Research Spotlight

Cortes, J., H. S. Rugo, A. Awada, C. Twelves, E. A. Perez, S. A. Im, P. Gomez-Pardo, L. S. Schwartzberg, V. Dieras, D. A. Yardley, D. A. Potter, A. Mailliez, A. Moreno-Aspitia, J. S. Ahn, C. Zhao, U. Hoch, M. Tagliaferri, A. L. Hannah and J. O’Shaughnessy (2017). “Prolonged survival in patients with breast cancer and a history of brain metastases: Results of a preplanned subgroup analysis from the randomized phase iii beacon trial.” Breast Cancer Res Treat 165(2): 329-341.

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PURPOSE: Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. METHODS: The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician’s choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted. RESULTS: In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P < 0.01) versus TPC; median OS was 10.0 and 4.8 months, respectively. Improvement in OS was observed in both poorer and better GPA prognostic groups. Survival rates at 12 months were 44.4% for EP versus 19.4% for TPC. Consistent with the overall BEACON population, fewer patients on EP experienced grade >/=3 toxicity (50 vs. 70%). CONCLUSIONS: The significant improvement in survival in BCBM patients provides encouraging data for EP in this difficult-to-treat subgroup of patients. A phase three trial of EP in BCBM patients is underway.

Bastarrachea, R. A., J. Chen, J. W. Kent, Jr., E. J. Nava-Gonzalez, E. Rodriguez-Ayala, M. M. Daadi, B. Jorge, H. Laviada-Molina, A. G. Comuzzie, S. Chen and P. A. Grayburn (2017). “Engineering brown fat into skeletal muscle using ultrasound-targeted microbubble destruction gene delivery in obese zucker rats: Proof of concept design.” IUBMB Life 69(9): 745-755.

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Ultrasound-targeted microbubble destruction (UTMD) is a novel means of tissue-specific gene delivery. This approach systemically infuses transgenes precoupled to gas-filled lipid microbubbles that are burst within the microvasculature of target tissues via an ultrasound signal resulting in release of DNA and transfection of neighboring cells within the tissue. Previous work has shown that adenovirus containing cDNA of UCP-1, injected into the epididymal fat pads in mice, induced localized fat depletion, improving glucose tolerance, and decreasing food intake in obese diabetic mice. Our group recently demonstrated that gene therapy by UTMD achieved beta cell regeneration in streptozotocin (STZ)-treated mice and baboons. We hypothesized that gene therapy with BMP7/PRDM16/PPARGC1A in skeletal muscle (SKM) of obese Zucker diabetic fatty (fa/fa) rats using UTMD technology would produce a brown adipose tissue (BAT) phenotype with UCP-1 overexpression. This study was designed as a proof of concept (POC) project. Obese Zucker rats were administered plasmid cDNA contructs encoding a gene cocktail with BMP7/PRDM16/PPARGC1A incorporated within microbubbles and intravenously delivered into their left thigh. Controls received UTMD with plasmids driving a DsRed reporter gene. An ultrasound transducer was directed to the thigh to disrupt the microbubbles within the microcirculation. Blood samples were drawn at baseline, and after treatment to measure glucose, insulin, and free fatty acids levels. SKM was harvested for immunohistochemistry (IHC). Our IHC results showed a reliable pattern of effective UTMD-based gene delivery in enhancing SKM overexpression of the UCP-1 gene. This clearly indicates that our plasmid DNA construct encoding the gene combination of PRDM16, PPARGC1A, and BMP7 reprogrammed adult SKM tissue into brown adipose cells in vivo. Our pilot established POC showing that the administration of the gene cocktail to SKM in this rat model of genetic obesity using UTMD gene therapy, engineered a BAT phenotype with UCP-1 over-expression.

Asadollahi, R., M. Zweier, L. Gogoll, R. Schiffmann, H. Sticht, K. Steindl and A. Rauch (2017). “Genotype-phenotype evaluation of med13l defects in the light of a novel truncating and a recurrent missense mutation.” Eur J Med Genet 60(9): 451-464.

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A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation. The first patient indicates some facial resemblance to Kleefstra syndrome as a novel differential diagnosis, and the second patient shows, for the first time, recurrence of a MED13L missense mutation (p.(Asp860Gly)). Notably, our in silico modelling predicted this missense mutation to decrease the stability of an alpha-helix and thereby affecting the MED13L secondary structure, while the majority of published missense mutations remain variants of uncertain significance. Review of the reported patients with MED13L haploinsufficiency indicates moderate to severe ID and facial anomalies in all patients, as well as severe speech delay and muscular hypotonia in the majority. Further common signs include abnormal MRI findings of myelination defects and abnormal corpus callosum, ataxia and coordination problems, autistic features, seizures/abnormal EEG, or congenital heart defects, present in about 20-50% of the patients. With reference to facial anomalies, the majority of patients were reported to show broad/prominent forehead, low set ears, bitemporal narrowing, upslanting palpebral fissures, depressed/flat nasal bridge, bulbous nose, and abnormal chin, but macroglossia and horizontal eyebrows were also observed in approximately 30%. The latter are especially important in the differential diagnosis of 1p36 deletion and Kleefstra syndromes, while the more common facial gestalt shows some resemblance to 22q11.2 deletion syndrome. Despite the fact that MED13L was found to be one of the most common ID genes in the Deciphering Developmental Disorders Study, further detailed patient descriptions are needed to explore the full clinical spectrum, potential genotype-phenotype correlations, as well as the role of missense mutations and potential mutational hotspots along the gene.

Dabus, G., W. Brinjikji, A. P. Amar, J. E. Delgado Almandoz, O. M. Diaz, P. Jabbour, R. Hanel, F. Hui, M. Kelly, K. F. Layton, J. W. Miller, E. I. Levy, C. J. Moran, D. C. Suh, H. Woo, R. Sellar, B. Hoh, A. Evans and D. F. Kallmes (2017). “Angiographic and clinical outcomes of balloon remodeling versus unassisted coil embolization in the ruptured aneurysm cohort of the gel the nec study.” J Neurointerv Surg: 2017 Aug [Epub ahead of print].

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BACKGROUND AND PURPOSE: GEL THE NEC (GTN) was a multicenter prospective registry developed to assess the safety and efficacy of HydroSoft coils in treating intracranial aneurysms. We compared the angiographic and clinical outcomes of aneurysms treated with balloon assisted coil embolization (BACE) versus unassisted coil embolization (CE) in the ruptured aneurysm cohort. MATERIALS AND METHODS: GTN was performed at 27 centers in five countries. Patients aged 21-90 years with a ruptured aneurysm 3-15 mm in size were eligible for enrollment. We analyzed demographics/comorbidities, aneurysm location, and geometry, including maximum diameter, neck size, and dome to neck ratio, immediate and long term angiographic outcomes (graded by an independent core laboratory using the modified Raymond Scale), and procedure related adverse events. Angiographic and clinical outcomes were studied using chi2and t tests. RESULTS: Of the 599 patients in the GTN, 194 met the inclusion criteria. 84 were treated with BACE and 110 with CE. There were more prior smokers in the BACE group (p=0.01). The BACE group also had more vertebrobasilar aneurysms (p=0.006) and a larger mean neck size (p=0.02). More aneurysms were immediately completely occluded in the BACE group (p=0.02) Procedure- related major morbidity and mortality were no different between the techniques (p=0.4 and p=1, respectively). CONCLUSIONS: In this prospective ruptured aneurysm cohort from the GTN, BACE resulted in greater occlusion rates compared with unassisted CE with similar morbi-mortality.

Flores, A. and S. K. Asrani (2017). “The donor risk index: A decade of experience.” Liver Transpl 23(9): 1216-1225.

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In 2006, derivation of the donor risk index (DRI) highlighted the importance of donor factors for successful liver transplantation. Over the last decade, the DRI has served as a useful metric of donor quality and has enhanced our understanding of donor factors and their impact upon recipients with hepatitis C virus, those with low Model for End-Stage Liver Disease (MELD) score, and individuals undergoing retransplantation. DRI has provided the transplant community with a common language for describing donor organ characteristics and has served as the foundation for several tools for organ risk assessment. It is a useful tool in assessing the interactions of donor factors with recipient factors and their impact on posttransplant outcomes. However, limitations of statistical modeling, choice of donor factors, exclusion of unaccounted donor and geographic factors, and the changing face of the liver transplant recipient have tempered its widespread use. In addition, the DRI was derived from data before the MELD era but is currently being applied to expand the donor pool while concurrently meeting the demands of a dynamic allocation system. A decade after its introduction, DRI remains relevant but may benefit from being updated to provide guidance in the use of extended criteria donors by accounting for the impact of geography and unmeasured donor characteristics. DRI could be better adapted for recipients with nonalcoholic fatty liver disease by examining and including recipient factors unique to this population.