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Gold J.S.,Surgery Services | Gold J.S.,Brigham and Womens Hospital | Gold J.S.,Harvard University | Al Natour R.H.,Surgery Services | And 14 more authors.
Annals of Surgical Oncology | Year: 2013

Background: The benefit of adjuvant treatment in gastric adenocarcinoma was demonstrated by randomized, controlled trials of patients with locally advanced tumors. Thus, its role for stage IIB-IIIC disease is widely accepted. We aimed to identify patients with stage IA-IIA gastric adenocarcinoma who have a poor prognosis and thus may benefit from adjuvant treatment. Methods: Patients with gastric adenocarcinoma who underwent surgical resection with pathological evaluation of ≥15 lymph nodes and had available disease-specific survival (DSS) data were identified from the Surveillance Epidemiology and End Results Registry. Survival differences were evaluated with the log-rank test and Cox multivariate analysis. Results: Stage and TN grouping strongly predicted DSS (P < 0.001, P < 0.001). Stage IA tumors had an excellent outcome: 91 ± 1.2 % 5-year DSS. The TN groupings of stages IB and IIA had the next best outcomes with 5-year DSS from 66 ± 4.6 % to 81 ± 2.3 %. Older age (P < 0.001), higher grade (P = 0.004), larger tumor size (P < 0.001), and proximal tumor location (P < 0.001) were independent predictors of worse DSS in stage IB-IIA tumors. We devised a risk stratification scheme for stage IB-IIA tumors where 1 point was assigned for age >60 years, tumor size >5 cm, proximal tumor location, and grade other than well-differentiated. Five-year DSS was 100 % for patients with 0 points; 86 ± 4.3 %, 1 point; 76 ± 3 %, 2 points; 72 ± 2.8 %, 3 points; and 48 ± 4.9 %, 4 points (P < 0.001). Conclusions: Patients with stage IB-IIA gastric adenocarcinoma and ≥2 adverse features (age >60 years, tumor size >5 cm, proximal location, and high-grade) have 5-year DSS ≤76 %. Adjuvant therapy may be warranted for these patients. © 2013 Society of Surgical Oncology.

McEnaney R.M.,Surgery Services | McEnaney R.M.,University of Pittsburgh | Shukla A.,Surgery Services | Shukla A.,University of Pittsburgh | And 5 more authors.
Journal of Vascular Surgery | Year: 2016

Objective Arteriogenesis represents the maturation of preformed vascular connections in response to flow changes and shear stress. These collateral vessels can restore up to 60% of the native blood flow. Shear stress and vascular injury can induce the release of nucleotides from vascular smooth muscle cells and platelets that can serve as signaling ligands, suggesting they may be involved in mediating arteriogenesis. The P2Y2 nucleotide receptor (P2Y2R) has also been shown to mediate smooth muscle migration and arterial remodeling. Thus, we hypothesize that P2Y2R mediates arteriogenesis in response to ischemia. Methods Hind limb ischemia was induced by femoral artery ligation (FAL) in C57Bl/6NJ or P2Y2R negative mice (P2Y2 -/-). Hind limb perfusion was measured with laser Doppler perfusion imaging and compared with the sham-operated contralateral limb immediately and at 3, 7, 14, 21, and 28 days after ligation. Collateral vessel size was measured by Microfil casting. Muscle specimens were harvested and analyzed with immunohistochemistry for Ki67, vascular cell adhesion molecule, macrophages, and muscle viability by hematoxylin and essoin stain. Results Hind limb ischemia induced by FAL in C57Bl/6NJ mice resulted in significant ischemia as measured by laser Doppler perfusion imaging. There was rapid recovery to nearly normal levels of perfusion by 2 weeks. FAL in P2Y2 -/- mice resulted in severe ischemia with greater tissue loss. Recovery of perfusion was impaired, achieving only 40% compared with wild-type mice by 28 days. Collateral vessels in the P2Y2 -/- mice were underdeveloped, with reduced vascular cell proliferation and smaller vessel size. The collaterals were ∼65% the size of wild-type collateral vessels (P =.011). Angiogenesis at 28 days in the ischemic muscle, however, was greater in the P2Y2 -/- mice (P <.001), possibly related to persistent ischemia leading and angiogenic drive. Early macrophage recruitment was reduced by nearly 70% in P2Y2 -/- despite significantly more myocyte necrosis. However, inflammation was greater at 28 days in the P2Y2 -/- mice. Conclusions P2Y2R deficiency does not alter baseline collateral vessel formation but does significantly impair collateral maturation, with resultant persistent limb ischemia despite enhanced angiogenesis. These findings reinforce the importance of arteriogenesis in the recovery of perfusion in ischemic tissues compared with angiogenesis. They also support the role of P2Y2R in mediating this process. The mechanism by which P2Y2R mediates arteriogenesis may involve the recruitment of inflammatory cells to the ischemic tissues, which is essential to arteriogenesis. Approaches to target P2Y2R may yield new therapeutic strategies for the treatment of arterial occlusive disease.

Madigan M.C.,Surgery Services | Madigan M.C.,University of Pittsburgh | McEnaney R.M.,Surgery Services | McEnaney R.M.,University of Pittsburgh | And 12 more authors.
Molecular Medicine | Year: 2015

Chronic, nonhealing wounds result in patient morbidity and disability. Reactive oxygen species (ROS) and nitric oxide (NO) are both required for normal wound repair, and derangements of these result in impaired healing. Xanthine oxidoreductase (XOR) has the unique capacity to produce both ROS and NO. We hypothesize that XOR contributes to normal wound healing. Cutaneous wounds were created in C57Bl6 mice. XOR was inhibited with dietary tungsten or allopurinol. Topical hydrogen peroxide (H2O2, 0.15%) or allopurinol (30 μg) was applied to wounds every other day. Wounds were monitored until closure or collected at d 5 to assess XOR expression and activity, cell proliferation and histology. The effects of XOR, nitrite, H2O2 and allopurinol on keratinocyte cell (KC) and endothelial cell (EC) behavior were assessed. We identified XOR expression and activity in the skin and wound edges as well as granulation tissue. Cultured human KCs also expressed XOR. Tungsten significantly inhibited XOR activity and impaired healing with reduced ROS production with reduced angiogenesis and KC proliferation. The expression and activity of other tungsten- sensitive enzymes were minimal in the wound tissues. Oral allopurinol did not reduce XOR activity or alter wound healing but topical allopurinol significantly reduced XOR activity and delayed healing. Topical H2O2 restored wound healing in tungsten-fed mice. In vitro, nitrite and H2O2 both stimulated KC and EC proliferation and EC migration. These studies demonstrate for the first time that XOR is abundant in wounds and participates in normal wound healing through effects on ROS production. © 2015, Uninversity of Michigan. All rights reserved.

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