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As commonly defined, complementary and alternative medicine (CAM) is a broad category that includes biologically based practices, mind-body medicine, manipulative and bodybased practices, and energy medicine as well as complete medical systems such as naturopathy, homeopathy, Ayurvedic medicine, and traditional Chinese medicine. Several CAM methodologies show promise for the treatment of chronic conditions such as depression and pain disorders or have demonstrated effects upon the immune response in experimental studies. There is growing interest in the use of integrative medicine——the combination of CAM methodologies with a conventional medical approach——for the optimization of treatment of various cancers. The Ohio State University Center for Integrative Medicine has developed a specialized nutrigenomic protocol for integrative cancer care. The center uses a comprehensive nutritional and medical evaluation, including a panel of proinflammatory molecules and physiologic parameters, to guide a program of individualized dietary interventions. Dietary supplementation is a current focus of study, including: (1) Omega-3 fatty acids and B vitamins, which are thought to play important roles in immunomodulation; (2) Magnesium oxide, which has been shown to decrease inflammation and improve insulin resistance and lipid profiles; and (3) Cinnamon extract, which reportedly decreases serum glucose levels. This article presents a brief overview of CAM and integrative medicine and a discussion of the relevant nutraceuticals. [ABSTRACT FROM AUTHOR]

Interleukin-2 (IL-2) activates extracellular signal-regulated protein kinase (ERK) within immune cells. To examine the profile of phosphorylated ERK (p-ERK) in IL-2 stimulated immune cells of normal donors and patients receiving IL-2 therapy, we developed a dual parameter flow-cytometric assay. An analysis of PBMCs stimulated with IL-2 indicated that IL-2 exposure induced p-ERK in CD56bright NK cells and CD14+ monocytes, but not in CD3+ T cells or CD21+ B cells. CD3+ T cells that were induced to express functional high-affinity IL-2R did not exhibit enhanced p-ERK following IL-2 treatment. Measurement of p-ERK within PBMCs from cancer patients 1 h following their first dose of IL-2 revealed a complete absence of circulating NK cells, consistent with earlier observations. However, the total number of circulating CD14+ monocytes increased in these samples and 97% of these cells exhibited ERK activation. p-ERK was not observed in T cells post-IL-2 therapy. Analysis of PBMCs obtained 3 weeks post-IL-2 therapy revealed high-p-ERK levels in CD56bright NK cells in a subset of patients, while levels of p-ERK returned to baseline in monocytes. These studies reveal an effective method to detect ERK activation in immune cells and demonstrate that IL-2 activates ERK in a subset of NK cells and monocytes but not T cells. [ABSTRACT FROM AUTHOR]

Carcinoid and islet cell tumors are known to be highly vascular. There is no effective systemic therapy currently available for metastatic disease. We conducted a phase II trial to evaluate the efficacy of the anti-antiangiogenic agent thalidomide in metastatic neuroendocrine tumors. Eighteen patients with measurable, histologically proven metastatic carcinoid neuroendocrine carcinomas (well-differentiated, n = 13; moderately-differentiated, n = 5) were enrolled on this study. The majority of the patients had gastrointestinal primaries (small bowel, 8; pancreas, 5; colon, 1). All but one patient had hepatic metastases, and 12 patients (67%) had carcinoid syndrome. All patients had Eastern Cooperative Oncology Group performance status of zero or one. Eight patients (44%) had received previous hepatic artery chemoembolization and 11 (61%) had undergone surgical resection. Patients were started on oral thalidomide at a daily dose of 200 mg that was escalated to the target dose of 400 mg daily after 2 weeks. Tumor response was assessed at 12-week intervals using RECIST criteria. Planned treatment duration was 24 weeks unless unacceptable toxicity or disease progression was observed. No patient achieved a partial remission or a complete remission. Best response was stable disease (SD) in 11 of 16 response-evaluable patients (69%). Serum pancreastatin results did not correlate with clinical response. Grade 3 toxicities included dizziness with orthostatic hypotension ( n = 5), sensory neuropathy ( n = 2), fatigue ( n = 2), hemorrhagic cystitis ( n = 1), and deep venous thrombosis ( n = 1). Frequent Grade 1–2 toxicities were: fatigue ( n = 13), constipation ( n = 13), dry mouth ( n = 12), somnolence ( n = 12), dizziness/syncope ( n = 10), weight gain ( n = 5), and peripheral neuropathy (n = 5). Thalidomide was fairly well tolerated in patients with metastatic carcinoid/islet cell tumors, but failed to reveal any objective responses. The single stage design of the trial makes it difficult to determine whether observed SD in a subset of patients was attributable to the indolent nature of these tumors, or to beneficial effect of thalidomide. [ABSTRACT FROM AUTHOR]

Background: Transarterial chemoembolization (TACE) is commonly used to treat metastatic carcinoid tumors; however, the management of progressive disease is less clear. We sought to determine if patients with disease progression after TACE would benefit from repeat TACE.Methods: The records of 27 patients undergoing repeat TACE for radiologic or symptomatic progression after TACE for metastatic carcinoid were reviewed and compared to 122 undergoing first TACE. Overall and progression-free survivals were estimated by the Kaplan-Meier method.Results: Mean disease-free interval after first TACE was 11.8 months. Radiologic response was observed in 61% compared to 82% after first TACE (p=0.058); hormone response in 64% compared to 80% (p=0.159); and symptomatic response in 77% compared to 92% (p=0.053). The complication rate after repeat TACE was lower than after first TACE (p=0.03). Median overall survival was similar after repeat (28.1 months) and first TACE (33.3 months) (p=0.53). Progression-free survival was shorter after repeat TACE but not significantly so. No factor examined could predict survival after repeat TACE.Conclusion: Repeat TACE for patients with hepatic carcinoid metastases failing first TACE or having evidence of disease progression is safe and offers a viable treatment option. [ABSTRACT FROM AUTHOR]

Background: We previously reported that cancer-related psychological stress is associated with reduced natural killer (NK) cell lysis. We hypothesized that reduced NK cell cytotoxicity in patients with increased levels of stress would correlate with alterations in the expression of inhibitory NK cell receptors (killer immunoglobulin-like receptors, or KIRs). The specific aim of this study was to examine KIR expression in patients with high or low levels of psychologic stress and correlate alterations in KIR expression with NK cell function. Materials and Methods: Two hundred twenty-seven patients underwent baseline evaluation of cancer-related psychological stress and were randomized to psychosocial intervention versus observation. From this population, two groups were defined based on pretreatment measurements of NK lytic activity, stress levels, and the availability of cryopreserved peripheral blood mononuclear cells (PBMC). Group I (n = 9) had low stress by the Impact of Events Scale (IES), and high NK cell lysis at the 50:1 effector: target ratio (NK50 = 52–89%). Group II (n = 8) had high stress and low NK50 (27–52%). Lymphokine activated killer (LAK) activity, antibody dependent cellular cytotoxicity (ADCC), and expression of cytokine receptors, adhesion molecules, and killer immunoglobulin-like receptors (KIRs) were assessed in PBMC. Results: Incubation of PBMC with NK-stimulatory cytokines (IL-2, IL-12, or IL-15) led to significant increases in cytotoxic activity regardless of IES/NK50 scores. There were no significant group differences in NK cell surface expression of the IL-2 receptor components CD25 and CD122, antibody-dependent lysis of HER2/neu-positive SKBr3 cells treated with an anti-HER2/neu monoclonal antibody, expression of adhesion molecules (CD2, CD11a, CD18) and markers of activation (CD69), or expression of the KIRs CD158a, NKG2a, NKB1, and CD161. However, levels of CD158b were significantly higher in Group I after incubation in media alone or with IL-2, and CD94 expression was significantly lower in Group I after incubation with IL-2. Conclusions: In this study of a small subset of breast cancer patients chosen from a previous clinical trial of psychosocial intervention for breast cancer, impaired NK lysis in breast cancer patients with high levels of psychological stress was associated with alterations in surface expression of killer immunoglobulin-like receptors. However, immune effectors retained the ability to lyse antibody-coated targets and to initiate lymphokine-activated killer activity, irrespective of stress levels or baseline NK50. [Copyright &y& Elsevier]

Activation of G protein-coupled receptors is known to stimulate cell migration, but receptor-mediated signals inhibiting cell migration have not been identified. We investigated the ability of transfected human M3 muscarinic acetylcholine receptors (mAChR) to regulate the migration of Chinese hamster ovary (CHO) cells. Single cells migrated on colloidal gold applied to fibronectin-coated plates, and videomicroscopy was used to measure cell spreading and migration. Activation of M3 mAChR with the agonist carbachol was found to inhibit cell migration, whereas direct activation of protein kinase C (PKC) with PMA was found to stimulate migration. The amount of cell adhesion and spreading was found to be equivalent for carbachol- and PMA-treated cells. Selective inactivation of conventional PKC isoforms with Go6976 (C24H18N4O) abolished the PMA-mediated increase in cell migration. In contrast, the mAChR-mediated decrease in migration was not altered by Go6976, but was abolished when both novel and conventional PKC isoforms were inactivated by calphostin C or chelerythrine. These findings suggest involvement of conventional PKC isoforms in the stimulation of migration and of novel PKC isoforms in the inhibition of migration. Carbachol- but not PMA-treated cells exhibited an elongated morphology reminiscent of migrating cells that cannot detach their trailing edges from the substratum. Similarly, carbachol-treated cells detached less readily from fibronectin than control or PMA-treated cells when integrin activity was diminished by the chelation of Ca2+ and Mg2+. Finally, the carbachol-induced diminution of cell detachment was preserved after inhibition of the conventional PKC isoforms with Go6976, but was abrogated by treatment with either calphostin C or chelerythrine. These findings suggest that mAChR activation diminishes the ability of cells to detach from the substratum, resulting in diminished migration. This is in contrast to the direct activation of PKC with PMA, which stimulates migration. [Copyright &y& Elsevier]