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588 Background: CALGB/SWOG 80405 found no difference in overall survival (OS) or progression-free survival (PFS) in 1137 patients with KRAS wild-type metastatic colorectal cancer (mCRC) treated with either the anti-VEGF agent bevacizumab (Bev) or the anti-EGFR agent cetuximab (Cet) in combination with chemotherapy (FOLFOX or FOLFIRI) as first-line therapy. Additional molecular biomarkers are required for the optimization of treatment choices for patients with mCRC. Methods: Levels of 24 proteins were assayed in EDTA-plasma samples using multiplex ELISA techniques. Plasma samples were collected at baseline and cycle 2 day 1 (C2D1). Analyses of baseline markers have been presented previously. Changes from baseline to C2D1 were expressed as an L-ratio (LR, log2 of C2D1 divided by baseline measure). LRs dichotomized at 0 were analyzed for potential prognostic and predictive effects on OS and PFS using Cox models while adjusting for confounders (post-hoc optimized cutpoints were used for PLGF, TIMP1, VCAM1, and VEGFR3 due to skew in the distributions of these markers). P-values are not corrected for multiple testing. Results: Baseline and matched C2D1 samples from 446 patients (212 Bev/234 Cet) were available for analysis. Thirteen markers were differentially modulated between arms (p < 0.05). Early increases in CD73 (p = 0.001), ICAM1 (p = 0.022), TIMP1 (p = 0.001), TSP2 (p = 0.024), and VEGFR3 (p = 0.006) were prognostic for shorter OS. Increases in ICAM1 (p = 0.008), TIMP1 (p = 0.042), and TGFB1 (p = 0.039) were prognostic for shorter PFS. Changes in VEGFR3 (pint = 0.097) and TGFBR3 (pint = 0.052) were predictive for OS and PFS, respectively. No other markers were predictive for OS or PFS (p < 0.1). Conclusions: Changes in circulating plasma protein biomarkers observed in patients enrolled in CALGB/SWOG 80405 were both prognostic and predictive for OS and PFS and warrant further study. Such changes could provide valuable information and help guide treatment decisions. Support: U10CA180821, U10CA180882, U10CA180888, U10CA180830; ClinicalTrials.gov: NCT00265850. [Table: see text]

Alpha‐1 antitrypsin deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression, despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies in patients with AATD. We examined the contribution of DNA methylation (5‐methylcytosine [5mC]) to AATD liver disease heterogeneity because 5mC responds to environmental and genetic cues and its deregulation is a major driver of liver disease. Using liver biopsies from adults with early‐stage AATD and the ZZ genotype, genome‐wide 5mC patterns were interrogated. We compared DNA methylation among patients with early AATD, and among patients with normal liver, cirrhosis, and hepatocellular carcinoma derived from multiple etiologic exposures, and linked patient clinical/demographic features. Global analysis revealed significant genomic hypomethylation in AATD liver–impacting genes related to liver cancer, cell cycle, and fibrosis, as well as key regulatory molecules influencing growth, migration, and immune function. Further analysis indicated that 5mC changes are localized, with hypermethylation occurring within a background of genome‐wide 5mC loss and with patients with AATD manifesting distinct epigenetic landscapes despite their mutational homogeneity. By integrating clinical data with 5mC landscapes, we observed that CpGs differentially methylated among patients with AATD disease are linked to hallmark clinical features of AATD (e.g., hepatocyte degeneration and polymer accumulation) and further reveal links to well‐known sex‐specific effects of liver disease progression. Conclusion: Our data reveal molecular epigenetic signatures within this mutationally homogeneous group that point to ways to stratify patients for liver disease risk.

AbstractA major challenge in the development of cancer nanomedicine is the inability for nanomaterials to efficiently penetrate and deliver therapeutic agents into solid tumors. Previous studies have shown that tumor vasculature and extracellular matrix regulate the transvascular and interstitial transport of nanoparticles, both critical for successfully delivering nanomedicine into solid tumors. Within the malignant tumor microenvironment, blood vessels are morphologically abnormal and functionally exhibit substantial permeability. Furthermore, the tumor extracellular matrix (ECM), unlike that of the normal tissue parenchyma, is densely packed with collagen. These pathophysiological properties greatly impede intratumoral delivery of nanomaterials. By using an antivascular endothelial growth factor receptor antibody, DC101, and an antitransforming growth factor β1 (TGF‐β1) antibody, normalization of the tumor vasculature and ECM is achieved, respectively, in a syngeneic murine glioma model. This normalization effect results in a more organized vascular network, improves tissue perfusion, and reduces collagen density, all of which contribute to enhanced nanoparticle delivery and distribution within tumors. These findings suggest that combined vascular and ECM normalization strategies can be used to remodel the tumor microenvironment and improve nanomedicine delivery into solid tumors, which has significant implications for developing more effective combinational therapeutic strategies using cancer nanomedicine.

Abstract Posterior pilon fractures involve the medial malleolus (MM). Our purpose was to define the characteristics of posterior pilon fractures, and propose a classification system based on fracture morphology and type of management. The records of patients with posterior pilon fractures treated from 2011 to 2015 were retrospectively reviewed. The injury mechanism, fracture morphology, surgical approach, and follow-up results were reviewed and analyzed. This study was approved by the Institutional Review Board of PLA Army General Hospital. Thirty-six patients, 18 males and 18 females (mean age: 48.9 years) were included in the study. Four characteristics were used to define posterior pilon fractures. A simple posterolateral approach or a combined posterolateral and posteromedial approach was used for reduction and fixation in all patients. The mean follow-up time was 28.2 months, and at the end of follow-up, the mean American Orthopedic Foot and Ankle Society Score (AOFAS) was 82.5 points (range: 35–100 points). Based on injury mechanism and fracture morphology, we classified posterior pilon fractures into 3 types that suggest the optimal surgical approach: type I, a single complete fracture fragment; type II, a posterior malleolus fracture with 2 subtypes; type III, a posterior malleolus fracture associated with complete MM fracture with 2 subtypes. The proposed classification system based on injury mechanism and fracture morphology can guide the surgical approach to maximize outcomes.

Anastrozole is a widely prescribed aromatase inhibitor for the therapy of estrogen receptor positive (ER+) breast cancer. We performed a genome‐wide association study (GWAS) for plasma anastrozole concentrations in 687 postmenopausal women with ER+ breast cancer. The top single‐nucleotide polymorphism (SNP) signal mapped across SLC38A7 (rs11648166, P = 2.3E‐08), which we showed to encode an anastrozole influx transporter. The second most significant signal (rs28845026, P = 5.4E‐08) mapped near ALPPL2 and displayed epistasis with the SLC38A7 signal. Both of these SNPs were cis expression quantitative trait loci (eQTL)s for these genes, and patients homozygous for variant genotypes for both SNPs had the highest drug concentrations, the highest SLC38A7 expression, and the lowest ALPPL2 expression. In summary, our GWAS identified a novel gene encoding an anastrozole transporter, SLC38A7, as well as epistatic interaction between SNPs in that gene and SNPs near ALPPL2 that influenced both the expression of the transporter and anastrozole plasma concentrations.