90Y Radioembolization versus Drug-eluting Bead Chemoembolization for Unresectable Hepatocellular Carcinoma: Results from the TRACE Phase II Randomized Controlled Trial.

Background Transarterial chemoembolization (TACE) is the recommended treatment for intermediate hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer guidelines. Prospective uncontrolled studies suggest that yttrium 90 (90Y) transarterial radioembolization (TARE) is a safe and effective alternative. Purpose To compare the efficacy and safety of TARE with TACE for unresectable HCC. Materials and Methods In this single-center prospective randomized controlled trial (TRACE), 90Y glass TARE was compared with doxorubicin drug-eluting bead (DEB) TACE in participants with intermediate-stage HCC, extended to Eastern Cooperative Oncology Group performance status 1 and those with early-stage HCC not eligible for surgery or thermoablation. Participants were recruited between September 2011 and March 2018. The primary end point was time to overall tumor progression (TTP) (Kaplan-Meier analysis) in the intention-to-treat (ITT) and per-protocol (PP) groups. Results At interim analysis, 38 participants (median age, 67 years; IQR, 63-72 years; 33 men) were randomized to the TARE arm and 34 (median age, 68 years; IQR, 61-71 years; 30 men) to the DEB-TACE arm (ITT group). Median TTP was 17.1 months in the TARE arm versus 9.5 months in the DEB-TACE arm (ITT group hazard ratio [HR], 0.36; 95% CI: 0.18, 0.70; P = .002) (PP group, 32 and 34 participants, respectively, in each arm; HR, 0.29; 95% CI: 0.14, 0.60; P < .001). Median overall survival was 30.2 months after TARE and 15.6 months after DEB-TACE (ITT group HR, 0.48; 95% CI: 0.28, 0.82; P = .006). Serious adverse events grade 3 or higher (13 of 33 participants [39%] vs 19 of 36 [53%] after TARE and DEB-TACE, respectively; P = .47) and 30-day mortality (0 of 33 participants [0%] vs three of 36 [8.3%]; P = .24) were similar in the safety groups. At the interim, the HR for the primary end point, TTP, was less than 0.39, meeting the criteria to halt the study. Conclusion With similar safety profile, yttrium 90 radioembolization conferred superior tumor control and survival compared with chemoembolization using drug-eluting beads in selected participants with early or intermediate hepatocellular carcinoma. Clinical trial registration no. NCT01381211 © RSNA, 2022 Online supplemental material is available for this article.

No Advantage of Expanded Polytetrafluoroethylene and Fluorinated Ethylene Propylene-Covered Stents over Uncovered Nitinol Stents for Percutaneous Palliation of Malignant Infrahilar Biliary Obstruction: Results of a Single-Center Prospective Randomized Trial.

PURPOSE: To prove that covered stents are more efficacious than uncovered stents regarding patency, safety, enabling of chemotherapy, and survival in percutaneous palliation of malignant infrahilar biliary obstruction. MATERIALS AND METHODS: After failed endoscopic treatment, 154 patients with obstructive jaundice caused by unresectable infrahilar malignancy were randomly allocated to receive an expanded polytetrafluoroethylene and fluorinated ethylene propylene-covered or an uncovered nitinol stent. Occlusion rate, patency, and survival were assessed. Safety and clinical success in terms of chemotherapy were compared. RESULTS: Three patients were excluded post hoc. Fifteen patients died within 7 d and were excluded from patency analysis. Occlusion rates were 32% (21 of 66) for covered and 29% (20 of 70) for uncovered stents (P = .7). Estimated median patency durations were 308 d (95% confidence interval [CI], 178-438 d) for covered and 442 d (95% CI, 172-712 d) for uncovered stents (P = .1). Serious adverse events (P = 1.0) and 30-day mortality (P = .5) were equivalent between groups. At hospital discharge, median bilirubin reduction of 8 mg/dL was found in both groups (P < .001). In the covered stent group, 35 patients (48%) received palliative chemotherapy, vs 29 (37%) in the uncovered stent group (P = .2). Estimated median survival times were 96 days (95% CI, 68-124 d) with covered stents and 75 days (95% CI, 42-108 d) with uncovered stents (P = .6). CONCLUSIONS: In malignant infrahilar biliary obstruction not amenable to endoscopy, no improvement in patency or survival with percutaneously placed covered stents could be confirmed. Covered and uncovered stent types exhibit similar safety profiles and clinical success rates.

Benign anastomotic biliary strictures untreatable by ERCP: a novel percutaneous balloon dilatation technique avoiding indwelling catheters.

OBJECTIVE: To evaluate long-term patency rates of a novel percutaneous threefold balloon dilatation protocol in benign anastomotic biliary strictures. METHODS: Patients with a benign biliary stricture after hepatobiliary surgery or liver transplantation, untreatable with endoscopy, underwent a percutaneous treatment cycle consisting of a 20-min balloon dilatation session on day one, repeated on days three and five. No catheters were left behind after the last dilatation session. Technical and clinical success as well as complications were analysed. Mean primary and secondary patency times were assessed. Cumulative primary and secondary patency rates at 6 months and 1, 2 and 3 years were determined. RESULTS: Seventy patients underwent 135 dilatation treatment cycles (mean 1.9) with a technical success rate of 99%. Clinical success was achieved in 87% of the patients. Fifty-eight of 135 (43%) patients had minor and 15/135 (11%) had major complications. Mean primary and secondary patency times were 26 months and 46 months, respectively, with a median follow-up of 69 months. Cumulative primary patency rate at 6 months was 67%, at 1 year 56%, at 2 years 41% and at 3 years 36%. The cumulative secondary patency rate at 6 months was 83%, at 1 year 79%, at 2 years 70% and at 3 years 64%. CONCLUSION: In benign anastomotic biliary strictures, a percutaneous threefold balloon dilatation treatment is effective. As long indwelling catheters are avoided, patient comfort improves. KEY POINTS: • Percutaneous threefold balloon dilatation treatment is effective in benign anastomotic biliary strictures. • As indwelling catheters after dilatation are avoided, patient comfort improves. • The dilatation protocol can be repeated efficiently in case of recurrent stricture.

Analysis of Invasion Dynamics of Matrix-Embedded Cells in a Multisample Format.

In vitro tests of cancer cell invasion are the "first line" tools of preclinical researchers for screening the multitude of chemical compounds or cell perturbations that may aid in halting or treating cancer malignancy. In order to have predictive value or to contribute to designing personalized treatment regimes, these tests need to take into account the cancer cell environment and measure effects on invasion in sufficient detail. The in vitro invasion assays presented here are a trade-off between feasibility in a multisample format and mimicking the complexity of the tumor microenvironment. They allow testing multiple samples and conditions in parallel using 3D-matrix-embedded cells and deal with the heterogeneous behavior of an invading cell population in time. We describe the steps to take, the technical problems to tackle and useful software tools for the entire workflow: from the experimental setup to the quantification of the invasive capacity of the cells. The protocol is intended to guide researchers to standardize experimental set-ups and to annotate their invasion experiments in sufficient detail. In addition, it provides options for image processing and a solution for storage, visualization, quantitative analysis, and multisample comparison of acquired cell invasion data.

An end-to-end software solution for the analysis of high-throughput single-cell migration data.

The systematic study of single-cell migration requires the availability of software for assisting data inspection, quality control and analysis. This is especially important for high-throughput experiments, where multiple biological conditions are tested in parallel. Although the field of cell migration can count on different computational tools for cell segmentation and tracking, downstream data visualization, parameter extraction and statistical analysis are still left to the user and are currently not possible within a single tool. This article presents a completely new module for the open-source, cross-platform CellMissy software for cell migration data management. This module is the first tool to focus specifically on single-cell migration data downstream of image processing. It allows fast comparison across all tested conditions, providing automated data visualization, assisted data filtering and quality control, extraction of various commonly used cell migration parameters, and non-parametric statistical analysis. Importantly, the module enables parameters computation both at the trajectory- and at the step-level. Moreover, this single-cell analysis module is complemented by a new data import module that accommodates multiwell plate data obtained from high-throughput experiments, and is easily extensible through a plugin architecture. In conclusion, the end-to-end software solution presented here tackles a key bioinformatics challenge in the cell migration field, assisting researchers in their high-throughput data processing.

CellMissy: a tool for management, storage and analysis of cell migration data produced in wound healing-like assays.

SUMMARY: Automated image processing has allowed cell migration research to evolve to a high-throughput research field. As a consequence, there is now an unmet need for data management in this domain. The absence of a generic management system for the quantitative data generated in cell migration assays results in each dataset being treated in isolation, making data comparison across experiments difficult. Moreover, by integrating quality control and analysis capabilities into such a data management system, the common practice of having to manually transfer data across different downstream analysis tools will be markedly sped up and made more robust. In addition, access to a data management solution creates gateways for data standardization, meta-analysis and structured public data dissemination. We here present CellMissy, a cross-platform data management system for cell migration data with a focus on wound healing data. CellMissy simplifies and automates data management, storage and analysis from the initial experimental set-up to data exploration. AVAILABILITY AND IMPLEMENTATION: CellMissy is a cross-platform open-source software developed in Java. Source code and cross-platform binaries are freely available under the Apache2 open source license at http://cellmissy.googlecode.com.

The XTT cell proliferation assay applied to cell layers embedded in three-dimensional matrix.

Cell proliferation, a main target in cancer therapy, is influenced by the surrounding three-dimensional (3D) extracellular matrix (ECM). In vitro drug screening is, thus, optimally performed under conditions in which cells are grown (embedded or trapped) in dense 3D matrices, as these most closely mimic the adhesive and mechanical properties of natural ECM. Measuring cell proliferation under these conditions is, however, technically more challenging compared with two-dimensional (2D) culture and other "3D culture conditions," such as growth on top of a matrix (pseudo-3D) or in spongy scaffolds with large pore sizes. Consequently, such measurements are only slowly applied on a wider scale. To advance this, we report on the equal quality (dynamic range, background, linearity) of measuring the proliferation of cell layers embedded in dense 3D matrices (collagen, Matrigel) compared with cells in 2D culture using the easy (one-step) and in 2D well-validated, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT)-assay. The comparison stresses the differences in proliferation kinetics and drug sensitivity of matrix-embedded cells versus 2D culture. Using the specific cell-layer-embedded 3D matrix setup, quantitative measurements of cell proliferation and cell invasion are shown to be possible in similar assay conditions, and cytostatic, cytotoxic, and anti-invasive drug effects can thus be reliably determined and compared in physiologically relevant settings. This approach in the 3D matrix holds promise for improving early-stage, high-throughput drug screening, targeting either highly invasive or highly proliferative subpopulations of cancers or both.

Phosphosite conservation in single domain orthologs versus paralogs: a way to combine differential regulation with redundant core functions.

Evolutionary conservation for structure function relations is commonly accepted. Here we hypothesize that closely related single domain paralogous proteins, having similar expression profiles and redundant biochemical core functions, additionally evolved to allow and maintain isoform specific differential regulation by single conserved amino acid substitutions. To substantiate this, we considered two families of closely related actin binding proteins combined with data mining of phosphorylated residues in human and mouse proteins. We show that such residues are identical in other orthologs whereas paralogs have a different, but also conserved, non-phosphorylatable residue at the equivalent positions.

Ins and outs of ADF/cofilin activity and regulation.

The actin-binding proteins of the actin-depolymerisation factor (ADF)/cofilin family were first described more than three decades ago, but research on these proteins still occupies a front role in the actin and cell migration field. Moreover, cofilin activity is implicated in the malignant, invasive properties of cancer cells. The effects of ADF/cofilins on actin dynamics are diverse and their regulation is complex. In stimulated cells, multiple signalling pathways can be initiated resulting in different activation/deactivation switches that control ADF/cofilin activity. The output of this entire regulatory system, in combination with spatial and temporal segregation of the activation mechanisms, underlies the contribution of ADF/cofilins to various cell migration/invasion phenotypes. In this framework, we describe current views on how ADF/cofilins function in migrating and invading cells.