Research Spotlight

Cedars, A., K. M. Tecson, A. N. Zaidi, A. Lorts and P. A. McCullough (2019). “Impact of Durable Ventricular Assist Device Support on Outcomes of Patients with Congenital Heart Disease Waiting for Heart Transplant.” ASAIO J Jul 15. [Epub ahead of print].

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The number of congenital heart disease (CHD) patients with heart failure is expanding. These patients have a high probability of dying, while awaiting heart transplant. The potential for durable ventricular assist devices (VAD) to improve waiting list survival in CHD is unknown. We conducted an analysis of the Scientific Registry of Transplant Recipients database for the primary outcome of death or delisting due to clinical worsening, while listed for heart transplant. We compared CHD patients with non-CHD patients matched for listing status. Multivariable models were constructed to account for confounding variables. Congenital heart disease patients were less likely to have a VAD and were more likely to experience the primary outcome of death or delisting due to clinical worsening compared to non-CHD patients. Ventricular assist devices decreased the probability of experiencing the primary outcome for non-CHD but not for CHD patients with a final listing status of 1A. Ventricular assist devices increased the probability of experiencing the primary outcome among CHD patients for those with a final listing status of 1B with no impact in non-CHD patients. Among non-CHD patients who died or were delisted, the time to the primary outcome was delayed by VAD, with a similar trend in CHD. Except for patients with a final listing status of 1B, VAD does not adversely affect waiting list outcomes in CHD patients listed for heart transplant. Ventricular assist devices may prolong waiting list survival among high-risk CHD patients.

van der Knaap, M. S., R. Schiffmann, F. Mochel and N. I. Wolf (2019). “Diagnosis, prognosis, and treatment of leukodystrophies.” Lancet Neurol Jul 12. [Epub ahead of print].

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Leukodystrophies comprise a large group of rare genetic disorders primarily affecting CNS white matter. Historically, the diagnostic process was slow and patient prognosis regarded as poor because curative treatment was only available for very few leukodystrophies in early stages of the disease. Whole-exome sequencing has both greatly increased the number of known leukodystrophies and improved diagnosis. Whether MRI keeps its central place in diagnosis and what the role is of whole-exome sequencing are relevant questions for neurologists. Improved diagnosis has revealed the phenotypic variability of leukodystrophies, requiring adaptation of prognostication. Technological advance in molecular techniques and improved insight into the pathophysiology of individual leukodystrophies have led to therapeutic developments, including drug design and gene therapy. Despite this progress, therapies are only beneficial early in the disease course, emphasising the need for a speedy diagnosis and for research on regenerative approaches to repair the damage already present.

Zerhouni, Y. A., J. W. Scott, C. Ta, P. C. Hsu, M. Crandall, S. C. Gale, A. J. Schoenfeld, A. J. Bottiggi, E. E. Cornwell, 3rd, A. Eastman, J. K. Davis, B. Joseph, B. R. H. Robinson, S. Shafi, C. Q. White, B. H. Williams, E. R. Haut and A. H. Haider (2019). “Impact of the Affordable Care Act on trauma and emergency general surgery: An Eastern Association for the Surgery of Trauma systematic review and meta-analysis.” J Trauma Acute Care Surg 87(2): 491-501.

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BACKGROUND: Trauma and emergency general surgery (EGS) patients who are uninsured have worse outcomes as compared with insured patients. Partially modeled after the 2006 Massachusetts Healthcare Reform (MHR), the Patient Protection and Affordable Care Act was passed in 2010 with the goal of expanding health insurance coverage, primarily through state-based Medicaid expansion (ME). We evaluated the impact of ME and MHR on outcomes for trauma patients, EGS patients, and trauma systems. METHODS: This study was approved by the Eastern Association for the Surgery of Trauma Guidelines Committee. Using Grading of Recommendations Assessment, Development and Evaluation methodology, we defined three populations of interest (trauma patients, EGS patients, and trauma systems) and identified the critical outcomes (mortality, access to care, change in insurance status, reimbursement, funding). We performed a systematic review of the literature. Random effect meta-analyses and meta-regression analyses were calculated for outcomes with sufficient data. RESULTS: From 4,593 citations, we found 18 studies addressing all seven predefined outcomes of interest for trauma patients, three studies addressing six of seven outcomes for EGS patients, and three studies addressing three of eight outcomes for trauma systems. On meta-analysis, trauma patients were less likely to be uninsured after ME or MHR (odds ratio, 0.49; 95% confidence interval, 0.37-0.66). These coverage expansion policies were not associated with a change in the odds of inpatient mortality for trauma (odds ratio, 0.96; 95% confidence interval, 0.88-1.05). Emergency general surgery patients also experienced a significant insurance coverage gains and no change in inpatient mortality. Insurance expansion was often associated with increased access to postacute care at discharge. The evidence for trauma systems was heterogeneous. CONCLUSION: Given the evidence quality, we conditionally recommend ME/MHR to improve insurance coverage and access to postacute care for trauma and EGS patients. We have no specific recommendation with respect to the impact of ME/MHR on trauma systems. Additional research into these questions is needed. LEVEL OF EVIDENCE: Review, Economic/Decision, level III.

Wen, P. Y., D. A. Reardon, T. S. Armstrong, S. Phuphanich, R. D. Aiken, J. C. Landolfi, W. T. Curry, J. J. Zhu, M. Glantz, D. M. Peereboom, J. Markert, R. LaRocca, D. M. O’Rourke, K. Fink, L. Kim, M. Gruber, G. J. Lesser, E. Pan, S. Kesari, A. Muzikansky, C. Pinilla, R. G. Santos and J. S. Yu (2019). “A Randomized Double-Blind Placebo-Controlled Phase 2 Trial Of Dendritic Cell Vaccine ICT-107 In Newly Diagnosed Patients With Glioblastoma.” Clin Cancer Res Jul 18. [Epub ahead of print].

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PURPOSE: To evaluate the efficacy of ICT-107. PATIENTS AND METHODS: We conducted a double-blinded randomized phase II trial of ICT-107 in newly-diagnosed glioblastoma (GBM) patients and tested efficacy, safety, quality of life (QoL), and immune response. HLA-A1+ and/or -A2+ resected patients with residual tumor 1 cm3 received radiotherapy and concurrent temozolomide. Following completion of radiotherapy 124 patients, randomized 2:1, received ICT-107 (autologous dendritic cells (DCs) pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL-13Ralpha2) or matching control (unpulsed DC). Patients received induction ICT-107 or control weekly x 4 followed by twelve months of adjuvant temozolomide. Maintenance vaccinations occurred at one, three, and six months and every six months thereafter. RESULTS: ICT-107 was well-tolerated, with no difference in adverse events between the treatment and control groups. The primary endpoint, median overall survival (OS), favored ICT-107 by 2.0 months in the intent-to-treat (ITT) population but was not statistically significant. Progression-free survival (PFS) in the intention-to-treat (ITT) population was significantly increased in the ICT-107 cohort by 2.2 months (p=0.011). Frequency of HLA-A2 primary tumor antigen expression was higher than that for HLA-A1 patients, and HLA-A2 patients had higher immune response (via Elispot). HLA-A2 patients achieved a meaningful therapeutic benefit with ICT-107, in both the MGMT methylated and unmethylated pre-specified subgroups, whereas only HLA-A1 methylated patients had an OS benefit. CONCLUSION: PFSl was significantly improved in ICT-107 treated patients with maintenance of QoL. Patients in the HLA-A2 subgroup showed increased ICT-107 activity clinically and immunologically.

Wood, D. A., Z. Krajcer, J. Sathananthan, N. Strickman, C. Metzger, W. Fearon, M. Aziz, L. F. Satler, R. Waksman, M. Eng, S. Kapadia, A. Greenbaum, M. Szerlip . . . and J. G. Webb (2019). “Pivotal Clinical Study to Evaluate the Safety and Effectiveness of the MANTA Percutaneous Vascular Closure Device.” Circ Cardiovasc Interv 12(7): 1-11 e007258.

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BACKGROUND: Open surgical closure and small-bore suture-based preclosure devices have limitations when used for transcatheter aortic valve replacement, percutaneous endovascular abdominal aortic aneurysm repair, or percutaneous thoracic endovascular aortic aneurysm repair. The MANTA vascular closure device is a novel collagen-based technology designed to close large bore arteriotomies created by devices with an outer diameter ranging from 12F to 25F. In this study, we determined the safety and effectiveness of the MANTA vascular closure device. METHODS AND RESULTS: A prospective, single arm, multicenter investigation in patients undergoing transcatheter aortic valve replacement, percutaneous endovascular abdominal aortic aneurysm repair, or thoracic endovascular aortic aneurysm repair at 20 sites in North America. The primary outcome was time to hemostasis. The primary safety outcomes were accessed site-related vascular injury or bleeding complications. A total of 341 patients, 78 roll-in, and 263 in the primary analysis cohort, were entered in the study between November 2016 and September 2017. For the primary analysis cohort, transcatheter aortic valve replacement was performed in 210 (79.8%), and percutaneous endovascular abdominal aortic aneurysm repair or thoracic endovascular aortic aneurysm repair was performed in 53 (20.2%). The 14F MANTA was used in 42 cases (16%), and the 18F was used in 221 cases(84%). The mean effective sheath outer diameter was 22F (7.3 mm). The mean time to hemostasis was 65+/-157 seconds with a median time to hemostasis of 24 seconds. Technical success was achieved in 257 (97.7%) patients, and a single device was deployed in 262 (99.6%) of cases. Valve Academic Research Consortium-2 major vascular complications occurred in 11 (4.2%) cases: 4 received a covered stent (1.5%), 3 had access site bleeding (1.1%), 2 underwent surgical repair (0.8%), and 2 underwent balloon inflation (0.8%). CONCLUSIONS: In a selected population, this study demonstrated that the MANTA percutaneous vascular closure device can safely and effectively close large bore arteriotomies created by current generation transcatheter aortic valve replacement, percutaneous endovascular abdominal aortic aneurysm repair, and thoracic endovascular aortic aneurysm repair devices. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02908880.