Citations

Purpose To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial. Patients and Methods Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months. Results Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%. Conclusion The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.

Object The operative management of combined intrapelvic and extrapelvic sciatic notch dumbbell-shaped tumors is challenging. The relatively rare occurrence of these tumors and the varied extent of disease have made it difficult for surgeons to establish definitive surgical indications or predict favorable neurological outcomes based on preoperative imaging data. Methods In the past 3 years, the authors treated five patients presenting with radiating leg pain as a result of benign sciatic notch dumbbell-shaped tumors. These tumors in three patients with unilateral leg symptoms were considered unresectable by other neurosurgeons because of presumed direct intrinsic neural involvement. After high-resolution magnetic resonance (MR) imaging demonstrated that the extensive tumors were separate from the sciatic nerve and the lumbosacral plexus, however, these patients underwent a combined one-stage transabdominal and posterior transgluteal complete resection. Normal neurological status was maintained postoperatively in these three patients, and after more than 1 year of postoperative follow up, there were no tumor recurrences. In two patients with bilateral symptoms and extensive tumor burden, serial MR images showed that innumerable tumors directly involved the entire cross-sectional area of the sciatic nerves and extended longitudinally to the lumbosacral plexuses. Tumor debulking or resection in these patients would have resulted in neurological deficits and would not have addressed their neuropathic pain, and therefore no surgery was performed. These two patients were treated pharmacologically and advised to monitor their tumor status over the course of their lifetimes in case of malignant transformation of the tumor. Conclusions A combined one-stage transabdominal and transgluteal approach allows safe resection of selected benign but extensive sciatic notch tumors. High-resolution MR imaging is a useful tool in the management of these tumors because it allows the surgeon to visualize the anatomical relationships of the tumor to the sciatic nerve. The authors believe that as this imaging technology advances, it will provide surgeons with a method to predict definitively which sciatic notch tumors displace rather than directly involve the sciatic nerve, and therefore indicate which tumors can be resected safely and completely.

Purpose In the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response. Patients and Methods For these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy. Results Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders. Conclusion In both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.

Background— Current risk models predict in-hospital mortality after either coronary artery bypass graft surgery or percutaneous coronary interventions separately, yet the overlap suggests that the same variables can define the risks of alternative coronary reperfusion therapies. Our goal was to seek a preprocedure risk model that can predict in-hospital mortality after either percutaneous coronary intervention or coronary artery bypass graft surgery. Methods and Results— We tested the ability of the recently validated, integer-based Mayo Clinic Risk Score (MCRS) for percutaneous coronary intervention, which is based solely on preprocedure variables (age, creatinine, ejection fraction, myocardial infarction ≤24 hours, shock, congestive heart failure, and peripheral vascular disease), to predict in-hospital mortality among 370 793 patients in the Society of Thoracic Surgeons database undergoing isolated coronary artery bypass graft surgery from 2004 to 2006. For the Society of Thoracic Surgeons coronary artery bypass graft surgery population studied, the median age was 66 years (quartiles 1 to 3, 57 to 74 years), with 37.2% of patients ≥70 years old. A high prevalence of comorbid conditions, including diabetes mellitus (37.1%), hypertension (80.5%), peripheral vascular disease (15.3%), and renal disease (creatinine ≥1.4 mg/dL; 11.8%), was present. A strong association existed between the MCRS and the observed mortality in the Society of Thoracic Surgeons database. The in-hospital mortality ranged between 0.3% (95% confidence interval 0.3% to 0.4%) with a score of 0 on the MCRS and 33.8% (95% confidence interval 27.3% to 40.3%) with an MCRS score of 20 to 24. The discriminatory ability of the MCRS was moderate, as measured by the area under the receiver operating characteristic curve (C-statistic=0.715 to 0.784 among various subgroups); performance was inferior to the Society of Thoracic Surgeons model for most categories tested. Conclusions— This model, which is based on 7 preprocedure risk variables, may be useful for providing patients with individualized, evidence-based estimates of procedural risk as part of the informed consent process before percutaneous or surgical revascularization.

In vitro and animal studies suggest that oxidative stress is associated with endothelial dysfunction. We tested whether local oxidative stress and nitric oxide (NO) bioavailability in the coronary circulation is associated with coronary endothelial dysfunction in humans. Blood samples were obtained simultaneously from the left main coronary artery and the coronary sinus for measurement of F2-isoprostanes, myeloperoxidase, nitrotyrosine, and superoxide dismutase in 20 patients without significant coronary disease. Afterward, coronary blood flow and the vascular response to intracoronary acetylcholine and N G -monomethyl- L -arginine (L-NMMA) were assessed. The gradient of isoprostanes between the arterial levels and coronary sinus correlated with the change in coronary artery diameter in response to acetylcholine ( r =−0.79, P <0.0001). Isoprostanes net production across the left anterior descending artery territory correlated with a decrease in superoxide dismutase activity ( r =0.66, P =0.002) and decrease in coronary artery diameter in response to L-NMMA (r s =0.48, P <0.05). Myeloperoxidase and nitrotyrosine gradients were similar in patients with endothelial dysfunction and controls. The effect of L-NMMA was similar in both groups. We conclude that coronary endothelial dysfunction in humans is characterized by local enhancement of oxidative stress without a decrease in basal NO release. This study supports the hypothesis that local oxidative stress has a role in reduction of NO bioavailability in humans with coronary endothelial dysfunction.

Abstract Purpose: The glutathione S-transferases (GSTs) catalyze the glutathione conjugation of reactive electrophiles, including carcinogens and many antineoplastic drugs. GSTT1 and GSTM1 are polymorphically deleted, but the full range of genetic variation in these two genes has not yet been explored. We set out to systematically identify common polymorphisms in GSTT1 and GSTM1, followed by functional genomic studies. Experimental Design: First, multiplex PCR was used to determine GSTT1 and GSTM1 copy number in 400 DNA samples (100 each from 4 ethnic groups). Exons, splice junctions, and 5′-flanking regions (5′-FR) were then resequenced using DNA samples that contained at least one copy of GSTT1 or GSTM1. Results: Gene deletion frequencies among ethnic groups were from 33.5% to 73.5% for GSTT1 and from 50.5% to 78.0% for GSTM1. GSTT1 deletion data correlated with the results of mRNA microarray expression studies. The 18 single nucleotide polymorphisms (SNP) observed in GSTT1 included three nonsynonymous coding SNPs (cSNPs) and one single-nucleotide deletion, whereas the 51 GSTM1 SNPs included two nonsynonymous cSNPs. Two of the GSTT1 nonsynonymous cSNPs resulted in decreases in levels of immunoreactive protein to 56% and 12% of wild type (WT), whereas those in GSTM1 resulted in modest increases in protein levels. Reporter gene assays showed that one GSTT1 5′-FR haplotype, with a frequency of 32% in African-American subjects, resulted in an increase in transcription in JEG-3 cells to 351% of that for the WT sequence, and one GSTM1 5′-FR haplotype resulted in an increase in transcription in JEG-3 cells to 129% of WT. Conclusions: These observations suggest that functionally significant pharmacogenomic variation beyond GSTT1 and GSTM1 gene deletion may contribute to carcinogenesis or individual variation in antineoplastic drug therapy response.