The Role Of Tumor-Associated Macrophages In Human Skin Cancer

Inflammation has long been associated with tumorigenesis. Macrophages are cells of the innate immune system, whose density within tumors correlates with a worsening clinical prognosis in most types of tumors. Macrophages have been demonstrated to contribute to the initiation, growth, invasion, and metastasis of tumors. We hypothesized that macrophage density and phenotype differs between squamous cell carcinomas and basal cell carcinomas, two skin cancers with relatively aggressive and indolent clinical behaviors, respectively. Through immunohistochemical analysis, we determined that squamous cell carcinomas have a 5-fold higher density of macrophages than basal cell carcinomas. Tumor-associated macrophages exhibit two classic states of activation. M1 macrophages are inflammatory and are involved in clearance of microorganisms and tumor cells. By contrast, M2 macrophages are involved in tissue remodeling, angiogenesis, and are tumor-promoting. Using flow cytometric analysis of fresh clinical specimens, we determined that macrophages from squamous cell carcinomas express significantly higher levels of M1 (CD40, CD127) and M2 (arginase I) markers as well as higher levels of MMP-9, a pivotal enzyme in tumor matrix remodeling and tumor invasion, than macrophages from the basal cell carcinomas. To determine whether the Toll-like receptor (TLR) agonist imiquimod, an FDA-approved treatment for superficial basal cell carcinoma and actinic keratoses, alters the activation state of tumor-associated macrophages, we studied in vitro and in vivo effects of imiquimod on macrophages. We determined that imiquimod activates primary macrophages from human squamous cell carcinoma to an M1, pro-inflammatory immunophenotype. This phenotype was associated with enhanced macrophage-induced apoptosis of cultured epidermoid carcinoma cells and enhanced phagocytosis of fluorescently labeled tumor cells. Our findings suggest that tumor-associated macrophages play a critical role in pathophysiology of two common human skin cancers. Further, we provide a novel mechanism of action of imiquimod, which provides potential insights in the utilization of immunomodulatory therapies in the treatments of a wider variety of cancers

Generalized bullous fixed drug eruption treated with cyclosporine

Fixed drug eruptions (FDE) comprise 10 percent of alladverse cutaneous drug reactions and generalizedbullous fixed drug eruptions (GBFDE) are a raresubset of FDEs. We present a patient with severeGBFDE caused by ibuprofen successfully treated withcyclosporine. Further work is needed to determine ifcyclosporine can be an effective therapy for GBFDE

Regional differences in treatment for osteoporosis. The Global Longitudinal Study of Osteoporosis in Women (GLOW).

PurposeTo determine if important geographic differences exist in treatment rates for osteoporosis and whether this variation can be explained by regional variation in risk factors.MethodsThe Global Longitudinal Study of Osteoporosis in Women is an observational study of women ≥55 years sampled from primary care practices in 10 countries. Self-administered questionnaires were used to collect data on patient characteristics, risk factors for fracture, previous fractures, anti-osteoporosis medication, and health status.ResultsAmong 58,009 women, current anti-osteoporosis medication use was lowest in Northern Europe (16%) and highest in U.S.A. and Australia (32%). Between 48% (U.S.A., Southern Europe) and 68% (Northern Europe) of women aged ≥65 years with a history of spine or hip fracture since age 45 were untreated. Among women with osteoporosis, the percentage of treated cases was lowest in Europe (45-52% versus 62-65% elsewhere). Women with osteopenia and no other risk factors were treated with anti-osteoporosis medication most frequently in U.S.A. (31%) and Canada (31%), and least frequently in Southern Europe (12%), Northern Europe (13%), and Australia (16%). After adjusting for risk factors, U.S. women were threefold as likely to be treated with anti-osteoporosis medication as Northern European women (odds ratio 2.8; 95% confidence interval 2.5-3.1) and 1.5 times as likely to be treated as Southern European women (1.5, 1.4-1.6). Up to half of women reporting previous hip or spine fracture did not receive treatment.ConclusionsThe likelihood of being treated for osteoporosis differed between regions, and cannot be explained by variation in risk factors. Many women at risk of fracture do not receive prophylaxis

Impact of prevalent fractures on quality of life: baseline results from the global longitudinal study of osteoporosis in women.

ObjectiveTo examine several dimensions of health-related quality of life (HRQL) in postmenopausal women who report previous fractures, and to provide perspective by comparing these findings with those in other chronic conditions (diabetes, arthritis, lung disease).Patients and methodsFractures are a major cause of morbidity among older women. Few studies have examined HRQL in women who have had prior fractures and the effect of prior fracture location on HRQL. In this observational study of 57,141 postmenopausal women aged 55 years and older (enrollment from December 2007 to March 2009) from 17 study sites in 10 countries, HRQL was measured using the European Quality of Life 5 Dimensions Index (EQ-5D) and the health status, physical function, and vitality questions of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36).ResultsReductions in EQ-5D health-utility scores and SF-36-measured health status, physical function, and vitality were seen in association with 9 of 10 fracture locations. Spine, hip, and upper leg fractures resulted in the greatest reductions in quality of life (EQ-5D scores, 0.62, 0.64, and 0.61, respectively, vs 0.79 without prior fracture). Women with fractures at any of these 3 locations, as well as women with a history of multiple fractures (EQ-5D scores, 0.74 for 1 prior fracture, 0.68 for 2, and 0.58 for >/=3), had reductions in HRQL that were similar to or worse than those in women with other chronic diseases (0.67 for diabetes, 0.69 for arthritis, and 0.71 for lung disease).ConclusionPrevious fractures at a variety of bone locations, particularly spine, hip, and upper leg, or involving more than 1 location are associated with significant reductions in quality of life

Regional differences in treatment for osteoporosis: The global longitudinal study of osteoporosis in women(GLOW)

Among 58,009 women, current anti-osteoporosis medication use was lowest in Northern Europe (16%) and highest in USA and Australia (32%). Between 48% (USA, Southern Europe) and 68% (Northern Europe) of women aged ? 65 years with a history of spine or hip fracture since age 45 were untreated. Among women with osteoporosis, the percentage of treated cases was lowest in Europe (45–52% versus 62–65% elsewhere). Women with osteopenia and no other risk factors were treated with anti-osteoporosis medication most frequently in USA (31%) and Canada (31%), and least frequently in Southern Europe (12%), Northern Europe (13%), and Australia (16%). After adjusting for risk factors, US women were threefold as likely to be treated with anti-osteoporosis medication as Northern European women (odds ratio 2.8; 95% confidence interval 2.5–3.1) and 1.5 times as likely to be treated as Southern European women (1.5, 1.4–1.6). Up to half of women reporting previous hip or spine fracture did not receive treatment.<br/

Impact of prevalent fractures on quality of life: baseline results from the global longitudinal study of osteoporosis in women

OBJECTIVE: To examine several dimensions of health-related quality of life (HRQL) in postmenopausal women who report previous fractures, and to provide perspective by comparing these findings with those in other chronic conditions (diabetes, arthritis, lung disease). PATIENTS AND METHODS: Fractures are a major cause of morbidity among older women. Few studies have examined HRQL in women who have had prior fractures and the effect of prior fracture location on HRQL. In this observational study of 57,141 postmenopausal women aged 55 years and older (enrollment from December 2007 to March 2009) from 17 study sites in 10 countries, HRQL was measured using the European Quality of Life 5 Dimensions Index (EQ-5D) and the health status, physical function, and vitality questions of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). RESULTS: Reductions in EQ-5D health-utility scores and SF-36–measured health status, physical function, and vitality were seen in association with 9 of 10 fracture locations. Spine, hip, and upper leg fractures resulted in the greatest reductions in quality of life (EQ-5D scores, 0.62, 0.64, and 0.61, respectively, vs 0.79 without prior fracture). Women with fractures at any of these 3 locations, as well as women with a history of multiple fractures (EQ-5D scores, 0.74 for 1 prior fracture, 0.68 for 2, and 0.58 for ?3), had reductions in HRQL that were similar to or worse than those in women with other chronic diseases (0.67 for diabetes, 0.69 for arthritis, and 0.71 for lung disease). CONCLUSION: Previous fractures at a variety of bone locations, particularly spine, hip, and upper leg, or involving more than 1 location are associated with significant reductions in quality of life. <br/