We have earlier shown that antisense morpholino oligomers are able to restore dystrophin expression by systemic delivery in body-wide skeletal muscles of dystrophic mdx mice. However, the levels of dystrophin expression vary considerably and, more importantly, no dystrophin expression has been achieved in cardiac muscle. In this study, we investigate the efficiency of morpholino-induced exon skipping in cardiomyoblasts and myocytes in vitro, and in cardiac muscle in vivo by dose escalation. We showed that morpholino induces targeted exon skipping equally effectively in both skeletal muscle myoblasts and cardiomyoblasts. Effective exon skipping was achieved in cardiomyocytes in culture. In the mdx mice, morpholino rescues dystrophin expression dose dependently in both skeletal and cardiac muscles. Therapeutic levels of dystrophin were achieved in cardiac muscle albeit at higher doses than in skeletal muscles. Up to 50 and 30% normal levels of dystrophin were induced by single systemic delivery of 3 g kg -1 of morpholino in skeletal and cardiac muscles, respectively. High doses of morpholino treatment reduced the serum levels of creatine kinase without clear toxicity. These findings suggest that effective rescue of dystrophin in cardiac muscles can be achieved by morpholino for the treatment of Duchenne muscular dystrophy.

Exon skipping has demonstrated great potential for treating Duchenne muscular dystrophy (DMD) and other diseases. We have developed a drug-screening system using C2C12 myoblasts expressing a reporter green fluorescent phosphate (GFP), with its reading frame disrupted by the insertion of a targeted dystrophin exon. A library of 2,000 compounds (Spectrum collection; Microsource Discovery System) was screened to identify drugs capable of skipping targeted dystrophin exons or enhancing the exon-skipping effect by specific antisense oligomers. The 6-thioguanine (6TG) was effective for inducing skipping of both human dystrophin exon 50 (hDysE50) and mouse dystrophin exon 23 (mDysE23) in the cell culture systems and increased exon skipping efficiency (more than threefolds) when used in combination with phosphorodiamidate morpholino oligomers (PMO) in both myoblasts and myotubes. Guanine and its analogues were unable to induce detectable skipping of exon 23 when used alone but enhanced PMO-induced exon skipping significantly (approximately two times) in the muscles of dystrophic mdx mouse in vivo. Our results demonstrate that small-molecule compounds could enhance specific exon skipping synergistically with antisense oligomers for experimental therapy to human diseases.

Long-term (12-year) aorta-specific survival after on-label endovascular repair of degenerative descending thoracic aneurysms in nonsyndromic patients is excellent (96%) with sustained protection from rupture, and a low rate of reintervention owing to endoleak (7%). Endovascular repair should be considered the treatment of choice for this pathology.

This study objectively determines the optimal timing of adjuvant chemotherapy for patients with resected colon cancer. Delay beyond 6 weeks is associated with compromised survival. These findings emphasize the importance of the timely initiation of therapy, and suggest that efforts to enhance recovery following surgery have the potential to improve survival by decreasing delay to adjuvant chemotherapy.

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Objective Thoracoabdominal aortic aneurysm (TAAA) repair remains a significant challenge with considerable perioperative morbidity and mortality. A hybrid approach visceral debranching with endovascular aneurysm exclusion has been used to treat high-risk patients and therefore to allow repair in more patients. Limited data exist regarding long-term outcomes with this procedure as well as comparison to conventional open repair. This study describes our institutional algorithmic approach to TAAA repair using both open and hybrid techniques. Methods Hybrid and open TAAA repairs performed between July 2005 and August 2015 were identified from a prospectively maintained institutional aortic surgery database. Perioperative morbidity and mortality, freedom from reintervention, and long-term and aorta-specific survival were calculated and compared between the two groups. Results During the study period, 165 consecutive TAAA repairs were performed, including 84 open repairs and 81 hybrid repairs. Patients in the hybrid repair group were significantly older, were more frequently female, and had a generally greater comorbid disease burden, including significantly more chronic kidney disease. Despite the older and sicker cohort, there was no difference in in-hospital mortality between the two groups (9.9% hybrid vs 7.1% open; P = .59). Major morbidity rates differed by procedure, with patients undergoing open repair having a significantly higher rate of postoperative stroke (9.5% open vs 0% hybrid; P = .017), whereas patients undergoing hybrid repair had a higher rate of new permanent dialysis (14.8% hybrid vs 3.6% open; P = .043). There was no difference between groups in the rate of postoperative permanent paraplegia/paresis (8.3% open vs 7.4% hybrid; P = .294). There was a significantly increased rate of reintervention in the hybrid repair group (12.3% hybrid vs 1.2% open, P = .004), with all hybrid reinterventions performed because of endoleak. One-year survival was similar between groups at 69% in hybrid repairs vs 77% in open repairs. Long-term survival was worse in the hybrid group (5-year survival, 32% hybrid vs 56% open), although late survival appeared to be influenced mainly by comorbid disease burden, given the similar long-term aorta-specific survival between groups. Conclusions Use of an algorithmic approach whereby higher risk patients with TAAA are treated by a hybrid approach and lower risk patients with conventional open repair yields satisfactory short- and long-term outcomes. The availability of multiple options for TAAA repair within a single center likely allows repair in more patients with consequent decrease in the risk of aorta-related death, at the expense of increased reinterventions for endoleak.

Objective The role of hybrid repair in the management of aortic arch pathology, and long-term outcomes with these techniques, remains uncertain. We report a decade of experience with hybrid arch repair (HAR) and assess institutional practice patterns with regard to the use of hybrid and open techniques. Methods Hybrid and open total and distal arch procedures performed between July 2005 and January 2015 were identified from a prospectively maintained, institutional aortic surgery database. Perioperative morbidity and mortality, freedom from reintervention, and long-term survival were calculated. Hybrid and open procedural volumes over the study period were assessed to evaluate for potential practice pattern changes. Results During the study period 148 consecutive procedures were performed for repair of transverse and distal aortic arch pathology, including 101 hybrid repairs and 47 open total or distal arch repairs. Patients in the hybrid repair group were significantly older with a greater incidence of chronic kidney disease, peripheral vascular disease, and chronic lung disease. Perioperative mortality and outcomes were not significantly different between the hybrid and open groups, aside from decreased median length of stay after hybrid repair. Need for subsequent reintervention was significantly greater after hybrid repair. Unadjusted long-term survival was superior after open repair (70% 5-year survival open vs 47% hybrid; P = .03), although aorta-specific survival was similar (98% 5-year aorta-specific survival open vs 93% hybrid; P = .59). Institutional use of HAR decreased over the final 3 years of the study, with an associated increased use of open total or distal arch repairs. This was primarily the result of decreased use of native zone 0 hybrid procedures. Concurrent with this apparent increased stringency around patient selection for HAR, perioperative morbidity and mortality was reduced, including avoidance of retrograde type A dissection. Conclusions HAR remains a viable option for higher-risk patients with transverse arch pathology with perioperative outcomes and long-term aorta-specific survival similar to open repair, albeit at a cost of increased reintervention. This observational single-institution study would suggest decreased use in more recent years in favor of open repair due to avoidance of native zone 0 hybrid procedures. This decline in the institutional use of native zone 0 hybrid repairs was associated with improved perioperative outcomes.

Background: Mortality rates following acute type A aortic dissection (ATAAD) repair are reduced when operations are performed by a high-volume acute aortic dissection (AAD) team, leading to efforts to centralize ATAAD care. Here, we describe our experience with ATAAD repair by our AAD team over the last 10 years, with a focus on patient selection, transfer protocols, operative approach, and volume trends over time.Methods: An AAD team was implemented at our institution in 2005, with dedicated high-volume AAD surgeons, a multidisciplinary approach to thoracic aortic disease management, and a standardized protocol for ATAAD repair. Further process improvements were made in 2013 to facilitate the rapid transfer of ATAAD patients to our institution using stream-lined triage, diagnostic, and transfer protocols for patients with suspected ATAAD (RACE-AD protocol). Volume trends and outcomes were assessed longitudinally over this period. in-hospital mortality rates of less than 10% were maintained over the study period.Conclusions: Centralization of ATAAD care has begun to occur at our center, with maintenance of low mortality rates for ATAAD repair. These data confirm a net positive impact on regional ATAAD outcomes through transfer of patients to a high-volume center with dedicated AAD surgeons.