A Phase I Protocol of Hydralazine and Valproic Acid in Advanced, Previously Treated Solid Cancers.

Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.

Treatment of venous thromboembolism: guidelines translated for the clinician.

Venous thromboembolism is a major cause of morbidity and mortality affecting over 2 million people in the United States each year. The American College of Chest Physicians (ACCP) published their first consensus statement on antithrombotic therapy in 1986, and the most recent guidelines from the ACCP on this topic were released in 2008. We aim to summarize the most recent ACCP guidelines on therapy for venous thromboembolism with practical application and interpretation for the practicing physician. We will briefly review the rating system used in the guidelines for the level of evidence and the strength of the recommendation. We will then discuss the recommendations for initial anticoagulant therapies including low molecular weight heparin, unfractionated heparin, and fondaparinux for patients with both deep vein thrombosis (DVT) and pulmonary embolism (PE). A discussion of the guidelines on duration of anticoagulant therapy with a vitamin K antagonist is also included. In addition, we will address the use of thrombolytic therapy and inferior vena cava filter placement for DVT and PE. Prevention of postphlebitic syndrome is discussed as well. We will conclude with a brief discussion of future directions including several novel therapeutic anticoagulants.