Citations

Purpose: To describe a bailout technique for use during branched/fenestrated thoracoabdominal aortic aneurysm (TAAA) repair to address celiac artery (CA) dissection. Technique: The technique is demonstrated in a 69-year-old man who underwent fenestrated stent-graft repair of a 6-cm type III TAAA. The main fenestrated stent-graft was positioned without difficulty, and the renal and superior mesenteric arteries were stented. A stent-graft was placed in the CA, but angiography showed the vessel to be occluded by dissection beyond the stent-graft. Wire manipulations to regain access to the true lumen culminated in perforation. At this point, the gastroduodenal artery was catheterized with a 0.035-inch guidewire, which was advanced in retrograde fashion into the CA true lumen and then snared back to the left brachial artery forming a loop. After exchange for a 0.014-inch system, self-expanding stents were deployed into the hepatic artery. Postoperative recovery was uneventful, and the patient was discharged on day 6. At 1-year follow-up, the patient was doing very well. Imaging demonstrated no endoleak, no graft migration, and sac shrinkage to a diameter of 5.1 cm. Conclusion: The “loop technique” can be a very useful and effective bailout maneuver in regaining access to the true lumen of a dissected CA in patients undergoing branched/fenestrated thoracoabdominal aortic aneurysm repair.

Purpose: To review outcomes of continuous motor/somatosensory-evoked potential (MEP/SSEP) monitoring, cerebrospinal fluid drainage, and selective use of iliofemoral conduits in patients undergoing endovascular repair of descending thoracic aneurysm (DTA) and thoracoabdominal aortic aneurysms (TAAAs). Methods: The clinical data of 49 patients (mean age 75±8 years; 38 men) who underwent endovascular repair of DTA and TAAAs (2011–2014) were reviewed. All patients had cerebrospinal fluid drainage, permissive hypertension (mean arterial pressure ≥80 mm Hg), and MEP/SSEP monitoring. There were 44 (90%) patients with TAAAs and 5 (10%) with DTA. Types I and II TAAAs were repaired in staged procedures. Iliofemoral conduits were used for small iliac arteries and to minimize time of lower extremity ischemia in patients with difficult anatomy. In patients with changes in MEP/SSEPs, a standardized protocol was employed to optimize spinal cord perfusion and restore lower extremity blood flow. Endpoints were mortality, spinal cord injury (SCI), and lower extremity ischemic complications. Results: Sixteen (33%) patients had staged TAAA repair. A total of 163 visceral arteries were targeted by fenestrations and branches (mean 3.7±1.0 vessels/patient). Temporary iliofemoral conduits were used in 16 limbs/14 patients. A stable MEP/SSEP was achieved in all patients. Thirty-one (63%) patients had a ≥75% decrease in MEP/SSEP amplitude in 50 limbs starting on average 75±28 minutes after obtaining vascular access. MEP/SSEP amplitude improved with maneuvers in 12 (39%) patients and returned to baseline with restoration of lower extremity flow in all except 1 patient who developed immediate SCI. Thirty-day mortality was 4%. Three (6%) patients had SCI, 2 permanent and 1 temporary at 14 days. There were no lower extremity ischemic complications. Conclusion: Neuromonitoring predicted immediate SCI and allowed use of a protocol to optimize spinal cord and lower extremity perfusion during complex endovascular aortic repair. Larger clinical experience is needed to evaluate the efficacy of neuromonitoring to prevent SCI.

Abstract Purpose: Pheochromocytomas and paragangliomas (PPGL) are genetically heterogeneous tumors of neural crest origin, but the molecular basis of most PPGLs is unknown. Experimental Design: We performed exome or transcriptome sequencing of 43 samples from 41 patients. A validation set of 136 PPGLs was used for amplicon-specific resequencing. In addition, a subset of these tumors was subjected to microarray-based transcription, protein expression, and histone methylation analysis by Western blotting or immunohistochemistry. In vitro analysis of mutants was performed in cell lines. Results: We detected mutations in chromatin-remodeling genes, including histone-methyltransferases, histone-demethylases, and histones in 11 samples from 8 patients (20%). In particular, we characterized a new cancer syndrome involving PPGLs and giant cell tumors of bone (GCT) caused by a postzygotic G34W mutation of the histone 3.3 gene, H3F3A. Furthermore, mutations in kinase genes were detected in samples from 15 patients (37%). Among those, a novel germline kinase domain mutation of MERTK detected in a patient with PPGL and medullary thyroid carcinoma was found to activate signaling downstream of this receptor. Recurrent germline and somatic mutations were also detected in MET, including a familial case and sporadic PPGLs. Importantly, in each of these three genes, mutations were also detected in the validation group. In addition, a somatic oncogenic hotspot FGFR1 mutation was found in a sporadic tumor. Conclusions: This study implicates chromatin-remodeling and kinase variants as frequent genetic events in PPGLs, many of which have no other known germline driver mutation. MERTK, MET, and H3F3A emerge as novel PPGL susceptibility genes. Clin Cancer Res; 22(9); 2301–10. ©2015 AACR.

Purpose: To present a rare case of disseminated intravascular coagulation (DIC) after thoracic endovascular aortic repair (TEVAR) and its novel treatment. Case Report: A 55-year-old man presented with DIC 10 months after TEVAR for chronic type B aortic dissection and descending thoracic aortic aneurysm. He had persistent retrograde flow in the false lumen with a stable aneurysm diameter. The false lumen was embolized with multiple Amplatzer plugs, which promoted false lumen thrombosis. Laboratory evaluation on postoperative day 7 demonstrated resolution of the coagulopathy. Follow-up at 18 months revealed no recurrent DIC; computed tomography angiography showed a stable aortic diameter and excluded thoracic aneurysm sac. Conclusion: This case demonstrates an unusual, potentially fatal postoperative complication of endovascular treatment of type B aortic dissections successfully treated with an innovative endovascular solution.

Abstract Radiotherapy is an important treatment regimen for prostate cancer. We have shown that the lymphangiogenic growth factor, Vascular Endothelial Growth Factor C (VEGF-C), induces docetaxel resistance and autophagy in prostate cancer (Muders et al., Cancer Res 2009 and Stanton et al., Cancer Res 2013). In this study we have evaluated the role of VEGF-C and VEGF-C induced autophagy in radioresistance of prostate cancer using cell culture experiments and human tissue samples. The human prostate carcinoma cell lines PC-3, LNCaP and DU145 were used in these cell culture experiments. Clonogenic survival of prostate cancer cells, after RNA interference (RNAi) of VEGF-C, autophagy related gene 5 (ATG5), and after addition of recombinant human VEGF-C following irradiation therapy, was evaluated. Autophagic flux was tested after ionizing irradiation using a Light-Chain-3 II immunoblot. To confirm our in vitro findings, human tissues of patients who underwent radical prostatectomy and adjuvant radiotherapy at Mayo Clinic were evaluated for VEGF-C expression. The quantity and intensity of VEGF-C staining was evaluated by two pathologists independently and correlated with biochemical relapse free survival (BRFS). The follow-up time is up to 23 years after radiotherapy. Multivariate Cox analysis was performed. VEGF-C levels correlated with a significantly higher radioresistance in colony formation assays and human tissue samples by multivariate analysis. The risk of biochemical recurrence increased 2.8 fold (95% confidence interval: 1.109 to 7.237; p = 0.03) when VEGF-C was highly expressed in prostatectomy patients with adjuvant radiotherapy. In line with our studies on autophagy in VEGF-C mediated docetaxel resistance of prostate cancer, autophagic flux was reduced after VEGF-C depletion during radiation. Interestingly, RNAi for ATG5 showed no effect on radiosensitivity which suggests that the decrease in autophagic flux after VEGF-C depletion is not responsible for the increased radiosensitivity. We conclude that VEGF-C is an important mediator of radiotherapy resistance in prostate cancer. In contrast to our published results on chemotherapy resistance, VEGF-C induced autophagy appears to be less important for resistance against ionizing radiation. Other VEGF-C dependent mechanisms for therapy resistance are under investigation. Citation Format: Steffi Haberlau, Pia Hönscheid, Rafael E. Jimenez, Gustavo B. Baretton, Donald J. Tindall, Mechthild Krause, Kaustubh Datta, Michael H. Muders. Role of Vascular Endothelial Growth Factor C in promoting radioresistance of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3304. doi:10.1158/1538-7445.AM2015-3304

Purpose: To report the use of an investigational stent-graft to treat an ascending aortic aneurysm in a patient with a heart transplant. Case Report: A 48-year-old man presented with a 3.5×1.5-cm saccular aneurysm in the mid anterior ascending aorta, abutting the sternum. The patient’s history was notable for placement of a left ventricular assist device followed by orthotopic heart transplantation 2 years prior to treat end-stage familial dilated cardiomyopathy. Under compassionate use, a custom-designed ascending aortic stent-graft (Zenith Ascend) was successfully delivered via an 18-F system and deployed just distal to the origin of the left main coronary artery under pulmonary artery catheter–guided rapid ventricular pacing. The patient was discharged the next day, and 6-month follow-up was unremarkable. Imaging at 5 months showed an excluded aneurysm sac with no endoleak or migration. Conclusion: The ideal ascending aortic stent-graft should be low profile, conformable to the arch anatomy, with short tip delivery system and a stepwise deployment mechanism that allows precise placement relative to the ostia of the coronary arteries and the innominate artery. This case illustrates the advancement of endovascular techniques to the most challenging segment of the aorta to decrease morbidity and mortality in high-risk patients.

ObjectiveExamine the effects of obesity and metabolic syndrome on outcome in bipolar disorder.MethodThe Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6‐month trial comparing lithium‐ and quetiapine‐based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models.ResultsAt baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome.ConclusionObesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium‐ or quetiapine‐based treatment.