PARP1 and phospho-p65 protein expression is increased in human HER2-positive breast cancers.

Previous studies have shown that basal breast cancers, which may have an inherent "BRCAness" phenotype and sensitivity to inhibitors of poly (ADP-Ribose) polymerase (PARP), express elevated levels of PARP1. Our lab recently reported that HER2+ breast cancers also exhibit sensitivity to PARP inhibitors (PARPi) by attenuating the NF-κB pathway. In this study, we assessed PARP1 and phospho-p65, a marker of activated NF-κB levels in human breast cancer tissues. PARP1 and PARP2 copy number, mRNA, and protein expression was assessed by interrogating the PAM-50 defined breast cancer patient set from the TCGA using cBioPortal. PARP1 and phospho-p65 immunohistochemistry and correlation to clinical parameters was conducted using 307 primary breast cancer specimens (132 basal, 82 luminal, 93 HER2+) through univariate and multivariate analyses. In the PAM50 breast cancer data set, PARP1 and 2 expression was altered in 24/58 (41 %) HER2+, 32/81 (40 %) basal, and 75/324 (23 %) luminal A/B breast cancer patients. This correlated with a statistically significant increase in PARP1 protein levels in HER2+ and basal but not luminal breast cancers (p = 0.003, p = 0.027, p = 0.289, respectively). No change in PARP2 protein level was observed. Interestingly, using breast cancer specimens from 307 patients, HER2 positivity correlated with elevated PARP1 expression (p < 0.0001) and was three times more likely than HER2 negative breast cancers to exhibit high PARP1 levels. No significant differences were noted between race, ER status, or PR status for PARP1 expression. Additionally, we found a significant correlation between HER2 status and phospho-p65 expression (p < 0.0001). Lastly, a direct correlation between PARP1 and phospho-p65 (p < 0.0001) was noted. These results indicate a potential connection between HER2, PARP1, and phospho-p65. Furthermore, these data suggest that the PARPi sensitivity we previously observed in HER2+ breast cancer cells may be due to elevated PARP1 expression.

Accelerated partial breast irradiation for early-stage breast cancer: controversies and current indications for use.

Radiation therapy options for early-stage breast cancer have evolved during the past 40 years. Several choices are currently available to certain patient subsets that allow radiation oncologists to individualize care. Multiple phase II and several phase III trials have been published that support the safety and efficacy of accelerated partial breast irradiation (APBI) as part of breast conservation in selected patients. In contrast, a recent large retrospective analysis of patients aged 67 or older who received brachytherapy for APBI has raised concerns about its effectiveness. As the radiation community awaits results from NSABP B-39/RTOG 0413, the largest randomized trial of whole breast radiation therapy (WBRT) versus APBI, to provide more conclusive data, many academic and private radiation oncology practices are utilizing APBI off-protocol to treat early-stage breast cancer patients. Because of this, the American Society for Radiation Oncology (ASTRO) published a consensus statement in 2009 to aid in proper patient selection (Table 1). Until more definitive data is garnered, we advocate strict adherence to these selection criteria to ensure optimal outcomes. Specifically, we caution against the use of APBI in lymph node-positive disease outside of a clinical trial. There is a paucity of comparative data to guide oncologists in selection of the best APBI delivery method. The current NSABP B-39/RTOG 0413 trial allows any of the three most common forms of delivery to be utilized (multicatheter interstitial brachytherapy, balloon intracavitary brachytherapy, and external beam 3D conformal therapy) and will be instrumental to compare outcome differences between these methods.

Superior mesenteric artery stent fracture producing stenosis and recurrent chronic mesenteric ischemia: case report.

Endovascular modalities are being increasingly employed in the treatment of a variety of vascular diseases. With new technologies come novel complications, and one such complication unique to endovascular surgery is stent fracture. We present two cases of stent fracture following stenting of the superior mesenteric artery and discuss possible causes and treatments.

Increasing endovascular intervention for claudication: impact on vascular surgery resident training.

PURPOSE: To audit the caseloads of vascular surgery residents in the management of disabling claudication and assess the influence of endovascular procedures on overall operative experience. METHODS: A retrospective review was conducted of vascular surgery resident experience in the open and endovascular management of lower limb claudication during two 3-year periods (January 2000 to December 2002 and January 2003 to December 2005). The time periods differed with regard to number of surgical faculty with advanced endovascular skills (3 in the first period and 4 in the second) and the availability of portable operating room angiography equipment. RESULTS: During the 6-year period, the operative logs of vascular surgery residents indicated participation in 283 procedures [170 (60%) open surgical interventions, including 146 suprainguinal procedures] performed for claudication. The number of procedures increased by 62% (p<0.05) from the first period (n=108) to the second (n=175). Endovascular intervention to treat aortoiliac occlusive disease increased 4-fold (14 versus 56 interventions, p=0.01) compared to a decrease in open (bypass grafting, endarterectomy) surgical repair (45 to 31 procedures, p=0.22). The greatest change in resident experience was in endovascular intervention of infrainguinal occlusive disease: the case volume increased from 4 to 39 procedures (p=0.07) during the 2 time intervals. By contrast, the number of open surgical bypass procedures was similar (45 versus 49) in each 3-year period. CONCLUSION: An audit of resident experience demonstrated intervention for claudication has increased during the past 6 years. The increased operative experience reflects more endovascular treatment (atherectomy, angioplasty, stent-graft placement) of femoropopliteal and aortoiliac occlusive disease, but no decrease in open surgical operative experience for claudication. This increase in endovascular intervention may be related to a decrease in the threshold for intervention.