Utilizing integrin αvß6-targeted PET imaging to longitudinally monitor radiation- induced pulmonary fibrosis in vivo.

PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a potentially serious and disabling late complication of radiation therapy. Monitoring RIPF progression is challenging due to the absence of early detection tools and the difficulty in distinguishing RIPF from other lung diseases using standard imaging methods. In the lungs, integrin αvß6 is crucial in the development of RIPF, acting as a significant activator of TGF-ß after radiation injury. This study aims to investigate integrin αvß6-targeted PET imaging ([64Cu]Cu-αvß6-BP) to study RIPF development in vivo. METHODS AND MATERIALS: We used a focal RIPF model (70 Gy delivered focally to a 3 mm spot in the lung) and a whole lung RIPF model (14 Gy delivered to the whole lung) in adult C57BL/6J mice. Small animal PET/CT images were acquired 1h post-injection of 11.1 MBq of [64Cu]Cu-αvß6-BP. Animals were imaged for eight weeks in the focal RIPF model and six months for the whole lung RIPF model. Immunohistochemistry for integrin αvß6 and trichrome staining were performed. RESULTS: In the focal RIPF model, there was focal uptake of [64Cu]Cu-αvß6-BP in the irradiated region at week four that progressively increased at week 6 and 8. In the whole lung RIPF model, minimal uptake of the probe was observed at four months post-RT, which significantly increased at months five and six. Expression of integrin αvß6 was validated histologically by immunohistochemistry in both models. CONCLUSIONS: Integrin αvß6-targeted PET imaging using [64Cu]Cu-αvß6-BP can serve as a useful tool to identify radiation-induced pulmonary fibrosis in vivo.

Photodynamic therapy outcome modelling for patients with spinal metastases: a simulation-based study.

Spinal metastases often occur in the advanced stages of breast, lung or prostate cancer, resulting in a significant impact on the patient's quality of life. Current treatment modalities for spinal metastases include both systemic and localized treatments that aim to decrease pain, improve mobility and structural stability, and control tumour growth. With the development of non-toxic photosensitizer drugs, photodynamic therapy (PDT) has shown promise as a minimally invasive non-thermal alternative in oncology, including for spinal metastases. To apply PDT to spinal metastases, predictive algorithms that optimize tumour treatment and minimize the risk of spinal cord damage are needed to assess the feasibility of the treatment and encourage a broad acceptance of PDT in clinical trials. This work presents a framework for PDT modelling and planning, and simulates the feasibility of using a BPD-MA mediated PDT to treat bone metastases at two different wavelengths (690 nm and 565 nm). An open-source software for PDT planning, PDT-SPACE, is used to evaluate different configurations of light diffusers (cut-end and cylindrical) fibres with optimized power allocation in order to minimize the damage to spinal cord or maximize tumour destruction. The work is simulated on three CT images of metastatically involved vertebrae acquired from three patients with spinal metastases secondary to colorectal or lung cancer. Simulation results show that PDT at a 565 nm wavelength has the ability to treat 90% of the metastatic lesion with less than 17% damage to the spinal cord. However, the energy required, and hence treatment time, to achieve this outcome with the 565 nm is infeasible. The energy required and treatment time for the longer wavelength of 690 nm is feasible ([Formula: see text] min), but treatment aimed at 90% of the metastatic lesion would severely damage the proximal spinal cord. PDT-SPACE provides a simulation platform that can be used to optimize PDT delivery in the metastatic spine. While this work serves as a prospective methodology to analyze the feasibility of PDT for tumour ablation in the spine, preclinical studies in an animal model are ongoing to elucidate the spinal cord damage extent as a function of PDT dose, and the resulting short and long term functional impairments. These will be required before there can be any consideration of clinical trials.

Balloon catheter-based radiofrequency ablation monitoring in porcine esophagus using optical coherence tomography.

We present a microscopic image guidance platform for radiofrequency ablation (RFA) using a clinical balloon-catheter-based optical coherence tomography (OCT) system, currently used in the surveillance of Barrett's esophagus patients. Our integrated thermal therapy delivery and monitoring platform consists of a flexible, customized bipolar RFA electrode array designed for use with a clinical balloon OCT catheter and a processing algorithm to accurately map the thermal coagulation process. Non-uniform rotation distortion was corrected using a feature tracking-based technique, which enables robust, frame-to-frame analysis of the temporal fluctuation of the complex OCT signal. With proper noise calibration, precise delineation of the thermal therapy zone was demonstrated using cumulative complex differential variance in porcine esophagus ex vivo with the integrated OCT-RFA system, as validated by nitroblue tetrazolium chloride (NBTC) histology. The ability to directly and accurately visualize the thermal coagulation process at high resolution is critical to the precise delivery of thermal energy to a wide range of epithelial lesions.

Laser thermal therapy monitoring using complex differential variance in optical coherence tomography.

Conventional thermal therapy monitoring techniques based on temperature are often invasive, limited by point sampling, and are indirect measures of tissue injury, while techniques such as magnetic resonance and ultrasound thermometry are limited by their spatial resolution.  The visualization of the thermal coagulation zone at high spatial resolution is particularly critical to the precise delivery of thermal energy to epithelial lesions. In this work, an integrated thulium laser thermal therapy monitoring system was developed based on complex differential variance (CDV), which enables the 2D visualization of the dynamics of the thermal coagulation process at high spatial and temporal resolution with an optical frequency domain imaging system. With proper calibration to correct for noise, the CDV-based technique was shown to accurately delineate the thermal coagulation zone, which is marked by the transition from high CDV upon heating to a significantly reduced CDV once the tissue is coagulated, in 3 different tissue types ex vivo: skin, retina, and esophagus. The ability to delineate thermal lesions in multiple tissue types at high resolution opens up the possibility of performing microscopic image-guided procedures in a vast array of epithelial applications ranging from dermatology, ophthalmology, to gastroenterology and beyond.

Preventing Scars after Injury with Partial Irreversible Electroporation.

Preventing the formation of hypertrophic scars, especially those that are a result of major trauma or burns, would have enormous impact in the fields of regenerative and trauma medicine. In this report, we introduce a noninvasive method to prevent scarring based on nonthermal partial irreversible electroporation. Contact burn injuries in rats were treated with varying treatment parameters to optimize the treatment protocol. Scar surface area and structural properties of the scar were assessed with histology and non-invasive, longitudinal imaging with polarization-sensitive optical coherence tomography. We found that partial irreversible electroporation using 200 pulses of 250 V and 70 µs duration, delivered at 3 Hz every 20 days during a total of five therapy sessions after the initial burn injury, resulted in a 57.9% reduction of the scar area compared with untreated scars and structural features approaching those of normal skin. Unlike humans, rats do not develop hypertrophic scars. Therefore, the use of a rat animal model is the limiting factor of this work.

Longitudinal, 3D Imaging of Collagen Remodeling in Murine Hypertrophic Scars In Vivo Using Polarization-Sensitive Optical Frequency Domain Imaging.

Hypertrophic scars (HTS), frequently seen after traumatic injuries and surgery, remain a major clinical challenge because of the limited success of existing therapies. A significant obstacle to understanding HTS etiology is the lack of tools to monitor scar remodeling longitudinally and noninvasively. We present an in vivo, label-free technique using polarization-sensitive optical frequency domain imaging for the 3D, longitudinal assessment of collagen remodeling in murine HTS. In this study, HTS was induced with a mechanical tension device for 4-10 days on incisional wounds and imaged up to 1 month after device removal; an excisional HTS model was also imaged at 6 months after injury to investigate deeper and more mature scars. We showed that local retardation and degree of polarization provide a robust signature for HTS. Compared with normal skin with heterogeneous local retardation and low degree of polarization, HTS was characterized by an initially low local retardation, which increased as collagen fibers remodeled, and a persistently high degree of polarization. This study demonstrates that polarization-sensitive optical frequency domain imaging offers a powerful tool to gain significant biological insights into HTS remodeling by enabling longitudinal assessment of collagen in vivo, which is critical to elucidating HTS etiology and developing more effective HTS therapies.

The discovery of Arylex™ active and Rinskor™ active: Two novel auxin herbicides.

Multiple classes of commercially important auxin herbicides have been discovered since the 1940s including the aryloxyacetates (2,4-D, MCPA, dichlorprop, mecoprop, triclopyr, and fluroxypyr), the benzoates (dicamba), the quinoline-2-carboxylates (quinclorac and quinmerac), the pyrimidine-4-carboxylates (aminocyclopyrachlor), and the pyridine-2-carboxylates (picloram, clopyralid, and aminopyralid). In the last 10 years, two novel pyridine-2-carboxylate (or picolinate) herbicides were discovered at Dow AgroSciences. This paper will describe the structure activity relationship study that led to the discovery of the 6-aryl-picolinate herbicides Arylex™ active (2005) and Rinskor™ active (2010). While Arylex was developed primarily for use in cereal crops and Rinskor is still in development primarily for use in rice crops, both herbicides will also be utilized in additional crops.

Diaryloxyacetate herbicides.

The discovery and investigation of a novel family of herbicides containing a diaryl acetal are described. The stability of the acetal limited herbicidal efficacy and recognizing that fact led to the design of analogs with commercial levels of post-emergence activity on broadleaf weeds. These compounds inhibited acetolactate synthase and in vitro activity data were used to guide target design. However, no members of this family provided a commercially valuable combination of herbicidal efficacy and crop selectivity.