There were no objective responses seen with single-agent fosbretabulin as administered in this trial, and we did not observe a doubling of survival as our primary endpoint. This is among the largest prospective trials ever conducted for ATC. Fosbretabulin has an acceptable safety profile in patients with advanced ATC, and one-third survived more than 6 months. Despite a small sample size, low baseline sICAM levels were predictive of event-free survival. Further prospective validation of sICAM as a therapeutic biomarker and exploring combination regimens with fosbretabulin are warranted.

Vascular disrupting agents (VDAs), or endothelial disrupting agents, attempt to exploit the vascular endothelium that supplies rapidly dividing neoplasms. Unlike antiangiogenesis agents (e.g. the monoclonal antibody bevacizumab; and tyrosine kinase inhibitors sorafenib and sunitinib) that disrupt endothelial cell survival mechanisms and the development of a new tumor blood supply, VDAs are designed to disrupt the already established abnormal vasculature that supports tumors, by targeting their dysmorphic endothelial cells. Tumor vascular endothelium is characterized by its increased permeability, abnormal morphology, disorganized vascular networks, and variable density. VDAs induce rapid shutdown of tumor blood supply, causing subsequent tumor death from hypoxia and nutrient deprivation. The safety profile of this class of compounds is more indicative of agents that are indeed 'vascularly' active. For example, VDAs can cause: acute coronary and other thrombophlebitic syndromes; alterations in blood pressure, heart rate, and ventricular conduction; transient flush and hot flashes; neuropathy; and tumor pain. Despite these cardiovascular concerns some patients have benefited from VDAs in early clinical trials. Further drug development of VDAs must include the combination of these agents with other novel biological agents, cytotoxic chemotherapy, and radiotherapy. Close monitoring of patients receiving VDAs for any cardiovascular toxicity is imperative.

No abstract

There are three US Food and Drug Administration-approved angiogenesis inhibitors for the treatment of cancer that specifically target vascular endothelial growth factor (VEGF) signaling. Bevacizumab (monoclonal antibody to VEGF) has been shown to confer a survival advantage when used in combination with cytotoxic chemotherapy in patients with colorectal cancer and nonsmall-cell lung cancer. 1,2 Sorafenib and sunitinib are orally bioavailable, small-molecule tyrosine kinase inhibitors that target the intracellular tyrosine kinase domain of the VEGF receptor (VEGFR) among other tyrosine kinase targets. Sorafenib has been shown to increase progression-free survival in patients with renal cell carcinoma. 3 Sunitinib has been shown to increase progressionfree survival in patients with renal cell carcinoma and GI stromal tumors. [4][5][6] A plethora of new small-molecule tyrosine kinase inhibitors are in preclinical development and early-phase clinical trials that target VEGFR with varying degrees of specificity, including AZD2171, which is the subject of a published report by Drevs et al in this issue of the Journal of Clinical Oncology. 7,8 Notable clinical and biologic observations reported in their phase I study were correlation between AZD2171 pharmacokinetics and perturbation of tumor blood flow in part A of their study (not confirmed in part B, perhaps attributable to smaller dose range investigated); increased VEGF levels and decreased VEGFR-2 for which there were no clear pharmacodynamic correlations, and only a possible hint of a dose-response effect; and demonstrable clinical activity. The appearance of hypertension as the most common dose-limiting toxicity and hypertensive crisis in three patients, we feel, is also very interesting, and it is the subject of our invited commentary. There is a possible dose-response effect but a missed opportunity to correlate hypertensive changes with either drug concentration or exposure and perhaps even clinical response (though limited in phase I setting). Hypertension with this class of anticancer compounds is an emerging toxicity that oncologists must be comfortable in managing. Furthermore, it is

Isolated pulmonic valve infective endocarditis is an uncommon clinical entity. We report our experience with three patients diagnosed with pulmonic valve endocarditis from our institution. Two cases were caused by Enterococcus faecalis (one was resistant to vancomycin) and one by coagulase-negative staphylococci (CNS). One of the cases of isolated pulmonic valve endocarditis due to the E. faecalis was nosocomially acquired; the case of CNS pulmonic valve endocarditis was dialysis catheter related. Each patient with isolated pulmonic valve endocarditis presented with hypotension and interstitial pulmonary infiltrates. Two patients were treated with linezolid. Both vancomycin-resistant enterococci (VRE) and CNS were eliminated from blood cultures on linezolid therapy. The challenges inherent in the management of pulmonic valve endocarditis mandate the development of individual patient-specific guidelines.

US Department of Veterans Affairs Cooperative Studies Program.

No abstract

Myocardial stunning, known as stress cardiomyopathy, broken-heart syndrome, transient left ventricular apical ballooning, and Takotsubo cardiomyopathy, has been reported after many extracardiac stressors, but not following chemotherapy. We report 2 cases with characteristic electrocardiographic and echocardiographic features following combined modality therapy with combretastatin, a vascular-disrupting agent being studied for treatment of anaplastic thyroid cancer. In 1 patient, an ECG performed per protocol 18 hours after drug initiation showed deep, symmetric T-wave inversions in limb leads I and aVL and precordial leads V 2 through V 6 . Echocardiography showed mildly reduced overall left ventricular systolic function with akinesis of the entire apex. The patient had mild elevations of troponin I. Coronary angiography revealed no epicardial coronary artery disease. The electrocardiographic and echocardiographic abnormalities resolved after several weeks. The patient remains stable from a cardiovascular standpoint and has not had a recurrence during follow-up. An electrocardiogram performed per protocol in a second patient showed deep, symmetric T-wave inversions throughout the precordial leads and a prolonged QT interval. Echocardiography showed mildly reduced left ventricular function with hypokinesis of the apical-septal wall. Acute coronary syndrome was ruled out, and both the electrocardiographic and echocardiographic changes resolved at follow-up. Although the patient remained pain-free without recurrence of anginal symptoms during long-term follow-up, the patient developed progressive malignancy and died. IntroductionMyocardial stunning, known as stress cardiomyopathy, broken heart syndrome, left ventricular apical ballooning, and Takotsubocardiomyopathyis defined as: left ventricular apical ballooning on echocardiography or ventriculography; no angiographic stenoses > 50%; and no history of known cardiomyopathy. While the patient in the first of our 2 case reports fulfills these criteria, the second patient had a positive stress test following the incident but did not undergo coronary angiography, so ischemic heart disease was not excluded.Combretastatin may precipitate acute coronary syndrome. 1 A 57-year-old male with pancreatic cancer developed chest pain 80 minutes after combretastatin, and ECG showed acute myocardial infarction. Coronary angiography demonstrated an occluded distal left anterior descending artery. A 77-year-old male developed ECG changes and elevated troponin I following combretastatin. Coronary angiography revealed 2-vessel coronary artery disease.