Faculty Bibliography

PURPOSE/OBJECTIVES: To assess the effects of high blood sugar at the levels of diabetic or prediabetic states during cancer treatment because patients undergoing chemotherapy (CTX) experience multiple symptoms that vary among individuals and may be affected by glucose levels. DESIGN: Descriptive, cross-sectional. SETTING: Two comprehensive cancer centers, one Veterans Affairs hospital, and four community-based oncology programs. SAMPLE: 244 outpatients with breast, gastrointestinal, gynecologic, and lung cancers. METHODS: Patients completed demographic and symptom questionnaires. Glycosylated hemoglobin A1c (HbA1c) was evaluated to determine diabetic state. Descriptive statistics and one-way analyses of variance were used in the analyses. MAIN RESEARCH VARIABLES: HbA1c, symptom severity scores, patient and clinical characteristics (e.g., age, gender, comorbidities, sociodemographic information, body mass index [BMI], lifestyle factors). FINDINGS: HbA1c results showed 9% of the sample in the diabetic and 26% in the prediabetic state. Patients in the diabetic state reported a higher number of comorbid conditions and were more likely to be African American. Patients in the prediabetic state were older aged. Patients in the diabetic and prediabetic states had a higher BMI compared to nondiabetic patients. No differences in symptom severity or quality-of-life (QOL) scores were found among the three diabetic states. CONCLUSIONS: This study is the first to evaluate for associations between diabetic states and symptom severity and QOL scores in patients receiving CTX. This study confirmed that older age, as well as having higher BMI and having multiple comorbidities, were associated with increased mean glycemic levels. IMPLICATIONS FOR NURSING: Clinicians should assess and identify patients with diabetes or prediabetes undergoing treatment for cancer. Patients who are older aged, those with a high BMI, and those with multiple comorbid conditions may be at increased risk for higher glycemic states.

Purpose: Oral squamous cell carcinoma (SCC) invasion and metastasis result in treatment failure and correlate with increased pain. We have previously shown that the "endothelin axis," consisting of endothelin A and B receptors (ETAR and ETBR), mediates oral SCC pain, and that inhibiting ETAR with macitentan alleviates pain. We now hypothesize that the endothelin axis also mediates oral SCC growth and metastasis. We explore the therapeutic effect of concurrent ETAR antagonism (with macitentan) and ETBR re-expression on oral SCC growth and invasion in vitro and in vivo. Methods: We quantified the effect of macitentan treatment and targeted ETBR re-expression on oral SCC cell invasion and proliferation, in vitro indices of metastasis and growth, using a Matrigel invasion chamber assay and the Real Time Cell Analyzer (RTCA). We then created an oral SCC mouse model to determine the effect of macitentan treatment on oral SCC growth. Results: Macitentan treatment or ETBR re-expression alone significantly inhibited oral SCC proliferation and invasion in a dose-dependent manner; macitentan combined with ETBR re-expression had the strongest inhibitory effect on cancer proliferation and invasion. In the oral SCC mouse model, macitentan treatment and ETBR re-expression had significant anti-proliferative and anti-metastatic effects compared to control treatment. Conclusion: Our strategy of targeting the endothelin axis inhibited cancer growth and invasion in vitro and in a preclinical model. These results establish the therapeutic potential of macitentan, an orally available ETAR antagonist, for oral SCC metastasis

CONTEXT: Fatigue is the most common symptom in oncology patients during chemotherapy (CTX). Little is known about the predictors of interindividual variability in initial levels and trajectories of morning fatigue severity in these patients. OBJECTIVES: An evaluation was done to determine which demographic, clinical, and symptom characteristics were associated with initial levels as well as the trajectories of morning fatigue and to compare findings with our companion paper on evening fatigue. METHODS: A sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (N=586) completed demographic and symptom questionnaires a total of six times over two cycles of CTX. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling (HLM) was used to answer the study objectives. RESULTS: A large amount of interindividual variability was found in the morning fatigue trajectories. A piecewise model fit the data best. Patients with higher body mass index (BMI), who did not exercise regularly, with a lower functional status, and who had higher levels of state anxiety, sleep disturbance and depressive symptoms, reported higher levels of morning fatigue at enrollment. Variations in the trajectories of morning fatigue were predicted by the patients' ethnicity and younger age. CONCLUSION: The modifiable risk factors that were associated with only morning fatigue were BMI, exercise, and state anxiety. Modifiable risk factors that were associated with both morning and evening fatigue included functional status, depressive symptoms, and sleep disturbance. Using this information, clinicians can identify patients at higher risk for more severe morning fatigue and evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors.

CONTEXT: Fatigue is a distressing, persistent sense of physical tiredness that is not proportional to a person's recent activity. Fatigue impacts patients' treatment decisions and can limit their self-care activities. While significant interindividual variability in fatigue severity has been noted, little is known about predictors of interindividual variability in initial levels and trajectories of evening fatigue severity in oncology patients receiving chemotherapy (CTX). OBJECTIVES: To determine whether demographic, clinical, and symptom characteristics were associated with initial levels as well as the trajectories of evening fatigue. METHODS: A sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (N=586) completed demographic and symptom questionnaires a total of six times over two cycles of CTX. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling (HLM) was used to answer the study objectives. RESULTS: A large amount of interindividual variability was found in the evening fatigue trajectories. A piecewise model fit the data best. Patients who were White, diagnosed with breast, gynecological, or lung cancer, and who had more years of education, child care responsibilities, lower functional status, and higher levels of sleep disturbance and depression reported higher levels of evening fatigue at enrollment. CONCLUSION: This study identified both non-modifiable (e.g., ethnicity) and modifiable (e.g., child care responsibilities, depressive symptoms, sleep disturbance) risk factors for more severe evening fatigue. Using this information, clinicians can identify patients at higher risk for more severe evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors.

CONTEXT.: Approximately 30% of women report pain in the affected breast prior to breast cancer surgery. OBJECTIVES: The purpose of this secondary analysis of our prospective study was to determine how women who experienced both preoperative and persistent postsurgical breast pain (n=107) differed from women who did not report preoperative breast pain and did (n=158) or did not (n=122) experience persistent postsurgical breast pain. METHODS: Differences in demographic and clinical characteristics were evaluated. Linear mixed effects (LME) modeling was used to evaluate for group differences in symptom severity, function, sensation, and quality of life (QOL) over time. RESULTS: Between-group differences in demographic and clinical characteristics as well as trajectories of shoulder function and QOL were identified. Women with both preoperative and persistent postsurgical breast pain were younger; were more likely to report swelling, strange sensations, hardness, and numbness in the affected breast prior to surgery; and were more likely to have reconstruction at the time of surgery. Women with both preoperative and persistent postsurgical breast pain had more biopsies in the prior year, more lymph nodes removed, and reported more severe acute postsurgical pain than women without preoperative breast pain. LME modeling revealed significant group effects for the majority of outcomes evaluated. Over the six months of the study, women with both preoperative and persistent postsurgical pain had persistently poorer shoulder flexion and physical well-being than women without preoperative breast pain. CONCLUSION: Investigations of the etiology and molecular mechanisms of preoperative breast pain, as well as interventions for this high risk group, are needed.

Differential thermal nociception across inbred mouse strains has genetic determinants. Thermal nociception is largely attributed to the heat/capsaicin receptor TRPV1; however, the contribution of this channel to the genetics of thermal nociception has not been revealed. In this study we compared TRPV1 expression levels and electrophysiological properties in primary sensory neurons and thermal nociceptive behaviors between two (C57BL/6 and BALB/c) inbred mouse strains. Using immunofluorescence and patch-clamp physiology methods, we demonstrated that TRPV1 expression was significantly higher in isolectin B4 (IB4) -positive trigeminal sensory neurons of C57BL/6 relative to BALB/c; the expression in IB4-negative neurons was similar between the strains. Furthermore, using electrophysiological cell classification (current signature method), we showed differences between the two strains in capsaicin sensitivity in IB4-positive neuronal cell types 2 and 13, that were previously reported as skin nociceptors. Otherwise electrophysiological membrane properties of the classified cell types were similar in the two mouse strains. In publicly available nocifensive behavior data and our own behavior data from the using the two mouse strains, C57BL/6 exhibited higher sensitivity to heat stimulation than BALB/c, independent of sex and anatomical location of thermal testing (the tail, hind paw and whisker pad). The TRPV1 selective antagonist JNJ-17203212 inhibited thermal nociception in both strains; however, removing IB4-positive trigeminal sensory neurons with IB4-conjugated saporin inhibited thermal nociception on the whisker pad in C57BL/6, but not in BALB/c. These results suggest that TRPV1 expression levels in IB4-positive type 2 and 13 neurons contributed to differential thermal nociception in skin of C57BL/6 compared to BALB/c.

More than half of all cancer patients have significant pain during the course of their disease. The strategic localization of TMPRSS2, a membrane-bound serine protease, on the cancer cell surface may allow it to mediate signal transduction between the cancer cell and its extracellular environment. We show that TMPRSS2 expression is not only dramatically increased in the primary cancers of patients but TMPRSS2 immunopositivity is also directly correlated with cancer pain severity in these patients. TMPRSS2 induced proteolytic activity, activated trigeminal neurons, and produced marked mechanical hyperalgesia when administered into the hind paw of wild-type mice but not PAR2-deficient mice. Coculture of human cancer cells with murine trigeminal neurons demonstrated colocalization of TMPRSS2 with PAR2. These results point to a novel role for a cell membrane-anchored mediator in cancer pain, as well as pain in general.

Cancer pain sends a message. It is frightening to the patient. It heralds progression or recurrence to the oncologist. It is a biological readout of the cancer-nerve interaction for the scientist. Nerves have been considered bystanders within the cancer microenvironment. However, emerging information suggests that nerves are recruited and participate in the carcinogenic process. These newly formed fibers respond to mediators secreted by constituents of the cancer microenvironment. In this manner, these nerves serve as bellwethers and sensors embedded within the cancer. When we rigorously assess patients' cancer pain, we gain insight into the action of cancer. An enhanced understanding of cancer pain offers biological questions that if answered might not only provide relief from cancer pain but might also improve survival.