Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers.

BACKGROUND AND AIMS: Vascular invasion (VI) is a critical risk factor for HCC recurrence and poor survival. The molecular drivers of vascular invasion in HCC are open for investigation. Deciphering the molecular landscape of invasive HCC will help identify therapeutic targets and noninvasive biomarkers. APPROACH AND RESULTS: To this end, we undertook this study to evaluate the genomic, transcriptomic, and proteomic profile of tumors with VI using the multiplatform cancer genome atlas (The Cancer Genome Atlas; TCGA) data (n = 373). In the TCGA Liver Hepatocellular Carcinoma cohort, macrovascular invasion was present in 5% (n = 17) of tumors and microvascular invasion in 25% (n = 94) of tumors. Functional pathway analysis revealed that the MYC oncogene was a common upstream regulator of the mRNA, miRNA, and proteomic changes in VI. We performed comparative proteomic analyses of invasive human HCC and MYC-driven murine HCC and identified fibronectin to be a proteomic biomarker of invasive HCC (mouse fibronectin 1 [Fn1], P = 1.7 × 10-11 ; human FN1, P = 1.5 × 10-4 ) conserved across the two species. Mechanistically, we show that FN1 promotes the migratory and invasive phenotype of HCC cancer cells. We demonstrate tissue overexpression of fibronectin in human HCC using a large independent cohort of human HCC tissue microarray (n = 153; P < 0.001). Lastly, we showed that plasma fibronectin levels were significantly elevated in patients with HCC (n = 35; mean = 307.7 µg/mL; SEM = 35.9) when compared to cirrhosis (n = 10; mean = 41.8 µg/mL; SEM = 13.3; P < 0.0001). CONCLUSIONS: Our study evaluates the molecular landscape of tumors with VI, identifying distinct transcriptional, epigenetic, and proteomic changes driven by the MYC oncogene. We show that MYC up-regulates fibronectin expression, which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising noninvasive proteomic biomarker of VI in HCC.

Developing and Evaluating a Simulator for Complex IVC Filter Retrieval.

RATIONALE AND OBJECTIVES: Simulation models allow trainees to acquire and develop procedural skills without compromising patient safety. Complex inferior vena cava (IVC) filter retrieval requires the operator to be proficient at using devices, such as endobronchial forceps, and advanced techniques to carefully dissect free embedded filter tips encased in fibrous tissue adherent to the IVC. Therefore, it is important to develop an effective, inexpensive model to simulate tip-embedded IVC filter retrieval. MATERIALS AND METHODS: Silicone tubes (Flexi-Seal SIGNAL, ConvaTec Inc., Skilman, NJ), IVC filters (Cook Günther Tulip Vena Cava Filter, Cook Medical, Bloomington, IN), and endobronchial forceps (Lymol Medical, Woburn, MA) were obtained to assemble the model. A total of 12 combinations of adhesive binding methods were used to adhere IVC filter fragments to the silicone tubes, and these were blind tested. A single operator with over 10 years of experience using forceps scored the adhesives subjectively on a three-point scale for adherence, elasticity, and tactile feel. The adhesive most similar to IVC fibrous tissue was selected to assemble the final tip-embedded IVC filter model. 20 trainees were then assigned to practice on the model. A 3-point scale scoring metric objectively measured confidence before and after training on the model. RESULTS: Sil-poxy Silicone Adhesive (Smooth-On, Macungie, PA) was found to be the most similar to human IVC fibrous tissue with an average score of 3 of 3 on all metrics. Comparing scores from before and after use of the model, trainee confidence improved significantly (p < 0.1) in all three categories from 1.20 to 2.10 (handling forceps), 1.05 to 2.15 (understanding tactile feel of fibrous tissue), and 1.05 to 1.70 (overall confidence). CONCLUSION: The development of a low-cost simulator for embedded IVC filters is feasible and can be used to improve trainee confidence and skill for complex IVC filter retrieval.

Electronic Patient-Reported Outcomes: Semi-Automated Data Collection in the Interventional Radiology Clinic.

INTRODUCTION: Patient-reported outcomes are important for clinical research and will likely be used in the near future as a metric for physician reimbursement. This study aims to evaluate the implementation of an electronic data collection system for deep vein thrombosis and lymphedema quality-of-life (QOL) questionnaires in a tertiary care interventional radiology practice. METHODS: A single provider's clinic patients were automatically e-mailed validated questionnaires 1 week before their appointments. If not completed via e-mail, the questionnaire was administered on an electronic tablet in clinic by a research coordinator. Patients were also sent postprocedure questionnaires. RESULTS: In all, 106 patients visited the clinic for a pre-intervention venous consultation. Of them, 96% (n = 102 of 106) completed the pre-intervention questionnaire: 48% (n = 47 of 98) via e-mail and 52% (n = 51 of 98) via tablet. Of the patients who had procedures and were sent questionnaires, 49% (n = 26 of 53) were seen in person. Of the postprocedure in-person clinic patients, 76% (n = 20 of 26) completed the questionnaire via e-mail, and the remainder with the tablet in clinic. Twenty-seven of the 53 (51%) patients did not return for follow-up and instead were sent an electronic questionnaire as their only source of follow-up, of which 74% (n = 20 of 27) complied. CONCLUSION: After an initial introduction to electronic QOL reporting, patients were more likely to complete the questionnaires remotely for their follow-up appointment. A semi-automated electronic QOL system allows physicians to collect patient outcome data even in the absence of a clinic visit.

Quantification of Activity Lost to Delivery-System Residual and Decay in Yttrium-90 Radioembolization.

PURPOSE: To measure the decay activity loss and delivery system residual activity loss of yttrium-90 (Y90) radioembolization treatments across resin and glass microsphere activities. MATERIALS AND METHODS: For Y90 administrations between December 2009 and June 2017 at the study institution, the prescribed activity, prepared activity, and delivered activity were recorded. Six hundred sixty-two administrations were reviewed-345 glass (0.21-8.52 GBq) and 317 resin (0.18-3.28 GBq). Twenty-five patients (all resin) were excluded for arterial stasis or catheter clogging. The percentage and actual losses of activity lost to decay and to delivery system residual were calculated for glass and resin microspheres. RESULTS: The median time between activity premeasurement and administration was 2.20 hours, resulting in a median activity lost to decay of 0.030 GBq or 2.35%, with no significant difference observed between glass and resin despite differences in preparation (P = .0697). Resin showed significantly higher activity lost to delivery system residual than glass (0.039 GBq vs 0.010 GBq, 3.01% vs 0.61%, P < .001). The percent activity lost to residual varied with activity prepared, with a maximum of 20.1% and 16.2% for the smallest activities of resin and glass, respectively. CONCLUSIONS: Residual activity loss differs between glass and resin microspheres. For resin microspheres in particular, percent residual activity loss increases with lower prepared activities. Protocols for activity calculation and preparation, patient dosimetry, and regulatory compliance must take these losses into consideration prospectively.

A Call for Mixed Methods in Competency-Based Medical Education: How We Can Prevent the Overfitting of Curriculum and Assessment.

Competency-based medical education (CBME) has been the subject of heated debate since its inception in medical education. Despite the many challenges and pitfalls of CBME that have been recognized by the medical education community, CBME is now seeing widespread implementation. However, the biggest problems with CBME still have not been solved. Two of these problems, reductionism and loss of authenticity, present major challenges when developing curricula and assessment tools.The authors address these problems by making a call for flexibility in competency definitions and for the use of mixed methods in CBME. First, they present the issue of reductionism and a similar concept from the field of data science, overfitting. Then they outline several solutions, both conceptual and concrete, to prevent undue reductionist tendencies in both competency definitions and in tools of assessment. Finally, they propose the reintroduction of qualitative methods to balance the historically quantitative emphasis of assessment in medical education.The authors maintain that mixed-methods assessment with multiple assessors in differing contexts can yield a more accurate representation of a medical trainee's skills and abilities, deter the loss of authenticity, and increase the willingness of medical educators to adopt a feasible form of CBME. Finally, they propose the deployment of dedicated faculty assessors and physician coaches (which will reduce training requirements for other faculty), as well as the use of formal qualitative tools of assessment alongside established quantitative tools, to encourage a truly mixed-methods approach to assessment.

Determining the Optimal Number of Core Needle Biopsy Passes for Molecular Diagnostics.

PURPOSE: The number of core biopsy passes required for adequate next-generation sequencing is impacted by needle cut, needle gauge, and the type of tissue involved. This study evaluates diagnostic adequacy of core needle lung biopsies based on number of passes and provides guidelines for other tissues based on simulated biopsies in ex vivo porcine organ tissues. METHODS: The rate of diagnostic adequacy for pathology and molecular testing from lung biopsy procedures was measured for eight operators pre-implementation (September 2012-October 2013) and post-implementation (December 2013-April 2014) of a standard protocol using 20-gauge side-cut needles for ten core biopsy passes at a single academic hospital. Biopsy pass volume was then estimated in ex vivo porcine muscle, liver, and kidney using side-cut devices at 16, 18, and 20 gauge and end-cut devices at 16 and 18 gauge to estimate minimum number of passes required for adequate molecular testing. RESULTS: Molecular diagnostic adequacy increased from 69% (pre-implementation period) to 92% (post-implementation period) (p < 0.001) for lung biopsies. In porcine models, both 16-gauge end-cut and side-cut devices require one pass to reach the validated volume threshold to ensure 99% adequacy for molecular characterization, while 18- and 20-gauge devices require 2-5 passes depending on needle cut and tissue type. CONCLUSION: Use of 20-gauge side-cut core biopsy needles requires a significant number of passes to ensure diagnostic adequacy for molecular testing across all tissue types. To ensure diagnostic adequacy for molecular testing, 16- and 18-gauge needles require markedly fewer passes.

Administering Blood Products Before Selected Interventional Radiology Procedures: Developing, Applying, and Monitoring a Standardized Protocol.

PURPOSE: To apply and monitor a single institution's adherence to internally established guidelines for the preoperative administration of platelets and/or fresh frozen plasma (FFP) before a specified subset of minimally invasive interventional radiology (IR) procedures. MATERIALS AND METHODS: Beginning in December 2008, we implemented a set of restrictive guidelines for preoperative platelet and/or FFP administration before IR procedures at a single academic hospital. Basing our program on the methodology of Lean Six Sigma, we compared the number and appropriateness of transfusions between the months of January and October in 2008 (prepolicy), again in 2010 (postpolicy), and finally in 2015 (follow-up). Patients with a platelet count less than or equal to 50,000 or an international normalized ratio greater than or equal to 1.7 met criteria for receiving platelets or FFP, respectively, before their IR procedure. For all three periods, we compared the rates of transfusion, hemorrhagic complications, and proportion of appropriate versus inappropriate blood product administration (BPA) per our guidelines. RESULTS: There was a significant increase in the number of appropriate BPAs between 2008 and 2010 from 58% to 76% (P = .021). Between 2010 and 2015, the rate trended up further, from 76% to 88% (P = .051). Overall, between 2008 and 2015, the improvement from 58% to 88% was significant (P < .001). The rate of hemorrhagic complications was extremely low in all three groups. CONCLUSION: Restrictive guidelines for receiving platelets and FFP administrations before IR procedures can sustainably decrease the rate of overall BPA while increasing the proportion of appropriate BPA without impacting the rate of hemorrhagic complications.