Background: Multimodal treatment associating surgery (pleurectomy/decortication, P/D) then IV adjuvant chemotherapy (platinum/pemetrexed) is an effective therapeutic option for some selected malignant pleural mesothelioma (MPM) patients. Intra-operative pleural photodynamic therapy (iPDT) has emerged as a promising option to improve this multimodal treatment outcome (Friedberg J, Ann Thorac Surg. 2017). The MesoPDT trial (NCT02662504) aimed at assessing the feasibility of such procedure outside the only two US expert centers performing multimodal treatment including iPDT to date. Methods: A single-center pilot clinical trial was designed to assess the feasibility of iPDT protocol in Lille University Hospital. A pool of maximum six patients was expected in order to apply the iPDT protocol, and to assess its applicability and safety outside US center expert. Results: In 2016-2017, four consecutive assessable patients were included and treated per protocol, reaching the study achievement cut-off. iPDT specific procedures have been applied and managed in partnership with US experts. The safety profile was favorable. The main and most specific adverse event was acute lung injury occurring within 72 hours after iPDT, which may lead to reversible respiratory distress, manageable with adequate intensive care. The 4 patients achieved the full scheduled protocol. Conclusion: The iPDT multimodal treatment for MPM is applicable and manageable in a European expert center, involving local skills and dedicated teams. The safety profile of the iPDT in Lille center was favorable, as validated by an external board. Median overall survival was promising (≈28 months), similar to previous US results. Our center is expected to join soon a large phase II randomized, multicentric US trial assessing MPM multimodal treatment (P/D, chemotherapy) ±iPDT (NCT02153229; UPENN, USA).
Photodynamic therapy (PDT) is an established treatment for actinic keratosis (AK). The conventional approved PDT protocol in Europe (C-PDT) involves red-light photoactivation at irradiances higher than 60 mW/cm2 , making the treatment painful. Several clinical studies have reported similar efficacy and better tolerability when using red-light photoactivation at lower irradiances. The aim of the study was to investigate whether there is a minimum irradiance threshold for red-light photoactivation above which there is no further improvement in efficacy. A photodiode sensor connected to a power meter was used to measure the irradiance delivered to 114 AKs on the scalp and forehead of 19 patients during C-PDT using the Aktilite CL 128 (Galderma SA, Switzerland). The widely ranging measured irradiances, resulting from the heterogeneous photoactivation over the treatment area provided by the Aktilite CL 128, were cross-referenced with the clinically evaluated complete responses (CR) at 3 months. The 66 AKs in CR at 3 months received an average irradiance of 30.9 mW/cm2 (standard deviation: 16.7 mW/cm2 ) compared to 33.3 mW/cm2 (standard deviation: 17.9 mW/cm2 ) for the 48 AKs in incomplete response. No significant effect of the irradiance on the CR at 3 months was found (odds ratio for a 6 mW/cm2 -unit change, 0.96; 95% confidence interval, 0.83 to 1.10; p=0.53). No minimum irradiance threshold could therefore be determined in the considered irradiance range. A red-light device enabling homogeneous irradiation at a lower irradiance than the Aktilite CL 128 may therefore provide similar efficacy and higher treatment tolerability than C-PDT.
Photodynamic therapy (PDT) for dermatological conditions relies on the photoactivation of the photosensitizer protoporphyrin IX (PpIX). Many light sources have been or are being investigated. The stronger the overlap of the spectral irradiance of the light source with the absorption spectrum of PpIX is, the more powerful to photoactivate PpIX is the light source. This overlap can be quantified using the PpIX-weighted irradiance, which results from the weighting of the spectral irradiance of the light source by the normalized PpIX absorption spectrum. We have previously developed a freely available website (http://www.oncothai.fr/light-efficiency-calculator/), which aims to compute the PpIX-weighted irradiance of any uploaded spectral irradiance. Through this website, we have assessed a variety of light sources proposed for use in dermatological PDT. The spectral irradiances of these light sources were collected by either extraction from the literature or request to manufacturers. Due to the variations in position, shape, and amplitude of the spectral irradiances with regard to the PpIX normalized absorption spectrum, a wide range of PpIX-weighted irradiances has been obtained. The maximal PpIX-weighted irradiance was achieved with daylight on a clear sunny day.
Whether preclinical studies either involve a cell or animal model, the distribution of light plays a determinant role in the reproducibility of results of photodynamic therapy (PDT) studies. Unfortunately, only few illumination devices dedicated to preclinical studies are available and are for the most, very expensive. Most research teams use home-made solutions that may not always be reproducible because of undefined light distribution, additive thermal emission, or unsuitable for shapes and volumes to illuminate. To address these issues, we developed illumination devices dedicated to our preclinical studies, which embed knitted light emitting fabrics (LEF) technology. LEF technology offers a homogeneous light distribution, without thermal emission and can be coupled with various light sources allowing investigation of several PDT modalities (irradiance, wavelength, illumination duration/mode). For in-vitro studies, we designed light plates, each allowing illumination of up to four 96-cells plates. For in-vivo studies, we designed mice boxes allowing three animals placement in prone position, equally surrounded by LEF and ensuring homogeneous extracorporeal illumination. Optical validation was performed and reproducibility of both preclinical systems were assessed. Both systems can deliver homogeneous light with an irradiance that can reach several mW/cm2, with varying durations and wavelengths. First results of preclinical studies demonstrate a high reproducibility, with an easy setup, and a great adaptability of illumination modalities with these devices based on light emitting fabrics.
Glioblastoma is a malignant brain tumor with a poor prognosis. Currently, complete resection is rarely feasible, since tumor cells usually infiltrate the surrounding brain. Recently, the INDYGO clinical trial has been achieved to assess the toxicity of photodynamic therapy (PDT) delivered intraoperatively to treat newly diagnosed glioblastoma. Today, we believe that the PDT effect obtained in the INDYGO clinical trial can be improved by a higher light dose. The DOSINDYGO clinical trial aims to achieve a light-dose escalation increasing up to four times the initial light dose used in the INDYGO trial. An increase of both light power and treatment time should allow to treat deeper in the surrounding tissues (up to 8mm) and thus decrease the recurrence risk. First light dose will be reached by doubling the treatment time used in the INDYGO trial, the other one will be achieved by increasing light power only. This methodology was chosen in order to maintain an acceptable treatment time for anesthesia but also to prevent higher fluence rate that could induce a lower tolerance as observed in our preclinical results. Primary endpoint will be to determine the optimum light-dose regarding the ratio efficacy and tolerance of the treatment. Primary criterion is the assessment of the progression free survival within the bed border’s cavity. Finally, although no adverse effect has been noticed during the INDYGO trial, increasing light dose in this DOSINDYGO trial could result in other direct and indirect biological effects.
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