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Significance: Photodynamic therapy (PDT) is an established cancer treatment utilizing light-activated photosensitizers (PS). Effective treatment hinges on the PDT dose-dependent on PS concentration and light fluence-delivered over time. We introduce an innovative eight-channel PDT dose dosimetry system capable of concurrently measuring light fluence and PS concentration during treatment. Aim: We aim to develop and evaluate an eight-channel PDT dose dosimetry system for simultaneous measurement of light fluence and PS concentration. By addressing uncertainties due to tissue variations, the system enhances accurate PDT dosimetry for improved treatment outcomes. Approach: The study positions eight isotropic detectors strategically within the pleural cavity before PDT. These detectors are linked to bifurcated fibers, distributing signals to both a photodiode and a spectrometer. Calibration techniques are applied to counter tissue-related variations and improve measurement accuracy. The fluorescence signal is normalized using the measured light fluence, compensating for variations in tissue properties. Measurements were taken in 78 sites in the pleural cavities of 20 patients. Results: Observations reveal minimal Photofrin concentration variation during PDT at each site, juxtaposed with significant intra- and inter-patient heterogeneities. Across 78 treated sites in 20 patients, the average Photofrin concentration for all 78 sites is 4.98 µM, with a median concentration of 4.47 µM. The average PDT dose for all 78 sites is 493.17 µMJ/cm², with a median dose of 442.79 µMJ/cm². A significant variation in PDT doses is observed, with a maximum difference of 3.1 times among all sites within one patient and a maximum difference of 9.8 times across all patients. Conclusions: The introduced eight-channel PDT dose dosimetry system serves as a valuable real-time monitoring tool for light fluence and PS concentration during PDT. Its ability to mitigate uncertainties arising from tissue properties enhances dosimetry accuracy, thus optimizing treatment outcomes and bolstering the effectiveness of PDT in cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: We have demonstrated that a fractionated PDT scheme, delivered using a two-hour interval between two light delivery treatments, significantly improves long-term efficacy of Photofrin-mediated PDT while reducing side effects. Reactive Oxygen Species Explicit Dosimetry (ROSED), utilizing direct measurements of in vivo light fluence, in vivo Photofrin concentration, and in vivo tissue oxygenation concentration, were used to determine the concentration of reacted reactive oxygen species, [ROS]rx, as a dosimetry quantity for PDT treatment. We found that a threshold Photofrin dose of 0.78 mM is required for the complete cure (90-day survival) of RIF tumors using fractionated Photofrin-mediated PDT treatment. To our knowledge, this is the first report of this parameter. This study investigates the effect of fractionated (two-part) PDT on the long-term local control rate (LCR) using the concentration of reactive oxygen species ([ROS]rx) as a dosimetry quantity. Groups with different fractionation schemes are examined, including a 2 h interval between light delivery sessions to cumulative fluences of 135, 180, and 225 J/cm2. While the total treatment time remains constant within each group, the division of treatment time between the first and second fractionations are explored to assess the impact on long-term survival at 90 days. In all preclinical studies, Photofrin is intravenously administered to mice at a concentration of 5 mg/kg, with an incubation period between 18 and 24 h before the first light delivery session. Fluence rate is fixed at 75 mW/cm2. Treatment ensues via a collimated laser beam, 1 cm in diameter, emitting light at 630 nm. Dosimetric quantities are assessed for all groups along with long-term (90 days) treatment outcomes. This study demonstrated a significant improvement in long-term survival after fractionated treatment schemes compared to single-fraction treatment, with the optimal 90-day survival increasing to 63%, 86%, and 100% vs. 20%, 25%, and 50%, respectively, for the three cumulative fluences. The threshold [ROS]rx for the optimal scheme of fractionated Photofrin-mediated PDT, set at 0.78 mM, is significantly lower than that for the single-fraction PDT, at 1.08 mM. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has been used to treat malignant pleural mesothelioma. Current practice involves delivering light to a prescribed light fluence with a point source, monitored by eight isotropic detectors inside the pleural cavity. An infrared (IR) navigation system was used to track the location of the point source throughout the treatment. The recorded data were used to reconstruct the pleural cavity and calculate the light fluence to the whole cavity. An automatic algorithm was developed recently to calculate the detector positions based on recorded data within an hour. This algorithm was applied to patient case studies and the calculated results were compared to the measured positions, with an average difference of 2.5 cm. Calculated light fluence at calculated positions were compared to measured values. The differences between the calculated and measured light fluence were within 14% for all cases, with a fixed scattering constant and a dual correction method. Fluence‐surface histogram (FSH) was calculated for photofrin‐mediated PDT to be able to cover 80% of pleural surface area to 50 J cm−2(83.3% of 60 J cm−2). The study demonstrates that it will be possible to eliminate the manual measurement of the detector positions, reducing the patient's time under anesthesia. [ABSTRACT FROM AUTHOR]

Introduction: Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning. Methods: The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation. We deployed a parabolic partial differential equation to account for the generalized radiation oxygen depletion, tissue oxygen diffusion, and metabolic processes to investigate oxygen distribution in 1D, 2D, and 3D solution space. Dose and dose rates, particle LET, vasculature spacing, and blood oxygen supplies were considered. Using a similar framework for the hypoxic reduction factor (HRF) developed previously, the FEDMF was derived as the ratio of the cumulative normoxic-equivalent dose (CNED) between CONV and UHDR deliveries. Results: Dynamic equilibrium between oxygen diffusion and tissue metabolism can result in tissue hypoxia. The hypoxic region displayed enhanced radioresistance and resulted in lower CNED under UHDR deliveries. In 1D solution, comparing 15 Gy proton dose delivered at CONV 0.5 and UHDR 125 Gy/s, 61.5% of the tissue exhibited ≥20% FEDMF at 175 mm vasculature spacing and 18.9 mM boundary condition. This percentage reduced to 34.5% and 0% for 8 and 2 Gy deliveries, respectively. Similar trends were observed in the 3D solution space. The FLASH versus CONV differential effect remained at larger vasculature spacings. A higher FLASH dose rate showed an increased region with ≥20% FEDMF. A higher LET near the proton Bragg peak region did not appear to alter the FLASH effect. Conclusion: We developed 1D, 2D, and 3D oxygen depletion simulation process to obtain the dynamic HRF and derive the proton FEDMF related to the dose delivery parameters and the local tissue vasculature information. The phenomenological model can be used to simulate or predict FLASH effects based on tissue vasculature and oxygen concentration data obtained from other experiments. [ABSTRACT FROM AUTHOR]

FLASH is a high-dose-rate form of radiation therapy that has the reported ability, compared with conventional dose rates, to spare normal tissues while being equipotent in tumor control, thereby increasing the therapeutic ratio. The mechanism underlying this normal tissue sparing effect is currently unknown, however one possibility is radiochemical oxygen depletion (ROD) during dose delivery in tissue at FLASH dose rates. In order to investigate this possibility, we used the phosphorescence quenching method to measure oxygen partial pressure before, during and after proton radiation delivery in model solutions and in normal muscle and sarcoma tumors in mice, at both conventional (Conv) (∼0.5 Gy/s) and FLASH (∼100 Gy/s) dose rates. Radiation dosimetry was determined by Advanced Markus Chamber and EBT-XL film. For solutions contained in sealed glass vials, phosphorescent probe Oxyphor PtG4 (1 µM) was dissolved in a buffer (10 mM HEPES) containing glycerol (1 M), glucose (5 mM) and glutathione (5 mM), designed to mimic the reducing and free radical-scavenging nature of the intracellular environment. In vivo oxygen measurements were performed 24 h after injection of PtG4 into the interstitial space of either normal thigh muscle or subcutaneous sarcoma tumors in mice. The "g-value" for ROD is reported in mmHg/Gy, which represents a slight modification of the more standard chemical definition (µM/Gy). In solutions, proton irradiation at conventional dose rates resulted in a g-value for ROD of up to 0.55 mmHg/Gy, consistent with earlier studies using X or gamma rays. At FLASH dose rates, the g-value for ROD was ∼25% lower, 0.37 mmHg/Gy. pO2 levels were stable after each dose delivery. For normal muscle in vivo, oxygen depletion during irradiation was counterbalanced by resupply from the vasculature. This process was fast enough to maintain tissue pO2 virtually unchanged at Conv dose rates. However, during FLASH irradiation there was a stepwise decrease in pO2 (g-value ∼0.28 mmHg/Gy), followed by a rebound to the initial level after ∼8 s. The g-values were smaller and recovery times longer in tumor tissue when compared to muscle and may be related to the lower initial endogenous pO2 levels in the former. Considering that the FLASH effect is seen in vivo even at doses as low as 10 Gy, it is difficult to reconcile the amount of protection seen by oxygen depletion alone. However, the phosphorescence probe in our experiments was confined to the extracellular space, and it remains possible that intracellular oxygen depletion was greater than observed herein. In cell-mimicking solutions the oxygen depletion g-vales were indeed significantly higher than observed in vivo. [ABSTRACT FROM AUTHOR]

Treatment de‐escalation is sought in the management of precursor lesions of early stage breast cancer, driving the appeal of adjuvant modalities to lumpectomy that reduce toxicity and minimally detract from patient quality of life. We investigate photodynamic therapy (PDT), with the photosensitizing prodrug, 5‐aminolevulinic acid (ALA), as adjuvant therapy to complete resection of murine mammary tumor (propagated from TUBO cells). ALA was delivered either systemically (oral, 250 mg kg−1) at 5 h before 632 nm illumination or topically (20% solution) to the resection site at 10 min before light delivery to 135 J cm−2. Treatment with either oral‐ALA‐PDT (oALA‐PDT) or topical‐ALA‐PDT (tALA‐PDT) to the mammary fat pad after TUBO complete resection (CR) produced long‐term tumor control with 90‐day complete response rates of 21% and 32%, respectively, compared to control rates of 0–5% in mice receiving only CR. Thus, CR/tALA‐PDT was equipotent to CR/oALA‐PDT despite ~10‐fold lower levels of ALA‐induced protoporphyrin XI as photosensitizer after topical versus oral‐ALA administration. CR/oALA‐PDT produced more vascular damage, greater proportion of tissue‐resident neutrophils and stronger inflammation when compared to CR/tALA‐PDT. Collectively, these data provide rationale for ongoing investigation of ALA‐PDT as adjuvant therapy after lumpectomy for increased probability of local control in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Immune checkpoints including PD‐1 and CTLA‐4 help to regulate the intensity and timeframe of the immune response. Since they become upregulated in cancer and prevent sufficient antitumor immunity, monoclonal antibodies against these checkpoints have shown clinical promise for a range of cancers. Multimodal treatment plans combining immune checkpoint inhibitors with other therapies, including photodynamic therapy (PDT), may help to expand treatment efficacy and minimize side effects. PDT's cytotoxic effects are spatially limited by the light activation process, constraining PDT direct effects to the treatment field. The production of damage‐associated molecular patterns and tumor‐associated antigens from PDT can encourage accumulation and maturation of antigen‐presenting cells and reprogram the tumor microenvironment to be more susceptible to therapies targeting immune checkpoints. [ABSTRACT FROM AUTHOR]

Peritoneal carcinomatosis (PC) can occur as an advanced consequence of multiple primary malignancies. Surgical resection, radiation or systemic interventions alone have proven inadequate for this aggressive cancer presentation, since PC still has a poor survival profile. Photodynamic therapy (PDT), in which photosensitive drugs are exposed to light to generate cytotoxic reactive oxygen species, may be an ideal treatment for PC because of its ability to deliver treatment to a depth appropriate for peritoneal surface tumors. Additionally, epidermal growth factor receptor (EGFR) signaling plays a variety of roles in cancer progression and survival as well as PDT‐mediated cytotoxicity, so EGFR inhibitors may be valuable in enhancing the therapeutic index of intraperitoneal PDT. This study examines escalating doses of benzoporphyrin derivative (BPD)‐mediated intraperitoneal PDT combined with the EGFR‐inhibitor cetuximab in a canine model. In the presence or absence of small bowel resection (SBR) and cetuximab, we observed a tolerable safety and toxicity profile related to the light dose received. Additionally, our findings that BPD levels are higher in the small bowel compared with other anatomical regions, and that the risk of anastomotic failure decreases at lower light doses will help to inform the design of similar PC treatments in humans. [ABSTRACT FROM AUTHOR]

As part of a preclinical trial for the treatment of peritoneal carcinomatosis (PC) with photodynamic therapy (PDT), we have assessed changes in optical properties, tissue oxygenation and drug concentration as a result of benzoporphyrin derivative (BPD)‐mediated PDT using diffuse reflectance and fluorescence measurements. PDT can effectively treat superficial disease spread, but treatment efficacy is influenced by physical properties of the treated tissue which can change over the treatment time. In this study, healthy canines were given BPD and irradiated with 690 nm light during a partial bowel resection, and spectroscopic and fluorescence measurements were made using an in‐house built spectroscopic probe. Hemoglobin concentration, oxygenation and optical properties were determined to be highly heterogeneous between canines and at different anatomical locations within the same subject, so further development of PDT dosimetry systems will need to address this patient and location‐specific dose optimization. Compared to other photosensitizers, we found no apparent BPD photobleaching after PDT. [ABSTRACT FROM AUTHOR]

The distributions of light and tissue oxygenation (StO2) within the chest cavity were determined for 15 subjects undergoing macroscopic complete resection followed by intraoperative photodynamic therapy (PDT) as part of a clinical trial for the treatment of malignant pleural mesothelioma (MPM). Over the course of light delivery, detectors at each of eight different sites recorded exposure to variable fluence rate. Nevertheless, the treatment‐averaged fluence rate was similar among sites, ranging from a median of 40–61 mW cm−2 during periods of light exposure to a detector. StO2 at each tissue site varied by subject, but posterior mediastinum and posterior sulcus were the most consistently well oxygenated (median StO2 >90%; interquartile ranges ~85–95%). PDT effect on StO2 was characterized as the StO2 ratio (post‐PDT StO2/pre‐PDT StO2). High StO2 pre‐PDT was significantly associated with oxygen depletion (StO2 ratio < 1), although the extent of oxygen depletion was mild (median StO2 ratio of 0.8). Overall, PDT of the thoracic cavity resulted in moderate treatment‐averaged fluence rate that was consistent among treated tissue sites, despite instantaneous exposure to high fluence rate. Mild oxygen depletion after PDT was experienced at tissue sites with high pre‐PDT StO2, which may suggest the presence of a treatment effect. [ABSTRACT FROM AUTHOR]

Explicit dosimetry of treatment light fluence and implicit dosimetry of photosensitizer photobleaching are commonly used methods to guide dose delivery during clinical PDT. Tissue oxygen, however, is not routinely monitored intraoperatively even though it is one of the three major components of treatment. Quantitative information about in vivo tissue oxygenation during PDT is desirable, because it enables reactive oxygen species explicit dosimetry (ROSED) for prediction of treatment outcome based on PDT‐induced changes in tumor oxygen level. Here, we demonstrate ROSED in a clinical setting, Photofrin‐mediated pleural photodynamic therapy, by utilizing tumor blood flow information measured by diffuse correlation spectroscopy (DCS). A DCS contact probe was sutured to the pleural cavity wall after surgical resection of pleural mesothelioma tumor to monitor tissue blood flow (blood flow index) during intraoperative PDT treatment. Isotropic detectors were used to measure treatment light fluence and photosensitizer concentration. Blood‐flow‐derived tumor oxygen concentration, estimated by applying a preclinically determined conversion factor of 1.5 × 109 μMs cm−2 to the blood flow index, was used in the ROSED model to calculate the total reacted reactive oxygen species [ROS]rx. Seven patients and 12 different pleural sites were assessed and large inter‐ and intrapatient heterogeneities in [ROS]rx were observed although an identical light dose of 60 J cm−2 was prescribed to all patients. [ABSTRACT FROM AUTHOR]

Uniform light fluence distribution for patients undergoing photodynamic therapy (PDT) is critical to ensure predictable PDT outcomes. However, current practice when delivering intrapleural PDT uses a point source to deliver light that is monitored by seven isotropic detectors placed within the pleural cavity to assess its uniformity. We have developed a real‐time infrared (IR) tracking camera to follow the movement of the light point source and the surface contour of the treatment area. The calculated light fluence rates were matched with isotropic detectors using a two‐correction factor method and an empirical model that includes both direct and scattered light components. Our clinical trial demonstrated that we can successfully implement the IR navigation system in 75% (15/20) of the patients. Data were successfully analyzed in 80% (12/15) patients because detector locations were not available for three patients. We conclude that it is feasible to use an IR camera‐based system to track the motion of the light source during PDT and demonstrate its use to quantify the uniformity of light distribution, which deviated by a standard deviation of 18% from the prescribed light dose. The navigation system will fail when insufficient percentage of light source positions is obtained (<30%) during PDT. [ABSTRACT FROM AUTHOR]

We have demonstrated that lung‐sparing surgery with intraoperative photodynamic therapy (PDT) achieves remarkably extended survival for patients with malignant pleural mesothelioma (MPM). Nevertheless, most patients treated using this approach experience local recurrence, so it is essential to identify ways to enhance tumor response. We previously reported that PDT transiently activates EGFR/STAT3 in lung and ovarian cancer cells and inhibiting EGFR via erlotinib can increase PDT sensitivity. Additionally, we have seen higher EGFR expression associating with worse outcomes after Photofrin‐mediated PDT for MPM, and the extensive desmoplastic reaction associated with MPM influences tumor phenotype and therapeutic response. Since extracellular matrix (ECM) proteins accrued during stroma development can alter EGF signaling within tumors, we have characterized novel 3D models of MPM to determine their response to erlotinib combined with Photofrin‐PDT. Our MPM cell lines formed a range of acinar phenotypes when grown on ECM gels, recapitulating the locally invasive phenotype of MPM in pleura and endothoracic fascia. Using these models, we confirmed that EGFR inhibition increases PDT cytotoxicity. Together with emerging evidence that EGFR inhibition may improve survival of lung cancer patients through immunologic and direct cell killing mechanisms, these results suggest erlotinib‐enhanced PDT may significantly improve outcomes for MPM patients. Here, we report the development of a novel 3‐D malignant pleural mesothelioma cell culture model using a patient‐derived cell line and its use to quantify photodynamic therapy (PDT) dose–response (figure). The translational potential of this system in further demonstrated in evaluating efficacy of molecularly targeted therapeutics in combination with PDT. [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]

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]

Abstract: The ability to produce nanotherapeutics at large‐scale with high drug loading efficiency, high drug loading capacity, high stability, and high potency is critical for clinical translation. However, many nanoparticle‐based therapeutics under investigation suffer from complicated synthesis, poor reproducibility, low stability, and high cost. In this work, a simple method for preparing multifunctional nanoparticles is utilized that act as both a contrast agent for magnetic resonance imaging and a photosensitizer for photodynamic therapy for the treatment of cancer. In particular, the photosensitizer protoporphyrin IX (PpIX) is used to solubilize small nanoclusters of superparamagnetic iron oxide nanoparticles (SPIONs) without the use of any additional carrier materials. These nanoclusters are characterized with a high PpIX loading efficiency; a high loading capacity, stable behavior; high potency; and a synthetic approach that is amenable to large‐scale production. In vivo studies of photodynamic therapy (PDT) efficacy show that the PpIX‐coated SPION nanoclusters lead to a significant reduction in the growth rate of tumors in a syngeneic murine tumor model compared to both free PpIX and PpIX‐loaded poly(ethylene glycol)‐polycaprolactone micelles, even when injected at 1/8th the dose. These results suggest that the nanoclusters developed in this work can be a promising nanotherapeutic for clinical translation. [ABSTRACT FROM AUTHOR]

Background We report on a Phase 1 trial of photodynamic therapy (PDT) for superficial head and neck (H&N) lesions. Due to known oxygen dependencies of PDT, translational measurements of lesion hemoglobin oxygen saturation (S t O 2 ) and blood volume (tHb) were studied for associations with patient outcomes. Methods PDT with aminolevulinc acid (ALA) and escalating light doses was evaluated for high-grade dysplasia, carcinoma-in-situ, and microinvasive carcinomas of the H&N. Among 29 evaluable patients, most (18) had lesions of the tongue or floor of mouth (FOM). Disease was intact in 18 patients and present at surgical margins in 11 patients. In 26 patients, lesion S t O 2 and tHb was measured. Results Local control (LC) at 24 months was 57.5% among all patients. In patients with tongue/FOM lesions LC was 42.7%, and it was 50.1% for those with intact lesions. Lesion tHb was not associated with 3-month complete response (CR), but S t O 2 was higher in patients with CR. In tongue/FOM lesions, baseline S t O 2 [mean(SE)] was 54(4)% in patients (n = 12) with CR versus 23(8)% in patients (n = 6) with local recurrence/persistence (p = 0.01). Similarly, for intact disease, baseline S t O 2 was 54(3)% in patients (n = 10) with CR versus 28(8)% in patients (n = 5) without CR (p = 0.03). In patients with intact disease, higher baseline S t O 2 associated with 24-month local control (p = 0.02). Conclusions Measurement of the physiologic properties of target lesions may allow for identification of patients with the highest probability of benefiting from PDT. This provides opportunity for optimizing light delivery based on lesion characteristics and/or informing ongoing clinical decision-making in patients who would most benefit from PDT. [ABSTRACT FROM AUTHOR]

Intralipid is a lipid emulsion used in photodynamic therapy ( PDT) for its light scattering and tissue-simulating properties. The purpose of this study is to determine whether or not Intralipid undergoes photooxidation, and we have carried out an Intralipid peroxide trapping study using a series of phosphines [2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate, 3-(diphenylphosphino)benzenesulfonate, triphenylphosphine-3,3′,3′′-trisulfonate and triphenylphosphine]. Our new findings are as follows: (1) An oxygen atom is transferred from Intralipid peroxide to the phosphine traps in the dark, after the photooxidation of Intralipid. 3-(Diphenylphosphino)benzenesulfonate is the most suitable trap in the series owing to a balance of nucleophilicity and water solubility. (2) Phosphine trapping and monitoring by 31P NMR are effective in quantifying the peroxides in H2O. An advantage of the technique is that peroxides are detected in H2O; deuterated NMR solvents are not required. (3) The percent yield of the peroxides increased linearly with the increase in fluence from 45 to 180 J cm−2 based on our trapping experiments. (4) The photooxidation yields quantitated by the phosphines and 31P NMR are supported by the direct 1H NMR detection using deuterated NMR solvents. These data provide the first steps in the development of Intralipid peroxide quantitation after PDT using phosphine trapping and 31P NMR spectroscopy. [ABSTRACT FROM AUTHOR]

This preclinical study examines light fluence, photodynamic therapy ( PDT) dose and 'apparent reacted singlet oxygen,' [1O2]rx, to predict local control rate ( LCR) for Photofrin-mediated PDT of radiation-induced fibrosarcoma ( RIF) tumors. Mice bearing RIF tumors were treated with in-air fluences (50-250 J cm−2) and in-air fluence rates (50-150 mW cm−2) at Photofrin dosages of 5 and 15 mg kg−1 and a drug-light interval of 24 h using a 630-nm, 1-cm-diameter collimated laser. A macroscopic model was used to calculate [1O2]rx and PDT dose based on in vivo explicit dosimetry of the drug concentration, light fluence and tissue optical properties. PDT dose and [1O2]rx were defined as a temporal integral of drug concentration and fluence rate, and singlet oxygen concentration consumed divided by the singlet oxygen lifetime, respectively. LCR was stratified for different dose metrics for 74 mice (66 + 8 control). Complete tumor control at 14 days was observed for [1O2]rx ≥ 1.1 m m or PDT dose ≥1200 μ m J cm−2 but cannot be predicted with fluence alone. LCR increases with increasing [1O2]rx and PDT dose but is not well correlated with fluence. Comparing dosimetric quantities, [1O2]rx outperformed both PDT dose and fluence in predicting tumor response and correlating with LCR. [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]

Photodynamic therapy (PDT) of the thoracic cavity can be performed in conjunction with surgery to treat cancers of the lung and its pleura. However, illumination of the cavity results in tissue exposure to a broad range of fluence rates. In a murine model of intrathoracic PDT, we studied the efficacy of 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH; Photochlor®)-mediated PDT in reducing the burden of non-small cell lung cancer for treatments performed at different incident fluence rates (75 versus 150 mW/cm). To better understand a role for growth factor signaling in disease progression after intrathoracic PDT, the expression and activation of epidermal growth factor receptor (EGFR) was evaluated in areas of post-treatment proliferation. The low fluence rate of 75 mW/cm produced the largest reductions in tumor burden. Bioluminescent imaging and histological staining for cell proliferation (anti-Ki-67) identified areas of disease progression at both fluence rates after PDT. However, increased EGFR activation in proliferative areas was detected only after treatment at the higher fluence rate of 150 mW/cm. These data suggest that fluence rate may affect the activation of survival factors, such as EGFR, and weaker activation at lower fluence rate could contribute to a smaller tumor burden after PDT at 75 mW/cm. [ABSTRACT FROM AUTHOR]