Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer.

PURPOSE: Incapacitating symptom burden in cancer patients contributes to poor quality of life (QOL) and can influence treatment outcomes because of poor tolerance to therapy. In this study, the role of circulating cytokines in the production symptoms in cancer patients is evaluated. EXPERIMENTAL DESIGN: Eighty patients with metastatic colorectal cancer with either normal (group I, n = 40) or dampened (group II, n = 40) 24-hour rest/activity patterns measured by actigraphy were identified. Actigraphy patterns were correlated with QOL indices, serum cortisol obtained at 8:00 a.m. and 4:00 p.m. and with serum levels of transforming growth factor-alpha, tumor necrosis factor-alpha, and interleukin 6 (IL-6) obtained at 8:00 a.m. and analyzed in duplicate by ELISA. Cytokine levels and survival were also correlated. RESULTS: Group II patients had significantly higher pre treatment levels of all three cytokines, displayed significantly poorer emotional and social functioning, had higher fatigue, more appetite loss, and poorer performance status compared with group I patients. Transforming growth factor-alpha (TGF-alpha) and IL-6 were significantly increased in the patients with WHO performance status >1 and in those with appetite loss. Fatigue was significantly associated with elevated TGF-alpha only. IL-6 was increased in those patients with extensive liver involvement and multiple organ replacement, and it was significantly correlated with dampened cortisol rhythm. In a multivariate analysis, IL-6 was correlated with poor treatment outcome. CONCLUSIONS: Significant correlations were found between serum levels of TGF-alpha and IL-6, circadian patterns in wrist activity and serum cortisol and tumor-related symptoms in patients with metastatic colorectal cancer. These data support the hypothesis that some cancer patient's symptoms of fatigue, poor QOL, and treatment outcome are related to tumor or host generated cytokines and could reflect cytokine effects on the circadian timing system. This interplay between cytokine signaling pathways, the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, and efferent pathways of the suprachiasmatic nucleus that control circadian physiology, opens the way to new rational interventions for symptom management in cancer patients.     

Identification of HLA-DRB1*1501-restricted T-cell epitopes from prostate-specific antigen.

The development of immunotherapy for prostate cancer based on the induction of autoimmunity to prostate tissue is very attractive because prostate is not a vital organ beyond the reproductive years. CD4 T cells play an important role in the development of antitumor immune responses, yet the identification of naturally processed MHC Class II-restricted epitopes derived from prostate differentiation antigens has not been described. To facilitate the search for prostate-specific antigen (PSA)-derived MHC class II-restricted peptides, we immunized mice transgenic for HLA-DRB1*1501 with human PSA and showed a robust dose-dependent immune response to the antigen. Screening a library of overlapping 20-mer peptides that span the entire PSA sequence identified two 20-mer peptides, PSA(171-190) and PSA(221-240), which were responsible for this reactivity. Immunization of DR2b transgenic mice with these peptides induced specific responses to the peptide and whole PSA. Identified peptides were used to stimulate CD4 T cells from HLA-DRB1*1501+ patients with a rare condition, granulomatous prostatitis, and who seem to have a preexisting immune response directed against the prostate gland. We previously showed a linkage of granulomatous prostatitis to HLA-DRB1*1501, suggesting that this disease may have an autoimmune etiology. Peptide-specific CD4 T-cell lines were generated from the peripheral blood of these patients as well as one patient with prostate cancer. These lines also recognized whole, processed PSA in the context of HLA-DRB1*1501. This study will be instrumental in understanding the interaction between circulating self-reactive T cells, organ-specific autoimmunity, and antitumor immune response. The use of these peptides for the immunotherapy of prostate cancer is under investigation.     

Secondary Prevention of Cardiovascular Disease in Older Adults

Atherosclerotic cardiovascular disease is extremely common in older adults and the potential benefits of secondary prevention are perhaps greater in this population than in younger patients. While there is good evidence that secondary prevention efforts are justified in patients up to 80 years of age, limited data are available on secondary prevention in octogenarians and there is no evidence to guide treatment in patients ≥ 90 years of age. Further, the value of secondary prevention may be confounded by prevalent comorbidities, polypharmacy, and limited life expectancy. It is therefore essential that all management decisions be made in relation to individual preferences and goals of care, with understanding by patients that benefits as well as risks may increase with age. Furthermore, research is needed to refine markers to better delineate which older adults are most likely to benefit from preventive therapies.     

Antidepressant drug use and suicide prevention

Depression has been identified as occurring in the majority of people who commit suicide. Effective antidepressant medications have been available for over half a century. It seems logical to conclude that treatment of depression with antidepressants would have a suicide preventive effect. This has been difficult to demonstrate due to the infrequency of suicide and methodological problems in prospectively testing the hypothesis. Pooled data from controlled clinical trials of antidepressants have not demonstrated a suicide preventive effect, but patient selection and the brief time of most trials limits the power of the data. Some reports from either long-term or very large databases have provided evidence that antidepressants prevent suicide. All but one study using aggregated data from naturalistic settings have shown inverse relationships between use of antidepressants and suicide rates in various populations. Definite conclusions cannot be drawn from naturalistic studies since unknown confounders cannot be excluded. The number of geographically widespread studies reporting positive results with varying methods leads us to conclude, however, that antidepressants do exert a suicide preventive effect.     

Consensus on melanonychia nail plate dermoscopy

This statement, focused on melanonychia and nail plate dermoscopy, is intended to guide medical professionals working with melanonychia and to assist choosing appropriate management for melanonychia patients. The International Study Group on Melanonychia was founded in 2007 and currently has 30 members, including nail experts and dermatopathologists with special expertise in nails. The need for common definitions of nail plate dermoscopy was addressed during the Second Meeting of this Group held in February 2008. Prior to this meeting and to date (2010) there have been no evidence-based guidelines on the use of dermoscopy in the management of nail pigmentation.     

Santé mentale des adolescents selon leur attirance sexuelle : enquête en milieu scolaire

IntroductionAlthough homosexuality is a subject often addressed by the media, little is said about homosexuality in adolescents who are particularly affected by the question of sexual orientation. This work aims to study the mental health of adolescents who report being exclusively attracted to members of the same sex. We explore the evidence for an association between homosexuality and depression, suicide attempts, and consulting a psychiatrist or a psychologist.MethodsWe used data from the cross-sectional study “Adolescent Portraits – A Multicenter Epidemiological Survey in Schools in 2013” (CHU Fondation Vallée, Inserm CESP U1018). Data were gathered through the use of an anonymous, self-administered questionnaire (348 questions) given to students between the “4^e” and “terminale school” years (comparable to the 8th and 12th grade in the U.S. education system) in three contrasting French geographical areas. The risk of depression was measured using the Adolescent Depression Rating Scale (ADRS).ResultsThe results reflect the survey responses provided by 15,235 young people. Of these, 1.5 % reported only being attracted to members of the same sex (homosexual group). This group contained twice as many girls as boys. Students who did not report sexual attraction, who reported bisexual attraction, or who did not answer the question were excluded from the results (830 students). In the homosexual group, 24 % presented with depression versus 11.5 % of those attracted exclusively to members of the opposite sex (heterosexual group). There is also a significant difference between sexes: 13.2 % of boys in the homosexual group were depressed compared to 29.3 % of girls in the same group; 6.7 % of boys in the heterosexual group reported being depressed versus 16.1 % of girls in the same group. In the heterosexual group, 10.7 % of respondents reported having already made at least one suicide attempt versus 20.7 % of those in the homosexual group. There was a difference according to sex, since 6.3 % of boys in the heterosexual group had a history of attempted suicide versus 14.9 % of girls in the same group. This gap disappeared completely within the homosexual group, as 21.4 % of boys and 20.4 % of girls had already made at least one suicide attempt at the time of the survey. Depressed adolescents in the homosexual group also reported a higher number of previous suicide attempts than those in the heterosexual group (46.9 % versus 31.6 %). In terms of sex, 25.3 % of depressed boys in the heterosexual group made at least one suicide attempt versus 34.1 % of girls. In the homosexual group, 44.4 % of depressed boys reported having made at least one suicide attempt versus 47.5 % of depressed girls. Adolescents in the homosexual group were significantly more likely to report having consulted a psychiatrist or psychologist than those in the heterosexual group (14.6 % versus 6.5 %), regardless of sex (16.7 % versus 4.7 % for boys; 13.5 % versus 8.2 % for girls). This difference was also found among depressed subjects (26.0 % in the homosexual group versus 15.4 % in the heterosexual group). Sexual activity (having already had sex) was higher in the homosexual group than in the heterosexual group (53.7 % versus 37.5 %), and this difference remained significant after adjusting for age. Fifty percent of the sexually active homosexual respondents reported having engaged in sexual activity of a homosexual nature versus 0.7 % of sexually active heterosexual respondents. In the homosexual group, mental suffering appeared to be more severe among sexually active subjects, in terms of dark thoughts (64 % versus 46 %) and a prior history of attempted suicide (29.3 % versus 10 %), but not in terms of depression (27.9 % versus 18.9 %; NS).ConclusionYoung people who reported being exclusively attracted to members of the same sex presented a higher level of mental distress compared to those who reported being attracted to members of the opposite sex. This was especially the case for boys. These findings led to the identification of risk and protective factors that can inform the development of appropriate preventive measures.