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BACKGROUND: Intra-arterial administration of melphalan chemotherapy has shown promise in the treatment of retinoblastoma. This report describes our results using superselective intra-arterial melphalan in patients with newly diagnosed retinoblastoma and those who were treated for progression after systemic chemotherapy. METHODS: This is a retrospective review of all retinoblastoma patients treated with intra-arterial melphalan at the University of California, San Francisco from March 2010 to August 2012. Twenty eyes (16 patients) underwent 40 intra-arterial melphalan infusions, and dose was determined by age. Patients were treated at monthly intervals and received a range of 1-5 treatments. Response to therapy, toxicity, and procedural radiation exposure was assessed. RESULTS: All patients are alive without metastatic disease at a median follow-up of 14.5 (1-29) months. Treatment with enucleation or external beam radiation was avoided in 11/20 eyes (55%) overall [6/12 (50%) in newly diagnosed eyes and 5/8 (63%) in refractory/relapsed eyes]. Response rates (per the International Classification of Retinoblastoma) were as follows: 6/7 (86%) in groups A-C and 5/13 (38%) in groups D and E. Nonhematologic and hematologic toxicities were minimal and comparable with those in previous reports. The mean procedural radiation dose was 20.2 ± 11.9 mGy per eye per procedure. CONCLUSION: Superselective intra-arterial melphalan therapy is effective for less advanced eyes but further modifications to therapy are required to improve results in eyes with advanced retinoblastoma.

Introduction: Triage of patients is critical to patient safety, yet no clear information exists as to the utility of initial vital signs in identifying critically ill older emergency department (ED) patients. The objective of this study is to evaluate a set of initial vital sign thresholds as predictors of severe illness and injury among older adults presenting to the ED.Methods: We reviewed all visits by patients aged 75 and older seen during 2007 at an academic ED serving a large community of older adults. Patients’ charts were abstracted for demographic and clinical information including vital signs, via automated electronic methods. We used bivariate analysis to investigate the relationship between vital sign abnormalities and severe illness or injury, defined as intensive care unit (ICU) admission or ED death. In addition, we calculated likelihood ratios for normal and abnormal vital signs in predicting severe illness or injury.Results: 4,873 visits by patients aged 75 and above were made to the ED during 2007, and of these 3,848 had a complete set of triage vital signs. For these elderly patients, the sensitivity and specificity of an abnormal vital sign taken at triage for predicting death or admission to an ICU were 73% (66,81) and 50% (48,52) respectively (positive likelihood ratio 1.47 (1.30,1.60); negative likelihood ratio 0.54 (0.30,0.60).Conclusion: Emergency provider assessment and triage scores that rely primarily on initial vital signs are likely to miss a substantial portion of critically ill older adults. [West J Emerg Med. 2013;14(5):453–460.]

ObjectiveTissue glucocorticoid (GC) levels are regulated by the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme is expressed in cells and tissues arising from mesenchymal stromal cells. Proinflammatory cytokines dramatically increase expression of 11β-HSD1 in stromal cells, an effect that has been implicated in inflammatory arthritis, osteoporosis, obesity, and myopathy. Additionally, GCs act synergistically with proinflammatory cytokines to further increase enzyme expression. The present study was undertaken to investigate the mechanisms underlying this regulation.MethodsGene reporter analysis, rapid amplification of complementary DNA ends (RACE), chemical inhibition experiments, and genetic disruption of intracellular signaling pathways in mouse embryonic fibroblasts (MEFs) were used to define the molecular mechanisms underlying the regulation of 11β-HSD1 expression.ResultsGene reporter, RACE, and chemical inhibitor studies demonstrated that the increase in 11β-HSD1 expression with tumor necrosis factor α (TNFα)/interleukin-1β (IL-1β) occurred via the proximal HSD11B1 gene promoter and depended on NF-κB signaling. These findings were confirmed using MEFs with targeted disruption of NF-κB signaling, in which RelA (p65) deletion prevented TNFα/IL-1β induction of 11β-HSD1. GC treatment did not prevent TNFα-induced NF-κB nuclear translocation. The synergistic enhancement of TNFα-induced 11β-HSD1 expression with GCs was reproduced by specific inhibitors of p38 MAPK. Inhibitor and gene deletion studies indicated that the effects of GCs on p38 MAPK activity occurred primarily through induction of dual-specificity phosphatase 1 expression.ConclusionThe mechanism by which stromal cell expression of 11β-HSD1 is regulated is novel and distinct from that in other tissues. These findings open new opportunities for development of therapeutic interventions aimed at inhibiting or stimulating local GC levels in cells of mesenchymal stromal lineage during inflammation.

BackgroundA few recent studies have demonstrated heightened hypothalamic-pituitary-adrenal (HPA) axis reactivity to acute stress in animals exposed to heavy metal contaminants, particularly lead. However, Pb-induced dysregulation of the HPA axis has not yet been studied in humans.ObjectiveIn this study, we examined children's cortisol response to acute stress (the glucocorticoid product of HPA activation) in relation to low-level prenatal and postnatal Pb exposure.MethodsChildren's prenatal blood Pb levels were determined from cord blood specimens, and postnatal lead levels were abstracted from pediatrician and state records. Children's adrenocortical responses to an acute stressor were measured using assays of salivary cortisol before and after administration of a standard cold pressor task.ResultsPb exposure was not associated with initial salivary cortisol levels. After an acute stressor, however, increasing prenatal and postnatal blood Pb levels were independently associated with significantly heightened salivary cortisol responses.ConclusionsOur results suggest that relatively low prenatal and postnatal blood lead levels--notably those below the 10 microg/dL blood lead level identified by the Centers for Disease Control and Prevention for public health purposes--can alter children's adrenocortical responses to acute stress. The behavioral and health consequences of this Pb-induced HPA dysregulation in children have yet to be determined.

PurposeCancer cachexia is a devastating and understudied illness in patients with head and neck squamous cell carcinoma (HNSCC). The primary objective was to identify clinical characteristics and serum levels of cytokines and cachexia-related factors in patients with HNSCC. The secondary objective was to detect the occurrence of cytokine and cachexia-related factor gene expression in HNSCC tumors.Experimental designFor the primary objective, cross-sectional data were obtained from prospectively recruited patients identified as cachexia cases and matching cachexia-free controls. For the secondary objective, a retrospective cohort design with matched controls was used.ResultsClinical characteristics associated with cancer cachexia in HNSCC were T(4) status (P = 0.01), increased C-reactive protein (P = 0.01), and decreased hemoglobin (P < 0.01). Exploratory multiplex analysis of serum cytokine levels found increased interleukin (IL)-6 (P = 0.04). A highly sensitive ELISA confirmed the multiplex result for increased IL-6 in cachectic patients (P = 0.02). Quality of life was substantially reduced in patients with cachexia compared with noncachectic patients (P < 0.01). All tumors of HNSCC patients both with and without cachexia expressed RNA for each cytokine tested and the cachexia factor lipid-mobilizing factor. There were no statistically significant differences between the cytokine and cachexia factor RNA expression of cachectic and noncachectic patients (each P > 0.05). No tumors expressed the cachexia factor proteolysis-inducing factor.ConclusionWe have identified clinical characteristics and pathophysiologic mechanisms associated with cancer cachexia in a carefully defined population of patients with HNSCC. The data suggest that the acute-phase response and elevated IL-6 are associated with this complex disease state. We therefore hypothesize that IL-6 may represent an important therapeutic target for HNSCC patients with cancer cachexia.

Stromal cells such as fibroblasts play an important role in defining tissue-specific responses during the resolution of inflammation. We hypothesized that this involves tissue-specific regulation of glucocorticoids, mediated via differential regulation of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Expression, activity and function of 11beta-HSD1 was assessed in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid arthritis or osteoarthritis. 11beta-HSD1 was expressed in fibroblasts from all tissues but mRNA levels and enzyme activity were higher in synovial fibroblasts (2-fold and 13-fold higher mRNA levels in dermal and synovial fibroblasts, respectively, relative to bone marrow). Expression and activity of the enzyme increased in all fibroblasts following treatment with tumour necrosis factor-alpha or IL-1beta (bone marrow: 8-fold and 37-fold, respectively, compared to vehicle; dermal fibroblasts: 4-fold and 14-fold; synovial fibroblasts: 7-fold and 31-fold; all P < 0.01 compared with vehicle). Treatment with IL-4 or interferon-gamma was without effect, and there was no difference in 11beta-HSD1 expression between fibroblasts (from any site) obtained from patients with rheumatoid arthritis or osteoarthritis. In the presence of 100 nmol/l cortisone, IL-6 production--a characteristic feature of synovial derived fibroblasts--was significantly reduced in synovial but not dermal or bone marrow fibroblasts. This was prevented by co-treatment with an 11beta-HSD inhibitor, emphasizing the potential for autocrine activation of glucocorticoids in synovial fibroblasts. These data indicate that differences in fibroblast-derived glucocorticoid production (via the enzyme 11beta-HSD1) between cells from distinct anatomical locations may play a key role in the predeliction of certain tissues to develop persistent inflammation.