Objective. An association between depression and inflammation has been suggested. In patients with rheumatoid arthritis (RA), pain is a major symptom associated with depression and inflammation. We examined the independent associations between depression, the inflammation marker C-reactive protein (CRP) level, and pain in patients with RA. Methods. In total, 218 RA outpatients completed self-administered questionnaires, using the Beck Depression Inventory II to measure depressive symptoms and a visual analog scale to quantify their perceived pain. Functional disability and CRP level were also measured. Results. Depression scores were mildly and positively correlated with the CRP level (r ‫؍‬ 0.46, P < 0.001). Both the depression score (standardized ␤ ‫؍‬ 0.35, P < 0.001) and the CRP level (standardized ␤ ‫؍‬ 0.35, P < 0.001) were significantly associated with pain, even after adjustment for clinical covariates in regression analysis. In logistic analysis, the combined effects on the risk of severe pain (pain score in the upper tertile) increased with depression scores and CRP levels linearly. Conclusion. Depression severity and inflammation were associated with each other and appeared to have independent effects on perceived pain. Therefore, a clinical approach that takes into account both the body and the mind could have benefits and could enable optimal pain control. INTRODUCTIONRheumatoid arthritis (RA) is a chronic autoimmune disorder causing inflammation of the joints and surrounding tissues (1). Patients with RA experience pain, stiffness, swelling, and deterioration of joints. Severe chronic pain accompanied by progressive joint destruction, disability, and disfigurement is known to increase the risk of experiencing emotional disturbances (2). Indeed, depression is common among patients with RA (3,4); these patients are twice as likely to be depressed as people in the general population (5).The association between systemic inflammation and depression has recently attracted attention (6 -8). Depression could promote inflammation by fostering poor health practices, dysregulation of hormonal systems, and susceptibility to atherogenic infections (9,10). Alternatively, it has been suggested that systemic inflammation might induce depressive symptoms by activating the immune-brain pathway (11,12). Various inflammation markers have been reported to have positive associations with depression. C-reactive protein (CRP) is a nonspecific acute-phase protein synthesized in the liver in response to stimulation from interleukin-6 (IL-6) and IL-1. According to a recent review (8), CRP and its precursors IL-6 and IL-1 are the most intensively examined inflammation markers in relation to depression, and a positive association has been confirmed consistently in community and clinical samples. Associations between depression and leukocytosis, increased CD4:CD8 ratios, reduced proliferative response to mitogen, and reduced natural killer cell cytotoxity were also suggested in an earlier meta-analysis (13,14).To date, the asso...

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BackgroundWe previously conducted a phase I trial for advanced colorectal cancer (CRC) using five HLA-A*2402-restricted peptides, three derived from oncoantigens and two from vascular endothelial growth factor (VEGF) receptors, and confirmed safety and immunological responses. To evaluate clinical benefits of cancer vaccination treatment, we conducted a phase II trial using the same peptides in combination with oxaliplatin-based chemotherapy as a first-line therapy.MethodsThe primary objective of the study was the response rates (RR). Progression free survival (PFS), overall survival (OS), and immunological parameters were evaluated as secondary objective. The planned sample size was more than 40 patients for both HLA2402-matched and -unmatched groups. All patients received a cocktail of five peptides (3 mg each) mixed with 1.5 ml of IFA which was subcutaneously administered weekly for the first 12 weeks followed by biweekly administration. Presence or absence of the HLA-A*2402 genotype were used for classification of patients into two groups.ResultsBetween February 2009 and November 2012, ninety-six chemotherapy naïve CRC patients were enrolled under the masking of their HLA-A status. Ninety-three patients received mFOLFOX6 and three received XELOX. Bevacizumab was added in five patients. RR was 62.0% and 60.9% in the HLA-A*2402-matched and -unmatched groups, respectively (p = 0.910). The median OS was 20.7 months in the HLA-A*2402-matched group and 24.0 months in the unmatched group (log-rank, p = 0.489). In subgroup with a neutrophil/lymphocyte ratio (NLR) of < 3.0, patients in the HLA-matched group did not survive significantly longer than those in the unmatched group (log-rank, p = 0.289) but showed a delayed response.ConclusionsAlthough no significance was observed for planned statistical efficacy endpoints, a delayed response was observed in subgroup with a NLR of < 3.0. Biomarkers such as NLR might be useful for selecting patients with a better treatment outcome by the vaccination.Trial registrationTrial registration: UMIN000001791.

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Abstract. to test the safety and immune responses of a novel peptide vaccine derived from RNF43 (ring finger protein 43) and tOmm34 (34-kda translocase of the outer mitochondrial membrane) administered in combination with chemotherapy in patients with metastatic colorectal cancer, a phase I clinical trial with 21 HLA-A2402-positive metastatic colorectal cancer patients was conducted. Patients received a weekly peptide vaccine (1 mg of each peptide in incomplete Freund's adjuvant) in combination with oral UFT (300 mg/m 2 /day) and UZEL (75 mg/day) for 4 weeks, followed by 1 week of rest. The protocol consisted of at least two cycles of this regimen. After the 2nd cycle, vaccinations were given biweekly or monthly, depending on the condition of the patient. Clinical responses were judged 10 weeks after the 2nd cycle by performing computed tomography (CT) scans and assessing the cytotoxic T lymphocyte (CTL) responses against RNF43 and TOMM34 in peripheral lymphocytes. The vaccinations were well tolerated without any serious adverse events. CTL responses were induced against both antigens in 8 patients and against one antigen in 12 patients, while 1 patient had no CTL response. The rate of stable disease was 83%. The group with CTL responses against both antigens had the most long-term survivors, followed by the group showing CTL responses against one antigen (p=0.0079). The patients with no CTL responses had the lowest survival. The safety and immunological responsiveness of the present combination therapy suggests that it is clinically beneficial for metastatic colorectal cancer. Further clinical trials are warranted.