demonstrated that the BDNF Val66Met genetic polymorphism is associated with lower odds of subjective CRCI in the multitasking and verbal ability domains among breast cancer patients receiving chemotherapy. To further assess our previous findings, we evaluated the association of BDNF Val66Met polymorphism with subjective and objective CRCI in a temporally separate cohort of patients and pooled findings from both the original (n = 145) and current (n = 193) cohorts in a meta-analysis. Subjective CRCI was assessed using FACT-Cog. Objective CRCI was evaluated using computerized neuropsychological tests. Genotyping was carried out using Sanger sequencing. The association of BDNF Val66Met genotypes and CRCI was examined with logistic regression. A fixed-effect meta-analysis was conducted using the inverse variance method. In the meta-analysis (n = 338), significantly lower odds of CRCI were associated with Met allele carriers based on the global FACT-Cog score (OR = 0.52, 95% CI 0.29-0.94). Furthermore, Met allele carriers were at lower odds of developing impairment in the domains of memory (OR = 0.34, 95% CI: 0.17-0.70), multitasking (OR = 0.33, 95% CI: 0.18-0.59), and verbal ability (OR = 0.46, 95% CI: 0.24-0.88). Consistent with the previous study, lower odds of subjective CRCI among patients with the BDNF Met allele was observed after adjusting for potential confounders in the multitasking (OR = 0.30, 95% CI: 0.14-0.67) domain. In conclusion, carriers of the BDNF Met allele were protected against global subjective CRCI, particularly in the domains of memory, multitasking, and verbal ability. Our findings further contribute to the understanding of CRCI pathophysiology.

Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer.

BACKGROUND: Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment. METHODS: Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy-Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates. RESULTS: Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08-0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12-0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15-0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism. CONCLUSIONS: This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings.