Photodynamic Diagnosis of Non-muscle-invasive Bladder Cancer with Hexaminolevulinate Cystoscopy: A Meta-analysis of Detection and Recurrence Based on Raw Data.

BACKGROUND: Studies on hexaminolevulinate (HAL) cystoscopy report improved detection of bladder tumours. However, recent meta-analyses report conflicting effects on recurrence. OBJECTIVE: To assess available clinical data for blue light (BL) HAL cystoscopy on the detection of Ta/T1 and carcinoma in situ (CIS) tumours, and on tumour recurrence. DESIGN, SETTING, AND PARTICIPANTS: This meta-analysis reviewed raw data from prospective studies on 1345 patients with known or suspected non-muscle-invasive bladder cancer (NMIBC). INTERVENTION: A single application of HAL cystoscopy was used as an adjunct to white light (WL) cystoscopy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We studied the detection of NMIBC (intention to treat [ITT]: n=831; six studies) and recurrence (per protocol: n=634; three studies) up to 1 yr. DerSimonian and Laird's random-effects model was used to obtain pooled relative risks (RRs) and associated 95% confidence intervals (CIs) for outcomes for detection. RESULTS AND LIMITATIONS: BL cystoscopy detected significantly more Ta tumours (14.7%; p<0.001; odds ratio [OR]: 4.898; 95% CI, 1.937-12.390) and CIS lesions (40.8%; p<0.001; OR: 12.372; 95% CI, 6.343-24.133) than WL. There were 24.9% patients with at least one additional Ta/T1 tumour seen with BL (p<0.001), significant also in patients with primary (20.7%; p<0.001) and recurrent cancer (27.7%; p<0.001), and in patients at high risk (27.0%; p<0.001) and intermediate risk (35.7%; p=0.004). In 26.7% of patients, CIS was detected only by BL (p<0.001) and was also significant in patients with primary (28.0%; p<0.001) and recurrent cancer (25.0%; p<0.001). Recurrence rates up to 12 mo were significantly lower overall with BL, 34.5% versus 45.4% (p=0.006; RR: 0.761 [0.627-0.924]), and lower in patients with T1 or CIS (p=0.052; RR: 0.696 [0.482-1.003]), Ta (p=0.040; RR: 0.804 [0.653-0.991]), and in high-risk (p=0.050) and low-risk (p=0.029) subgroups. Some subgroups had too few patients to allow statistically meaningful analysis. Heterogeneity was minimised by the statistical analysis method used. CONCLUSIONS: This meta-analysis confirms that HAL BL cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9-12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer.

Correlation of photodynamic activity and fluorescence signaling for free and pegylated mTHPC in mesothelioma xenografts

Rapport de synthèse : Introduction : Les premières applications cliniques de la thérapie photodynamique (PDT) remontent à plus d'une vingtaine d'années. Basée sur l'activation d'un médicament photosensibilisateur par une source lumineuse à une longueur d'onde spécifique, la PDT permet la destruction sélective de tissus contenant le produit actif. Ce procédé a été expérimenté dans le traitement de cancers en raison de la propriété du médicament à se concentrer dans les tumeurs tout en épargnant les structures normales contigües. Cependant, les photosensibilisateurs utilisés jusqu'à ce jour n'ont pas démontré une accumulation exclusive dans les tissus néoplasiques mais également dans les structures saines avoisinantes induisant une destruction tissulaire non sélective. Notamment, d'importantes complications ont été rapportées suite à l'utilisation de la PDT dans la cavité thoracique après la résection de mésothéliomes pleuraux, et ce malgré l'arrivée de photosensibilisateurs de secondes générations. De ce fait, plusieurs études expérimentales ont été menées afin d'améliorer la sélectivité tumorale du médicament en modulant différentes conditions de traitement et en modifiant la structure du photosensibilisateur par pégylation. Le but de cette étude expérimentale est de corréler l'activité photodynamique, la phototoxicité et la distribution du m-tetrahydroxyphenylchlorin (mTHPC) et de sa forme pégylée, le PEG-mTHPC. De ce fait, un modèle de souris nues porteur de xenogreffes de mésothéliome humain a été utilisé pour étudier les deux photosensibilisateurs. De récents travaux avec ce modèle ont montré que la mesure de la concentration tissulaire du mTHPC et de sa forme pégylée par HPLC restait limitée afin de prédire l'activité photodynamique. De ce fait, nous pensons que les mesures de fluorescence peuvent être plus appropriée. Le signalement fluorescent est mesuré dans le tissu tumoral et dans une région contrôle de la peau afin d'étudier la distribution et l'intensité des deux sensibilisateurs. Méthode : Des souris nues (cd1nu/nu mice) de 8 semaines ont été transplantées avec des fragments de mésothéliome malin humain (H-meso-1). Ces derniers ont été obtenus à partir d'une suspension cellulaire. Au moins trois passages ont été faits dans les animaux, avant que le traitement soit initié. Deux groupes de 6 souris chacun ont été utilisés pour l'injection intraveineuse par la queue du mTHPC à 0.15 mg/kg et du PEG-mTHPC à dose équimolaire. Après trois jour, la tumeur ainsi qu'une région contrôle de la cuisse ont été illuminées sur une surface d'un diamètre de 1.2 cm et pendant 133 secondes avec un laser à une longueur d'onde à 652 nm (fluence 20 J/cm2, fluence rate 150 mW/cm2). Les animaux ont été ensuite sacrifiés 72 heures après l'illumination. L'étendue de la nécrose tumorale et de la région contrôle ont été déterminées en aveugle par histomorphometrie par un pathologue (HJA). La fluorescence microscopique a été évaluée dans 12 souris à une concentration de 0.15 et 0.5 mg/kg pour le mTHPC, et à doses équimolaires pour le PEG-mTHPC. Trois animaux ont été injectés avec le mTHPC à 0.15 mg/kg, 3 autres à dose équimolaire avec la forme pégylée et 6 souris avec le mTHPC à 0.5 mg/kg et à dose équimolaire. Les animaux ont été sacrifiés 72 heures après injection. L'intensité fluorescente des sensibilisateurs a été mesurée dans la tumeur et la région contrôle. Suite à cela, les coupes ont été fixées par H&E et superposées aux images fluorescentes, afin de localiser la distribution des deux photosensibilisateurs dans les différents compartiments tissulaires. Six souris transplantées n'ayant ni été injectées avec les sensibilisateurs ou illuminées ont servi de groupe contrôle. Résultats : Trois jours après l'illumination, la PDT provoque une nécrose tumorale de 10 ±5.4 mm2 pour le mTHPC à 0.15mg/kg et 5.2 ± 4.6 mm2 pour sa forme pégylée à dose équimolaire. Cependant, la nécrose tumorale induite par les deux formulations du sensibilisateur est significativement plus élevée que dans le groupe contrôle (0.33 ± 0.58 mm2) (P=0.02). Toutefois, le mTHPC pégylé provoque une photosensibilité cutanée moins importante que la forme non-pegylée. Dans les deux groupes, aucune nécrose n'a été observée dans la cuisse des animaux. Trois jours après l'injection du mTHPC et de la forme pégylée à 0.15 mg/kg, aucune activité fluorescente n'a été détectée. Cependant, à 0.5 mg/kg, la fluorescence microscopique révèle une distribution hétérogène des deux photo-sensibilisateurs dans le tissu tumoral avec une accumulation prédominante dans les régions peri-vasculaires. Les deux médicaments montrent une distribution intracellulaire homogène dans le cytoplasme et une absence de signalement dans le nucleus. La mesure de l'intensité fluorescente du mTHPC à 0.5mg/kg ne montre pas de différence significative entre le tissu tumoral et la région contrôle. Par contre, le PEG-mTHPC montre une intensité fluorescente supérieure dans le tissu tumoral que dans la peau (ratio tumeur- peau 0.94 pour le mTHPC et 1.73 pour le PEG-mTHPC). Conclusion : L'utilisation du mTHPC à 0.15mg/kg induit une nécrose tumorale similaire à celle du PEG-mTHPC à dose équimolaire. Cependant, ce dernier démontre une photo-toxicité plus atténuée de la peau. La fluorescence microscopique permet de localiser les deux sensibilisateurs dans les différents compartiments tissulaires à partir d'une dose de 0.5 mg/kg. Le PEG-mTHPC induit un signalement fluorescent supérieur dans le tissu tumoral par rapport à la peau. La mesure du signalement fluorescent a le potentiel de prédire l'activité photodynamique du mTHPC et de sa forme pégylée dans les xénogreffes de mésothéliome humain dans un modèle de souris nue.

Evaluation of the new photosensitizer Stakel (WST-11) for photodynamic choroidal vessel occlusion in rabbit and rat eyes.

PURPOSE: To evaluate the photodynamic potential of a new hydrosoluble photosensitizer (WST-11, Stakel; Steba Biotech, Toussus-Le-Noble, France), for use in occlusion of normal choroidal vessels in the rabbit eye and CNV (choroidal neovascularization) in the rat eye. METHODS: Occlusive and nonocclusive parameters of Stakel and verteporfin photodynamic therapy (PDT) were investigated in pigmented rabbits. Eyes were followed by fluorescein angiography (FA) and histology at various intervals after PDT. RESULTS: When occlusive parameters (fluence of 50 J/cm(2), 5 mg/kg drug dose and DLI [distance to light illumination] of 1 minute) were used, Stakel PDT was efficient immediately after treatment without associated structural damage of the RPE and retina overlying the treated choroid in the rabbit eye. Two days later, total occlusion of the choriocapillaries was seen in 100% of the treated eyes, along with accompanying histologic structural changes in the overlying retina. When the occlusive parameters (fluence, 100 J/cm2; drug dose, 12 mg/m2; and DLI, 5 minutes) of verteporfin PDT were used, occlusion of the choriocapillaries was observed in 89% of the treated eyes. Histology performed immediately after treatment demonstrated structural damage of the overlying retina and RPE layer. Weaker, nonocclusive Stakel PDT parameters (25 J/cm2, 5 mg/kg, and DLI of 10 minutes) did not induce choriocapillary occlusion or retinal lesions on FA or histology. Weaker, nonocclusive verteporfin PDT parameters (10 J/cm2, 0.2 mg/kg, and DLI of 5 minutes) did not induce choriocapillary occlusion. However, histology of these eyes showed the presence of damage in the retinal and choroidal tissues. Moreover, preliminary results indicate that selective CNV occlusion can be achieved with Stakel PDT in the rat eye. CONCLUSIONS: Unlike verteporfin PDT, Stakel PDT does not cause direct damage to the RPE cell layer or retina. These observations indicate that Stakel PDT may have a high potential for beneficial therapeutic outcomes in treatment of AMD.

Photodynamic therapy enhances lipodoxorubcin distribution in sarcoma lung metastasis by lowering tumor interstitial fluid pressure in a rodent model

Objective: The management of sarcoma metastasis by systemic chemotherapy is often unsatisfactory. This has paradoxally been attributed to the leakiness of tumor neovessels which induce high intratumor interstitial fluid pressure (IFP) and limit convection forces that are important for drug distribution. In a rodent model, we have recently shown that photodynamic (PDT) pre treatment of lung metastasis could enhance their uptake of chemotherapy. We hypothesized that PDT transiently decreases tumor IFP which enhances convection and promotes drug distribution.Methods: Sarcoma tumors were generated sub-pleurally in the lungs of 12 rats. Animals were randomized at 10 days into i. no pre-treatment (control) and ii. low dose PDT pre-treatment (0・0625 mg/kg Visudyne, 10J/cm2 and 35 mW/cm2) followed by intravenous Liposomal doxorubicin (LiporubicinTM) administration. Using the wick-in-needle technique, we determined tumor and normal tissue IFP before, during and after PDT. In parallel, the uptake of LiporubicinTM was determined by high performance liquid chromatography in tumor and lung tissues.Results: Tumor IFP was significantly higher than normal tissue IFP in all animals. PDT pre-treatment did not affect normal tissue IFP but caused a significant decrease in tumor IFP (mean decrease by 2+/− 1mmHg) which lasted an average of 30 minutes before reaching baseline values. Tumor but not normal lung tissue LiporubicinTM uptake was significantly increased by 67% with PDT pre-treatment when liporubicin was allowed to circulate for one hour.Conclusion: Photodynamic therapy pre-treatment enhances LiporubicinTM uptake in sarcoma lung metastasis by transiently decreasing tumor IFP. These PDT conditions seem to specifically modulate tumor neovessels but not normal lung vessels.

Photodynamic therapy induces selective extravasation of macromolecules: Insights using intravital microscopy.

Photodynamic therapy (PDT) with Visudyne acts by direct cellular phototoxicity and/or by an indirect vascular-mediated effect. Here, we demonstrate that the vessel integrity interruption by PDT can promote the extravasation of a macromolecular agent in normal tissue. To obtain extravasation in normal tissue PDT conditions were one order of magnitude more intensive than the ones in tissue containing neovessels reported in the literature. Fluorescein isothiocyanate dextran (FITC-D, 2000 kDa), a macromolecular agent, was intravenously injected 10 min before (LK0 group, n=14) or 2h (LK2 group, n=16) after Visudyne-mediated PDT in nude mice bearing a dorsal skin fold chamber. Control animals had no PDT (CTRL group, n=8). The extravasation of FITC-D from blood vessels in striated muscle tissue was observed in both groups in real-time for up to 2500 s after injection. We also monitored PDT-induced leukocyte rolling in vivo and assessed, by histology, the corresponding inflammatory reaction score in the dorsal skin fold chambers. In all animals, at the applied PDT conditions, FITC-D extravasation was significantly enhanced in the PDT-treated areas as compared to the surrounding non-treated areas (p<0.0001). There was no FITC-D leakage in the control animals. Animals from the LK0 group had significantly less FITC-D extravasation than those from the LK2 group (p=0.0002). In the LK0 group FITC-D leakage correlated significantly with the inflammation (p<0.001). At the selected conditions, Visudyne-mediated PDT promotes vascular leakage and FITC-D extravasation into the interstitial space of normal tissue. The intensity of vascular leakage depends on the time interval between PDT and FITC-D injection. This concept could be used to locally modulate the delivery of macromolecules in vivo.

Photodynamic therapy for enhanced drug delivery to tumor

Photodynamic therapy (PDT) has been used as an adjunct to cytoreductive surgery in patients with malignant pleura mesothelioma (MPM). However, it was associated with substantial side effects and found to be only of modest clinical benefit. In contrast, Visudyne®-mediated low-dose PDT has been shown to selectively increase the concentration of macromolecular cytostatic compounds in various tumors grown subpleurally on rodent lungs. Consequently, it was thought that PDT-assisted enhanced tumor penetration for cytostatic agents might be better suited to achieve additional tumor control after cytoreductive surgery for mesothelioma. This effect seems to be mainly related to PDT-mediated modulations of tumor vessels which improve the distribution of circulating, systemically administered chemotherapeutic macromolecular agents. However, the mechanisms involved and the optimization of this effect for therapeutic implications remain to be solved. By using the dorsal skin fold chamber method we demonstrated that both angiogenesis and microcirculation of human mesothelioma xenografts can be continuously assessed in vivo by intravital microscopy. We described a new, simple, reproducible and reliable scoring system for the assessment of tumor angiogenesis and microcirculation in this model, thereby allowing the quantitative description of the neo-vascular network development while avoiding a complicated technical setup. This method can serve as a useful tool for the assessment of novel vessel-targeted therapies against MPM. We then applied this newly established model so as to elucidate the underlying mechanisms of PDT-induced extravasation of macromolecular compounds across the endothelial barrier in tumors and surrounding normal tissue. We found that low-dose PDT selectively enhanced the uptake of macromolecular compounds in human mesothelioma xenografts compared to surrounding normal tissue. Interestingly, this increase of effective permeability of tumor vasculature was not related to the inflammatory stimuli generated by PDT such as the mobilization of leucocytes and their adhesion and penetration of the injured vessel wall. We then used the model for optimizing the drug-light conditions of low- dose PDT in order to obtain maximal leakage of the macromolecular compounds in the tumor with minimal uptake in normal surrounding tissue and we were able to identify such a therapeutic window. With these optimized PDT treatment conditions, we assessed the therapeutic effect of this new treatment concept in vivo by measuring tumor growth rates on subcutaneously grown mesothelioma xenografts in nude mice after low-dose PDT of the tumors following systemically administered liposomal (macromolecular) cisplatin, a cytostatic compound commonly used in clinical practice. We were able to demonstrate that low-dose PDT with optimized drug-light conditions combined with systemic chemotherapy indeed resulted in a reduction in tumor growth compared to chemotherapy or PDT alone. In conclusion, our work demonstrates that low-dose PDT may selectively enhance the uptake of macromolecular cytostatic drugs in superficially growing tumors such as mesotheliomas and opens new perspectives for the treatment of these diseases. - Les effets cytotoxiques de la thérapie photodynamique (PDT) sur le mésothéliome pleural malin (MPM) n'ont pas apporté de bénéfice clinique significatif. Toutefois, une application innovante non cytotoxique de la PDT serait la bienvenue en supplément des chimiothérapies pour améliorer le contrôle local de la tumeur. Le prétraitement des néovaisseaux tumoraux par une PDT à bas régime, qui améliorerait la distribution d'une chimiothérapie administrée par voie systémique de façon concomitante, a attiré une attention particulière pour de futures applications cliniques. Toutefois, les mécanismes impliqués dans cet événement et les implications thérapeutiques de ces changements physiopathologiques restent non résolus. Dans cette thèse, nous avons observé en premier que l'angiogenèse et la microcirculation dans les xénogreffes de mésothéliomes humains peuvent être observées et analysées in vivo par microscopie intravitale. Le nouveau système de score appliqué pour l'évaluation de l'angiogenèse et de la microcirculation tumorale dans cette étude est une méthode simple, reproductible et fiable servant à décrire de manière quantitative le réseau néo-vasculaire en développement, tout en évitant d'utiliser une installation technique compliquée. Ce modèle sert de nouvel outil pour l'évaluation des thérapies anti-vasculaires dirigées contre le MPM. Le modèle animal nouvellement établi a alors été utilisé pour élucider les mécanismes sous-jacents de Γ extravasation d'agents macromoléculaires induite par PDT dans les vaisseaux tumoraux et normaux. Nous avons trouvé que la PDT à fable dose améliore la distribution ciblée de drogues macromoléculaires dans des greffes de mésothéliome humain, de manière sélective pour la tumeur. La perméabilité vasculaire tumorale n'est pas influencée par les stimuli inflammatoires générés par la PDT, ce qui joue un rôle important dans la sélectivité de notre photodynamic drug delivery. Ensuite, nous avons recherché la fenêtre thérapeutique optimale de la PDT pour obtenir une accumulation sélective du colorant macromoléculaire dans le tissu tumoral ainsi qu'une efficacité de la PDT combinée avec une chimiothérapie macromoléculaire sur la croissance tumorale. Nous avons démontré que la PDT à faible dose combinée avec une administration systémique de cisplatine liposomale mène à un ralentissement de la croissance tumorale dans notre modèle de mésothéliome malin humain. En conclusion, l'utilisation de la PDT comme prétraitement pour améliorer sélectivement la distribution d'agents thérapeutiques dans des tumeurs poussant superficiellement est prometteuse. Cette observation fourni une preuve du concept remarquable et garanti la suite des investigations, éventuellement ayant pour but de développer de nouveaux concepts de thérapie pour les patients atteints de mésothéliome. Une PDT intra cavitaire à faible dose après pleuro- pneumonectomie pourrait améliorer la pénétration des agents cytostatiques administrés de façon concomitante par voie systémique dans les îlots tumoraux résiduels, et ainsi améliorer le contrôle local.

Thrombin-sensitive photodynamic agents: a novel strategy for selective synovectomy in rheumatoid arthritis.

Protease-sensitive macromolecular prodrugs have attracted interest for bio-responsive drug delivery to sites with up-regulated proteolytic activities such as inflammatory or cancerous lesions. Here we report the development of a novel polymeric photosensitizer prodrug (T-PS) to target thrombin, a protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients, for minimally invasive photodynamic synovectomy. In T-PS, multiple photosensitizer units are tethered to a polymeric backbone via short, thrombin-cleavable peptide linkers. Photoactivity of the prodrug is efficiently impaired due to energy transfer between neighbouring photosensitizer units. T-PS activation by exogenous and endogenous thrombin induced an increase in fluorescence emission by a factor of 16 after in vitro digestion and a selective fluorescence enhancement in arthritic lesions in vivo, in a collagen-induced arthritis mouse model. In vitro studies on primary human synoviocytes showed a phototoxic effect only after enzymatic digestion of the prodrug and light irradiation, thus demonstrating the functionality of T-PS induced PDT. The developed photosensitizer prodrugs combine the passive targeting capacity of macromolecular drug delivery systems with site-selective photosensitizer release and activation. They illuminate lesions with pathologically enhanced proteolytic activity and induce cell death, subsequent to irradiation.

Photodynamic therapy for polypoidal choroidal vasculopathy.

The first effective therapy for exudative macular degeneration (AMD) was Photodynamic Therapy (PDT). Diagnosis of the disease was to a large extent by fluorescein angiography (FA). Distinguishing between the leaky choroidal neovessels (CNV) associated with exudative AMD, and the polypoidal structures associated with Polypoidal Choroidal Vasculopathy (PCV) is not always easy using FA alone. The switch to Indocyanine Green angiography helped to pinpoint PCV, and thus to study the efficacy of photodynamic therapy of this particular form of retinal disease, which is more frequently encountered among pigmented individuals. The results appear to be quite promising, and in the year following treatment only a small fraction of the patients had to be retreated. Alternatively, treating PCV with repeated intravitreal VEGF blocking agents was not as successful as it was in the treatment of wet AMD. However, combining PDT-induced angio-occlusion of the polypoidal lesions with anti-vascular endothelial growth factor therapy was shown to be quite effective, and the combination of PDT with an anti-angiogenic agent as well as a steroid, in a triple therapy, was recently also shown to be a quite promising option. In the present article we review the data on PDT of PCV, including combination therapies and alternative treatments. We also report on similarities and differences between AMD and PCV.

Angiostatic kinase inhibitors to sustain photodynamic angio-occlusion.

Targeted angiostatic therapy receives major attention for the treatment of cancer and exudative age-related macular degeneration (AMD). Photodynamic therapy (PDT) has been used as an effective clinical approach for these diseases. As PDT can cause an angiogenic response in the treated tissue, combination of PDT with anti-angiogenic compounds should lead to improved therapy. This study was undertaken to test the clinically used small molecule kinase inhibitors Nexavar® (sorafenib), Tarceva® (erlotinib) and Sutent® (sunitinib) for this purpose, and to compare the results to the combination of Visudyne®-PDT with Avastin® (bevacizumab) treatment. When topically applied to the chicken chorioallantoic membrane at embryo development day (EDD) 7, a clear inhibition of blood vessel development was observed, with sorafenib being most efficient. To investigate the combination with phototherapy, Visudyne®-PDT was first applied on EDD11 to close all <100 μm vessels. Application of angiostatics after PDT resulted in a significant decrease in vessel regrowth in terms of reduced vessel density and number of branching points/mm(2) . As the 50% effective dose (ED50) for all compounds was approximately 10-fold lower, Sorafenib outperformed the other compounds. In vitro, all kinase inhibitors decreased the viability of human umbilical vein endothelial cells. Sunitinib convincingly inhibited the in vitro migration of endothelial cells. These results suggest the therapeutic potential of these compounds for application in combination with PDT in anti-cancer approaches, and possibly also in the treatment of other diseases where angiogenesis plays an important role.

Intraoperative photodynamic therapy of the chest cavity in malignant pleural mesothelioma bearing rats.

BACKGROUND AND OBJECTIVE: Experimental assessment of anticancer effect, normal tissue damage, and toxicity of intrathoracic mTHPC-mediated photodynamic therapy (PDT) combined to surgery in malignant pleural mesothelioma (MPM) bearing rats. STUDY DESIGN/MATERIALS AND METHODS: Six days after implantation of syngenic malignant mesothelioma cells in the left chest cavity of Fischer rats (n = 21) and 4 days after sensitization (0.1 mg/kg mTHPC), a left-sided pneumonectomy was performed, followed by intraoperative light delivery (652 nm, fluence 20 J/cm(2)), either by spherical illumination of the chest cavity (fluence rate 15 mW/cm(2)) or by focal illumination of a tumor area (fluence rate 150 mW/cm(2)). Controls comprised tumor-bearing untreated animals, tumor-bearing animals undergoing pneumonectomy, and tumor-bearing animals undergoing pneumonectomy and light delivery without sensitization or sensitization without light delivery. No thoracocentesis was performed during follow-up. RESULTS: An invasively growing sarcomatous type of mesothelioma was found in all animals at day 10, without tumor necrosis in control animals. PDT resulted in 0.5-1 mm deep inhomogeneous tumor necrosis after spherical, and in a 1-2 mm deep tumor necrosis after focal illumination. No injury to mediastinal organs was observed, neither after PDT with spherical nor with focal light delivery except focal interstitial lung fibrosis at the mediastinal area of the opposite lung. All animals with pneumonectomy followed by spherical PDT of the entire tumor-bearing chest cavity died within 72 hours whereas all other animals survived. All animals that died presented massive pleural effusion. CONCLUSIONS: PDT following pneumonectomy in mesothelioma bearing rats was technically feasible and allowed to study its effect on tumor and normal tissues. PDT-related tumor necrosis was observed after spherical and focal light delivery, however, pneumonectomy followed by PDT with spherical light delivery to the tumor-bearing chest cavity resulted in fatal complications.

Photodynamic therapy as an adjunct to surgery for malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is increasingly observed in industrial countries. Despite concerted efforts and combined treatments including surgery, chemotherapy and irradiation patients eventually succumb from relentless local progression of the disease. Recent publications have demonstrated an improved response rate with the cytostatic agent pemetrexed which will be tested in a neoadjuvant setting followed by surgery. However, effective tumor control requires new loco-regional treatment modalities, eventually in combination with neoadjuvant chemotherapy. Intraoperative photodynamic therapy (PDT) of the chest cavity has been proposed as an attractive treatment concept for MPM since a selective treatment of the tumor bed following resection has the potential to improve local tumor control. It has been shown to afford tumor destruction in patients with mesothelioma but efficiency and selectivity is not yet sufficient for routine clinical application. Experimental work on MPM has shown that tumor selectivity of PDT depend on treatment conditions and can be improved by structural modification and improved targeting of the sensitizers. Refinements of PDT for mesothelioma will depend on a more detailed understanding of the pathways for preferential sensitizer accumulation within the tumor as well as on synergistic effects between PDT and chemotherapeutic agents.

Photodynamic therapy selectively enhances liposomal doxorubicin uptake in sarcoma tumors to rodent lungs.

BACKGROUND: In specific conditions, photodynamic therapy (PDT) can enhance the distribution of macromolecules across the endothelial barrier in solid tumors. It was recently postulated that tumor neovessels were more responsive to PDT than the normal vasculature. We hypothesized that Visudyne(R)-mediated PDT could selectively increase liposomal doxorubicin (Liporubicin) uptake in sarcoma tumors to rodent lungs while sparing the normal surrounding tissue. MATERIALS AND METHODS: Sarcoma tumors were generated subpleurally in the left lower lung lobe of 66 Fischer rats. Ten days following sarcoma implantation, tumors underwent different pre-treatment schemes: no PDT (controls), low-dose PDT (0.0625 mg/kg Visudyne(R), 10 J/cm(2) and 35 mW/cm(2)) and high-dose PDT (0.125 mg/kg Visudyne(R), 10 J/cm(2) and 35 mW/cm(2)). Liporubicin was then administered and allowed to circulate for 1, 3, or 6 hours. At the end of each treatment scheme, we assessed the uptake of Liporubicin in tumor and lung tissues by high-performance liquid chromatography and fluorescence microscopy. RESULTS: In all PDT-treated groups, there was a significant enhancement of Liporubicin uptake in tumors compared to controls after 3 and 6 hours of drug circulation. In addition, Liporubicin distribution within the normal lung tissue was not affected by PDT. Thus, PDT pre-treatment significantly enhanced the ratio of tumor-to-lung drug uptake compared to controls. Finally, fluorescence microscopy revealed a well-detectable Liporubicin signaling throughout PDT-treated tumors but not in controls. CONCLUSIONS: PDT is a tumor-specific enhancer of Liporubicin distribution in sarcoma lung tumors which may find a translation in clinics.

Fluence plays a critical role on the subsequent distribution of chemotherapy and tumor growth delay in murine mesothelioma xenografts pre-treated by photodynamic therapy.

BACKGROUND: The pre-conditioning of tumor vessels by low-dose photodynamic therapy (L-PDT) was shown to enhance the distribution of chemotherapy in different tumor types. However, how light dose affects drug distribution and tumor response is unknown. Here we determined the effect of L-PDT fluence on vascular transport in human mesothelioma xenografts. The best L-PDT conditions regarding drug transport were then combined with Lipoplatin(®) to determine tumor response. in vivo. Lasers Surg. Med. 47:323-330, 2015. © 2015 Wiley Periodicals, Inc. METHODS: Nude mice bearing dorsal skinfold chambers were implanted with H-Meso1 cells. Tumors were treated by Visudyne(®) -mediated photodynamic therapy with 100 mW/cm(2) fluence rate and a variable fluence (5, 10, 30, and 50 J/cm(2) ). FITC-Dextran (FITC-D) distribution was assessed in real time in tumor and normal tissues. Tumor response was then determined with best L-PDT conditions combined to Lipoplatin(®) and compared to controls in luciferase expressing H-Meso1 tumors by size and whole body bioluminescence assessment (n = 7/group). RESULTS: Tumor uptake of FITC-D following L-PDT was significantly enhanced by 10-fold in the 10 J/cm(2) but not in the 5, 30, and 50 J/cm(2) groups compared to controls. Normal surrounding tissue uptake of FITC-D following L-PDT was significantly enhanced in the 30 J/cm(2) and 50 J/cm(2) groups compared to controls. Altogether, the FITC-D tumor to normal tissue ratio was significantly higher in the 10 J/cm(2) group compared others. Tumor growth was significantly delayed in animals treated by 10 J/cm2-L-PDT combined to Lipoplatin(®) compared to controls. CONCLUSIONS: Fluence of L-PDT is critical for the optimal distribution and effect of subsequently administered chemotherapy. These findings have an importance for the clinical translation of the vascular L-PDT concept in the clinics. Lasers Surg. Med. 47:323-330, 2015.