Research Spotlight

Lebwohl, M. G., A. Blauvelt, A. Menter, K. A. Papp, S. Guenthner, R. Pillai, R. J. Israel and A. Jacobson (2019). “Efficacy, Safety, and Patient-Reported Outcomes in Patients with Moderate-to-Severe Plaque Psoriasis Treated with Brodalumab for 5 Years in a Long-Term, Open-Label, Phase Ii Study.” Am J Clin Dermatol Sep 6. [Epub ahead of print].

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BACKGROUND: Chronic inflammatory diseases such as psoriasis require treatment options that maintain efficacy and tolerability during extended treatment. OBJECTIVE: The aim of the study was to assess the long-term efficacy and safety of brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: Patients who completed a 12-week, phase II, dose-ranging clinical trial received brodalumab 210 mg every 2 weeks in an open-label extension study. Efficacy was assessed by static physician’s global assessment (sPGA) and psoriasis area and severity index (PASI). Quality of life, assessed by dermatology life quality index (DLQI), and safety were also evaluated. RESULTS: Overall, 181 patients received brodalumab for a median of 264 weeks. Brodalumab treatment resulted in rapid improvements in sPGA, PASI, and DLQI that were maintained through week 264. Achieving PASI 90 to < 100 or PASI 100 at weeks 12, 240, and 264 was associated with greater likelihood for DLQI 0 or 1 compared with achieving PASI 75 to < 90. Over 5 years, one adverse event of suicidal ideation was reported, no suicides occurred, and no new safety signals emerged. CONCLUSIONS: Brodalumab demonstrated skin clearance and improved quality of life, with an acceptable safety profile, throughout 5 years of treatment. ClinicalTrials.gov/NCT01101100.

Lawrence, M. C., C. M. Darden, S. Vasu, K. Kumano, J. Gu, X. Wang, J. Chan, Z. Xu, B. F. Lemoine, P. Nguyen, C. Smitherman, B. Naziruddin and G. Testa (2019). “Profiling Gene Programs in the Blood During Liver Regeneration in Living Liver Donors.” Liver Transpl 25(10): 1541-1560.

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The human liver’s capacity to rapidly regenerate to a full-sized functional organ after resection has allowed successful outcomes for living donor liver transplantation (LDLT) procedures. However, the ability to detect and track physiological changes occurring during liver regeneration after resection and throughout the restoration process is still lacking. We performed a comprehensive whole-transcriptome RNA sequencing analysis of liver and circulating blood tissue from 12 healthy LDLT donors to define biomarker signatures for monitoring physiological activities during liver regeneration at 14 time points for up to a 1-year procedural follow-up. LDLT donor liver tissue differentially expressed 1238 coding and noncoding genes after resection, and an additional 1260 genes were selectively regulated after LDLT. A total of 15,011 RNA transcript species were identified in the blood in response to liver resection. The transcripts most highly regulated were sequentially expressed within 3 distinct peaks that correlated with sets of functional genes involved in the induction of liver resection-specific innate immune response (peak 1), activation of the complement system (peak 2), and platelet activation and erythropoiesis (peak 3). Each peak corresponded with progressive phases of extracellular matrix degradation, remodeling, and organization during liver restoration. These processes could be tracked by distinct molecular signatures of up-regulated and down-regulated gene profiles in the blood during phases of liver repair and regeneration. In conclusion, the results establish temporal and dynamic transcriptional patterns of gene expression following surgical liver resection that can be detected in the blood and potentially used as biomarker signatures for monitoring phases of liver regeneration.

Khush, K. K., J. Patel, S. Pinney, A. Kao, R. Alharethi, E. DePasquale, G. Ewald, P. Berman, M. Kanwar, D. Hiller, J. P. Yee, R. N. Woodward, S. Hall and J. Kobashigawa (2019). “Noninvasive Detection of Graft Injury after Heart Transplant Using Donor-Derived Cell-Free DNA: A Prospective Multicenter Study.” Am J Transplant 19(10): 2889-2899.

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Standardized donor-derived cell-free DNA (dd-cfDNA) testing has been introduced into clinical use to monitor kidney transplant recipients for rejection. This report describes the performance of this dd-cfDNA assay to detect allograft rejection in samples from heart transplant (HT) recipients undergoing surveillance monitoring across the United States. Venous blood was longitudinally sampled from 740 HT recipients from 26 centers and in a single-center cohort of 33 patients at high risk for antibody-mediated rejection (AMR). Plasma dd-cfDNA was quantified by using targeted amplification and sequencing of a single nucleotide polymorphism panel. The dd-cfDNA levels were correlated to paired events of biopsy-based diagnosis of rejection. The median dd-cfDNA was 0.07% in reference HT recipients (2164 samples) and 0.17% in samples classified as acute rejection (35 samples; P = .005). At a 0.2% threshold, dd-cfDNA had a 44% sensitivity to detect rejection and a 97% negative predictive value. In the cohort at risk for AMR (11 samples), dd-cfDNA levels were elevated 3-fold in AMR compared with patients without AMR (99 samples, P = .004). The standardized dd-cfDNA test identified acute rejection in samples from a broad population of HT recipients. The reported test performance characteristics will guide the next stage of clinical utility studies of the dd-cfDNA assay.

Jupiter, D. C., F. Saenz, W. Mileski and N. Shibuya (2019). “Acute Deep Venous Thrombosis and Pulmonary Embolism in Foot and Ankle Trauma in the National Trauma Data Bank: An Update and Reanalysis.” J Foot Ankle Surg 2019 Sep 19. [Epub ahead of print].

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The data regarding rates of deep venous thrombosis and pulmonary embolism after foot and ankle trauma remain sparse. In this study of the National Trauma Data Bank Data set (2007-2009 and 2010-2016), these rates were reexamined and risk factors associated with these complications were assessed. Data quality is improved in the later data set; the incidence of deep venous thrombosis and pulmonary embolism was 0.28% and 0.21%, respectively, in the 2010-2016 data. Prophylaxis, male gender, treatment in a university hospital, open reduction, chronic obstructive pulmonary disease, and hypertension were notable significant risk factors for pulmonary embolism. For deep venous thrombosis, male gender, bleeding disorder, angina, and prophylaxis were risk factors. Careful, individualized assessment of the risk factors associated with deep venous thrombosis and pulmonary embolism is important, and the merits of routine prophylaxis remain in question.

Jones, B. P., S. Saso, T. Bracewell-Milnes, M. Y. Thum, J. Nicopoullos, C. Diaz-Garcia, P. Friend, S. Ghaem-Maghami, G. Testa, L. Johannesson, I. Quiroga, J. Yazbek and J. R. Smith (2019). “Human Uterine Transplantation: A Review of Outcomes from the First 45 Cases.” BJOG 126(11): 1310-1319.

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Uterine transplantation restores reproductive anatomy in women with absolute uterine factor infertility and allows the opportunity to conceive, experience gestation, and acquire motherhood. The number of cases being performed is increasing exponentially, with detailed outcomes from 45 cases, including nine live births, now available. In light of the data presented herein, including detailed surgical, immunosuppressive and obstetric outcomes, the feasibility of uterine transplantation is now difficult to refute. However, it is associated with significant risk with more than one-quarter of grafts removed because of complications, and one in ten donors suffering complications requiring surgical repair. TWEETABLE ABSTRACT: Uterine transplantation is feasible in women with uterine factor infertility, but is associated with significant risk of complication.