Racial/Ethnic Differences in Comprehension of Biospecimen Collection: a Nationwide University of Rochester Cancer Center NCI Community Oncology Research Program Study.

To examine whether (a) non-minority participants differed from racial minority participants in the understanding of biospecimens collected for research purposes, (b) patients differed from comparison group in their understanding of the ways their biospecimens could be used by researchers, and (c) participants received adequate information before consenting to donate blood for research studies. We analyzed cross-sectional data from female breast cancer patients scheduled to receive chemotherapy at the National Cancer Institute (NCI) Community Oncology Research Program (NCORP) clinical sites and a healthy comparison group. After reading a consent form related to biospecimens and consenting to participate in a clinical trial, participants' understanding of biospecimen collection was evaluated. Linear models were used to compare scores between non-minority and racial minority participants as well as cancer and non-cancer comparisons adjusting for possible confounding factors. A total of 650 participants provided evaluable data; 592 were non-minority (Caucasian) and 58 participants were a racial minority (71% Black and 29% other). There were 427 cancer patients and 223 comparisons. Non-minority participants scored higher than racial minorities on relevance-to-care items (diff. = 0.48, CI 0.13-0.80, p = 0.001). Comparison group scored higher than cancer patients on relevance-to-care items (diff. = 0.58, CI 0.37-0.78). A moderate number of the participants exhibited a poor understanding of biospecimen collection across all racial/ethnic backgrounds, but racial minority participants' scores remained lower in the relevance-to-care subscale even after adjusting for education and reading level. Differences were also noted among the patients and comparison group. Researchers should facilitate comprehension of biospecimen collection for all study participants, especially racial minority participants.

Relationships between cytokines and cognitive function from pre- to post-chemotherapy in patients with breast cancer.

Cancer-related cognitive decline (CRCD) is a clinically important problem and negatively affects daily functioning and quality of life. We conducted a pilot longitudinal study from pre- to post-chemotherapy in patients with breast cancer to assess changes in inflammation and cognition over time, as well as the impact of baseline cytokine level on post-chemotherapy cognitive scores. We found that concentrations of IL-6, MCP-1, sTNFRI, and sTNFRII significantly increased in patients, while IL-1ß significantly decreased (p < 0.05). After controlling for covariates, increases in IL-6 and MCP-1 were associated with worse executive function and verbal fluency in patients from pre- to post-chemotherapy (p < 0.05). Higher baseline IL-6 was associated with better performance on executive function and verbal fluency post chemotherapy (p < 0.05). Overall, these results suggest that chemotherapy-associated increases in cytokines/receptors is associated with worse cognitive function. Larger studies are needed to confirm these findings.

Genomic and Transcriptomic Characterization of Relapsed SCLC Through Rapid Research Autopsy.

INTRODUCTION: Relapsed SCLC is characterized by therapeutic resistance and high mortality rate. Despite decades of research, mechanisms responsible for therapeutic resistance have remained elusive owing to limited tissues available for molecular studies. Thus, an unmet need remains for molecular characterization of relapsed SCLC to facilitate development of effective therapies. METHODS: We performed whole-exome and transcriptome sequencing of metastatic tumor samples procured from research autopsies of five patients with relapsed SCLC. We implemented bioinformatics tools to infer subclonal phylogeny and identify recurrent genomic alterations. We implemented immune cell signature and single-sample gene set enrichment analyses on tumor and normal transcriptome data from autopsy and additional primary and relapsed SCLC data sets. Furthermore, we evaluated T cell-inflamed gene expression profiles in neuroendocrine (ASCL1, NEUROD1) and non-neuroendocrine (YAP1, POU2F3) SCLC subtypes. RESULTS: Exome sequencing revealed clonal heterogeneity (intertumor and intratumor) arising from branched evolution and identified resistance-associated truncal and subclonal alterations in relapsed SCLC. Transcriptome analyses further revealed a noninflamed phenotype in neuroendocrine SCLC subtypes (ASCL1, NEUROD1) associated with decreased expression of genes involved in adaptive antitumor immunity whereas non-neuroendocrine subtypes (YAP1, POU2F3) revealed a more inflamed phenotype. CONCLUSIONS: Our results reveal substantial tumor heterogeneity and complex clonal evolution in relapsed SCLC. Furthermore, we report that neuroendocrine SCLC subtypes are immunologically cold, thus explaining decreased responsiveness to immune checkpoint blockade. These results suggest that the mechanisms of innate and acquired therapeutic resistances are subtype-specific in SCLC and highlight the need for continued investigation to bolster therapy selection and development for this cancer.

Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative.

Hereditary cancer syndromes infer high cancer risks and require intensive surveillance. Identification of high-risk individuals among patients with colorectal cancer (CRC) needs improvement. METHODS: Three thousand three hundred ten unselected adults who underwent surgical resection for primary invasive CRC were prospectively accrued from 51 hospitals across Ohio between January 1, 2013, and December 31, 2016. Universal Tumor screening (UTS) for mismatch repair (MMR) deficiency was performed for all, and pathogenic germline variants (PGVs) were identified using multigene panel testing (MGPT) in those who met at least one inclusion criterion: MMR deficiency, diagnosed < 50 years, multiple primary tumors (CRC or endometrial cancer), or with a first-degree relative with CRC or endometrial cancer. RESULTS: Five hundred twenty-five patients (15.9%) had MMR deficiency. Two hundred thirty-four of 3,310 (7.1%; 16% of the 1,462 who received MGPT) had 248 PGVs in cancer susceptibility genes. One hundred forty-two (4.3%) had a PGV in an MMR gene, and 101 (3.1%) had a PGV in a non-MMR gene. Ten with Lynch syndrome (LS) also had a non-MMR PGV and were included in both groups. Two (0.06%) had constitutional MLH1 hypermethylation. Of unexplained MMR-deficient patients, 88.4% (76 of 86) had double somatic MMR mutations. Testing for only MMR genes in MMR-deficient patients would have missed 18 non-MMR gene PGVs (7.3% of total PGVs identified). Had UTS been the only method used to screen for hereditary cancer syndromes, 38.6% (91 of 236) would have been missed, including 6.3% (9 of 144) of those with LS. These results have treatment implications as 5.3% (175 of 3,310) had PGVs in genes with therapeutic targets. CONCLUSION: UTS alone is insufficient for identifying a large proportion of CRC patients with hereditary syndromes, including some with LS. At a minimum, 7.1% of individuals with CRC have a PGV and pan-cancer MGPT should be considered for all patients with CRC.

Associations of inflammation with frailty in patients with breast cancer aged 50 and over receiving chemotherapy.

PURPOSE: Chronic inflammation is a significant physiologic feature of frailty; however, its role and clinical utility in cancer-related frailty remains unknown. We sought to determine if pre-chemotherapy inflammation is predictive of frailty after chemotherapy in patients with breast cancer. METHODS: Female patients (N = 144; age ≥ 50) with stage I-III breast cancer scheduled to receive chemotherapy and age-matched non-cancer controls (N = 142) were included in this secondary analysis and assessed pre- and post-chemotherapy. Controls were assessed at equivalent time-points. Frailty was assessed using a modified Fried's score (0-4) using self-reported measures of weakness, exhaustion, walking speed, and physical activity. Serum levels of interleukin (IL) 6, and soluble tumor necrosis factor-alpha (sTNFR) I and II were measured. Associations between pre-chemotherapy cytokine and receptors level (median as cutoff) and post-chemotherapy frailty were evaluated using t-tests. RESULTS: Pre-chemotherapy, patients with breast cancer were more frail than non-cancer controls (mean score: 1.17 vs 0.65; p < .01). Patients also became more frail post-chemotherapy (mean score: 1.17 vs 2.08; p < .01). Patients with pre-chemotherapy serum levels of IL-6, sTNFRI, and sTNFRII above the median were more frail after chemotherapy than those with levels below the median [IL-6 (2.31 vs. 1.86; p = .03), sTNFRI (2.30 vs. 1.88; p = .04), and sTNFRII (2.30 vs. 1.88; p = .04)]. No differences were observed in non-cancer controls within the same timeframe. CONCLUSIONS: Both cancer and chemotherapy were associated with frailty. Higher pre-chemotherapy inflammatory cytokine levels were associated with post-chemotherapy frailty. This supports the utility of inflammatory cytokines to identify patients who develop worsening of frailty characteristics with chemotherapy.

Multicenter Randomized Controlled Trial of Omega-3 Fatty Acids Versus Omega-6 Fatty Acids for the Control of Cancer-Related Fatigue Among Breast Cancer Survivors.

BACKGROUND: Cancer-related fatigue (CRF) is a common side effect of adjuvant therapy and becomes a chronic problem for approximately one-third of survivors. Omega-3 polyunsaturated fatty acids (O3-PUFA) demonstrated preliminary antifatigue effects in previous research, but have not been investigated in fatigued cancer survivors. METHODS: Breast cancer survivors 4-36 months posttreatment with a CRF score of 4 or more of 10 using the symptom inventory (SI) were randomly assigned to O3-PUFA (fish oil, 6 g/d), omega-6 PUFA (O6-PUFA; soybean oil, 6 g/d), or a low-dose combination of O3-/O6-PUFA (3 g/d O3-PUFA and O6-PUFA) for 6 weeks. CRF was assessed by the SI (screening question), the Brief Fatigue Inventory, and the Multidimensional Fatigue Symptom Index. Protein and mRNA levels of inflammatory and antioxidant biomarkers, along with fatty acid and lipid levels, were assessed at baseline and week 6. Statistical tests were two-sided. RESULTS: A total of 108 breast cancer survivors consented; 97 subjects were randomly assigned and 81 completed the trial. The SI CRF score decreased by 2.51 points at week 6 with O6-PUFA and by 0.93 points with O3-PUFA, with statistically significant between-group difference (effect size = -0.86, P < .01). Similar changes were observed for the Brief Fatigue Inventory and Multidimensional Fatigue Symptom Index but were not statistically significant. Stratified analyses showed the largest benefit was observed in those with severe baseline CRF (≥7). Compared with O3-PUFA, O6-PUFA supplementation statistically significantly decreased proinflammatory markers in the TNF-α signaling pathway. CONCLUSION: Contrary to our original hypothesis, O6-PUFA statistically significantly reduced CRF compared with O3-PUFA. Further research is needed to confirm these findings and to elucidate mechanisms of action.

Analytic validation and real-time clinical application of an amplicon-based targeted gene panel for advanced cancer.

Multiplex somatic testing has emerged as a strategy to test patients with advanced cancer. We demonstrate our analytic validation approach for a gene hotspot panel and real-time prospective clinical application for any cancer type. The TruSight Tumor 26 assay amplifies 85 somatic hotspot regions across 26 genes. Using cell line and tumor mixes, we observed that 100% of the 14,715 targeted bases had at least 1000x raw coverage. We determined the sensitivity (100%, 95% CI: 96-100%), positive predictive value (100%, 95% CI: 96-100%), reproducibility (100% concordance), and limit of detection (3% variant allele frequency at 1000x read depth) of this assay to detect single nucleotide variants and small insertions and deletions. Next, we applied the assay prospectively in a clinical tumor sequencing study to evaluate 174 patients with metastatic or advanced cancer, including frozen tumors, formalin-fixed tumors, and enriched peripheral blood mononuclear cells in hematologic cancers. We reported one or more somatic mutations in 89 (53%) of the sequenced tumors (167 passing quality filters). Forty-three of these patients (26%) had mutations that would enable eligibility for targeted therapies. This study demonstrates the validity and feasibility of applying TruSight Tumor 26 for pan-cancer testing using multiple specimen types.

Regulation of cardiac myocyte cell death.

Cardiac myocyte death, whether through necrotic or apoptotic mechanisms, is a contributing factor to many cardiac pathologies. Although necrosis and apoptosis are the widely accepted forms of cell death, they may utilize the same cell death machinery. The environment within the cell probably dictates the final outcome, producing a spectrum of response between the two extremes. This review examines the probable mechanisms involved in myocyte death. Caspases, the generally accepted executioners of apoptosis, are significant in executing cardiac myocyte death, but other proteases (e.g., calpains, cathepsins) also promote cell death, and these are discussed. The two principal cell death pathways (death receptor- and mitochondrial-mediated) are described in relation to the emerging structural information for the principal proteins, and they are discussed relative to current understanding of myocyte cell death mechanisms. Whereas the mitochondrial pathway is probably a significant factor in myocyte death in both acute and chronic phases of myocardial diseases, the death receptor pathway may prove significant in the longer term. The Bcl-2 family of proteins are key regulators of the mitochondrial death pathway. These proteins are described and their possible functions are discussed. The commitment to cell death is also influenced by protein kinase cascades that are activated in the cell. Whereas certain pathways are cytoprotective (e.g., phosphatidylinositol 3'-kinase), the roles of other kinases are less clear. Since myocyte death is implicated in a number of cardiac pathologies, attenuation of the death pathways may prove important in ameliorating such disease states, and possible therapeutic strategies are explored.

A placebo-controlled trial of a proprietary extract of North American ginseng (CVT-E002) to prevent acute respiratory illness in institutionalized older adults.

OBJECTIVES: To compare a proprietary extract of American ginseng, CVT-E002, with placebo in preventing acute respiratory illness (ARI) in an institutional setting during the influenza season. DESIGN: Two randomized, double-blind, placebo-controlled trials conducted late in the 2000 (8 week) and 2000-2001 (12 week) influenza seasons. SETTING: Long-term care setting that included nursing home and assisted living at three sites. PARTICIPANTS: Eighty-nine (2000) and 109 (2000-2001) enrolled subjects, average age 81 and 83.5, respectively; 74% women. Approximately 90% had received influenza vaccine in each of the 2 years. INTERVENTION: Oral twice-daily administration of a proprietary ginseng extract, CVT-E002, 200 mg or placebo. MEASUREMENTS: ARI was defined as two new respiratory symptoms or one with a constitutional symptom. Confirmation of viral ARI was by culture (influenza or respiratory syncytial virus (RSV)) or serology for influenza. Laboratory safety monitoring was done at 0, 4, and 8 or 12 weeks. RESULTS: An intent-to-treat analysis of pooled data corrected for drug exposure time showed that the incidence of laboratory-confirmed influenza illness (LCII) was greater in placebo- (7 cases/101 subjects) than CVT-E002-treated (1/97) groups (odds ratio (OR)=7.73, P=.033). Combined data for LCII and RSV illness were also greater in placebo- (9/101) than CVT-E002-treated (1/97) groups (OR=10.50, P=.009), for an overall 89% relative risk reduction of ARI in the CVT-E002 group. CONCLUSION: CVT-E002 was shown to be safe, well tolerated, and potentially effective for preventing ARI due to influenza and RSV.

Cultivating future nurse leaders with student nurses associations.

Student nurses associations (SNAs) assist in developing tomorrow's nurse leaders. In this article, executive board members of an SNA in a traditional baccalaureate nursing program at a public regional university recounted common themes in their participation in an SNA. These broad themes included leadership, mentorship and communication, all which foster professional development through the acquisition of specific knowledge, skills and experiences.

Effect of congestive heart failure on humoral and ex vivo cellular immune responses to influenza vaccination in older adults.

This study examined the effect of congestive heart failure (CHF) on immune responses to influenza vaccination (2000-2001 preparation) in three groups of older adults including healthy, Class II and Class III/IV CHF. Serum antibody titers measured by hemagglutination inhibition (HI), and interferon-gamma (IFN-gamma), interleukin-10 (IL-10) and granzyme B (GrzB) levels in ex vivo virus-activated mononuclear cell cultures showed significant responses from pre-vaccination to 4 and 12 weeks post-vaccination (P<0.01). There was a trend for lower GrzB and higher IFN-gamma and IL-10 levels in healthy versus CHF groups (P<0.06) for all viral strains at 4 weeks. HI titers did not differ between groups. In the regression model, Grz B levels were significantly predicted by the IFN-gamma:IL-10 ratio and performance on the 6 min Walk Test; age and CHF dropped out of the model. In conclusion, CHF in older adults predicts GrzB responses to influenza vaccination due to cytokine and physical ability differences.