Faculty Publications

To our knowledge, no comprehensive, interdisciplinary initiatives have been taken to examine the role of genetic variants on patient-reported qualityof-life outcomes. The overall objective of this paper is to describe the establishment of an international and interdisciplinary consortium, the GENEQOL Consortium, which intends to investigate the genetic disposition of patient-reported quality-of-life outcomes. We have identified five primary patient-reported quality-of-life outcomes as initial targets: negative psychological affect, positive psychological affect, self-rated physical health, pain, and fatigue. The first tangible objective of the GENEQOL Consortium is to develop a list of potential biological pathways, genes and genetic variants involved in these quality-of-life outcomes, by reviewing current genetic knowledge. The second objective is to design a research agenda to investigate and validate those genes and genetic variants of patient-reported quality-of-life outcomes, by creating large datasets. During its first meeting, the Consortium has discussed draft summary documents addressing these questions for each patient-reported quality-of-life outcome. A summary of the primary pathways and robust findings of the genetic variants involved is presented here. The research agenda outlines possible research objectives and approaches to examine these and new quality-of-life domains. Intriguing questions arising from this endeavor are discussed. Insight into the genetic versus environmental components of patient-reported quality-of-life outcomes will ultimately allow us to explore new pathways for improving patient care. If we can identify patients who are susceptible to poor quality of life, we will be able to better target specific clinical interventions to enhance their quality of life and treatment outcomes.

With advances in treatment, colorectal cancer (CRC) is being transformed from a deadly disease into an illness that is increasingly curable. With this transformation has come increased interest in the unique problems, risks, needs, and concerns of survivors who have completed treatment and are cancer-free. Research has shown that physical and mental quality of life for CRC survivors was inferior compared with age-matched individuals without cancer. Although issues and symptoms were most prominent during the first 3 years, long-term effects of treatment can persist and include fatigue, sleep difficulty, fear of recurrence, anxiety, depression, negative body image, sensory neuropathy, gastrointestinal problems, urinary incontinence, and sexual dysfunction. The unique challenges and issues of CRC survivors can and should be addressed by health care providers and the research community to ensure effective interventions and models of care to manage these problems. This article discusses what is known about the long-term effects of CRC treatment on quality of life, the care of survivors, and existing models of survivorship care.

This study investigated treatment-related symptom clusters and the influence of selected demographic/clinical variables on symptom clustering in breast cancer patients across a treatment trajectory. A secondary analysis of 282 breast cancer patients receiving chemotherapy or radiotherapy was done to determine the clustering of oncologic treatment-related symptoms at selected time points of treatment. Two distinct clusters were identified: a psychoneurological cluster and an upper gastrointestinal cluster. The clustering of symptoms was generally stable across the treatment trajectory. The clustering, however, was weaker when the time lapse after the completion of treatment became longer. Demographic and clinical variables did not significantly influence symptom clustering. Psychoneurological symptoms had a tendency to occur together across the treatment trajectory, as did upper gastrointestinal symptoms. Effective symptom assessment/management strategies need to take into account this co-occurrence of symptoms. The findings from this study underscore the need for further investigation of the common biological basis of symptoms to attain more effective management of multiple symptoms. J Pain Symptom Manage 2008;36:468-479. (C) 2008 U.S. Cancer pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Guided by the theory of planned behavior, this analysis explores the communication skills of women who had genetic testing for BRCA1 and BRCA2. The key outcome was intention to tell test results to adult first-degree relatives. The theory predicts that global and specific attitudes, global and specific perceived social norms, and perceived control will influence the communication of genetic test results. A logistic regression model revealed that global attitude (p < .05), specific social influence (p < .01), and perceived control (p < .05) were significant predictors of intention to tell. When gender and generation of relatives were added to the regression, participants were more likely to convey genetic test results to female than to male relatives (p < .05) and were also more likely to communicate test results to children (p < .01) or siblings (p < .05) than to parents. However, this association depended on knowing the relative's opinion of genetic testing. Intention to tell was lowest among participants who did not know their relative's opinion. These results extend the theory of planned behavior by showing that gender and generation influence intention when the relative's opinion is unknown. (PsycINFO Database Record (c) 2008 APA, all rights reserved).

PG - 237-52 AB - The molecular basis of CD4:CD8 lineage commitment, in particular the mechanism by which the precise correlation between lineage choice and T-cell receptor (TCR) specificity toward class I or II major histocompatibility complex is achieved, remains controversial. Both stochastic/selective and instructive models in various forms have been proposed to explain this correlation. The two main experimental approaches previously employed to elucidate this process have focused on the beginning and end of the process, i.e. the influence of TCR signaling and the alternate transcriptional control of the CD4 and CD8 loci during commitment. The recent finding that the transcription factor Th-POK is necessary and sufficient for CD4 commitment has now provided a direct entry point for studying the intracellular pathways that govern lineage commitment. Here, we review data leading to the identification and characterization of this factor and discuss the implications of these studies in the context of current models of lineage commitment. AD - Fox Chase Cancer Center, Philadelphia, PA, USA. FAU - Kappes, Dietmar J AU - Kappes DJ FAU - He, Xi AU - He X FAU - He, Xiao AU - He X LA - eng PT - Journal Article PL - Denmark TA - Immunol Rev JT - Immunological reviews. JID - 7702118 SB - IM Recent insights into the signals that control alphabeta/gammadelta-lineage fate BRCA1-associated complexes: new targets to overcome breast cancer radiation resistance Symptom cluster research: conceptual, design, measurement, and analysis issues Fully human therapeutic monoclonal antibodies Incorporating novel agents with gemcitabine-based treatment of NSCLC. PG - S8-9 AB - First-line treatment with a two-drug combination chemotherapy regimen comprising of a platinum-based agent with a third-generation agent has been the accepted standard of care in most countries for the treatment of advanced non-small-cell lung cancer (NSCLC). Previously, the addition of a third agent to standard chemotherapy regimens has failed to improve survival in the majority of randomized trials that have been conducted. However, recent findings suggest that the addition of the novel targeted agent bevacizumab to a standard paclitaxel/carboplatin regimen significantly improves survival. The addition of novel agents to gemcitabine-based regimens is therefore a logical approach to improving the treatment of advanced NSCLC. Several trials of gemcitabine-based regimens with bevacizumab are ongoing. During thymopoiesis, two major types of mature T cells are generated that can be distinguished by the clonotypic subunits contained within their T-cell receptor (TCR) complexes: alphabeta T cells and gammadelta T cells. Although there is no consensus as to the exact developmental stage where alphabeta and gammadelta T-cell lineages diverge, gammadelta T cells and precursors to the alphabeta T-cell lineage (bearing the pre-TCR) are thought to be derived from a common CD4(-)CD8(-) double-negative precursor. The role of the TCR in alphabeta/gammadelta lineage commitment has been controversial, in particular whether different TCR isotypes intrinsically favor adoption of the corresponding lineage. Recent evidence supports a signal strength model of lineage commitment, whereby stronger signals promote gammadelta development and weaker signals promote adoption of the alphabeta fate, irrespective of the TCR isotype from which the signals originate. Moreover, differences in the amplitude of activation of the extracellular signal-regulated kinase- mitogen-activated protein kinase-early growth response pathway appear to play a critical role. These findings will be placed in context of previous analyses in an effort to more precisely define the signals that control T-lineage fate during thymocyte development. Since BRCA1 was cloned a decade ago, significant progress has been made in defining its biochemical and biological functions, as well as its role in breast and ovarian cancers. BRCA1 has been implicated in many cellular processes, including DNA repair, cell cycle checkpoint control, protein ubiquitination and chromatin remodeling. This review examines the role(s) of BRCA1 in mediating these cellular processes, and discusses its potential involvement in the resistance of breast cancer to radiation-based therapies. Finally, the possibility that BRCA1-associated proteins may serve as new targets for breast cancer radiation therapy is explored. The activation or inactivation of these BRCA1-associated proteins may modify both the risk of developing cancers in BRCA1 mutation carriers and the efficacy of breast cancer therapy, including radiation. AD - Department of Medical Oncology, Fox Chase Cancer Center, PA 19111-2409, USA. xiaowei.chen@fccc.edu Cancer patients may experience multiple concurrent symptoms caused by the cancer, cancer treatment, or their combination. The complex relationships between and among symptoms, as well as the clinical antecedents and consequences, have not been well described. This paper examines the literature on cancer symptom clusters focusing on the conceptualization, design, measurement, and analytic issues. The investigation of symptom clustering is in an early stage of testing empirically whether the characteristics defined in the conceptual definition can be observed in cancer patients. Decisions related to study design include sample selection, the timing of symptom measures, and the characteristics of symptom interventions. For self-report symptom measures, decisions include symptom dimensions to evaluate, methods of scaling symptoms, and the time frame of responses. Analytic decisions may focus on the application of factor analysis, cluster analysis, and path models. Studying the complex symptoms of oncology patients will yield increased understanding of the patterns of association, interaction, and synergy of symptoms that produce specific clinical outcomes. It will also provide a scientific basis and new directions for clinical assessment and intervention. AD - Fox Chase Cancer Center (A.M.B.), Cheltenham, Pennsylvania; University of Cincinnati (K.W.), Cincinnati, Ohio; Oregon Health & Science University (L.M.N.), Portland, Oregon; and University of Utah (S.L.B., W.N.D.), Salt Lake City, Utah, USA. Monoclonal antibody (mAb) therapy has been facilitated by a number of technologic advances over the past 30 years. Whereas hybridoma development of murine mAbs was requisite for the development of mAbs as drugs, the inherent immunogenicity of rodent sequences in humans has presented obstacles to the clinical application of mAbs. Sensitization to mAb therapeutics poses significant risk to the patient and may blunt the efficacy of these therapies. The advent of chimeric antibodies lessened but did not eliminate the rodent content of mAbs; thus, immunogenicity remained a concern. Further elimination of rodent sequences enabled the production of humanized mAbs, followed by current technology using phage display and, finally, transgenic mice technology, which allows for the generation of fully human therapeutic mAbs. The reduced immunogenicity of this new generation of mAbs is expected to enhance efficacy, safety, and ease of use. In addition to providing replacements for existing mAb drugs, new technologies have greatly facilitated the optimization and modification of mAbs, opening numerous therapeutic avenues. AD - Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. Louis.Weiner@fccc.edu

Background. Patients with cancer grapple with a confusing array of disease- and treatment-related symptoms while trying to maintain functioning in usual roles and daily activities. Research is needed to sort out and identify symptom clusters as a basis for a rational approach to symptom management. Objective: The aim of this study was to test, through secondary analysis, a mediation hypothesis about the direct and indirect relationships between fatigue and depressive symptoms through a pathway involving functional status. Methods: Data from the experimental and control groups of a randomized clinical intervention trial for fatigue management, collected after the second chemotherapy treatment or during the last week of radiotherapy, were analyzed. The mediation pathway from fatigue to depressive symptoms through functional status was tested separately for groups receiving either an energy conservation intervention or a control intervention, equating for time and attention. Results: For the control group, the results indicate support for partial mediation. The previously significant relationship between fatigue and depressive symptoms was reduced after functional status was controlled, accounting for 43% of the total mediated effect. The mediation hypothesis was not supported in the energy conservation group, indicating that the intervention may have changed the role of functional status in mediating the effect of fatigue on depressive symptoms. Discussion: In the control group, when routine activities became more difficult because of fatigue, individuals had more depressive symptoms. The results suggest that functional status is an important factor to consider in symptom management for fatigue. An appropriate intervention for fatigue would have two targets: the fatigue and strategies to reduce the likelihood of impaired functioning that could result in elevated depressive symptoms.

The purpose of this article is to analyze the concept of symptom clusters and to discuss its application to cancer nursing to promote communication and enhance scientific knowledge. Rodgers' evolutionary method of concept analysis served as the framework for reviewing literature from psychology/psychiatry, general medicine, and nursing. Attributes of symptom clusters were relationships of symptoms and relationships of clusters, concurrence, underlying dimensions, stability, and common etiology. The major antecedent was the presence of 2 or more symptoms. Consequences were poorer physical health status, interference with activities of daily living, emotional distress, and increased financial burden. A symptom cluster is defined as consisting of 2 or more symptoms that are related to each other and that occur together. Symptom clusters are composed of stable groups of symptoms, are relatively independent of other clusters, and may reveal specific underlying dimensions of symptoms. Relationships among symptoms within a cluster should be stronger than relationships among symptoms across different clusters. Symptoms in a cluster may or may not share the same etiology. Symptom should be broadened to include both subjective (self-reported) symptoms and objective (observed) signs. Implications for researchers include the need to use a clear definition, determine the optimal methods of identifying etiology and nature of symptom clusters in various populations, assess the clinical utility of symptom clusters, and test interventions. Implications for practitioners include the need to comprehensively assess symptoms over the entire cancer trajectory, select interventions that target single and multiple symptoms, and evaluate outcomes that include quality of life and economic variables. © 2005 Lippincott Williams & Wilkins, Inc.

This report summarizes findings related to the psychometric properties (internal consistency and construct validity) of the Pittsburgh Sleep Quality Index (PSQI) and discusses issues related to its use based on data from two clinical studies with diverse samples of cancer patients. Subjects completed a questionnaire that included the PSQI, the Schwartz Cancer Fatigue Scale, and specific demographic, disease, and treatment variables. There were complete data on 170 (of 214) cases in Study 1 and 249 (of 259) cases in Study 2. The Cronbach's alpha for the Global Sleep Quality scale was 0.81 in Study 1 and 0.77 in Study 2. A comparison of Global Sleep Quality in two contrasting groups with low and high fatigue yielded statistically significant differences in both samples. Psychometric evaluation supports its internal consistency reliability and construct validity. However, the scoring is rather cumbersome and raises questions regarding level of measurement and appropriate analys! is techniques. (C) 2004 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.