Physical health-related quality of life trajectories over two years following breast cancer diagnosis in older women: a secondary analysis.

PURPOSE: To identify distinct trajectories of physical health-related quality of life (HRQoL) in older women over the first two years following breast cancer diagnosis, and to examine characteristics associated with trajectory group membership. METHODS: A secondary analysis of a longitudinal study of women diagnosed with stage I-III breast cancer who completed surveys within eight months of diagnosis and six, twelve, and eighteen months later that focuses on a subset of women aged ≥ 65 years (N = 145).Physical HRQoL was assessed using the Physical Component Score (PCS) of the SF-36 Health Survey. Finite mixture modeling identified distinct PCS trajectories. Multivariable logistic regression identified variables predictive of low PCS group membership. RESULTS: Two distinct patterns of PCS trajectories were identified. The majority (58%) of women had PCS above the age-based SF-36 population norms and improved slightly over time. However, 42% of women had low PCS that remained low over time. In multivariable analyses, older age, difficulty paying for basics, greater number of medical comorbidities, and higher body mass index were associated with low PCS group membership. Cancer treatment and psychosocial variables were not significantly associated. CONCLUSION: A large subgroup of older women reported very low PCS that did not improve over time. Older age, obesity, multiple comorbidities, and lower socioeconomic status may be risk factors for poorer PCS in women with breast cancer. Incorporating routine comprehensive geriatric assessments that screen for these factors may help providers identify older women at risk for poorer physical HRQoL post breast cancer treatment.

Depressive Symptoms and Associated Health-Related Variables in Older Adult Breast Cancer Survivors and Non-Cancer Controls.

OBJECTIVES: To examine the prevalence of depressive symptoms and associated risk factors in older adult breast cancer survivors (BCS) and age-matched non-cancer controls. SAMPLE & SETTING: Using the Surveillance, Epidemiology, and End Results-Medicare Health Outcome Survey linked dataset from 1998 to 2012, BCS and non-cancer controls aged 65 years or older were identified. METHODS & VARIABLES: Depressive symptoms, comorbidities, functional limitations, socio-demographics, and health-related information were examined. Univariate and multivariable logistic regression and marginal models were performed. RESULTS: 5,421 BCS and 21,684 controls were identified. BCS and non-cancer controls had similar prevalence of depressive symptoms. Having two or more comorbidities and functional limitations were strongly associated with elevated risk of depressive symptoms in BCS and non-cancer controls. IMPLICATIONS FOR NURSING: Having multiple comorbidities and multiple functional status are key factors associated with depressive symptoms in older adult BCS and non-cancer controls. Nurses are in an ideal position to screen older adult BCS and non-cancer controls at risk for depressive symptoms.

Associations Among Sleep Latency, Subjective Pain, and Thermal Pain Sensitivity in Gynecologic Cancer.

OBJECTIVE: Pain is common among women with gynecologic cancer and contributes to depressed mood, sleep disturbances, and likelihood of future chronic pain. Little is known about how psychosocial factors are associated with central sensitization of pain in gynecologic cancer. This study examined relations among depressive symptoms, sleep, subjective pain, and aftersensation pain (a proxy for central sensitization of pain) in gynecologic cancer. METHODS: Participants were 42 women (mean age [SD] = 59.60 [10.11] years) enrolled in a randomized clinical trial examining psychological intervention effects on sleep, pain, mood, and stress hormones/cytokines in gynecologic cancer. Six to eight weeks after surgery, participants completed an assessment of depressive symptoms, sleep, and subjective pain and a temporal summation of pain protocol via quantitative sensory testing (QST). RESULTS: Controlling for recent chemotherapy, history of chronic pain, and analgesic medication use, regression analyses revealed that longer sleep onset latency (SOL; B = 3.112, P = 0.039, bias-corrected and accelerated (BCa) 95% confidence interval [CI] = 0.371 to 6.014) and greater sensory pain (B = 0.695, P = 0.023, BCa 95% CI = 0.085 to 1.210) were associated with greater aftersensation pain at 15 seconds. Greater sensory pain scores were associated with greater aftersensation pain at 30 seconds (B = 0.286, P = 0.045, BCa 95% CI = 0.008 to 0.513). Depression was not associated with aftersensation pain. The overall models accounted for 44.5% and 40.4% of the variance in aftersensation pain at 15 and 30 seconds, respectively. Conclusions. Longer SOL and higher subjective sensory pain were related to greater aftersensation of experimentally induced pain in women postsurgery for gynecologic cancers. Interventions that improve sleep and subjective sensory pain during the perisurgical period may reduce risk for central sensitization of pain.

Health-related quality of life and medical comorbidities in older patients with pancreatic adenocarcinoma: An analysis using the 1998-2011 surveillance, epidemiology, and end results-medicare health outcomes survey data.

OBJECTIVES: This study compares health-related quality of life (HRQoL) of older patients with pancreatic ductal adenocarcinoma (PDAC) to controls without cancer, and examines the impact of medical comorbidities on HRQoL. MATERIALS AND METHODS: We conducted a case-control study using the 1998-2011 Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey (SEER-MHOS) linked dataset. Cases were Medicare beneficiaries aged 65 and older diagnosed with PDAC (N = 128) and matched controls were without a history of cancer (N = 512). We used the Short Form 36 (SF-36) and Veterans-RAND-12 (VR-12) to examine HRQoL and calculated mental (MCS) and physical (PCS) component scores. Linear regression and mixed effects models were used to examine the impact of medical comorbidities on MCS and PCS for cases and controls, respectively. RESULTS: Cases reported significantly poorer PCS (29.3 vs. 36.3) and MCS (44.8 vs. 49.9) compared to controls. Comorbidities were significantly associated with lower PCS and MCS in controls. However, neither total number of comorbidities or comorbidities grouped by organ systems (cardiopulmonary disease, musculoskeletal disease, diabetes) were significantly related to PCS or MCS for cases. Comparison of regression coefficients estimates did not indicate that lack of significance was due to differences in sample size. CONCLUSIONS: The results of this study highlight the poor HRQoL reported by older patients with PDAC. HRQoL scores were very low in this population, particularly in physical health status, which were not explained by comorbidities.

Cognitive functioning following brain irradiation as part of cancer treatment: Characterizing better cognitive performance.

OBJECTIVE: Although brain radiation therapy (RT) impacts cognitive function, little is known about the subset of survivors with minimal cognitive deficits. This study compares the characteristics of patients receiving brain irradiation as part of cancer treatment with minimal cognitive deficits to those with poorer cognitive functioning. METHODS: Adults at least 6 months postbrain RT (N = 198) completed cognitive measures of attention, memory, and executive functions. Cognitive functioning was categorized into better- and poorer-performing groups, with better-performing survivors scoring no worse than 1.5 standard deviations below the published normative mean on all cognitive measures. Logistic regression was used to identify variables associated with better-performing group membership. RESULTS: Approximately 25% of the sample met the criteria for the better-performing group. In unadjusted analyses, RT type (whole brain irradiation and partial brain irradiation), sedating medications, and fatigue were independently associated with cognition. Sociodemographic and other clinical characteristics were not significant. In adjusted analyses, only fatigue remained significantly associated with group membership (OR = 1.05, 95% CI = 1.01-1.09, P = .009). CONCLUSIONS: There is a subgroup of survivors with minimal long-term cognitive deficits despite undergoing a full course of brain RT as part of cancer treatment. Lower fatigue had the strongest association with better cognitive performance. Interventions targeting cancer-related fatigue may help buffer the neurotoxic effects of brain RT.

Using photography to explore psychological distress in patients with pancreatic cancer and their caregivers: a qualitative study.

PURPOSE: The quality of life (QOL) experiences of patients with pancreatic cancer and their caregivers is poorly understood. Psychological distress is high, but few studies examine the factors associated with psychological distress. The purpose of this study is to gain a richer understanding of the factors associated with psychological distress from patient and caregiver perspectives. METHODS: Twenty participants (13 patients, 7 caregivers) completed group discussions on the experiences of living with pancreatic cancer. Using photovoice methods, participants took photographs and provided narratives depicting the distress they experienced. Participant-produced photographs and group discussion transcripts were analyzed to identify key themes using thematic analysis. RESULTS: Commonalities between patient and caregiver sources of distress emerged despite their distinct roles. Findings revealed four major areas of distress: diagnosis of an unexpected advanced cancer, changes in roles and identity, management of weight loss and gastrointestinal problems, and fear of the future. Participants also discussed unique perspectives such as the stigma of pancreatic cancer and caregiver guilt. CONCLUSIONS: Photovoice provides a unique insight into the lives of patients with pancreatic cancer and their caregivers. Our findings contribute to the gap in the current literature by providing a better understanding of the factors surrounding pancreatic cancer distress. We also identify several clinical recommendations to improve cancer care delivery and areas for future research.

Pyrosequencing of the CYP2C9 -1766T>C polymorphism as a means of detecting the CYP2C9*8 allele.

The CYP2C9 c.449G>A (p.R150H, rs7900194) polymorphism, which confers the CYP2C9*8 allele, is common in persons of African descent and results in reduced clearance of the narrow therapeutic index drugs, warfarin and phenytoin. Because of significant homology in DNA sequence at the 449G>A locus among CYP2C genes, the 449G>A variant cannot be reliably detected via PCR-based genotyping assays that require a short PCR product, such as pyrosequencing. Herein, we propose genotyping for the CYP2C9 c.-1766T>C polymorphism via pyrosequencing as an alternative and accurate means of identifying the CYP2C9*8 allele.

Identification and validation of genetic variants that influence transcription factor and cell signaling protein levels.

Many genetic variants associated with human disease have been found to be associated with alterations in mRNA expression. Although it is commonly assumed that mRNA expression changes will lead to consequent changes in protein levels, methodological challenges have limited our ability to test the degree to which this assumption holds true. Here, we further developed the micro-western array approach and globally examined relationships between human genetic variation and cellular protein levels. We collected more than 250,000 protein level measurements comprising 441 transcription factor and signaling protein isoforms across 68 Yoruba (YRI) HapMap lymphoblastoid cell lines (LCLs) and identified 12 cis and 160 trans protein level QTLs (pQTLs) at a false discovery rate (FDR) of 20%. Whereas up to two thirds of cis mRNA expression QTLs (eQTLs) were also pQTLs, many pQTLs were not associated with mRNA expression. Notably, we replicated and functionally validated a trans pQTL relationship between the KARS lysyl-tRNA synthetase locus and levels of the DIDO1 protein. This study demonstrates proof of concept in applying an antibody-based microarray approach to iteratively measure the levels of human proteins and relate these levels to human genome variation and other genomic data sets. Our results suggest that protein-based mechanisms might functionally buffer genetic alterations that influence mRNA expression levels and that pQTLs might contribute phenotypic diversity to a human population independently of influences on mRNA expression.

Protein quantitative trait loci identify novel candidates modulating cellular response to chemotherapy.

Annotating and interpreting the results of genome-wide association studies (GWAS) remains challenging. Assigning function to genetic variants as expression quantitative trait loci is an expanding and useful approach, but focuses exclusively on mRNA rather than protein levels. Many variants remain without annotation. To address this problem, we measured the steady state abundance of 441 human signaling and transcription factor proteins from 68 Yoruba HapMap lymphoblastoid cell lines to identify novel relationships between inter-individual protein levels, genetic variants, and sensitivity to chemotherapeutic agents. Proteins were measured using micro-western and reverse phase protein arrays from three independent cell line thaws to permit mixed effect modeling of protein biological replicates. We observed enrichment of protein quantitative trait loci (pQTLs) for cellular sensitivity to two commonly used chemotherapeutics: cisplatin and paclitaxel. We functionally validated the target protein of a genome-wide significant trans-pQTL for its relevance in paclitaxel-induced apoptosis. GWAS overlap results of drug-induced apoptosis and cytotoxicity for paclitaxel and cisplatin revealed unique SNPs associated with the pharmacologic traits (at p<0.001). Interestingly, GWAS SNPs from various regions of the genome implicated the same target protein (p<0.0001) that correlated with drug induced cytotoxicity or apoptosis (p ≤ 0.05). Two genes were functionally validated for association with drug response using siRNA: SMC1A with cisplatin response and ZNF569 with paclitaxel response. This work allows pharmacogenomic discovery to progress from the transcriptome to the proteome and offers potential for identification of new therapeutic targets. This approach, linking targeted proteomic data to variation in pharmacologic response, can be generalized to other studies evaluating genotype-phenotype relationships and provide insight into chemotherapeutic mechanisms.

EPS8 inhibition increases cisplatin sensitivity in lung cancer cells.

Cisplatin, a commonly used chemotherapeutic, is associated with ototoxicity, renal toxicity and neurotoxicity, thus identifying means to increase the therapeutic index of cisplatin may allow for improved outcomes. A SNP (rs4343077) within EPS8, discovered through a genome wide association study of cisplatin-induced cytotoxicity and apoptosis in lymphoblastoid cell lines (LCLs), provided impetus to further study this gene. The purpose of this work was to evaluate the role of EPS8 in cellular susceptibility to cisplatin in cancerous and non-cancerous cells. We used EPS8 RNA interference to determine the effect of decreased EPS8 expression on LCL and A549 lung cancer cell sensitivity to cisplatin. EPS8 knockdown in LCLs resulted in a 7.9% increase in cisplatin-induced survival (P = 1.98 × 10(-7)) and an 8.7% decrease in apoptosis (P = 0.004) compared to control. In contrast, reduced EPS8 expression in lung cancer cells resulted in a 20.6% decrease in cisplatin-induced survival (P = 5.08 × 10(-5)). We then investigated an EPS8 inhibitor, mithramycin A, as a potential agent to increase the therapeutic index of cisplatin. Mithramycin A decreased EPS8 expression in LCLs resulting in decreased cellular sensitivity to cisplatin as evidenced by lower caspase 3/7 activation following cisplatin treatment (42.7% ± 6.8% relative to control P = 0.0002). In 5 non-small-cell lung carcinoma (NSCLC) cell lines, mithramycin A also resulted in decreased EPS8 expression. Adding mithramycin to 4 NSCLC cell lines and a bladder cancer cell line, resulted in increased sensitivity to cisplatin that was significantly more pronounced in tumor cell lines than in LCL lines (p<0.0001). An EGFR mutant NSCLC cell line (H1975) showed no significant change in sensitivity to cisplatin with the addition of mithramycin treatment. Therefore, an inhibitor of EPS8, such as mithramycin A, could improve cisplatin treatment by increasing sensitivity of tumor relative to normal cells.

A pharmacogenetics service experience for pharmacy students, residents, and fellows.

OBJECTIVE: To utilize a comprehensive, pharmacist-led warfarin pharmacogenetics service to provide pharmacy students, residents, and fellows with clinical and research experiences involving genotype-guided therapy. DESIGN: First-year (P1) through fourth-year (P4) pharmacy students, pharmacy residents, and pharmacy fellows participated in a newly implemented warfarin pharmacogenetics service in a hospital setting. Students, residents, and fellows provided genotype-guided dosing recommendations as part of clinical care, or analyzed samples and data collected from patients on the service for research purposes. ASSESSMENT: Students', residents', and fellows' achievement of learning objectives was assessed using a checklist based on established core competencies in pharmacogenetics. The mean competency score of the students, residents, and fellows who completed a clinical and/or research experience with the service was 97% ±3%. CONCLUSION: A comprehensive warfarin pharmacogenetics service provided unique experiential and research opportunities for pharmacy students, residents, and fellows and sufficiently addressed a number of core competencies in pharmacogenetics.

Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients.

A whole-genome approach was used to investigate the genetic determinants of cytarabine-induced cytotoxicity. We performed a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines (LCLs) from individuals of European, African, Asian, and African American ancestry. Several of the highest-ranked single-nucleotide polymorphisms (SNPs) were within the mutated in colorectal cancers (MCC) gene. MCC expression was induced by cytarabine treatment from 1.7- to 26.6-fold in LCLs. A total of 33 SNPs ranked at the top of the meta-analysis (P < 10(-5)) were successfully tested in a clinical trial of patients randomized to receive low-dose or high-dose cytarabine plus daunorubicin and etoposide; of these, 18 showed association (P < .05) with either cytarabine 50% inhibitory concentration in leukemia cells or clinical response parameters (minimal residual disease, overall survival (OS), and treatment-related mortality). This count (n = 18) was significantly greater than expected by chance (P = .016). For rs1203633, LCLs with AA genotype were more sensitive to cytarabine-induced cytotoxicity (P = 1.31 × 10(-6)) and AA (vs GA or GG) genotype was associated with poorer OS (P = .015), likely as a result of greater treatment-related mortality (P = .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084.

National Center for Complementary and Alternative Medicine perspectives for complementary and alternative medicine research in cardiovascular diseases.

The National Center for Complementary and Alternative Medicine (NCCAM) was established in 1998 by the US Congress to conduct and support basic and applied research and research training and disseminate information with respect to identifying, investigating, and validating complementary and alternative therapies. Because of limited appropriations, NCCAM prioritizes its research programs according to the relative use of a modality, the evidence supporting its value and safety, and opportunities to advance the relevant fields of science. While NCCAM's top priority is supporting clinical trials of alternative therapeutics, increasingly it is supporting basic and preclinical research. To accomplish its mission, NCCAM encourages the research community to undertake high-quality and rigorous research in complementary and alternative medicine (CAM). In the area of cardiovascular diseases, NCCAM is supporting clinical trials, specialized centers, research training, and investigator-initiated projects. Virtually all aspects of CAM modalities are open for investigation. Current NCCAM projects are investigating Tai Chi (Taiji) exercise, hawthorn, phytoestrogens, biofeedback, Ayurvedic herbals, acupuncture, qigong, Reiki, meditation, spirituality, Ginkgo biloba, ethylenediaminetetraacetic acid chelation therapy, and special diets.