Citations

Abstract Because numerous chemotherapeutic agents exert their cytotoxic effects through generation of reactive oxygen species, the use of antioxidant supplements during treatment is controversial. There are published recommendations to suspend antioxidant supplement use during treatment, despite lack of empirical data from clinical studies; however, it is unclear if patients follow these recommendations. We examined use of multivitamins and vitamin supplements (MV/SP) during treatment for breast cancer, particularly in relation to physician recommendations. High-risk breast cancer patients (n=855) were queried regarding physician recommendations and use of MV/SP via self-administered questionnaires in an ancillary study embedded in a phase III trial of dose-dense compared to metronomic administration of doxorubicin/cyclophosphamide + paclitaxel (SWOG S0221). Of the 658 patients who reported discussing use of supplements during treatment with their physicians, 390 (59%) received no counseling regarding MV/SP use, 85 (13%) received recommendations not to take MV/SP, and 183 (28%) received recommendations to use MV/SP. MV/SP use during treatment was compared to use prior to diagnosis in relation to physician recommendations, with the reference group comprised of those receiving no recommendations. Of those using MV ≥ once/week before diagnosis, recommendations not to take MV/SP were associated with a tenfold reduction in MV use to < once/week during treatment. (OR=10.0, 95% CI=3.7-27.0). MV use was less likely to decrease among patients receiving recommendations to use MV/SP (OR=0.23, 95% CI=0.12-0.44). Similar findings were observed among patients who reported use of vitamin C and vitamin E supplements ≥ once/week before diagnosis, with patients who were advised to take no supplements other than a MV more than 5 times as likely to decrease use of antioxidant supplements. MV use during treatment among previous non-users increased almost sixfold among those whose physicians recommended MV/SP use during treatment (OR=5.92, 95% CI=3.29-10.6). For those reporting vitamin C or vitamin E use < once/week before diagnosis, patients whose physicians recommended MV/SP during treatment were more likely to increase their use of vitamin C (OR=2.05, 95% CI=1.00-4.19) and vitamin E (OR=5.28, 95% CI=2.24-12.4). In this study, physician recommendations were strongly associated with patient use of MV/SP during chemotherapy, regardless of the patient's frequency of use prior to diagnosis. These findings highlight the critical need to better understand the mechanisms by which antioxidants may influence chemotherapeutic outcomes, and to determine if supplement use affects toxicity and/or recurrence. Yearly follow-up in this ongoing study will allow us to assess the impact of MV/SP use treatment outcomes, providing a basis for physician recommendations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4681. doi:10.1158/1538-7445.AM2011-4681

Abstract Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. We previously demonstrated significant synergy of the mTOR inhibitor sirolimus with RT in glioma xenografts. This Phase I study evaluated the safety and tolerability of combined therapy with the mTOR inhibitor RAD001, RT and TMZ. Methods: All patients received weekly oral RAD001, starting 1 week prior to RT/TMZ and continuing until progression, with a break from therapy between RT/TMZ and adjuvant TMZ. RAD001 was dose escalated in cohorts of 6 patients. In addition to RAD001, all pts received standard treatment with RT (60 Gy)/TMZ (75 mg/m2 daily) and adjuvant TMZ (200 mg/m2 daily × 5 every 28 days). DLTs were defined during therapy with RAD001 combined with TMZ/RT. Results: A total of 18 patients were enrolled. Combined RAD001/RT/TMZ was well tolerated at all dose levels with 1 of 6 patients with a DLT at each dose level. DLTs were Grade 3 fatigue (RAD001 25 mg/week), Grade 4 hematologic toxicity (RAD001 50 mg/week), and Grade 4 liver function elevation (RAD001 70 mg/week). With adverse event information available for all 18 patients, no grade 5 events were seen. Nine grade 4 events (thrombosis, fatigue, anemia, neutropenia, thrombocytopenia, leukopenia, SGPT (ALT), SGOT (AST), bilirubin elevation) were seen in 3 patients. On the basis of these results, the recommended Phase II dose currently being tested is RAD001 70 mg/week in combination with standard RT/TMZ and adjuvant TMZ. FDG PET scans were also obtained prior to the first dose of RAD001 and within 24 hours of the second dose of RAD001, prior to starting RT or TMZ, and changes in maximum standard uptake values (SUV) were compared between scans for each patient. Two patients at 25 mg RAD001/week had a 21% and 24% change in SUV, and 2 patients receiving 70 mg/week had a change in SUV uptake of −33% and −16%. Additional follow-up will be required to evaluate whether these SUV changes are associated with outcome. Conclusions: RAD001 in combination with RT/TMZ and adjuvant TMZ was well tolerated, and the imaging results support continued evaluation of PET imaging as an early predictor of response to therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C56.

Background —Electron beam CT (EBCT) is an accurate, noninvasive method to detect and quantify coronary artery calcification, a marker of coronary artery disease (CAD). This investigation examined the accuracy of EBCT to detect obstructive CAD (≥50% stenosis) and determined the optimal strata for quantity of coronary artery calcification to facilitate clinical decision-making. Methods and Results —Clinical research patients (n=213) were examined with coronary angiography and EBCT (angiography group), and 765 research participants were examined with only EBCT (nonangiography group). Of the angiography group, 53% had obstructive CAD. After adjustment for verification bias, the estimated sensitivity and specificity for calcium score ≥1 were 97.0% and 72.4%, respectively. Likelihood ratios for strata of calcium score associated with obstructive CAD were calculated in each sex and 2 age groups. Among those ≥50 years old, the same 4 strata of EBCT calcium scores were identified in each sex; likelihood ratios ranged from 0.03 (calcium score 0) to 12.85 (calcium score ≥200). The same 3 strata of EBCT calcium scores were identified in each sex among those <50 years old; likelihood ratios ranged from 0.13 (calcium score 0) to 190 (calcium score ≥100). Conclusions —A calcium score ≥200 among those ≥50 years old and calcium score ≥100 among those <50 years old provided strong evidence that patients of either sex had obstructive CAD. A calcium score of 0 provided strong evidence that patients ≥50 years old did not have obstructive CAD.

Background —We previously demonstrated that in vivo electron-beam computed tomography (EBCT)–based indicator-dilution methods provide an estimate of intramyocardial blood volume (BV) and perfusion (F), which relate as BV=aF+b√F, where a characterizes the recruitable (exchange) and b the nonrecruitable (conduit) component of the myocardial microcirculation. In the present study, we compared BV and F with intracoronary Doppler ultrasound–based coronary blood flow (CBF) as a method for detecting and quantifying differential responses of these microvascular components to vasoactive drugs in normal (control) and hypercholesterolemic (HC) pigs. Methods and Results —BV and F values were obtained from contrast-enhanced EBCT studies in 14 HC and 14 control pigs. BV, F, and CBF values were obtained at baseline (intracoronary infusion of saline) and after 5 minutes each of intracoronary infusion of adenosine (100 μg · kg − 1 · min − 1 ) and nitroglycerin (40 μg/min). BV and CBF reserves in response to adenosine were attenuated in HC pigs compared with controls (90±36% versus 127±42%, P <0.03, and 485±182% versus 688±160%, P <0.01, respectively). The relationship between BV and F showed consistently lower recruitable BV in HC versus control pigs. Nonrecruitable BV reserve in response to adenosine was attenuated in HC compared with controls (77±20% versus 135±28%, P <0.001). Our findings are consistent with HC-induced impairment of intramyocardial resistance vessel function. Conclusions —EBCT technology allows minimally invasive evaluation of intramyocardial microcirculatory function and permits assessment of microvascular BV distribution in different functional components. This method may be of value in evaluating the coronary microcirculation in pathophysiological states such as hypercholesterolemia.

Background With the thrombogenic tendency and permanent implant nature of metallic stents, synthetic polymers have been proposed as candidate materials for stents and local drug delivery designs. We investigated the biocompatibility of several synthetic polymers after experimental placement in the coronary artery. Methods and Results Five different biodegradable polymers (polyglycolic acid/polylactic acid [PGLA], polycaprolactone [PCL], polyhydroxybutyrate valerate [PHBV], polyorthoester [POE], and polyethyleneoxide/polybutylene terephthalate [PEO/PBTP]) and three nonbiodegradable polymers (polyurethane [PUR], silicone [SIL], and polyethylene terephthalate [PETP]) were tested as strips deployed longitudinally across 90° of the circumferential surface of coil wire stents. Appropriately sized polymer-loaded stents were implanted in porcine coronary arteries of 2.5- to 3.0-mm diameter. Four weeks after implantation, stent patency was assessed by angiography followed by microscopic examination of the coronary arteries. The biodegradable PCL, PHBV, and POE and the nonbiodegradable PUR and SIL evoked extensive inflammatory responses and fibrocellular proliferation (thickness of tissue response: 0.79±0.22, 1.12±0.01, 2.36±0.60, 1.24±0.36, and 1.43±0.15 mm, respectively). Less but still severe responses were observed for the biodegradable PGLA and PEO/PBTP (0.46±0.18 and 0.61±0.23 mm, respectively) and for the nonbiodegradable PETP (0.46±0.11 mm). Conclusions An array of both biodegradable and nonbiodegradable polymers has been demonstrated to induce a marked inflammatory reaction within the coronary artery with subsequent neointimal thickening, which was not expected on the basis of in vitro tests. The observed tissue response may be attributable to a combination of parent polymer compound, biodegradation products, and possibly implant geometry.

Background Coronary artery calcium identified by electron beam computed tomography (EBCT) has potential for noninvasive localization of coronary atherosclerotic disease. However, the effect of a patient’s sex on its diagnostic capability has not been examined in a clinical population. Methods and Results Fifty women and 89 men had EBCT scans done an average of 1 day after coronary arteriography. Maximum arteriographic percent luminal diameter stenosis of any artery was paired with the total EBCT coronary calcium score for each subject. The women (age, 56±11 years [mean±SD]) were older than the men (age, 47±7 years), but the subjects were matched for indications for arteriography and extent of disease as assessed by arteriography. Sensitivity, specificity, and positive and negative predictive values for coronary calcium were nearly identical for men and women, regardless of the degree of arteriographic disease. EBCT was highly sensitive to the presence of arteriographic disease (range, 94% to 100%), but had only moderate specificity (57% to 66%) for significant disease (≥50% stenosis) and low specificity (35% to 38%) for any arteriographic disease (>0% stenosis). Negative predictive values in men and women ranged from 79% to 91% for any arteriographic disease and from 95% to 100% for significant disease, respectively. Numerical calcium scores were significantly different between subjects with normal arteriograms and those with significant disease; however, calcium score had limited power to separate trivial, moderate, and significant disease. Receiver operating characteristic curve areas, determined as an extension of the analyses of sensitivity and specificity, were high for EBCT-defined calcium scores for both any arteriographic disease and significant arteriographic disease, and were not different between the sexes. Conclusions In a middle-aged population, noninvasive definition of coronary calcium by EBCT has similar predictive value for arteriographic coronary artery disease in men and women.

Hypercholesterolemia and hypertension are both risk factors for end-stage renal disease. This study was designed to examine whether their coexistence augmented impairment in renal function and redox status. Regional renal hemodynamics and function in response to vasoactive challenges with acetylcholine or sodium nitroprusside were quantified by using electron-beam computed tomography in pigs after 12 weeks of either a normal (n=10) or hypercholesterolemic (n=10) diet, renovascular hypertension (n=7), or combined hypercholesterolemia+hypertension (n=6). The hypercholesterolemic and hypercholesterolemic+hypertensive groups had significantly increased serum cholesterol levels, whereas in the hypertensive and hypercholesterolemic+hypertensive groups, mean arterial pressure was significantly elevated compared with the group fed a normal diet. Basal regional renal perfusion and glomerular filtration rates were similar among the groups. In response to acetylcholine, cortical perfusion increased in normal animals (15.6±4.7%, P =0.002) but not in hypercholesterolemic or hypertensive animals (8.0±7.4% and 8.2±5.9%, respectively; P >0.05). Moreover, in the hypercholesterolemic+hypertensive group, cortical perfusion response was further attenuated (2.5±4.8%, P =0.02) and significantly different from the group fed a normal diet ( P <0.05). The response to sodium nitroprusside followed a similar pattern, and the impairment was augmented in the hypercholesterolemic+hypertensive group. The functional abnormalities in hypercholesterolemia or hypertension were associated with a decrease in systemic and/or renal tissue levels of oxygen radical scavengers that was again accentuated in hypercholesterolemia+hypertension. These results demonstrate that concurrent hypercholesterolemia and hypertension have a greater detrimental effect on renal perfusion responses compared with hypercholesterolemia or hypertension alone, associated with a marked pro-oxidant shift in redox status. These effects may potentially augment renal functional impairment and play a role in the initiation and progression of renal injury in hypertension and atherosclerosis.

Four cases of ventricular septal defect and ventricular aneurysm after myocardial infarction are reported. The clinical findings and surgical results in these four cases and in eight previously reported patients with this combination of complications are summarized. Resection of the ventricular aneurysm and closure of the ventricular septal defect appear indicated, both on theoretical grounds and in view of the excellent results observed in six patients who underwent combined repair. In one of our patients, closure of the ventricular septal defect and resection of the ventricular aneurysm were possible with only a single suture line, as these defects were anatomically contiguous.

Obstructive pulmonary vascular disease (PVD) was evaluated in lung sections taken at autopsy in 53 patients with complete transposition of the great arteries. Twentythree had intact ventricular septa and 30 had ventricular septal defects. Children of similar age and associated defects had widely differing degrees of PVD and presented a spectrum of disease. In a small number of patients, the presence of pulmonic stenosis (congenital or acquired by pulmonary artery banding in infancy), a small ventricular septal defect, or a large atrial septal defect was not protective against the development of severe PVD. The findings of this study demonstrate the need for thorough hemodynamic evaluation of patients with complete transposition of the great arteries prior to repair by present technics. In addition, operation should probably be performed as soon as technically feasible.

Complete surgical correction of transposition of the great arteries associated with subvalvular pulmonary stenosis carries a high mortality rate. A new surgical technique that achieves redirection of the ventricular outflows and relieves pulmonary stenosis by bypassing it, was successfully used to repair complete transposition of the great arteries associated with ventricular septal defect (VSD) and valvular and subvalvular pulmonary stenosis in a 14½-year-old patient. The repair consists of (1) division of the pulmonary artery, the cardiac end of which is oversewn, (2) repair of the VSD with a patch in such a way as to connect the left ventricle with the aorta, and (3) reconstruction of the pulmonary artery with an aortic homograft, including the aortic valve, which is anastomosed between the distal end of the pulmonary artery and the right ventricle. A review of the cases in which the current techniques were used indicates that the location and nature of the obstruction in the left ventricular outflow tract defies successful repair in most instances. Localized ridges and diffuse hypoplastic outflow tracts are recognized causes of obstruction, but anomalies of the mitral valve commonly contribute to or are the primary cause of subvalvular obstruction.