This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Research Questions 1. What is the nature and variation in spiritual well-being in unresectable Stage IIIB and IV lung cancer patients, and patients with primary pancreatic adenocarcinoma that is unresectable, recurrent, or metastatic.? 2. To what extent are these patients depressed, and to what extent is greater spiritual well-being associated with lower levels of depression? 3. How does greater spiritual well-being modify the relationship between proinflammatory cytokines and depression? Rationale for Research The overall goal of this developmental study is to determine the extent to which a natural coping mechanism, spirituality, influences the depression that often accompanies advanced non-small cell lung cancer and prancreatic cancer. Spirituality has many meanings, some that encompass religion and some that do not. Broadly, spirituality may be defined as the way in which people understand ultimate meaning and value in their lives. Growing evidence supports the hypothesis that spiritual well-being helps to improve psychological functioning and diminish depression in serious illness. Depression is a common source of suffering in patients with advanced lung and pancreatic cancer, although it is often unrecognized and difficult to treat with conventional therapies due to side effects and lack of efficacy. Depression also predicts increased functional impairment, poorer quality of life, and reduced survival. Spirituality might be an important factor in the large burden of depression in patients with lung or pancreatic cancer, but little is known about the relationship between spirituality and depression in lung and pancreatic cancer patients. Therefore, the logical first steps are to better understand the relationship between spirituality and depression in this population and to explore a biological model that could guide development and evaluation of future interventions. Evidence suggests that proinflammatory cytokines may mediate the relationship between illness and depression in cancer. This can be examined using a psychoneuroimmunological (PNI) model. While up to 50% of advanced lung and pancreatic cancer patients may have depression, 50% are free of major depression, offering the opportunity to examine the role of spiritual well-being and biological variables in those who are 'resilient' as well as those who are depressed. In this secondary objective, we will test the hypothesis that greater spiritual well-being modifies the association between elevated cytokines and depression. We will also test whether this association is independent of clinically influential variables (including therapy and stage of disease). Lung and Pancreatic Cancer Globally, lung cancer is the most common cancer and the leading cause of cancer deaths, accounting for over 900,000 deaths per year (1;2). In the United States, one-third of cancer deaths are caused by lung cancer (3). Prognosis is grim with a 5-year survival rate of 14 percent (4). Palliative treatments thus play a major role through the management pain, dyspnea, fatigue, anorexia, and sleep disturbances (5). Pancreatic adenocarcinoma is the fourth leading cancer killer in America and is known to be resistant to most life prolonging treatments, metastasizing long before diagnosis. (82). While traditional pharmacotherapeutic modalities contribute to alleviation of symptoms, interventions that focus on prayer, spiritual well-being, and psychosocial factors may provide additional benefits for patients by improving their ability to cope with their illness. Depression in Cancer Depression has been termed the 'hidden symptom in advanced cancer' (6). It is associated with increased functional impairment and poor quality life in patients with cancer and may predict cancer progression and mortality (7). Following a recent increase in research in palliative care, clinicians have grown more adept at evaluating and treating physical symptoms, such as pain and nausea. However, major depression is a relatively common source of suffering in patients with cancer that often unrecognized (8). Previous research shows that 23%-53% of patients with advanced cancer experience depression (9). It has been estimated that 20-25% of patients with cancer endure unrecognized and untreated long-term depression (10). More specifically, depression is common in lung cancer and predicts decreased functioning and earlier mortality (11;12). In a study of 900 patients, 33% were found to have depression at the time of diagnosis and an additional 17% developed symptoms while receiving treatment. This suggests that 50% of lung cancer patients have some protection against depression. In a study of pain and depression in pancreatic cancer, 38% of patients had BDI scores of > 15, (clinically significant depression), prior to treatment whether surgical or chemotherapy (80). Internal spiritual well-being may be a protective mechanism for both lung and prancreatic cancer. Spirituality and Cancer Spirituality may be defined as 'the way in which people understand their lives in view of their ultimate meaning and value' (13) while religion refers to a set of beliefs and practices based in the worship of a deity (14). Persons can be spiritual through religion or other means. Spirituality is important to how people cope with cancer (15). Hospitalized patients with cancer and other medical illnesses often use spirituality or religion to cope with their illness. Research has shown that these practices are associated with improved health status (16;17). Spirituality is important in advanced illness, palliative care, and at the end of life. Patients with pulmonary illness report that spiritual or religious beliefs would influence medical decisions if they were to become gravely ill (18). Critical care patients also value attention to spirituality as an important part of medical care (19). 'Coming to peace with God' was one of the most important factors in end of life care according to seriously ill patients, as well as talking about the meaning of death (20). Spirituality is thus a concept that is worthy of being examined in the CAM context. Spirituality and Depression in Cancer and Other Medical IllnessMultiple studies in medically ill patients in the United States over the age of 60 have reported an inverse relationship between religiosity/spirituality and depression. In a longitudinal study of patients admitted for acute medical problems and evaluated for depression, greater intrinsic religious beliefs and experience independently predicted shorter time to remission of depression (21). Another study with 455 participants found that religious attitudes, practices, and coping were found to be important to patients, prevalent, and related to social, psychological and physical health (22). A third study in a medically-healthy population further supported the inverse relationship between spirituality and depression by reporting that positive religious coping and spirituality predicted less depression (23). The effects of spirituality remained after adjusting for social support, demographic, and clinical variables. Spirituality may protect against depression and desire for death. Spiritual well-being has been associated with decreased depression and despair in terminally ill patients with cancer and AIDS recruited from palliative care facilities (24;25). Psychoneuroimmunological (PNI) Model Depression, anxiety, and psychological stress are associated with numerous abnormalities in proinflammatory cytokines and neuroendocrine markers. The pathways involving these effects are bidirectional (26). The wealth of evidence suggests that 'the nervous and immune systems can be viewed as components of an integrated system of adaptive processes' (see 'Biological Theoretical Model'). Extensive research demonstrates that psychological factors affect progression of cancer through psychosocial influences on immune and neuroendocrine function (27). Depression and anxiety increase production of proinflammatory cytokines (28;29). These cytokines influence thyroid function and induce corticotrophin-releasing hormone (CRH) hypersecretion, affecting the hypothalamic-pituitary-adrenal axis (30;31). Depression is associated with decreased natural killer (NK) cell function (32-34); this association may be mediated through proinflammatory cytokines and neurohumoral peptides (34-36). NK cells are important in the destruction of malignantly transformed cells. Distress and anxiety have other effects on the immune system: they have been associated with delayed and partially ineffective responses to vaccines (37); these persons also have increased illness and longer lasting infections (38). Illness and infection then lead to increased proinflammatory cytokine production, forming a cycle. Conversely, positive coping styles are associated with improved immune function (39). As described earlier, spirituality is used as a method of coping with cancer. Previous research findings show multiple mediators of depression in patients with cancer, including neuroendocrine factors and immune functioning (see 'Biological Theoretical Model') (40). A 2001 National Cancer Institute (NCI) working group found that inflammatory cytokines associated with both cancer and treatment of cancer may mediate both of these mechanisms (41). Other research has corroborated the association between inflammatory cytokines and depression in cancer (42-45). Specifically, both IL-6 and TNF-? have been implicated in depression in patients with cancer (46-48). Patients with pancreatic cancer have high levels of proinflammatory cytokines, especially Il-6, and these have been associated with earlier mortality, poor functional status, and weight t loss (81). The use of spirituality has been an important part of coping with cancer and the beneficial effects of this coping have been reflected in immune function. Greater spirituality has been associated with enhanced immune function in patients with breast cancer (49), and religious attendance has been associated with healthier immune and cytokine function in elderly adults (50). Research by Breitbart et al (24;25;51) found a relationship between spiritual well-being and depression in terminally-ill cancer and AIDS in palliative care units. The proposed study will add to the findings by enrolling outpatients instead of patients from palliative care units. The public health burden of depression in lung cancer and pancreatic cancer is much greater in outpatients compared to those in palliative care units. Characterizing the experience of outpatients, which may be different from the experience of inpatients on palliative care units, will extend both the scope and depth of our knowledge. In addition, a significant contribution of the proposed study is to develop and test a mechanistic hypothesis that explains how spiritual well-being affects depression. This hypothesis has not been considered in previous research (see 'Biological Theoretical Model'). (52). The theoretical framework draws on models developed for biopsychosocial interactions (53), the relationship between immunological and neuroendocrine mediators of depression (54), modifiable elements in advanced cancer (55), and the role of spirituality in illness experience (56). Increased proinflammatory cytokines are associated with cancer. Proinflammatory cytokines as well as other neuropeptides (not pictured) produced by cancer or treatment of cancer act on the central nervous system (CNS) (57). The brain mediates the effect of cytokines and other neuropeptides on mood (and many other experiences, e.g., fatigue, sleep disturbance, anorexia, etc.) through altered endocrine function and other mechanisms (not pictured), and depression may result (58). Depression (and stress in general) may also affect the CNS to alter cytokine levels and affect the immune system (26). Thus the pathway between the immune system and mood and the CNS is bidirectional and mediated through cytokines and other factors (59). Spiritual well-being may modify this pathway by acting through the CNS and diminishing depression. The purpose of this study is to evaluate that effect and a possible biological mechanism. Possible mechanisms include a diminished response to cytokines or decreased release of cytokines from the CNS. Methods Study Design This study will use a cross-sectional design to evaluate 60 patients with nonresectable Stage 3B and 4 non-small cell lung cancer (NSCLC), or primary pancreatic adenocarcinoma that is unresectable, recurrent, . Validated self-administered survey instruments will measure: (1) spiritual well-being, (2) depression, (3) physical symptoms, and (4) functional status. Population The sample will be identified from the oncology clinics at Johns Hopkins Hospital. Co-investigators Dr. Julie Brahmer and Dr. Michael Carducci will assist in coordinating recruitment. Patients will be included if they have 1) nonresectable Stage 3B and 4 lung cancer, or primary pancreatic adenocarcinoma that is unresectable, recurrent. 2) are aware of their diagnosis and prognosis, 3) are over age 18, and 4) are established patients (they have been to the clinic at least once before). Patients will be excluded if they are 1) unable to complete surveys due to a language barrier or 2) unable to give informed consent or 3) have a diagnosis of dementia of any type or 4) score 18 or less on a Mini-Mental State Examination. Procedures 1. Recruitment After obtaining a HIPAA partial waiver for recruitment, a member of the core research team will screen medical records of patients presenting to clinic for eligibility. Eligible patients can be then recruited in one of 3 ways. A physician or nurse practitioner can opt to discuss the study with the patients during a visit in the clinic. If patients are interested, they will be referred to a member of the core research team to discuss the study. A recruitment letter describing this study will be sent to eligible patients based on medical record review from a participating physician (attached). Patients will be informed that a member of the research team will be calling them to describe the study in more detail but that they may return a postcard if they do not want to be called. The postcard will be included in the envelope and a stamped, addressed envelope will also be included for patients to return the postcard in. The postcard will ask patients for their age, sex, and reason for refusal (not interested, too ill, not enough time, other) but will instruct patients that they may choose not to give this information. Two weeks after sending out the recruitment letter, members of the research team will call patients who have not returned postcards to explain the study in more detail and assess patients' interest in participation. The script for this phone conversation is attached. Patients who express interest in participating will be asked to arrive at their clinic appointment 1 hour early. The research team may call patients the day before their appointment to remind them to arrive 1 hour early if they expressed interest in participating in the study. For patients who refuse to participate during the phone call, the reason for refusal will be recorded (not interested, too ill, not enough time, other). The age and sex of refusers also will be recorded for patients who agree to tell the recruiter this information. Finally, physicians or nurse practitioners may also discuss the study with patients during a clinic or hospital visit and refer interested patients to the research coordinator, who will then screen the patients for eligibility. 2. Patient Enrollment Patients will complete study questionnaires at a clinic visit with the help of a member of the core research team. Estimated time for completion of surveys is 45-60 minutes. A member of the research team will conduct the Mini-Mental State Exam (MMSE) and will be available to assist patients with completing the questionnaires. Patients will also have a single sample of blood drawn for TNF-? and IL-6. The sample of blood will be drawn the same day that the questionnaires are completed. Five milliliters of blood will be collected. This tube will be identified by a study ID# that has no information identifying the patient on it. Any unused blood will be stored at -80 C for the duration of the study and then destroyed. 3. Analysis Scores from the FACIT-Sb will be examined for normality using the Shapiro-Wilks test. Psychometric properties will be examined using item-to-total score correlations and Cronbach's alpha for internal consistency. Based on the characteristics of the scores, further analyses will be carried out using either means and standard deviations, medians, or transformations to obtain normality if required in any further parametric analyses. Values will be explored relative to norms established in other populations. In addition, simple distributions will be examined by age, sex, and the clinical variables noted in the abstract. In this case, to avoid the bias of multiple statistical tests, for any statistical analyses, the significance level will be adjusted to 0.01. Depending on the distribution of the questionnaire scales, the appropriate statistical tests will be used to examine whether spiritual well-being differs in patients who do or do not have depression. Multivariate analysis will be used to adjust for any of the measured potential confounding variables that differ between patients who do and do not have depression. We will measure the proinflammatory cytokines IL-6 and TNF-?. After examining all bivariate relationships with the significance level adjusted for multiple looks (p=0.01), we will construct a parsimonious multiple linear regression model with depression as the dependent variable, and spiritual well-being, and cytokines as independent variables, examining the partial variance explained by each variable, using an incremental R2. Questionnaire/Interview Instrument The full questionnaire and semi-structured interview instrument are attached. Instrument (abbreviations explained in text) Domain of interest GDS-SF Depression BDI Depression FACIT-Sb Spiritual Well-Being Ironson-Woods SR index Religiosity/Spirituality ECOG Scale Functional Status MSAS-SF Physical Symptoms MMSE Cognitive Status The main predictor variable is spiritual well-being. Spiritual well-being will be evaluated using the Functional Assessment of Chronic Illness Therapy - Spiritual Well-Being (FACIT-SP) scale, a 12-item measure that was developed and validated in a large sample of cancer patients (60). This scale measures overall spiritual well-being and includes two subscales, meaning/peace and faith. The meaning/peace subscale measures a sense of meaning, peace and harmony, and purpose in life. The faith subscale assesses the relation between illness, faith, and spiritual beliefs, and how one finds consolation in one's faith (60). Internal consistency for total scale and the two subscales is strong (Cronbach's ? = .81-.88). Convergent validity has been demonstrated by comparing the measure to other measures of spirituality and religiousness (60). Finally, good evidence suggests that the scale measures a unique domain that is different from mood and overall quality of life (61;62). The measure has been used in multiple studies in patients with cancer (63-65). A second instrument, the Ironson-Woods Spirituality/Religiousness index (Ironson-Woods SR index), will be included to measure religiosity and religious behavior (66). Depression, the outcome variable, will be measured using the Geriatric Depression Scale (GDS) Short Form and the Beck Depression Inventory (BDI). The GDS is a self-report screening tool that has was created specifically for elderly, medically ill patients. It has been shown to be a reliable and valid screening tool for current depression in this population (67;68). It is widely used in elderly, medically-ill populations because it excludes somatic symptoms of depression while maintaining sensitivity (69;70). The BDI is frequently used in research on depression in patients with heart disease, cancer, and other chronic medical illnesses (71-73). The BDI will complement the GDS by measuring severity of 21 symptoms of depression (74). In contrast to the GDS, the BDI includes somatic symptoms of depression. Elderly patients often manifest depression through physical symptom complaints (75). At the same time, medically ill patients normally have physical symptoms as a result of their illness. By using two complementary instruments to measure the primary outcome variable, the study can examine this issue in more depth. The Memorial Symptom Assessment Scale-Short Form (MSAS-SF) will assess physical symptoms. This measure detects symptom frequency and amount of distress on a Likert scale as well as prevalence (76;77). Initially validated and tested for reliability in cancer patients, this scale has also been used in other medically-ill populations, including patients with severe heart failure (78). Functional status will be measured using the ECOG scale. The Mini-Mental State Exam (MMSE) will be administered to evaluate cognitive status (79). Demographic information will also be collected (age, gender, race, education level) as well as history of depression, treatment with antidepressants, recent sleep disturbance, and recent bereavement.

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