ABSTRACT
This quality improvement study evaluates the geographic distribution of clinical trials and assesses the distances patients with cancer must travel to access a clinical trial site.
ABSTRACT
Rural oncologist reflects on 20 years of providing vital cancer care in underserved areas.
Subject(s)
Medical Oncology , Rural Health Services , Humans , Medical Oncology/methods , Rural Health Services/standards , Neoplasms/therapy , Neoplasms/epidemiology , Rural PopulationSubject(s)
Carcinoma, Squamous Cell , Nose Neoplasms , Papilloma, Inverted , Paranasal Sinus Neoplasms , Cell Line , HumansABSTRACT
Tobacco is notably genotoxic and associated with head and neck carcinogenesis. Cigarette carcinogens have the capacity to alter early response gene expression in tobacco-related malignancies via genes such as nuclear factor kappa B (NFκB). A number of early response gene activation events are also facilitated by fos/jun activator protein 1 (AP-1) associated pathways. In the present study, we hypothesize that tobacco products may induce microenvironment alterations, promoting angiogenesis and providing a permissive environment for head and neck cancer progression. In an in vitro analysis, we employed immortalized oral keratinocyte (HOK-16B) and laryngeal squamous carcinoma (UM-SCC-11A) cells to investigate interleukin (IL)-8 and vascular endothelial growth factor (VEGF) induction by cigarette smoke condensate (CSC). IL-8 and VEGF expression is based on interactions between NFκB, AP-1, and NF-IL6. We identified at least 1.5-fold dose-dependent induction of AP-1, VEGF, and IL-8 promoter/reporter gene activity after 24 h exposure to CSC. Next, we stably transfected UM-SCC-11A cells with A-Fos, a dominant negative AP-1 protein. Treatment with CSC of the A-Fos cell lines compared to empty vector controls significantly down-regulated AP-1, VEGF, and IL-8 promoter/reporter gene expression. We also performed ELISAs and discovered significant up-regulation of IL-8 and VEGF secretion by UMSCC 11A after treatment with phorbol 12-myristate 13-acetate, tumor necrosis factor alpha, and CSC, which was down-regulated by the A-Fos dominant negative protein. We conclude tobacco carcinogens up-regulate AP-1 activity and AP-1 dependent IL-8 and VEGF gene expression in head and neck cancer. This up-regulation may promote an angiogenic phenotype favoring invasion in both premalignant and squamous cancer cells of the head and neck.
Subject(s)
Carcinogens/toxicity , Cytokines/metabolism , Head and Neck Neoplasms/metabolism , Neovascularization, Pathologic , Nicotiana/chemistry , Transcription Factor AP-1/metabolism , Up-Regulation/drug effects , Blotting, Western , Cell Line, Tumor , Genes, Reporter , Head and Neck Neoplasms/blood supply , Head and Neck Neoplasms/pathology , Humans , Transcription Factor AP-1/geneticsABSTRACT
In brain, monomeric immunoglobin G (IgG) is regarded as quiescent and only poised to initiate potentially injurious inflammatory reactions via immune complex formation associated with phagocytosis and tumor necrosis factor alpha (TNF-alpha) production in response to disease. Using rat hippocampal slice and microglial cultures, here we show instead that physiological levels (i.e., 0.2-20 microg/ml) of monomeric IgG unassociated with disease triggered benign low-level proinflammatory signaling that was neuroprotective against CA1 area excitotoxicity and followed a U-shaped or hormetic dose-response. The data indicate that physiological IgG levels activated microglia by enhancing recycling endocytosis plus TNF-alpha release from these cells to produce the neuroprotection. Minocycline, known for its anti-inflammatory and neuroprotective effects when given after disease onset, abrogated IgG-mediated neuroprotection and related microglial effects when given before injury. In contrast, E-prostanoid receptor subtype 2 (EP2) activation, which served as an exemplary paracrine stimulus like the one expected from neuronal activity, amplified IgG-mediated increased microglial recycling endocytosis and TNF-alpha production. Furthermore, like monomeric IgG these EP2 related effects took days to be effective, suggesting both were adaptive anabolic effects consistent with those seen from other long-term preconditioning stimuli requiring de novo protein synthesis. The data provide the first evidence that brain monomeric IgG at physiological levels can have signaling function via enhanced recycling endocytosis/TNF-alpha production from microglia unassociated with disease and that these IgG-mediated changes may be a means by which paracrine signaling from neuronal activity influences microglia to evoke neuroprotection. The data provide further support that low-level proinflammatory neural immune signaling unassociated with disease enhances brain function.
Subject(s)
Endocytosis/physiology , Immunoglobulin G/pharmacology , Microglia/drug effects , Microglia/physiology , Neuroprotective Agents/pharmacology , Tumor Necrosis Factor-alpha/metabolism , Animals , Cells, Cultured , Dinoprostone/pharmacology , Dose-Response Relationship, Drug , Ectodysplasins/metabolism , Endocytosis/drug effects , Glucose/deficiency , Hippocampus , Hypoxia , Immunoglobulin G/cerebrospinal fluid , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lysosomal-Associated Membrane Protein 1/metabolism , Minocycline/pharmacology , N-Methylaspartate/toxicity , Neurotoxins/toxicity , Organ Culture Techniques , Phosphopyruvate Hydratase/metabolism , Rats , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/pharmacology , rab GTP-Binding Proteins/metabolismABSTRACT
PURPOSE: Despite several new treatment options, single- and multi-institution analyses have not clarified whether survival patterns in follicular lymphoma (FL) patients have changed in recent decades. We undertook a study using a large population-based registry to analyze survival patterns among patients with FL. PATIENTS AND METHODS: Surveillance, Epidemiology, and End Results morphology codes were used to identify 14,564 patients diagnosed with FL between 1978 and 1999. Observed median survival times, Kaplan-Meier survival curves, proportional death hazard ratios, and relative survival rates were calculated. Joinpoint regression analysis was used to identify trends in annual adjusted death hazard ratios. RESULTS: An improvement in survival of all patients with FL was observed between each of three diagnosis eras (1978 to 1985, 1986 to 1992, and 1993 to 1999) by log-rank tests. Among patients with stage-specific data, the median survival time improved from 84 months (95% CI, 81 to 88 months) in the 1983 to 1989 era to 93 months (95% CI, 89 to 97 months) in the 1993 to 1999 era. Similar findings were identified across sex and age groups and for subsets including advanced-stage, large-cell FL and the combined subset of small cleaved- and mixed-cell FL. The inter-era survival advantage observed in white patients was not observed for black patients. The relative risk of death decreased by 1.8% per year over the 1983 to 1999 observation period. CONCLUSION: The survival of patients with FL in the United States has improved over the last 25 years. The survival improvement may be a result of the sequential application of effective therapies and improved supportive care.