Michael F. Tweedle

Residual or Retained Gadolinium: Practical Implications for Radiologists and Our Patients

We now have clear evidence that the administration of various gadolinium-based contrast agents results in notably varied levels of accumulation of residual gadolinium in the brain and bones of patients, even those with normal renal function.

Successful Translation of Fluorescence Navigation During Oncologic Surgery: A Consensus Report

Navigation with fluorescence guidance has emerged in the last decade as a promising strategy to improve the efficacy of oncologic surgery. To achieve routine clinical use, the onus is on the surgical community to objectively assess the value of this technique. This assessment may facilitate both Food and Drug Administration approval of new optical imaging agents and reimbursement for the imaging procedures. It is critical to characterize fluorescence-guided procedural benefits over existing practices and to elucidate both the costs and the safety risks. This report is the result of a meeting of the International Society of Image Guided Surgery (www.isigs.org) on February 6, 2015, in Miami, Florida, and reflects a consensus of the participants’ opinions. Our objective was to critically evaluate the imaging platform technology and optical imaging agents and to make recommendations for successful clinical trial development of this highly promising approach in oncologic surgery.

Probing peptide amphiphile self-assembly in blood serum.

There has been recent interest in designing smart diagnostic or therapeutic self-assembling peptide or polymeric materials that can selectively undergo morphological transitions to accumulate at a disease site in response to specific stimuli. Developing approaches to probe these self-assembly transitions in environments that accurately amalgamate the diverse plethora of proteins, biomolecules, and salts of blood is essential for creating systems that function in vivo. Here, we have developed a fluorescence anisotropy approach to probe the pH-dependent self-assembly transition of peptide amphiphile (PA) molecules that transform from spherical micelles at pH 7.4 to nanofibers under more acidic pHs in blood serum. By mixing small concentrations of a Ru(bipy)3(2+)-tagged PA with a Gd(DO3A)-tagged PA having the same lipid-peptide sequence, we showed that the pH dependence of self-assembly is minimally affected and can be monitored in mouse blood serum. These PA vehicles can be designed to transition from spherical micelles to nanofibers in the pH range 7.0-7.4 in pure serum. In contrast to the typical notion of serum albumin absorbing isolated surfactant molecules and disrupting self-assembly, our experiments showed that albumin does not bind these anionic PAs and instead promotes nanofibers due to a molecular crowding effect. Finally, we created a medium that replicates the transition pH in serum to within 0.08 pH units and allows probing self-assembly behavior using conventional spectroscopic techniques without conflicting protein signals, thus simplifying the development pathway from test tube to in vivo experimentation for stimuli-responsive materials.

A High-Affinity Near-Infrared Fluorescent Probe to Target Bombesin Receptors

PurposeThis study aimed to create new optical surgical navigation NIRF probes for prostate and breast cancers.ProceduresIR800-linker-QWAVGHLM-NH2 with linker = GSG, GGG, and G-Abz4 were synthesized and characterized. IC50 for bombesin receptors (BBN-R) in PC-3 prostate and T47D breast cancer cells, fluorescence microscopy in PC-3 cells, and NIRF imaging in mice PC-3 tumor xenografts were studied.ResultsGGG, GSG, and G-Abz4 derivatives had IC50 (nM) for BBN-R+ PC-3 cells = 187 ± 31, 56 ± 5, and 2.6 ± 0.2 and T47D cells = 383 ± 1, 57.4 ± 1.2, and 3.1 ± 1.1, respectively. By microscopy the Abz4 derivative showed the highest uptake, was competed with by BBN, and had little to no binding to BBN-R− cells. In NIRF imaging the G-Abz4 probe was brighter than GGG probe in BBN-R+ tissues in vivo and tissues, tumors, and tumor slices ex vivo. Uptake could be partially blocked in BBN-R+ pancreas but not visibly in tumor.ConclusionsLinker choice can dominate peptidic BBN-R binding. The G-Abz4 linker yields a higher affinity and specific BBN-R binder in this series of molecules.

Theranostic Imaging of Yttrium-90.

This paper overviews Yttrium-90 (90Y) as a theranostic and nuclear medicine imaging of 90Y radioactivity with bremsstrahlung imaging and positron emission tomography. In addition, detection and optical imaging of 90Y radioactivity using Cerenkov luminescence will also be reviewed. Methods and approaches for qualitative and quantitative 90Y imaging will be briefly discussed. Although challenges remain for 90Y imaging, continued clinical demand for predictive imaging response assessment and target/nontarget dosimetry will drive research and technical innovation to provide greater clinical utility of 90Y as a theranostic agent.

Optical Surgical Navigation for Precision in Tumor Resections

Optical imaging methods have significant potential as effective intraoperative tools to visualize tissues, cells, and biochemical events aimed at objective assessment of the tumor margin and guiding the surgeon to adequately resect the tumor while sparing critical tissues. The wide variety of approaches to guide resection, the range of parameters that they detect, and the interdisciplinary nature involving biology, chemistry, engineering, and medicine suggested that there was a need for an organization that could review, discuss, refine, and help prioritize methods to optimize patient care and pharmaceutical and instrument development. To address these issues, the World Molecular Imaging Society created the Optical Surgical Navigation (OSN) interest group to bring together scientists, engineers, and surgeons to develop the field to benefit patients. Here, we provide an overview of approaches currently under clinical investigation for optical surgical navigation and offer our perspective on upcoming strategies.

Gastrin-releasing peptide receptor (GRPr) promotes EMT, growth, and invasion in canine prostate cancer.

The gastrin‐releasing peptide receptor (GRPr) is upregulated in early and late‐stage human prostate cancer (PCa) and other solid tumors of the mammary gland, lung, head and neck, colon, uterus, ovary, and kidney. However, little is known about its role in prostate cancer. This study examined the effects of a heterologous GRPr agonist, bombesin (BBN), on growth, motility, morphology, gene expression, and tumor phenotype of an osteoblastic canine prostate cancer cell line (Ace‐1) in vitro and in vivo.

Regulatory Aspects of Optical Methods and Exogenous Targets for Cancer Detection

Considerable advances in cancer-specific optical imaging have improved the precision of tumor resection. In comparison to traditional imaging modalities, this technology is unique in its ability to provide real-time feedback to the operating surgeon. Given the significant clinical implications of optical imaging, there is an urgent need to standardize surgical navigation tools and contrast agents to facilitate swift regulatory approval. Because fluorescence-enhanced surgery requires a combination of both device and drug, each may be developed in conjunction, or separately, which are important considerations in the approval process. This report is the result of a one-day meeting held on May 4, 2016 with officials from the National Cancer Institute, the FDA, members of the American Society of Image-Guided Surgery, and members of the World Molecular Imaging Society, which discussed consensus methods for FDA-directed human testing and approval of investigational optical imaging devices as well as contrast agents for surgical applications. The goal of this workshop was to discuss FDA approval requirements and the expectations for approval of these novel drugs and devices, packaged separately or in combination, within the context of optical surgical navigation. In addition, the workshop acted to provide clarity to the research community on data collection and trial design. Reported here are the specific discussion items and recommendations from this critical and timely meeting. Cancer Res; 77(9); 2197-206. ©2017 AACR.

A Wearable Goggle Navigation System for Dual-Mode Optical and Ultrasound Localization of Suspicious Lesions: Validation Studies Using Tissue-Simulating Phantoms and an Ex Vivo Human Breast Tissue Model.

Surgical resection remains the primary curative treatment for many early-stage cancers, including breast cancer. The development of intraoperative guidance systems for identifying all sites of disease and improving the likelihood of complete surgical resection is an area of active ongoing research, as this can lead to a decrease in the need of subsequent additional surgical procedures. We develop a wearable goggle navigation system for dual-mode optical and ultrasound imaging of suspicious lesions. The system consists of a light source module, a monochromatic CCD camera, an ultrasound system, a Google Glass, and a host computer. It is tested in tissue-simulating phantoms and an ex vivo human breast tissue model. Our experiments demonstrate that the surgical navigation system provides useful guidance for localization and core needle biopsy of simulated tumor within the tissue-simulating phantom, as well as a core needle biopsy and subsequent excision of Indocyanine Green (ICG)—fluorescing sentinel lymph nodes. Our experiments support the contention that this wearable goggle navigation system can be potentially very useful and fully integrated by the surgeon for optimizing many aspects of oncologic surgery. Further engineering optimization and additional in vivo clinical validation work is necessary before such a surgical navigation system can be fully realized in the everyday clinical setting.

Gadolinium deposition: Is it chelated or dissociated gadolinium? How can we tell?

The methodology and published work aimed at speciation of gadolinium based contrast agents in tissues is reviewed. The discussion focusses on the context of Gd deposited long term in tissue following administration of the contrast agents. Detection of Gd without identification of the chemical form detected is simple and straight forward using a variety of methods. Determination of the chemical form of Gd detected is far more complex and most methods require inherently imperfect extraction steps that can alter the Gd chemical species detected. Control studies wherein Gd is not deposited biologically or is deposited in animal tissues are also inherently imperfect. Strengths and weaknesses of the various methods used and examples are demonstrated. It is concluded that a combination of spatially resolved mass spectral based methods, combined with extraction/HPLC analysis methods can provide sufficient sensitivity, spatial resolution and chemical species specificity to address the title question on ex vivo tissue samples.