Standardization phantom for intra-operative fluorescence molecular imaging.

Fluorescence-guided intervention is increasingly considered for real-time intra-operative oncological applications. Herein we propose a novel composite phantom for standardization and quality control, which could serve as a framework toward good clinical practices

The impact of intraoperative frozen section analysis on final resection margin status, recurrence, and patient outcome with oral squamous cell carcinoma

Background!#!The objective of this study was to evaluate the diagnostic value of intraoperative frozen section analysis (IFSA) of tumor bed margins in patients with oral squamous cell carcinoma (OSCC).!##!Methods!#!This retrospective study includes 194 primary OSCC cases. The impact of intraoperative information by IFSA on final margin status, local recurrence, and disease-specific survival were analyzed.!##!Results!#!IFSA revealed a 50% sensitivity and a 100% specificity, with a positive and negative predictive value of 100% and 89.1%, respectively. In 19 cases, margins were rated positive by IFSA and remained positive in eight cases (42.1%), despite immediate re-resection. This constellation led to higher recurrence and lower survival rates than in cases with consecutive R0 status (each p = 0.046). Positive margins in IFSA were associated with closer final margins (p = 0.022) and early recurrences (p = 0.050).!##!Conclusions!#!Achieving instant R0 status has a crucial impact on disease recurrence and patient survival. IFSA falls short to ensure secure definite surgical margins. Thus, improved intraoperative diagnostic information on the location and extent of OSCC could support patient treatment.!##!Clinical relevance!#!Considering that patient survival has not improved despite progress in surgical and adjuvant therapy, the process and outcome of IFSA was scrutinized as one part of the treatment concept

Multi-parametric standardization of fluorescence imaging systems based on a composite phantom.

Objective: Fluorescence molecular imaging (FMI) has emerged as a promising tool for surgical guidance in oncology, with one of the few remaining challenges being the ability to offer quality control and data referencing. This paper investigates the use of a novel composite phantom to correct and benchmark FMI systems. Methods: This paper extends on previous work by describing a phantom design that can provide a more complete assessment of FMI systems through quantification of dynamic range and determination of spatial illumination patterns for both reflectance and fluorescence imaging. Various performance metrics are combined into a robust and descriptive "system benchmarking score," enabling not only the comprehensive comparison of different systems, but also for the first time, correction of the acquired data. Results: We show that systems developed for targeted fluorescence imaging can achieve benchmarking scores of up to 70 & x0025;, while clinically available systems optimized for indocyanine green are limited to 50 & x0025;, mostly due to greater leakage of ambient and excitation illumination and lower resolution. The image uniformity can also be approximated and employed for image flat-fielding, an important milestone toward data referencing. In addition, we demonstrate composite phantom use in assessing the performance of a surgical microscope and of a raster-scan imaging system. Conclusion: Our results suggest that the new phantom has the potential to support high-fidelity FMI through benchmarking and image correction. Significance: Standardization of the FMI is a necessary process for establishing good imaging practices in clinical environments and for enabling high-fidelity imaging across patients and multi-center imaging studies

Comparison of a high-definition three-dimensional digital camera system with a conventional state-of-the-art operation microscope for microsurgical anastomoses

Abstract Since its clinical implementation, microvascular surgery has depended on the continuous improvement of magnification tools. One of the more recent developments is a high-definition three-dimensional (3D) digital system (exoscope), which provides an alternative to the state-of-the-art operating microscopes. This study aimed to evaluate the advantages and disadvantages of this technology and compare it with its predecessor. The study included 14 surgeons with varying levels of experience, none of which had used a 3D optical system previously. Six of these surgeons performed five arterial and five venous anastomoses in the chicken thigh model with both the VITOM 3D exoscope-guided system and the Pentero operating microscope. These anastomoses were then evaluated for their quality and anastomosis time. The participants and the other eight surgeons, who had used the digital 3D camera system for microsurgical training exercises and vascular sutures, answered a questionnaire. The anastomosis time and number of complications were lower with the conventional microscope. Participants rated the image quality with the conventional microscope as higher, whereas the field of view and ergonomics were favorable in the digital 3D camera system. Exoscopes are optics suitable for performing simple microvascular procedures and are superior to classical microscopes ergonomically. Thus far, they are inferior to classical microscopes in terms of image quality and 3D imaging

Stable Peptides Instead of Stapled Peptides: Highly Potent αvβ6-Selective Integrin Ligands

The αvβ6 integrin binds the RGD-containing peptide of the foot and mouth disease virus with high selectivity. In this study, the long binding helix of this ligand was downsized to an enzymatically stable cyclic peptide endowed with sub-nanomolar binding affinity toward the αvβ6 receptor and remarkable selectivity against other integrins. Computational studies were performed to disclose the molecular bases underlying the high binding affinity and receptor subtype selectivity of this peptide. Finally, the utility of the ligand for use in biomedical studies was also demonstrated here. The search for binding: The αvβ6 integrin binds the RGD-containing peptide of the foot and mouth disease virus with high selectivity. The long binding helix of this ligand was downsized to an enzymatically stable cyclic peptide endowed with sub-nanomolar binding affinity toward the αvβ6 receptor and remarkable selectivity against other integrins

The organometallic ferrocene exhibits amplified anti-tumor activity by targeted delivery via highly selective ligands to αvβ3, αvβ6, or α5β1 integrins

High levels of reactive oxygen species (ROS) in tumors have been shown to exert anti-tumor activity, leading to the concept of ROS induction as therapeutic strategy. The organometallic compound ferrocene (Fc) generates ROS through a reversible one-electron oxidation. Incorporation of Fc into a tumor-targeting, bioactive molecule can enhance its therapeutic activity and enable tumor specific delivery. Therefore, we conjugated Fc to five synthetic, Arg-Gly-Asp (RGD)-based integrin binding ligands to enable targeting of the cell adhesion and signaling receptor integrin subtypes αvβ3, α5β1, or αvβ6, which are overexpressed in various, distinct tumors. We designed and synthesized a library of integrin-ligand-ferrocene (ILF) derivatives and showed that ILF conjugates maintained the high integrin affinity and selectivity of their parent ligands. A thorough biological characterization allowed us to identify the two most promising ligands, an αvβ3 (L2b) and an αvβ6 (L3b) targeting ILF, which displayed selective integrin-dependent cell uptake and pronounced ferrocene-mediated anti-tumor effects in vitro, along with increased ROS production and DNA damage. Hence, ILFs are promising candidates for the selective, tumor-targeted delivery of ferrocene to maximize its anti-cancer efficacy and minimize systemic toxicity, thereby improving the therapeutic window of ferrocene compared to currently used non-selective anti-cancer drugs