Citations

Survival following surgical correction of congenital cardiovascular defects is unlikely if pulmonary hypertension cannot be decreased significantly. Infusions of acetylcholine decreased pulmonary vascular resistance in 6 of 11 patients having pulmonary hypertension associated with atrial or ventricular septal defects. When the acetylcholine was combined with the breathing of oxygen, resistance decreased further. These findings are consistent with the theory that, at some stage, the pulmonary hypertension in cases of congenital heart disease is maintained at least in part by vasoconstriction and therefore is potentially reversible.

Changes in pulmonary vascular (arteriolar) resistance were estimated in 58 patients with mitral stenosis following mitral valvotomy and during exercise. Evidence is presented that changes in "resistance" reflect active changes in the caliber of the vessels due to alteration in their smooth muscle tone, valvotomy being followed by a decrease in tone and exercise by an increase.

Inferior vena cava (IVC) filters are widely used to decrease the risk of pulmonary embolism in patients with contraindications to anticoagulation. Complications include local hematoma, access site deep venous thrombosis (DVT), filter migration and embolization, leg penetration through the IVC wall, IVC occlusion, and filter fracture with embolization. Other rare complications include leg penetration into adjacent organs including duodenum and ureter. Lumbar artery pseudoaneurysms are rare and may be spontaneous, iatrogenic, or traumatic. To date, there have been 3 case reports of lumbar artery pseudoaneurysms caused by IVC filters. We present an additional case of a lumbar artery pseudoaneurysm caused by a Gunther Tulip IVC filter treated successfully with selective embolization.

External iliac artery endofibrosis describes an intimal subendothelial fibrosis leading to wall thickening and stenosis that has been described in high-performance athletes. There are anatomical, mechanical, and probably metabolic factors that may contribute to this pathology. Ankle–brachial index (ABI) measurement with exercise testing, duplex ultrasound, computed tomography (CT) or magnetic resonance (MR) angiogram, and ultimately arteriography help to make the diagnosis. Management can be conservative, but most cases require surgical intervention. External iliac vein stenosis and thrombosis in cyclists has rarely been described in the literature. We report a case of extensive left lower limb deep venous thrombosis (DVT) including the external iliac vein diagnosed in a 57-year-old athletic cyclist with a history of external iliac artery thrombosis.

The inhibitory effects of the endothelium against ergonovine-induced contraction were examined in isolated porcine coronary arteries under normal conditions and after endothelial regeneration. Endothelium-dependent responses were examined in vitro in normal Yorkshire pigs (n = 16) and in pigs that had undergone balloon endothelium removal of the left anterior descending coronary artery (LAD) 4 weeks before the study (n = 10). The presence of a complete endothelial lining was confirmed histologically. In rings from normal arteries contracted with prostaglandin F2 alpha in the presence of indomethacin and ketanserin (a 5-HT2-serotonergic blocker), ergonovine caused endothelium-dependent relaxations. They were attenuated by rauwolscine (an alpha 2-adrenergic blocker), inhibited by methiothepin (a combined 5-HT1- and 5-HT2-serotonergic blocker) or by pertussis toxin (an inhibitor of several G proteins) and abolished by oxyhemoglobin (a selective inactivator of endothelium-derived relaxing factor). In quiescent rings from normal arteries, ergonovine caused contractions that were inhibited by the presence of the endothelium; this endothelium-dependent inhibition was abolished by oxyhemoglobin. The direct contractions were not affected by prazosin (an alpha 1-adrenergic blocker), rauwolscine, 6-hydroxydopamine (an agent causing chemical sympathetectomy), or diphenhydramine (an H1-histaminergic blocker) but were inhibited by ketanserin. In rings with regenerated endothelium contracted with prostaglandin F2 alpha, the endothelium-dependent relaxations to ergonovine were reduced significantly and were not inhibited by pertussis toxin. In quiescent rings with regenerated endothelium, the endothelium-dependent inhibition of ergonovine-induced contraction was less.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of the calcium ionophore A23187, arachidonic acid, and acetylcholine were studied in isolated canine basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in physiological saline. In unstimulated rings, A23187, arachidonic acid, and acetylcholine caused endothelium-dependent contractions. The contractions of rings caused by uridine 5'-triphosphate were not affected by removal of the endothelium. An inhibitor of cyclooxygenase, indomethacin (10(-5) M), prevented excitatory responses to A23187, arachidonic acid, and acetylcholine but did not alter contractions caused by KCl. An inhibitor of thromboxane synthetase, dazoxiben (10(-4) M), significantly reduced endothelium-dependent contractions to A23187 and arachidonic acid but did not significantly affect contractions caused by acetylcholine. These results demonstrate that A23187, arachidonic acid, and acetylcholine cause excitatory endothelium-dependent responses in canine cerebral blood vessels by increasing the release of product(s) of cyclooxygenase from endothelial cells; in the case of A23187 and arachidonic acid, thromboxane A2 contributes to the endothelium-dependent contractions.

Abstract Background: The non-steroidal reversible aromatase inhibitor (AI), anastrozole (A) is approved as adjuvant monotherapy in hormone receptor (HR) positive early breast cancer (EBC). The steroidal irreversible AI exemestane (E) is approved in sequence after an initial 2-3 years of tamoxifen. MA27 tested the hypothesis that exemestane would have greater efficacy and better end-organ safety than anastrozole for several reasons: E is an irreversible and more potent AI than A; unlike A, E does not induce intra-tumoral aromatase and; through its mild androgenic activity E may exert a second anti-tumor effect and a more favorable bone and lipid metabolism profile than A. Initially the study also tested the role of a cyclooxygenase-2 inhibitor, celecoxib, used in combination with an AI. However, celecoxib was discontinued early in MA27 following identification of cardiovascular toxicity with COX-2 inhibitors. Methods: Postmenopausal women with hormone receptor positive primary breast cancer were randomized after adequate local treatment to 5 years of adjuvant A (1mg/day) or E (25mg/day) with or without celecoxib/placebo (400mg/plac twice daily for 3 years). The primary objective is the comparison of event free survival (EFS) between women treated with A or E. Secondary objectives include overall survival (OS), distant recurrence (DDFS), incidence of contralateral breast cancer (CBC) and safety. Quality of Life in a subset of women has been evaluated, and a very extensive tissue bank created. Stratification included: prior chemotherapy; lymph node status, celecoxib (during use), aspirin use (during randomization to celecoxib), and trastuzumab use (since November 2005). The primary endpoint (EFS) will look for an improvement from 87.5% to 89.9%; HR 0.80, 2-sided 5% level and 80% power, with 644 events required. Results: 7576 women were randomized between June 2003 and July 2008. Celecoxib/placebo, was discontinued 2 years into the trial in December 2004 after 1635 patients had received celecoxib. The number of events required for final analysis was reached April 2010. Patient characteristics were balanced for age (median 64.1yrs); race; ECOG PS; mastectomy; TNM staging and; prior adjuvant chemotherapy. EFS, OS, DDFS, and CBC as well as clinical fractures, cardiovascular events and adverse events will be presented by arm in the final analysis. Conclusions: NCIC CTG MA.27 is the first definitive EBC trial comparing a non-steroidal and steroidal AI as initial adjuvant therapy. Exemestane is not currently approved as initial adjuvant treatment and superiority or equivalence will lead to its inclusion as a first-line option for EBC in postmenopausal HR positive breast cancer. Efficacy, clinical fractures, cardiovascular events and AI related symptoms will help to define the cost-benefit ratios of these two AIs. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-1.

Abstract Background: The MA.17 study showed that extended adjuvant endocrine therapy with letrozole (LET) after completing 5 years of tamoxifen (TAM) markedly reduced the risk of recurrence in women with ER+ early stage breast cancer and improved overall survival in women presenting with node +ve disease. The HOXB 13:IL17BR gene expression ratio (signature) has been shown to predict outcome in breast cancer patients treated with adjuvant tamoxifen monotherapy and provides additional information beyond that from known positive (ER and PR) and negative (Her-1 and Her-2) predictors of responsiveness to tamoxifen in node-ve women. We report a case control evaluation of the Breast Cancer Index (BCI; bioTheranostics, Inc.), which combines the HOXB13 and IL17BR twogene and the molecular grade index (MGI) gene expression signatures, with respect to distinguishing which patients are at risk of late recurrences and who would respond to extended endocrine therapy with LET. The prognostic and predictive utility of quantitative immunofluorescence of ER, PR, Her-2, tumor aromatase, COX-2, GATA3 and Nat1 in the TAM-PLACEBO and the TAM-LET cohorts will also be evaluated and compared to results derived by standard immunohistochemistry. Methods: FFPE tumor blocks were collected from patients who experienced a breast cancer recurrence up to unblinding of MA.17. Controls were matched 2:1 for age, tumor size, lymph node status, and prior chemotherapy, and were all disease free for longer than cases. All cases were reviewed for standard histopathology by two independent pathologists. RNA was extracted, amplified, converted to cDNA and subjected to RT-PCR with primers and probes to HOXB13, IL17BR, BUB1A, CENPA, NEK2, RACGAP1 and RRM2. ER, PR HER1, HER2, COX2, Aromatase, GATA3 and NAT1 will be analyzed by routine IHC techniques and by immunoflourescent Automated Quantitative Analysis (AQuA). Results: 105 cases and 210 matched controls are available for evaluation. All sections are under review and tissue microarrays have been performed on all cases and controls. Detailed results on the BCI and ER, PR, Her-2 will be available at the SABCS. Discussion: MA.17 has shown that extended adjuvant endocrine therapy after tamoxifen is effective at preventing disease recurrence given for an additional 5 years. Numerous clinical trials are exploring whether extending AIs will show this benefit, and there is an increasing need to improve the therapeutic index by distinguishing those at risk from those who are not. It is also important to determine which patients will benefit from the therapy and which will recur without benefit. The latter patients could be triaged to clinical trials of novel therapies to overcome endocrine resistance. This study will help to define these issues and pave the way for more effective selection of specific patients for adjuvant endocrine strategies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-26.

Abstract Background: Mammographic density, the variation in fat, epithelial and stromal tissues seen on screening mammography, is a strong risk factor for breast cancer and can be modified by hormonal agents. Changes in density from tamoxifen or postmenopausal hormone (PMH) use are associated with risk, suggesting that density may be a surrogate marker of therapeutic efficacy. Aromatase inhibitors (AIs) are given as adjuvant therapy in hormone receptor positive postmenopausal breast cancer and are known to decrease levels of estrone and estradiol in both serum and breast tissue. Our goal here was to examine the influence of AIs on mammographic density in women with early breast cancer. Methods: We conducted a case-control study of postmenopausal breast cancer patients initiating adjuvant AI therapy (anastrozole or exemestane) on protocols NCIC CTG MA27, NCCTG N063I and MC (Mayo Clinic) 0532. Eligibility included; an intact contralateral breast with no prior surgery; a screening mammogram within twelve months before AI initiation and at 9-15 months on therapy; no prior endocrine therapy and informed consent. Controls were sampled from the Mayo Mammography Health Study, a cohort of 19,924 receiving screening mammography at the Mayo Clinic, and matched to cases on age, prior PMH use, baseline body mass index (BMI) and interval between mammograms. Pre-treatment and on-study mammograms for cases (corresponding mammograms for controls) were digitized. Change in percent density was estimated on the craniocaudal view of the non-cancerous breast using two methods: a subjective assessment of change by an expert radiologist (within 5%; 5-10% increase, 10-25% increase, 25%+ increase, 5-10% decrease, 10-25% decrease and 25%+ decrease) and a quantitative assessment of absolute change using a computer-assisted thresholding program (Cumulus). Analyses compared magnitude of change in density by both the subjective and quantitative methods between cases and matched controls. Results: 574 pairs were eligible for analyses (MA27-505 cases; N063I-12 cases; MC0532-57 cases). Characteristics of the two groups are shown in the table below. Using either density estimation method, there was a greater decrease in density among women on AI therapy vs. matched controls. In 33% (95% CI: 29-37%) of pairs, there was at least a one greater category decrease for the case relative to her control by subjective estimation. In 14% (95% CI: 11-18%) of the pairs, there was at least a 5% greater decrease for the case relative to her control by quantitative estimation. Data will be available according to AI class (non-steroidal versus steroidal) in November. Conclusions: In the largest report to date to examine the influence of AI therapy on mammographic density, we provide evidence that AI is associated with decreases in density in a small subgroup of women. We are currently examining factors that influence these AI-associated decreases in density and whether these differences are unique to one class of AI. (Supported in part by NIH grants P50CA116201, U01GM61388, U10CA77202, U10CA25224) Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-03.