Search

Inflammatory cells, most especially neutrophils, can be a necessary component of the antitumor activity occurring after administration of photodynamic therapy. Generation of neutrophil responses has been suggested to be particularly important in instances when the delivered photodynamic therapy (PDT) dose is insufficient. In these cases, the release of neutrophil granules and engagement of antitumor immunity may play an important role in eliminating residual disease. Herein, we utilize in vivo imaging of luminol chemiluminescence to noninvasively monitor neutrophil activation after PDT administration. Studies were performed in the AB12 murine model of mesothelioma, treated with Photofrin‐PDT. Luminol‐generated chemiluminescence increased transiently 1 h after PDT, followed by a subsequent decrease at 4 h after PDT. The production of luminol signal was not associated with the influx of Ly6G+ cells, but was related to oxidative burst, as an indicator of neutrophil function. Most importantly, greater levels of luminol chemiluminescence 1 h after PDT were prognostic of a complete response at 90 days after PDT. Taken together, this research supports an important role for early activity by Ly6G+ cells in the generation of long‐term PDT responses in mesothelioma, and it points to luminol chemiluminescence as a potentially useful approach for preclinical monitoring of neutrophil activation by PDT. As neutrophils can be necessary for antitumor activity after photodynamic therapy, we utilized in vivo imaging of luminol chemiluminescence to noninvasively monitor neutrophil activation after its administration. In murine mesothelioma, chemiluminescence increased at 1 h after photodynamic therapy (PDT) and subsequently decreased at 4 h after PDT. Luminol signal was not representative of neutrophil influx, but instead with neutrophil function (oxidative burst). Importantly, greater luminol signal 1 h after PDT predicted tumors with no regrowth after 90 days. This supports an important role for early neutrophil activity in optimal PDT response and highlights luminol chemiluminescence as a useful approach for preclinical studies. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma remains difficult to treat, with high failure rates despite optimal therapy. We present a novel prospective trial combining proton therapy (PT) and photodynamic therapy (PDT) and the largest‐ever mesothelioma PT experience (n = 10). PDT photosensitizers included porfimer sodium (2 mg·kg−1; 24 h drug‐light interval) or 2‐[1‐hexyloxyethyl]‐2‐devinyl pyropheophorbide‐a (HPPH) (4 mg·m−2;48 h) with wavelengths of 630 nm to 60J·cm−2 and 665 nm to 15‐45J·cm−2, respectively. With a median age of 69 years, patients were predominantly male (90%) with epithelioid histology (100%) and stage III‐IV disease (100%). PT was delivered to a median of 55.0 CGE/1.8‐2.0 CGE (range 50–75 CGE) adjuvantly (n = 8) or as salvage therapy (n = 2) following extended pleurectomy/decortication (ePD)/PDT. Two‐year local control was 90%, with distant and regional failure rates of 50% and 30%, respectively. All patients received chemotherapy, and four received immunotherapy. Surgical complications included atrial fibrillation (n = 3), pneumonia (n = 2), and deep vein thrombosis (n = 2). Median survival from PT completion was 19.5 months (30.3 months from diagnosis), and 1‐ and 2‐year survival rates were 58% and 29%. No patient experienced CTCAEv4 grade ≥2 acute or late toxicity. Our prolonged survival in very advanced‐stage patients compares favorably to survival for PT without PDT and photon therapy with PDT, suggesting possible spatial or systemic cooperativity and immune effect. Malignant pleural mesothelioma (MPM) remains difficult to treat, with high failure rates despite optimal therapy. We present a novel trial combining proton therapy (PT) and photodynamic therapy (PDT) with porfimer sodium or 2‐[1‐hexyloxyethyl]‐2‐devinyl pyropheophorbide‐a in Stage III‐IV MPM. All patients received chemotherapy, and four received immunotherapy. Two‐year local control was 90%, with distant and regional failure rates of 50% and 30%, respectively. Median survival from PT completion was 19.5 months, and 1‐ and 2‐year survival rates were 58% and 29%. Our prolonged survival in very advanced‐stage patients compares favorably to survival for PT without PDT and photon therapy with PDT. [ABSTRACT FROM AUTHOR]

ABSTRACT Focal radiotherapy is frequently associated with skeletal damage within the radiation field. Our previous in vitro study showed that activation of Wnt/β-catenin pathway can overcome radiation-induced DNA damage and apoptosis of osteoblastic cells. Neutralization of circulating sclerostin with a monoclonal antibody (Scl-Ab) is an innovative approach for treating osteoporosis by enhancing Wnt/β-catenin signaling in bone. Together with the fact that focal radiation increases sclerostin amount in bone, we sought to determine whether weekly treatment with Scl-Ab would prevent focal radiotherapy-induced osteoporosis in mice. Micro-CT and histomorphometric analyses demonstrated that Scl-Ab blocked trabecular bone structural deterioration after radiation by partially preserving osteoblast number and activity. Consistently, trabecular bone in sclerostin null mice was resistant to radiation via the same mechanism. Scl-Ab accelerated DNA repair in osteoblasts after radiation by reducing the number of γ-H2AX foci, a DNA double-strand break marker, and increasing the amount of Ku70, a DNA repair protein, thus protecting osteoblasts from radiation-induced apoptosis. In osteocytes, apart from using similar DNA repair mechanism to rescue osteocyte apoptosis, Scl-Ab restored the osteocyte canaliculi structure that was otherwise damaged by radiation. Using a lineage tracing approach that labels all mesenchymal lineage cells in the endosteal bone marrow, we demonstrated that radiation damage to mesenchymal progenitors mainly involves shifting their fate to adipocytes and arresting their proliferation ability but not inducing apoptosis, which are different mechanisms from radiation damage to mature bone forming cells. Scl-Ab treatment partially blocked the lineage shift but had no effect on the loss of proliferation potential. Taken together, our studies provide proof-of-principle evidence for a novel use of Scl-Ab as a therapeutic treatment for radiation-induced osteoporosis and establish molecular and cellular mechanisms that support such treatment. © 2016 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

The goal of surgery in the multimodal treatment of pleural malignancies such as malignant pleural mesothelioma (MPM) or Non-small cell lung cancer with pleural spread (p-NSCLC) is to achieve a macroscopic compete resection (MCR). We have investigated the use of intraoperative photodynamic therapy to reduce the rate of local recurrence following MCR using a variety of photosensitizers, including porfimer sodium and HPPH. With lung sparing MCR and intraoperative PDT, patients with locally advanced, epithelial MPM experience median overall progression free and overall survival of 13 and 36 months, respectively. Similarly, patients with p-NSCLC experience median progression free and overall survival of 10 and 23 months, respectively. The results with MCR and PDT are highly encouraging. Nevertheless, a subset of patients treated with this approach experience aggressive local or systemic relapse of pleural disease within the first 12 months. In this study, we combine analysis of clinical data and pre-clinical models to examine the hypothesis that surgically mediated Inflammation affects outcomes following intraoperative PDT. In studies of clinical samples from patients with MPM undergoing surgery and intraoperative PDT, we found that increases in pro-inflammatory cytokines plasma levels from surgery prior to PDT experience earlier tumor recurrences than patients who did not experience a pro-inflammatory reaction to surgery. We have developed a preclinical model of surgically-mediated tumor injury (TI) that mimics these cytokine increases. Although PDT decreases tumor recurrences following partial debulking of tumors, we noted that TI reduces the efficacy of subsequently delivered PDT when compared to PDT of intact, size matched tumors. Mechanistically, this appears to involve surgically-mediated influx of myeloid derived suppressor cells into the tumor. Further analyses including RNAseq of clinical tumor samples and immunophenotyping of tumors and tumor draining lymph nodes in the TI model provide additional evidence to support the surgical inflammation hypothesis. Taken together, these results demonstrate that PDT can be safely and effectively adapted to treat the entire pleural surface and that PDT combined with multimodality, surgically based therapy demonstrates remarkably good patient outcomes. However, surgically induced inflammation impairs the full potential benefit of PDT. [ABSTRACT FROM AUTHOR]

We describe progress on a one-step photodynamic therapy ( PDT) technique that is simple: device tip delivery of sensitizer, oxygen and light simultaneously. Control is essential for their delivery to target sites to generate singlet oxygen. One potential problem is the silica device tip may suffer from biomaterial fouling and the pace of sensitizer photorelease is slowed. Here, we have used biomaterial ( e.g. proteins, cells, etc.) from SQ20B head and neck tumors and whole blood for an assessment of fouling of the silica tips by adsorption. It was shown that by exchanging the native silica tip for a fluorinated tip, a better nonstick property led to an increased sensitizer output by ~10%. The fluorinated tip gave a sigmoidal photorelease where singlet oxygen is stabilized to physical quenching, whereas the native silica tip with unprotected SiO-H groups gave a slower (pseudolinear) photorelease. A further benefit from fluorinated silica is that 15% less biomaterial adheres to its surface compared to native silica based on a bicinchoninic acid assay ( BCA) and X-ray photoelectron spectroscopy ( XPS) measurements. We discuss how the fluorination of the device tip increases biofouling resistance and can contribute to a new pointsource PDT tool. [ABSTRACT FROM AUTHOR]