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INTRODUCTION: Increased inflammation has been implicated in many psychiatric conditions across ages. We previously reported relationships between blood cytokine levels and anhedonia, the decreased capacity to experience pleasure, as well as with reward brain activation in adolescents with psychiatric symptoms. Here, we sought to extend this work in a larger cohort of adolescents with psychiatric symptoms and assess the relationships of C-Reactive Protein (CRP, inflammation biomarker) with clinical symptoms and reward-related brain activation. METHODS: Subjects were 64 psychotropic-medication-free adolescents with psychiatric symptoms (ages: 15.17 ± 2.10, 44 female). All had psychiatric evaluations and dimensional assessments for anxiety, depression, anhedonia, and suicidality. Neuroimaging included the Reward Flanker fMRI Task examining brain activation during reward anticipation, attainment and positive prediction error. Both whole-brain and ROI analyses focusing on reward circuitry were performed. All analyses were controlled for BMI, age, and sex at pFWE < 0.05. RESULTS: No relationships were identified between CRP and clinical symptom severity. CRP was positively associated with brain activation during reward attainment in regions of the visual and dorsal attention networks, as well as during positive prediction error in the cerebellum. In ROI analyses, CRP was negatively correlated with brain activation during reward anticipation in dorsal anterior cingulate cortex. When subject with high CRP was excluded, CRP was also positively correlated with positive predication error activation in nucleus accumbens. CONCLUSION: Despite lack of associations of CRP with clinical symptomatology, our fMRI findings suggest a relationship between inflammation and brain function early course of psychiatric conditions.
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BACKGROUND: Ipilimumab (IPI) and BRAF inhibitors (BRAFi) improve survival in melanoma, but not all patients will benefit and toxicity can be significant. Pretreatment neutrophil to lymphocyte ratio (NLR) has been associated with outcome in IPI-treated patients, but has not been studied during treatment or in BRAFi-treated patients. METHODS: Using a prospectively maintained database, patients with unresectable stage III or IV melanoma treated with IPI or a BRAFi (vemurafenib or dabrafenib as monotherapy) from 2006 to 2011 were identified. NLR was calculated before treatment and at 3-week intervals after treatment initiation until 9weeks. Baseline NLR was tested for association with overall survival (OS), progression free survival (PFS), and clinical response to treatment. On-treatment NLRs were tested for association with the same outcomes using landmark survival analyses and time-dependent Cox regression models. The association of relative change of NLR from baseline with outcomes was also examined. A multivariate model tested the association of NLR and OS/PFS with additional clinical factors. RESULTS: There were 197 IPI patients and 65 BRAFi patients. In multivariable analysis adjusting for M stage, and disease type (in OS)/gender (in PFS), an NLR value of 5 or above at every timepoint was associated with worse OS (HR 2.03-3.37, p<0.001), PFS (HR 1.81-2.51, p<0.001), and response to therapy (OR 3.92-9.18, p<0.007), in the IPI cohort. In addition, a >30% increase in NLR above baseline at any timepoint was associated with a worse OS and PFS (HR 1.81 and 1.66, p<0.004). In BRAFi patients, NLR was not consistently associated with outcomes. CONCLUSIONS: A high NLR, whether measured prior to or during treatment with IPI, is associated with worse OS, PFS, and clinical response in patients with advanced melanoma. An increasing NLR from baseline during treatment was correlated with worse OS and PFS in IPI-treated patients. In comparison, as NLR was not associated with outcomes in BRAFi patients, NLR may have a uniquely predictive value in patients treated with immunotherapy.
