This PDF file contains the front matter associated with SPIE Proceedings Volume 12359, including the Title Page, Copyright information, Table of Contents, and Conference Committee information.

Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal of human malignancies. The failure of myriad trials evaluating chemotherapy and/or targeted agent combinations to produce substantial gains in survival continues to motivate the investigation of new therapeutic strategies. Recent studies have demonstrated exciting potential of RNA medicine approaches to therapeutically target microRNAs (miRNA, small non-coding RNAs) which have been shown to regulate PDAC growth, survival and chemoresistance. However, while various miRNA therapies have been discussed for the past decade, challenges with delivery to most disease tissues have restricted their therapeutic use to liver and kidney disease. Here we explore the combination with photodynamic therapy (PDT) to enhance delivery of nanoparticles carrying RNA medicine agents through fibrotic PDAC stroma, and mechanistically synergize with depletion or enrichment of target miRNAs. Using transfection of miRNA mimics and inhibitors in PDAC cells we have evaluated a small panel of miRNAs that could serve as promising targets for either depletion or enrichment. In cell culture studies we find that PDT using verteporfin can enhance RNA medicine efficacy both through depletion of PDAC stroma (previously reported) to significantly enhance delivery to target tissue, and by synergizing mechanistically at the molecular level. In ongoing studies we are now examining the most promising combinations in murine xenografts. Taken together with clinical studies by others establishing the feasibility of PDT for PDAC these results indicate further promise of leveraging PDT to synergistically enhance emerging RNA medicine approaches.

We developed a simulation method for modeling the light fluence delivery in intracavity Photodynamic Therapy (icav-PDT) for pleural lung cancer using a moving light source. Due to the large surface area of the pleural lung cavity, the light source needs to be moved to deliver a uniform dose around the entire cavity. While multiple fixed detectors are used for dosimetry at a few locations, an accurate simulation of light fluence and fluence rate is still needed for the rest of the cavity. We extended an existing Monte Carlo (MC) based light propagation solver to support moving light sources by densely sampling the continuous light source trajectory and assigning the proper number of photon packages launched along the way. The performance of Simphotek GPU CUDA-based implementation of the method – PEDSy-MC – has been demonstrated on a life-size lung-shaped phantom, custom printed for testing icav-PDT navigation system at the Perlman School of Medicine (PSM) – calculations completed under a minute (for some cases) and within minutes have been achieved. We demonstrate results within a 5% error of the analytic solution for multiple detectors in the phantom. PEDSy-MC is accompanied by a dose-cavity visualization tool that allows real-time inspection of dose values of the treated cavity in 2D and 3D, which will be expanded to ongoing clinical trials at PSM. PSM has developed a technology to measure 8-detectors in a pleural cavity phantom using Photofrin-mediated PDT that has been used during validation.

Non-muscle invasive bladder cancer (NMIBC) is a form of cancer with a relatively high 5-year survival rate but also very high recurrence rate. Photodynamic diagnosis is commonly used in standard clinical practice to visualize bladder cancer lesions as part of a TURBT procedure but photodynamic treatments utilizing photosensitive drugs have had limited success in clinical setting partly because of limitations in light sources and light delivery optics. Bladder is somewhat challenging environment for PDT as it needs to be accessed cystoscopically and lesions might be difficult to target with traditional light delivery optics for example because of their close proximity to bladder entrance. The properties of different tumor types (papillary vs carcinoma in situ (CIS)) also require different illumination methods, so laser parameters and illumination modes need to be designed accordingly.

Modulight has developed its ML7710 laser platform further to optimally support a novel photosensitive drug for treatment of NMIBC in clinical setting. The laser system and its light delivery mechanism enable both focused illumination of localized papillary lesions and overall illumination of the entire bladder to cover possible scattered CIS lesions. Clinicians have been consulted on feasibility of different illumination modes and other practical matters related to e.g., treatment duration. The optimization of Modulight’s system for NMIBC has also included compatibility testing with flexible cystoscopes and investigation of the light delivery system performance in bladder-like environment. Connectivity features of the laser system have been tailored to support documentation requirements in clinical trials by enabling treatment configuration and realized treatment log storage in Modulight Cloud.

Laser systems, in ophthalmic applications, are utilized in the treatment of various ophthalmic diseases such as in ocular oncology and age-related macular degeneration through photochemical mechanism of photodynamic therapy. In addition, these lasers can be used to activate drug delivery systems in the retina to provide targeted drug therapy. PDT is a form of a combination treatment which utilizes light energy to activate a photoactive pharmaceutical (photosensitizer) to create a photodynamic reaction. Current photodynamic therapy devices out on the market are around 20 years old and the companies that manufacture the devices, do not provide yearly maintenance services for the devices. Therefore, Modulight has developed the multi-indication ML6710i ophthalmic laser platform and the beam shaping unit ML-SLA to address the need for supported PDT equipment and to target the treatment of oncological and various other diseases affecting the posterior of the eye with the capability to provide laser light ranging from 400 nm to 2000 nm depending on the specific customer needs. ML-SLA has been tested to yield a superior beam quality and enable a larger spot size range than any existing beam shaping unit in the market, thus eliminating the need for multi-spot treatment of larger lesions. The device connects to Modulight Cloud services, enhancing treatment planning and post-operative analysis. In addition, the ML6710i laser platform has the capability of including a camera module to record the intra-operative fundus view into Modulight Cloud to further assist in post-operative treatment analysis.

Photodynamic therapy (PDT) is an established modality for cancer treatment, and reactive oxygen species explicit dosimetry (ROSED), based on direct measurements of in-vivo light fluence (rate), in-vivo photofrin concentration, and tissue oxygenation concentration, has been proved to provide the best dosimetric quantity which can be used to predict non-fractionated PDT outcome. This study performed ROSED for Photofrin-mediated PDT for mice bearing radiation-induced fibrosacorma (RIF) tumor. As demonstrated by our previous study, fractionated PDT with a 2-hour time interval can significantly improve the long-term cure rate (from 15% to 65% at 90 days), and it tends to increase as the light dose for the first light fraction gets larger. This study focused on further improving the long-term cure rate without introducing apparent toxicity using combinations of different first light fraction lengths and total light fluences. Photofrin was injected through the mouse tail vein at a concentration of 5 mg/kg. After 18~24 hours, treatment was delivered with a collimated laser beam of 1 cm diameter at 630 nm. Mice were treated using two fractions of light fluences with a 2-hour dark interval. Different dose metrics were quantified, including light fluence, PDT dose, and [ROS]rx. In addition, the total reacted [ROS]rx and treatment outcomes were evaluated and compared to identify the optimal light fraction length and total light fluence.

Cherenkov images can be used for the quality assurance of dose homogeneity in total skin electron therapy (TSET). For the dose mapping purpose, this study reconstructed the patient model from 3D scans using registration algorithms and computer animation techniques. The Cherenkov light emission of the patient’s surface was extracted from multi-view Cherenkov images, converted into dose distribution, and projected onto the patient’s 3D model, allowing for dose cumulation and evaluation. The projected result from multiple Cherenkov cameras provides additional information about Cherenkov emission on the sides of the patients, which improves the agreement between the Cherenkov converted dose and the OSLD measurements.

Direct detection of singlet-state oxygen ([¹O₂]) constitutes the holy grail dosimetric method for type II PDT, a goal that can be quantified using multispectral singlet oxygen dosimetry (MSOLD). However, the short lifetime and extremely weak nature of the singlet oxygen signal produced has given rise to a need to improve MSOLD signal-to-noise ratio. This study examines methods for optimizing MSOLD signal acquisition, specifically employing an orthogonal arrangement between detection and PDT treatment light, consisting of two fiber optics - connected to a 632-nm laser and an InGaAs detector respectively. Light collected by the InGaAs detector is then passed through a filter wheel, where spectral emission measurements are taken at 1200 nm, 1240 nm, 1250 nm, 1270 nm, and 1300 nm. The data, after fitting to the fluorescence background and a gaussian-fit for the singlet oxygen peak, is established for the background-subtracted singlet oxygen emission signal. The MSOLD signal is then compared with the singlet oxygen explicit dosimetry (SOED) results, based on direct measurements of in-vivo light fluence (rate), in-vivo Photofrin concentration, and tissue oxygenation concentration. This study focuses on validating the sensitivity and minimum detectability of MSOLD signal in various in-vitro conditions. Finally, the MSOLD device will be tested in Photofrin-mediated PDT for mice bearing Radiation- Induced Fibrosarcoma (RIF) tumors.

We have developed a novel scanning protocol for a life-sized human phantom model using handheld threedimensional (3D) surface acquisition devices. This technology will be utilized to develop light fluence modeling of the internal pleural cavity space during Photodynamic Therapy (PDT) of malignant mesothelioma. The external aspect of the chest cavity phantom was prefabricated of a hardened synthetic polymer resembling ordinary human anatomy (pleural cavity space) and the internal aspect remained hollow without any characterizations. Both surfaces were layered with non-reflective adhesive paper to create non-uniformed surface topographies. These surface characteristics were established in randomized X-Y-Z coordinates ranging in dimensions from 1-15mm. This protocol utilized the handheld Occipital Scanner and the MEDIT i700. The Occipital device required a minimum scanner-to-surface distance of 24cm and the MEDIT device 1cm respectively. The external and internal aspects of the phantom model were successfully scanned acquiring digital measurements in actual value and converted into a digital image file. The initial surface rendering was acquired by the Occipital device and applied with proprietary software to guide the MEDIT device to fill voided areas. This protocol is accompanied by a visualization tool that allows for real-time inspection of surface acquisition in 2D and 3D. This scanning protocol can be utilized to scan the pleural cavity for real-time guidance for light fluence modeling during PDT, which will be expanded to ongoing clinical trials.

As part of our ongoing Phase 1 clinical trial to establish the safety and feasibility of methylene blue photodynamic therapy (MB-PDT) for human deep tissue abscess cavities, we have shown that determination of abscess wall optical properties is vital for the design of personalized treatment plans aiming to optimize light dose. To that end, we have developed and validated an optical spectroscopy system for the assessment of optical properties at the cavity wall, including a compact fiber-optic probe that can be inserted through the catheter used for the standard of care abscess drainage. Here we report preliminary findings from the first three human subjects to receive these optical spectroscopy measurements. We observed wide variability in concentrations of oxy- and deoxy-hemoglobin prior to MB administration, ranging from 7.3-213 μM and 0.1-47.2 μM, respectively. Reduced scattering coefficients also showed inter-patient variability, but recovered values were more similar between subjects (5.5-10.9 cm^-1 at 665 nm). Further, methylene blue uptake was found to vary between subjects, and was associated with a reduction in oxygen saturation. These measured optical properties, along with preprocedure computed tomography (CT) images, will be used with our previously developed Monte Carlo simulation framework to generate personalized treatment plans for individual patients, which could significantly improve the efficacy of MB-PDT while ensuring safety.

Cervical cancer, associated with persistent human papillomavirus (HPV) infections, continues to be common among women of reproductive age. With the development of HPV molecular diagnostic techniques, a growing number of people are tested positive for various high-risk HPV genotypes, the causative agent of cervical cancer. Consequently, there is a need to develop treatment methods for such potential cervical cancer patients. Standard treatments consist of excisional methods which do not target HPV infections and have been reported to increase the risk of reproductive problems. Previous studies have shown reduced HPV levels after photodynamic therapy (PDT) and its efficacy against cervical cancer. The coordinated application of light and photosensitizer is needed to limit cell death to the lesion and preserve the surrounding healthy tissue. However, localizing light exposure can be difficult, especially in minimally accessible areas such as the cervix. To address this, we investigated the in vitro and in vivo effect of a multi-beam PDT system, in which the light beams can be individually adjusted to match the lesion’s size and shape. The findings suggest that this multi-beam PDT system has the potential of becoming a more conservative fertility-sparing option that can localize treatment and meet patients’ reproductive needs.

Photodynamic therapy (PDT) has been used intraoperatively to treat patients with malignant pleural mesothelioma. For the efficiency of PDT, it is crucial to deliver light doses uniformly. The current procedure utilizes eight light detectors placed inside the pleural cavity to monitor the light. An updated navigation system, combined with a novel scanning system, is developed to provide real-time guidance for physicians during pleural PDT to improve light delivery. The scanning system consists of two handheld three-dimensional (3D) scanners to capture the pleural cavity's surface topographies quickly and precisely before PDT so that the target surface can be identified for real-time light fluence distribution calculation during PDT. An algorithm is developed to further process the scanned volume to denoise for accurate light fluence calculation and rotate the local coordinate system into any desired direction for a clear visualization during the real-time guidance. The navigation coordinate system is registered to the patient coordinate system utilizing at least three markers to track the light source point position within the pleural cavity throughout the treatment. During PDT, the light source position, the scanned pleural cavity, and the light fluence distribution for the cavity's surface will be displayed in 3D and 2D, respectively. For validation, this novel system is tested using phantom studies with a large chest phantom and 3D-printed lung phantoms of different volumes based on a personal CT scan, immersed in a liquid tissue-simulating phantom with different optical properties, and treated with eight isotropic detectors and the navigation system.