With the advent of targeted agents for the treatment of renal cell carcinoma (RCC), overall survival has improved, and patients are being treated continuously for increasingly long periods of time. This has raised challenges in the management of adverse events (AEs) associated with the six targeted agents approved in RCC-sorafenib, sunitinib, pazopanib, bevacizumab (in combination with interferon alpha), temsirolimus, and everolimus. Suggestions for monitoring and managing AEs have been published, but there are few consensus recommendations. In addition, there is a risk that patients will be subjected to multiple unnecessary investigations. In this review, we aimed to identify the level of supporting evidence for suggested AE management strategies to provide practical guidance on essential monitoring and management that should be undertaken when using targeted agents. Five databases were systematically searched for relevant English language articles (including American Society of Clinical Oncology abstracts) published between January 2007 and March 2011; European Society of Medical Oncology congress abstracts were hand searched. Strategies for AE management were summarized and categorized according to the level of recommendation. A total of 107 articles were identified that describe a large number of different investigations for monitoring AEs and interventions for AE management. We identify and summarize clear recommendations for the management of dermatologic, gastrointestinal, thyroid, cardiovascular, and other AEs, based predominantly on expert opinion. However, because the evidence for the suggested management strategies is largely anecdotal, there is a need for further systematic investigation of management strategies for AEs related to targeted therapies for RCC.

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Cell-based cardiac repair has emerged as an attractive approach to preventing or reversing heart failure resulting from myocyte dysfunction-e.g., due to infarction-and to enhancing the development of collaterals in patients with symptoms of myocardial ischemia. These two problems involve both overlapping and differing mechanisms, and these differences must be considered in cell-based therapies. In terms of myocardial dysfunction due to infarction, only committed cardiomyocytes have been shown to form new myocardium that is electrically coupled with the host heart. Despite this, multiple cell populations appear to improve function of the infarcted heart, including many that are clearly nonmyogenic. In terms of myocardial ischemia, although cell-based strategies improve ischemia in animal models, clinical trials to date have not shown robustly beneficial results. We review the evidence for potential mechanisms underlying the benefits of cell transplantation in the heart and discuss the clinical contexts in which they may be relevant.

Background-Thus far, it is unknown whether there is functional collateral flow through preexisting anastomoses in patients with angiographically normal coronary arteries. Such preformed coronary collateral vessels could form the basis for subsequently developing protective natural bypasses in the presence of coronary artery disease. Methods and Results-Among 100 patients, the collateral flow index (CFI) was measured in coronary arteries without stenotic lesions. The CFI was determined by simultaneous measurement of mean aortic pressure, central venous pressure, and coronary wedge pressure via a sensor-tipped guidewire at the end of a 1-minute balloon occlusion. Patients were divided in 2 groups according to complete angiographic absence (51 patients) or partial presence (49 patients) of stenotic lesions in coronary arteries other than that undergoing collateral measurement. CFI in all patients (61Ϯ10 years; men/women, 69/31) amounted to 0.18Ϯ0.08 (range, 0.04 to 0.36). It showed a normal Gaussian frequency distribution; 22 individuals had a CFI Ն0.25, a value that was empirically found to represent well-developed collaterals protective against myocardial ischemia during coronary occlusion. Accordingly, 17 patients did not reveal signs of myocardial ischemia during coronary balloon occlusion, as assessed from an intracoronary ECG, and 26 patients did not experience angina pectoris during occlusion. Conclusion-In humans with angiographically normal coronary arteries, there are functional collateral vessels to the extent that one fifth to one quarter of them do not show signs of myocardial ischemia during brief vascular occlusions.

Background— The prognostic relevance of the collateral circulation is still controversial. The goal of this study was to assess the impact on survival of quantitatively obtained, recruitable coronary collateral flow in patients with stable coronary artery disease during 10 years of follow-up. Methods and Results— Eight-hundred forty-five individuals (age, 62±11 years), 106 patients without coronary artery disease and 739 patients with chronic stable coronary artery disease, underwent a total of 1053 quantitative, coronary pressure–derived collateral measurements between March 1996 and April 2006. All patients were prospectively included in a collateral flow index (CFI) database containing information on recruitable collateral flow parameters obtained during a 1-minute coronary balloon occlusion. CFI was calculated as follows: equation where P occl is mean coronary occlusive pressure, P ao is mean aortic pressure, and CVP is central venous pressure. Patients were divided into groups with poorly developed (CFI <0.25) or well-grown collateral vessels (CFI ≥0.25). Follow-up information on the occurrence of all-cause mortality and major adverse cardiac events after study inclusion was collected. Cumulative 10-year survival rates in relation to all-cause deaths and cardiac deaths were 71% and 88%, respectively, in patients with low CFI and 89% and 97% in the group with high CFI ( P =0.0395, P =0.0109). Through the use of Cox proportional hazards analysis, the following variables independently predicted elevated cardiac mortality: age, low CFI (as a continuous variable), and current smoking. Conclusions— A well-functioning coronary collateral circulation saves lives in patients with chronic stable coronary artery disease. Depending on the exact amount of collateral flow recruitable during a brief coronary occlusion, long-term cardiac mortality is reduced to one fourth compared with the situation without collateral supply.

Background-Previous studies have demonstrated that macrophages and CD4ϩ T lymphocytes play pivotal roles in collateral development. Indirect evidence suggests that CD8 ϩ T cells also play a role. Ϫ/Ϫ mice immediately after femoral artery ligation, they selectively homed to the ischemic hind limb but were unable to recruit CD4 ϩ mononuclear cells and did not improve blood flow recovery. Conclusions-These results demonstrate that CD8ϩ T cells importantly contribute to the early phase of collateral development. After femoral artery ligation, CD8 ϩ T cells infiltrate the site of collateral vessel growth and recruit CD4 ϩ mononuclear cells through the expression of IL-16. Our study provides further evidence of the significant role of the immune system in modulating collateral development in response to peripheral ischemia. (Circulation. 2006;113:118-124.)

A subcutaneous-only, short-term protocol of GM-CSF is effective in promoting coronary collateral artery growth among patients with CAD. However, the drug's safety regarding the occurrence of acute coronary syndrome is questionable.

Background In humans, it is not known whether physical endurance exercise training promotes coronary collateral growth. The following hypotheses were tested: the expected collateral flow reduction after percutaneous coronary intervention of a stenotic lesion is prevented by endurance exercise training; collateral flow supplied to an angiographically normal coronary artery improves in response to exercise training; there is a direct relationship between the change of fitness after training and the coronary collateral flow change. Methods and results Forty patients (age 61 ± 8 years) underwent a 3-month endurance exercise training program with baseline and follow-up assessments of coronary collateral flow. Patients were divided into an exercise training group (n = 24) and a sedentary group (n = 16) according to the fact whether they adhered or not to the prescribed exercise program, and whether or not they showed increased endurance (V o 2max in ml/min per kg) and performance (W/kg) during follow-up versus baseline bicycle spiroergometry. Collateral flow index (no unit) was obtained using pressure sensor guidewires positioned in the coronary artery undergoing percutaneous coronary intervention and in a normal vessel. In the vessel initially undergoing percutaneous coronary intervention, there was an increase in collateral flow index among exercising but not sedentary patients from 0.155 ± 0.081 to 0.204 ± 0.056 (P=0.03) and from 0.189 ± 0.084 to 0.212 ± 0.077 (NS), respectively. In the normal vessel, collateral flow index changes were from 0.176 ± 0.075 to 0.227 ± 0.070 in the exercise group (P=0.0002), and from 0.219 ± 0.103 to 0.238 ± 0.086 in the sedentary group (NS). A direct correlation existed between the change in collateral flow index from baseline to follow-up and the respective alteration of V o 2max (P=0.007) and Watt (P=0.03). Conclusion A 3-month endurance exercise training program augments coronary collateral supply to normal vessels, and even to previously stenotic arteries having undergone percutaneous coronary intervention before initiating the program. There appears to be a dose–response relation between coronary collateral flow augmentation and exercise capacity gained.