ABSTRACT
Amyloidosis refers to a group of widely diverse conditions characterized by the deposition of insoluble protein within the extracellular space, leading to disruption of normal organ function. AL primary amyloidosis is associated with plasma cell dyscrasias and is caused by the deposition of insoluble kappa or lambda light chains. Cardiac involvement by AL primary amyloidosis has a very poor prognosis, and patients are treated with systemic chemotherapy. Clinically, the presence of cardiac amyloidosis in patients with plasma cell disorders is usually presumed to represent AL primary amyloidosis, and they are often managed as such. We reported four cases of elderly patients with plasma cell disorders who were found to have biopsy-proven cardiac senile transthyretin amyloidosis. Our cases demonstrated that cardiac amyloidosis in patients with plasma cell disorders does not necessarily represent AL primary amyloidosis. Cardiac biopsy is important in making the correct diagnosis. Accurate subtyping of the amyloid has significant implications in the management of patients and discussion of prognosis.
ABSTRACT
Highly active antiretroviral therapy (HAART) has significantly improved the outcome and survival of human immunodeficiency virus (HIV)-infected patients. Subsequently, long-term morbidities including cancer have become of major public health and clinical interest for this patient population. Plasma cell disorders occur at higher incidence in HIV-infected patients; however, the molecular mechanisms driving the plasma cell disease process and the optimal management for these patients remain to be defined. This article provides an up-to-date review of the characteristics and management of HIV-infected patients with plasma cell disorders. We first present 3 cases of plasma cell disorders in HIV-infected patients, ranging from polyclonal hypergammaglobulinemia to symptomatic multiple myeloma. We then discuss the epidemiology, clinical presentation, and management of each of these plasma cell disorders, with an emphasis on the molecular events underlying the progression of plasma cell diseases from monoclonal gammopathy to symptomatic multiple myeloma. We propose a three-step hypothesis for the development of multiple myeloma. Finally, we discuss the use of high dose chemotherapy and autologous hematopoietic stem cell transplantation in the treatment of HIV-infected patients with multiple myeloma. Our review includes the care of HIV-infected patients with plasma cell disorders in the current era of HAART and novel agents available for the treatment of multiple myeloma.
ABSTRACT
Many cancer drugs impact cancer cell redox regulatory mechanisms and disrupt redox homeostasis. Pharmacodynamic biomarkers that measure therapeutic efficacy or toxicity could improve patient management. Using immunoblot analyses and mass spectrometry, we identified that serpins A1 and A3 were S-glutathionylated in a dose- and time-dependent manner following treatment of mice with drugs that alter reactive oxygen or nitrogen species. Tandem mass spectrometry analyses identified Cys(256) of serpin A1 and Cys(263) of serpin A3 as the S-glutathionylated residues. In human plasma from cancer patients, there were higher levels of unmodified serpin A1 and A3, but following treatments with redox active drugs, relative S-glutathionylation of these serpins was higher in plasma from normal individuals. There is potential for S-glutathionylated serpins A1 and A3 to act as pharmacodynamic biomarkers for evaluation of patient response to drugs that target redox pathways.