The role of heparin in endovascular repair of blunt thoracic aortic injury.

OBJECTIVE: Early diagnosis and treatment are essential to improve survival of patients with blunt thoracic aortic injury (BTAI). Often, aortic surgical intervention may be delayed because of increased risk of bleeding with heparin, particularly in polytrauma victims. We believe that surgical delay may be remedied by proceeding without heparinization. This study reviewed the outcome of patients subjected to thoracic endovascular aortic repair (TEVAR) under full, low-dose, and no intraoperative systemic heparinization. METHODS: There were 77 cases of confirmed BTAI identified and retrospectively analyzed at a high-volume urban trauma center during a period of 15 years (March 2003-September 2017). Patients were stratified into three groups on the basis of the intraoperative use of heparin during TEVAR, as follows: full heparin (FH), low-dose heparin (LH), and no heparin (NH). Baseline characteristics including the patients' demographics, diagnostic laboratory data and imaging studies, operative reports, postoperative complications, embolic and bleeding outcomes, and mortality data were reviewed. RESULTS: Of the 77 total patients who underwent TEVAR for BTAI, 42 patients received full-dose heparinization, 18 received low-dose heparin, and 17 had no use of systemic heparin. There was no significant difference in age, sex, body mass index, or smoking history. The most common mechanism of injury was motor vehicle collision. Grade 3 (pseudoaneurysm) was the predominant type of BTAI (FH, 69.0%; LH, 61.1%; NH, 76.5%; P = .23). The mean interval between admission and repair was three times longer in the FH group than in the NH group (FH, 2.33 days; NH, 0.76 day; P = .091). The mean time in the intensive care unit was shorter in the NH group vs the FH group (15 days vs 26.21 days; P = .025). Thromboembolic and bleeding outcomes and mortality rates were comparable in all three groups; 57 patients continued follow-up for a mean time of 30.99 months. CONCLUSIONS: Our study shows no statistically significant difference in outcomes between the heparinized and nonheparinized groups. The primary benefit of the NH group is seen in time to repair. Although not statistically significant, the mean time to repair was three times longer in the FH group. Patients in the NH group also benefited from prompt intervention and treatment. Therefore, intraoperative heparinization in critically ill patients with BTAI undergoing TEVAR remains at the surgeon's discretion, although the lack of heparinization appears to be a safe and potentially faster alternative, particularly in the polytrauma patient.

Comparison of Ultrasound-Guided Thrombin Injection of Iatrogenic Pseudoaneurysms Based on Neck Dimension.

BACKGROUND: Ultrasound-guided thrombin injection (UGTI) of femoral artery pseudoaneurysms after endovascular procedures is an effective therapy. There is controversy in the literature regarding injecting pseudoaneurysms with short and/or wide necks. This article reports our experience in UGTI of pseudoaneurysms in 1 hospital regarding the efficacy of this treatment in all pseudoaneurysms regardless of the size of the necks. METHODS: A retrospective review of 46 patients diagnosed between 2011 and 2016 with groin pseudoaneurysms using established duplex ultrasound criteria. Mean age was 68 years (range 27-87). Ten pseudoaneurysms thrombosed spontaneously, 5 were thrombosed by ultrasound-guided compression, and 2 were treated surgically due to disqualifying criteria. In this retrospective review, we analyzed the remaining 29 pseudoaneurysms regarding the dimensions of their neck lengths and outcomes after attempting thrombin injection. RESULTS: The mean aneurysm neck length and width were 1.03 ± 0.9 cm and 0.30 ± 0.1 cm, respectively. All 29 patients were evaluated with respect to pseudoaneurysm size, neck length, neck width, and complexity. Successful treatment of 29 pseudoaneurysms (2 external iliac, 20 common femoral, 2 deep femoral, and 5 superficial femoral) with UGTI was achieved without complications in 100% of the cases, regardless of pseudoaneurysm size, neck dimensions, or complexity. Anticoagulation status did not affect the efficacy of the procedure. Nine of the 29 pseudoaneurysms (31.0%) had neck length less than 0.5 cm. CONCLUSIONS: This study demonstrates the safety and efficacy of UGTI in treating iatrogenic pseudoaneurysm in 29 of 29 patients, even in patients with pseudoaneurysm with short neck lengths. Our experiences support injecting all pseudoaneurysms irrespective of dimension.

Successful Revascularization of Aortic Arch in a 39-Year-Old Blunt Trauma Patient with Acute Diffuse Axonal Injury without the Use of Systemic Anticoagulation.

Blunt traumatic aortic injury is the second leading cause of death in trauma patients aged 4-34 years. Of the patients who are able to receive treatment, mortality rates as high as 40% have been reported. Endovascular repair options have allowed for more expeditious repairs with reduced iatrogenic trauma; however, when the injury involves the ascending aorta or arch, current endografts lack fenestrations needed for cerebral blood flow. Traditionally, on pump, cardiopulmonary bypass with systemic anticoagulation has been used to repair these injuries. In this paper, we describe a unique case of repairing a large traumatic aortic arch pseudoaneurysm in the setting of which systemic anticoagulation is contraindicated. The patient is a 39-year-old otherwise healthy Hispanic male who presented to Ryder Trauma Center in Miami, Florida, following a motor vehicle collision and found to have multiple intracranial hemorrhages and a large aortic pseudoaneurysm of the distal ascending aorta. In lieu of standard cardiopulmonary bypass, a hybrid approach was utilized. Cranial blood flow was maintained using a temporary extra-anatomical left femoral to bilateral carotid bypass during endovascular coverage of the aortic arch. Aortic arch revascularization was then achieved by means of in situ laser fenestration of the innominate artery followed by a right-to-left carotid-carotid-subclavian bypass. This case demonstrates the viability of a hybrid vascular repair of a complex aortic disruption without the use of systemic anticoagulation in the setting of contraindicated or unknown risk of systemic anticoagulation. Further research is warranted on whether emergent traumatic cases with contraindications to anticoagulation can be performed in a similar fashion to safely reduce the morbidity and mortality associated with aortic disruptions.

Powerful inhibition of experimental human pancreatic cancers by receptor targeted cytotoxic LH-RH analog AEZS-108.

Pancreatic carcinoma is one of the cancers with the worse prognosis, thus any therapeutic improvement is imperative. Cytotoxic LH-RH analog, AN-152 (proprietary designation, AEZS-108), consisting of doxorubicin (DOX) conjugated to D-Lys6LH-RH, is now in clinical trials for targeted therapy of several sex hormone-dependent tumors that express LH-RH receptors. We investigated LH-RH receptors in human pancreatic carcinoma and the effects of AN-152 (AEZS-108) on experimental pancreatic cancers. We determined LH-RH receptor presence in human pancreatic cancer samples by immunohistochemistry and, in three human pancreatic cancer lines (SW-1990, Panc-1 and CFPAC-1), by binding assays and Western blotting. The effects of the cytotoxic LH-RH analog were investigated on growth of these same cancer lines xenografted into nude mice. We also analyzed differences between the antitumor effects of the cytotoxic analog and its cytotoxic radical alone, doxorubicin (DOX), on the expression of cancer-related genes by PCR arrays. LH-RH receptors were expressed in two randomly selected surgically removed human pancreatic cancer samples and in all three cancer lines. Cytotoxic LH-RH analogs powerfully inhibited growth of all three tumor lines in nude mice; AN-152 was significantly stronger than DOX on Panc-1 and CFPAC-1 cancers. PCR array showed that cytotoxic LH-RH analog AN-152 affected the expression of genes associated with cellular migration, invasion, metastasis and angiogenesis more favorably than DOX, however the changes in gene expression varied considerably among the three cancer lines. Cytotoxic LH-RH analog, AEZS-108, may be a useful agent for the treatment of LH-RH receptor positive advanced pancreatic carcinoma.

Mechanisms of synergism between antagonists of growth hormone-releasing hormone and antagonists of luteinizing hormone-releasing hormone in shrinking experimental benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH) affects aging men. Combined therapy with antagonists of growth hormone-releasing hormone (GHRH) and of luteinizing hormone-releasing hormone (LHRH or GnRH) induces prostate shrinkage in rat models. We investigated the mechanisms of action of this combination on cell cycle traverse and expression of prostatic genes. METHODS: Effects of GHRH antagonist, JMR-132 (40 µg/day), the LHRH antagonist, cetrorelix (0.625 mg/kg), and their combination were evaluated on testosterone-induced benign prostatic hyperplasia in male Wistar rats. Influence of JMR-132, cetrorelix, and their combinations on cell viability was assessed by MTS assay in BPH-1 human prostate epithelial cells and WPMY-1 normal prostate stromal cells. Cell cycle was analyzed by laser flow cytometry. Real-time PCR arrays were performed. RESULTS: The combination of antagonists caused marked shrinkage of rat prostate (29.5%). In vitro, JMR-132 plus cetrorelix (both 5µM) produced synergistic (57.4%) inhibition of growth of BPH-1 cells, but a lesser inhibition (46%) of WPMY-1 cells. Co-treatment of with JMR-132 plus cetrorelix induced a significant increase of BPH-1 cells blocked in S-phase plus cells with lower G0 /G1 and G2 /M DNA content. Significant changes in expression of >40 gene transcripts related to growth factors, inflammatory cytokines, and signal transduction were identified. CONCLUSIONS: GHRH antagonist and LHRH antagonist combination potentiates rat prostate weight reduction and synergistically inhibits of growth of BPH-1 leading to cell cycle arrest in S-phase. These effects were lesser in normal stromal prostate cell line, WPMY-1. Our findings suggest that GHRH antagonists could be useful for BPH therapy, possibly in combination with LHRH antagonists.

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist.

Gastrin releasing-peptide (GRP) is a potent growth factor in many malignancies. Benign prostatic hyperplasia (BPH) is a progressive age-related proliferation of glandular and stromal tissues; various growth factors and inflammatory processes are involved in its pathogenesis. We have demonstrated that potent antagonists of GRP inhibit growth of experimental human tumors including prostate cancer, but their effect on models of BPH has not been studied. Here, we evaluated the effects of GRP antagonist RC-3940-II on viability and cell volume of BPH-1 human prostate epithelial cells and WPMY-1 prostate stromal cells in vitro, and in testosterone-induced BPH in Wistar rats in vivo. RC-3940-II inhibited the proliferation of BPH-1 and WPMY-1 cells in a dose-dependent manner and reduced prostatic cell volume in vitro. Shrinkage of prostates was observed after 6 wk of treatment with RC-3940-II: a 15.9% decline with 25 µg/d; and a 18.4% reduction with 50 µg/d (P < 0.05 for all). Significant reduction in levels of proliferating cell nuclear antigen, NF-κß/p50, cyclooxygenase-2, and androgen receptor was also seen. Analysis of transcript levels of genes related to growth, inflammatory processes, and signal transduction showed significant changes in the expression of more than 90 genes (P < 0.05). In conclusion, GRP antagonists reduce volume of human prostatic cells and lower prostate weight in experimental BPH through direct inhibitory effects on prostatic GRP receptors. GRP antagonists should be considered for further development as therapy for BPH.