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Biomedical subjects

Michael Broder

Publications and source records attributed to Michael Broder.

11 recordsLinked to original sources
PubMed2006

Treatment strategies for skeletal complications of cancer.

Skeletal complications are a common result of many cancers, particularly of multiple myeloma and bone metastases of solid tumors originating in the breast, prostate or lung. A number of treatment options are available, including radiotherapy, radiopharmaceuticals, surgery and chemotherapy. Recently, bisphosphonates have emerged as a promising new treatment option for bone complications of cancer. These agents are potent inhibitors of osteoclast activity that bind to the bone matrix, are released during bone resorption, and are subsequently internalized by osteoclasts, where they interfere with biochemical pathways and induce osteoclast apoptosis. Bisphosphonates also antagonize osteoclastogenesis and promote the differentiation of osteoblasts. As a result, bisphosphonates inhibit tumor-induced osteolysis and reduce skeletal morbidity. Bisphosphonates are generally well tolerated, although they have recently been associated with osteonecrosis of the jaw, a painful and debilitating side effect that is only beginning to be understood. Despite this concern, bisphosphonates are an important tool in the management of skeletal complications of cancer, providing benefits for the treatment of hypercalcemia, osteolytic lesions and fractures, as well as offering amelioration of pain and improvement in quality of life.

Bone Neoplasms↗
PubMed2006

Pathophysiology of bone metastases.

Normal bone remodeling maintains an appropriate balance between the action of osteoclasts (bone-resorbing cells) and osteoblasts (bone-forming cells). Skeletal malignancies, including bone metastases, disrupt the OPG-RANKL-RANK signal transduction pathway and promote enhanced osteoclast formation, thereby accelerating bone resorption and inducing bone loss. This osteolysis in turn leads to the release of bone-derived growth factors, contributing to a "vicious cycle" in which interactions between tumor cells and osteoclasts not only lead to increased osteoclastogenesis and osteolytic activity, but also aggressive growth and behavior of the tumor cells. The osteolytic complications associated with bone metastases are caused by tumor-induced alterations of the OPG-RANKL-RANK system, which are accompanied by enhanced bone resorption and disassociated from counterbalancing bone formation by osteoblasts.

Bone Neoplasms↗
PubMed2006

Bone complications in multiple myeloma.

Multiple myeloma is the malignant proliferation of plasma cells involving more than 10% of the bone marrow. The bone complications associated with multiple myeloma include bone pain, pathologic fractures, hypercalcemia of malignancy and cord compressions. The principal pathophysiology of bone disease in multiple myeloma is a shift in the balance of bone remodeling toward bone resorption. In recent years, bisphosphonates have become an important treatment for the bone complications of multiple myeloma. Potent inhibitors of osteoclast activity, bisphosphonates interfere with biochemical pathways and induce osteoclast apoptosis. Bisphosphonates also antagonize osteoclastogenesis and promote differentiation of osteoblasts, as well as inhibiting other aspects of osteoclast homeostasis and metabolism. Several studies have evaluated treatment with bisphosphonates in patients with multiple myeloma, and have demonstrated the efficacy of clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ; www.bonefos.com), pamidronate (Aredia; Novartis Pharmaceuticals Corp; East Hanover, NJ; www.pamidronate.com) and zoledronic acid (Zometa; Novartis Pharmaceuticals Corp; East Hanover, NJ; www.us.zometa.com) in reduction of pain, reduction of SREs and survival. Moreover, recent data suggest direct and indirect antimyeloma activity of pamidronate and zoledronic acid.

Bone Neoplasms↗
PubMed2006

Managing bone complications of solid tumors.

Bone metastases are a common occurrence in patients with breast cancer, lung cancer and prostate cancer. Bone metastases cause considerable morbidity including pain, impaired mobility, pathologic fracture, spinal cord or nerve root compression, bone marrow infiltration and hypercalcemia of malignancy. These complications result from the derangement of normal bone metabolism that arise from interactions between factors originating in tumor cells and others originating in the microenvironment of the bone. Fortunately, there is an increasing array of treatment options for the skeletal complications associated with bone metastases arising from breast, lung, and prostate cancer. The goals of treatment for such skeletal complications are to relieve pain and reduce the risk of fracture. Traditional therapies to treat skeletal malignancies include radiation, surgery, and chemotherapy. In recent years, bisphosphonates have become the treatment of choice because of their ability to reduce bone resorption, leading to decreases in hypercalcemia, new osteolytic lesions, and fractures, thereby ameliorating pain and improving quality of life.

Bone Neoplasms↗
PubMed2006

Tumor necrosis factor antagonists: different kinetics and/or mechanisms of action may explain differences in the risk for developing granulomatous infection.

OBJECTIVE: Tumor necrosis factor (TNF) antagonists fall into 2 classes:etanercept (ETA) is a soluble TNF receptor, while infliximab (INF) and adalimumab (ADA) are monoclonal antibodies against TNF. All 3 drugs are effective in treating rheumatoid arthritis. However, these agents have been associated with an increased risk of granulomatous infections, such as tuberculosis and histoplasmosis. Several reports indicate that the incidence of granulomatous infections may potentially be higher in individuals treated with INF than ETA. METHODS: We conducted a comprehensive literature search (1966 to 2004) to review the role of TNF in normal and disease states, and the mechanisms of action of the TNF inhibitors. Specifically, we searched for possible mechanisms for the apparent increase in granulomatous infections associated with TNF inhibitors and for reasons that there may be differences between them. RESULTS: Infection may result from a number of differences between ETA and INF or ADA. First, binding avidities are different, with ETA binding in a 1:1 ratio and INF/ADA binding in 2 to 3:1 ratios. Second, the clearances of ADA, ETA, and INF are different, being about 13 times higher for ETA than INF or ADA, thus resulting in higher steady-state drug levels for ADA and INF. Also, the methods of administration are different, intravenously (for INF) versus subcutaneously (for ETA and ADA), which results in lower peak concentrations for ETA and ADA, potentially explaining some of the differences in effects on granuloma formation. Third, INF and ADA have somewhat different mechanisms of action from ETA: INF and ADA are associated with antibody-mediated cell lysis, while ETA is not; INF may induce apoptosis in some tissues (eg, gastrointestinal [GI] mucosa) while ETA does not--although this is controversial and may not be true at steady state in synovium, where both drugs seem to cause apoptosis; ETA binds lymphotoxin-alpha while INF does not (ETA may thus be more efficient at preventing granuloma formation by this mechanism than INF); finally, ADA and INF seem to inhibit IFN-gamma expression (probably indirectly), while ETA does not. CONCLUSIONS: There are significant differences between the 2 classes of TNF antagonists in terms of both their kinetics and mechanisms of action. These differences may help explain the apparent differences in the incidence of granuloma-dependent infections among them.

Antirheumatic Agents↗
PubMed2005

Reactivation of latent granulomatous infections by infliximab.

Although infliximab and etanercept share tumor necrosis factor (TNF) as a common therapeutic target, accumulating data indicate that infliximab (an anti-TNF monoclonal antibody) poses a greater risk of reactivation of latent granulomatous infections than does etanercept (a soluble TNF receptor). Similarly, infliximab is effective for the treatment of chronic granulomatous inflammatory conditions (e.g., Crohn disease) for which etanercept is ineffective. The ability of infliximab to disrupt established granulomas may be distinct from its ability to neutralize soluble TNF. Further research to elucidate the mechanism of the antigranuloma activity of infliximab is warranted.

Antibodies, Monoclonal↗
PubMed2005

Does the collaborative model improve care for chronic heart failure?

BACKGROUND: Organizationally based, disease-targeted collaborative quality improvement efforts are widely applied but have not been subject to rigorous evaluation. We evaluated the effects of the Institute of Healthcare Improvement's Breakthrough Series (IHI BTS) on quality of care for chronic heart failure (CHF). RESEARCH DESIGN: We conducted a quasi-experiment in 4 organizations participating in the IHI BTS for CHF in 1999-2000 and 4 comparable control organizations. We reviewed a total of 489 medical records obtained from the sites and used a computerized data collection tool to measure performance on 23 predefined quality indicators. We then compared differences in indicator performance between the baseline and post-intervention periods for participating and non-participating organizations. RESULTS: Participating and control patients did not differ significantly with regard to measured clinical factors at baseline. After adjusting for age, gender, number of chronic conditions, and clustering by site, participating sites showed greater improvement than control sites for 11 of the 21 indicators, including use of lipid-lowering and angiotensin converting enzyme inhibition therapy. When all indicators were combined into a single overall process score, participating sites improved more than controls (17% versus 1%, P < 0.0001). The improvement was greatest for measures of education and counseling (24% versus -1%, P < 0.0001). CONCLUSIONS: Organizational participation in a common disease-targeted collaborative provider interaction improved a wide range of processes of care for CHF, including both medical therapeutics and education and counseling. Our data support the use of programs like the IHI BTS in improving the processes of care for patients with chronic diseases.

Chi-Square Distribution↗
PubMedDate not supplied

Estimating the frequency of tap-water exposures to Mycobacterium avium complex in the U.S. population with advanced AIDS.

Mycobacterium avium complex (MAC) is a group of ubiquitous and opportunistic bacterial pathogens included on the U.S. Environmental Protection Agency Drinking Water Contaminant Candidate List. The risk of contracting a disseminated MAC infection is primarily limited to the immunocompromised, including those with advanced acquired immunodeficiency syndrome (AIDS). These infections likely result from exposures to MAC-contaminated tap water, food, or soil, although the epidemiologic evidence is insufficient to implicate a specific medium. The objective of this study was to assess tap water exposure to MAC in the U.S. population with advanced AIDS, defined here as having fewer than 100 CD4(+) cells/mm(3) of blood. Using limited data on the detection of MAC and self-reported post-tap treatment practices, two exposure models were developed to simulate the likelihood of exposure to MAC via tap water consumption in this sensitive population. The first model integrated data from studies that described sources of water for consumption and post-tap treatment rates in cohorts infected with human immunodeficiency virus (HIV(+)). The second model used data from a study that categorized the fraction of water intake consisting of tap water that was not further treated. Approximately 1500 individuals with advanced AIDS were estimated to ingest tap water with detectable concentrations of MAC organisms daily. Additional studies on tap-water use in U.S. HIV(+) populations are needed to confirm these findings. Longitudinal and cross-sectional studies on the occurrence of MAC in tap water, particularly in regions with large HIV(+)/AIDS populations, would help address some of the uncertainty in these exposure estimates.

AIDS-Related Opportunistic Infections↗