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Light sources for PDT in dermatology
A14
Abstracts / Photodiagnosis and Photodynamic Therapy 17 (2017) A4–A78
Oral OA-026
PDT in dermatology
The synergistic antimicrobial activity of tetrapyrroles and PDT on antibiotic resistant clinical isolates of Staph. aureus
Oral ODe-027
N. Iluz 1,∗ , Y. Maor 2 , N. Keller 1 , Z. Malik 3 1
Clinical Microbiology, Sheba Medical Center, Tel Hashomer, Israel 2 Wolfson Medical Center, Sackler School of Medicine, Tel Aviv University, Israel 3 The Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel S. aureus is a major pathogen in clinical microbiology known to cause infections in various body sites and in many situation can be life threatening. Microbial resistance to first line antibiotic therapies such as Oxacillin, with reduced susceptibility to glycopeptides and the prevalence of Meticillin resistant Staph poses challenges in treating the pathogen. The antimicrobial effects of PDT have been a subject of studies for long time and may offer new strategies in treating resistant strains especially in body cavities such as sinuses and bladder. In our study we searched for a positive synergistic effect between tetra-pyrrole PDT, dark activity of Hemin combined with the antibiotics used to treat MRSA infections. The antimicrobial effects profile of Hematoporphyrin (HP), Deuteroporphyrin (DP) and Hemin exposed to light irradiation or dark conditions on both resistant and susceptible strains of S. aureus was determined; colony forming units per milliliter was calculated before and after different irradiation times and porphyrin concentrations. Electron Microscopy imaging revealed the major sites of damage. Minimal Inhibitory concentration of Oxacillin, Gentamycin, Vancomycin, Rifampin and Fusidic Acid showed a range of antimicrobial effects from clinical isolates on staph. With each strain the MIC value of the antibiotic was compared to the MIC of the antibiotics combined with pri-exposure of the strains to sub-inhibitory concentrations of HP or DP and irradiation. Screening for synergism of PDT and antibiotics of these strains revealed diverse susceptibility profiles. Synergistic effects were examined using 30 strains from fresh clinical isolates using the Checkerboard method. Hemin exhibited antimicrobial activities on some resistant strains in the dark. TEM imaging revealed damage of the cell genetic material arrangement and the appearance of mesosome like structures which designate strong oxidative stress on membranous targets. Screening results suggested no synergistic effect in combining PDT with Gentamycin, Vancomycin, Rifampin and Fusidic Acid. Positive synergistic effect was observed in PDT Oxacillin combination and confirmed by Checkerboard method. The effect was observed in all strains after 1 h of irradiation with small dosage of porphyrins 10 g/mL. Oxacillin MIC decreased below 2 g/mL in resistance strains under such conditions. The antimicrobial PDT activity of tetra-pyrroles and the dark activity of hemin show possible new therapeutic options in treating drug resistant S. aureus in body cavities accessible for irradiation such as sinuses and bladder in addition to coetaneous infections. http://dx.doi.org/10.1016/j.pdpdt.2017.01.032
Up-to-date PDT in dermatology A. Sidoroff Department of Dermatology, Venereology, and Allergology, Medical University of Innsbruck, Austria Photodynamic therapy (PDT) in dermatology looks back on a history that is more than a hundred years old. But only with the idea to use aminolevulinic acid (a precursor to the photosensitizing agent protoporphyrin IX) PDT started to make sense for the use in skin diseases, as systemic photosensitization could be avoided. The enthusiasm of a small number of research groups resulted in a large amount of data documenting the clinical efficacy and deep insight into the mechanisms of this treatment. All these data finally found interest in the pharmaceutical industry to conduct the necessary trials to make PDT a licensed therapy. At the time being, no other treatment modality against non-melanoma skin cancer (NMSC) is based on such a level of evidence (even according to randomized controlled trials (RCT) the gold standard of evidence based medicine (EBM)). And yet, in spite of trials, guidelines and clinical experience of the users, PDT is not a standard treatment in dermatology – the main reason being the fact that in general it is not reimbursed by insurance companies. The consequence is, that many patients that would profit from PDT have no access to it. Nevertheless – today clear guidelines and recommendations exist for the use of PDT with ALA or its methyl ester (MAL) for the treatment of actinic keratosis, superficial basal cell carcinoma and Bowen’s disease. Most of them concern “classical” topical PDT with an artificial light-source but now also for daylight-PDT that uses natural daylight as a lightsource is gaining more and more importance. With such a long evolution “up-to-date” PDT in dermatology is a combination of two major things: clinical data and personal experience. And one has to accept that the latter can never be replaced by theoretical information derived from publications. As with any procedure, it is the small details and the correct decisions that make the difference between an acceptable and a good treatment. http://dx.doi.org/10.1016/j.pdpdt.2017.01.033 Oral ODe-028 Light sources for PDT in dermatology T. Hommel ∗ , R.-M. Szeimies Department of Dermatology and Allergology, Klinikum Vest Academic Teaching Hospital Ruhr, University Bochum, D-45657 Recklinghausen, Germany Photodynamic therapy (PDT) has a long history in Medicine, especially in Dermatology. The easy access to skin surface and diseases situated at the superficial parts of the body made it easy to start even with sun exposure as presented by Jesionek and von Tappeiner in 1905 after repetitive application of eosine dye on epithelial skin cancer. Later light from coal bow arc lamps with collimating lenses have been utilized for illumination. Interestingly, the Nobel laureate Niels Ryberg Finsen used such lamps (Finsen lamp) for the treatment of cutaneous tuberculosis (lupus vulgaris) and recently researchers at the Bispebjerg Hospital in Copenhagen found out that the lenses used with his devices were made of simple glass and not of expensive quartz so that antibacterial activity based on PDT-effects on endogenous porphyrins in mycobacterium tuber-
Abstracts / Photodiagnosis and Photodynamic Therapy 17 (2017) A4–A78
culosis is actually the mode of action for his success on patients with lupus. After the long period with silent research in the field of PDT, the introduction of new drugs like hematoporphyrin-derivative again stimulated the use of PDT in dermatology. Thomas Dougherty used a xenon arc lamp for both surface and light fiber guided illumination of skin tumors. However, especially the introduction of photosensitizers with topical route of administration like 5-aminolevulinic acid (5-ALA) introduced by Kennedy and Pottier revolutionized the use of PDT in Dermatology. The selective accumulation of protoporphyrin IX in diseased tissue made it possible to treat a great variety of skin disorders, starting from localized skin cancer to large-field applications like in psoriasis vulgaris. Thus, the use of expensive laser-guided systems, equipped with microlenses like argon-ion pumped dye lasers was no longer necessary for the treatment of skin diseases, which made the treatment modality much cheaper in respect of costs for equipment and manpower. The first commercially available systems marketed together with a photosensitizer were then low pressure fluorescent lamps ® (Blu-U phototherapy unit, Dusa Pharmaceuticals, Wilmington, USA) emitting blue light at the Soret band in combination with 5® ® ALA (Levulan Kerastick ) for the treatment of actinic keratoses ® ® (AK). Later, the methyl ester of 5-ALA (MAL; Metvix , Metvixia , Galderma S.A., Lausanne, Switzerland) by Norwegian researchers (Peng, Moan, Warloe) was introduced with a red LED light source ® (Aktilite , Galderma) for the treatment of AK, Bowen’s disease and basal cell carcinoma. Due to the relatively low costs of these systems, PDT became relatively successful and is meanwhile a mainstay of treatment in the field of non-melanoma skin cancer worldwide. Over the years, a variety of other light sources have been investigated for the use in porphyrin based PDT in Dermatology. Since pain is a major side effect of cutaneous PDT, the use of pulsed laser systems matching one of the Q-bands of the porphyrin absorption spectrum have been successfully used. The relatively short pulses (<20 ms) do not alert the pain perception. Even longer pulses by the use of intense pulsed light sources frequently used for dermatological condition like removal of unwanted hair and wrinkle treatments or ectatic vessels were successful for pain reduction. However, again those devices are costly and application is not that easy especially when treating large areas. Therefore, the most recent developments in the field of light delivery for PDT in Dermatology were either dealing with sophis® ticated LED or OLED-devices (AKderm , Dermoscan, Regensburg, ® Germany; Ambulight , Ambicare Health, Livingston, Scotland) where light delivery is provided via direct contact of the light source to the sensitized skin area, or textile fabrics made from knitted optical fibers which are very flexible and able to cover easily curved surfaces. Those optical garments are for example able to cover a full scalp so that illumination of this curved surface can be done at once. Recent research projects run by Serge Mordon (INSERM, Lille, France) (Flexitheralight, PHOS-ISTOS) have proven that this technology is capable to treat successfully field cancerized areas of multiple AK at the scalp with PDT in one session. A very recent development which just hit the market is the use of natural daylight for PDT. MAL has received marketing authorization in July 2015 in combination with daylight and will be marketed soon for self-administration by the patient, followed by a 2 h light exposure to daylight immediately after application of the photosensitizer at home for the field-directed treatment of AK. http://dx.doi.org/10.1016/j.pdpdt.2017.01.034
A15
Oral ODe-029 Daylight PDT in the UK: An algorithm for accurate dosimetry, and when and where can we do it? P. O’Mahoney 1,∗ , K. Timmins 2 , M. Khazova 3 , M. Higlett 3 , T. Lister 4 , S. Ibbotson 1,5 , E. Eadie 5 1
University of Dundee, Dundee, UK University of St. Andrews, St. Andrews, UK 3 Public Health England, Didcot, UK 4 Salisbury NHS, Salisbury, UK 5 Photobiology Unit, NHS Tayside, Dundee, UK 2
Daylight photodynamic therapy (dPDT) is a convenient, virtually pain-free treatment for superficial pre-cancerous lesions (actinic keratosis; AK) [1]. Treatment efficacy is dependent on the patient receiving a minimum PpIX-weighted effective dose from visible wavelengths in daylight [2,3], which will be affected by weather conditions and a number of atmospheric factors. To quantify effective light dose, a method of conveniently and accurately measuring personal daylight exposure is required. There may then exist a need to convert this measurement to effective dose, if direct measurement of PpIX-effective irradiance is not possible. The conversion must consider multiple factors such as spectral changes in daylight, time of day and year, and location. As most centres who offer dPDT do not undertake daylight dosimetry, there is a need to understand the optimal times of the year and conditions in which to carry out dPDT in order to be able to offer guidance and confidence to dPDT practitioners. At the Photobiology Unit in Dundee, we accurately calibrate cheap, personal light meters, which are given to patients during dPDT, enabling the incident light, measured in illuminance, to be determined. Our work highlights the importance of calibration in a range of weather conditions, e.g. whether it is sunny, and if there is mild or heavy cloud cover, in order to obtain the most reliable readings. An algorithm, based on spectral irradiance measurements from sites in the UK, can then convert daylight illuminance to PpIXweighted light dose. To enable this conversion, knowledge of the illuminance recorded during treatment and the duration, date, time and location of treatment are required. This method is verified against true light dose values derived from measured spectral irradiance, and is found to give accurate values with a precision of ±6.8%. Applying the above analysis to historic illuminance data from several sites across the UK paints a picture of PpIX-weighted light dose, and gives an indication of when viable treatment can be expected. These data can be used as guidance for other clinics considering dPDT as a treatment option. Through this work we have gained a deeper understanding of the dosimetry associated with dPDT and we are now able to accurately calculate the light dose that a patient receives during treatment. References [1] S.R. Wiegell, et al., Br. J. Dermatol. 158 (2008) 740–746. [2] S.R. Wiegell, et al., J. Eur. Acad. Dermatol. Venereol. 26 (2012) 673–679. [3] S.M. O’Gorman, et al., JAMA Dermatol. (2016) 1–7.
http://dx.doi.org/10.1016/j.pdpdt.2017.01.035
Abstracts / Photodiagnosis and Photodynamic Therapy 17 (2017) A4–A78
Oral OA-026
PDT in dermatology
The synergistic antimicrobial activity of tetrapyrroles and PDT on antibiotic resistant clinical isolates of Staph. aureus
Oral ODe-027
N. Iluz 1,∗ , Y. Maor 2 , N. Keller 1 , Z. Malik 3 1
Clinical Microbiology, Sheba Medical Center, Tel Hashomer, Israel 2 Wolfson Medical Center, Sackler School of Medicine, Tel Aviv University, Israel 3 The Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel S. aureus is a major pathogen in clinical microbiology known to cause infections in various body sites and in many situation can be life threatening. Microbial resistance to first line antibiotic therapies such as Oxacillin, with reduced susceptibility to glycopeptides and the prevalence of Meticillin resistant Staph poses challenges in treating the pathogen. The antimicrobial effects of PDT have been a subject of studies for long time and may offer new strategies in treating resistant strains especially in body cavities such as sinuses and bladder. In our study we searched for a positive synergistic effect between tetra-pyrrole PDT, dark activity of Hemin combined with the antibiotics used to treat MRSA infections. The antimicrobial effects profile of Hematoporphyrin (HP), Deuteroporphyrin (DP) and Hemin exposed to light irradiation or dark conditions on both resistant and susceptible strains of S. aureus was determined; colony forming units per milliliter was calculated before and after different irradiation times and porphyrin concentrations. Electron Microscopy imaging revealed the major sites of damage. Minimal Inhibitory concentration of Oxacillin, Gentamycin, Vancomycin, Rifampin and Fusidic Acid showed a range of antimicrobial effects from clinical isolates on staph. With each strain the MIC value of the antibiotic was compared to the MIC of the antibiotics combined with pri-exposure of the strains to sub-inhibitory concentrations of HP or DP and irradiation. Screening for synergism of PDT and antibiotics of these strains revealed diverse susceptibility profiles. Synergistic effects were examined using 30 strains from fresh clinical isolates using the Checkerboard method. Hemin exhibited antimicrobial activities on some resistant strains in the dark. TEM imaging revealed damage of the cell genetic material arrangement and the appearance of mesosome like structures which designate strong oxidative stress on membranous targets. Screening results suggested no synergistic effect in combining PDT with Gentamycin, Vancomycin, Rifampin and Fusidic Acid. Positive synergistic effect was observed in PDT Oxacillin combination and confirmed by Checkerboard method. The effect was observed in all strains after 1 h of irradiation with small dosage of porphyrins 10 g/mL. Oxacillin MIC decreased below 2 g/mL in resistance strains under such conditions. The antimicrobial PDT activity of tetra-pyrroles and the dark activity of hemin show possible new therapeutic options in treating drug resistant S. aureus in body cavities accessible for irradiation such as sinuses and bladder in addition to coetaneous infections. http://dx.doi.org/10.1016/j.pdpdt.2017.01.032
Up-to-date PDT in dermatology A. Sidoroff Department of Dermatology, Venereology, and Allergology, Medical University of Innsbruck, Austria Photodynamic therapy (PDT) in dermatology looks back on a history that is more than a hundred years old. But only with the idea to use aminolevulinic acid (a precursor to the photosensitizing agent protoporphyrin IX) PDT started to make sense for the use in skin diseases, as systemic photosensitization could be avoided. The enthusiasm of a small number of research groups resulted in a large amount of data documenting the clinical efficacy and deep insight into the mechanisms of this treatment. All these data finally found interest in the pharmaceutical industry to conduct the necessary trials to make PDT a licensed therapy. At the time being, no other treatment modality against non-melanoma skin cancer (NMSC) is based on such a level of evidence (even according to randomized controlled trials (RCT) the gold standard of evidence based medicine (EBM)). And yet, in spite of trials, guidelines and clinical experience of the users, PDT is not a standard treatment in dermatology – the main reason being the fact that in general it is not reimbursed by insurance companies. The consequence is, that many patients that would profit from PDT have no access to it. Nevertheless – today clear guidelines and recommendations exist for the use of PDT with ALA or its methyl ester (MAL) for the treatment of actinic keratosis, superficial basal cell carcinoma and Bowen’s disease. Most of them concern “classical” topical PDT with an artificial light-source but now also for daylight-PDT that uses natural daylight as a lightsource is gaining more and more importance. With such a long evolution “up-to-date” PDT in dermatology is a combination of two major things: clinical data and personal experience. And one has to accept that the latter can never be replaced by theoretical information derived from publications. As with any procedure, it is the small details and the correct decisions that make the difference between an acceptable and a good treatment. http://dx.doi.org/10.1016/j.pdpdt.2017.01.033 Oral ODe-028 Light sources for PDT in dermatology T. Hommel ∗ , R.-M. Szeimies Department of Dermatology and Allergology, Klinikum Vest Academic Teaching Hospital Ruhr, University Bochum, D-45657 Recklinghausen, Germany Photodynamic therapy (PDT) has a long history in Medicine, especially in Dermatology. The easy access to skin surface and diseases situated at the superficial parts of the body made it easy to start even with sun exposure as presented by Jesionek and von Tappeiner in 1905 after repetitive application of eosine dye on epithelial skin cancer. Later light from coal bow arc lamps with collimating lenses have been utilized for illumination. Interestingly, the Nobel laureate Niels Ryberg Finsen used such lamps (Finsen lamp) for the treatment of cutaneous tuberculosis (lupus vulgaris) and recently researchers at the Bispebjerg Hospital in Copenhagen found out that the lenses used with his devices were made of simple glass and not of expensive quartz so that antibacterial activity based on PDT-effects on endogenous porphyrins in mycobacterium tuber-
Abstracts / Photodiagnosis and Photodynamic Therapy 17 (2017) A4–A78
culosis is actually the mode of action for his success on patients with lupus. After the long period with silent research in the field of PDT, the introduction of new drugs like hematoporphyrin-derivative again stimulated the use of PDT in dermatology. Thomas Dougherty used a xenon arc lamp for both surface and light fiber guided illumination of skin tumors. However, especially the introduction of photosensitizers with topical route of administration like 5-aminolevulinic acid (5-ALA) introduced by Kennedy and Pottier revolutionized the use of PDT in Dermatology. The selective accumulation of protoporphyrin IX in diseased tissue made it possible to treat a great variety of skin disorders, starting from localized skin cancer to large-field applications like in psoriasis vulgaris. Thus, the use of expensive laser-guided systems, equipped with microlenses like argon-ion pumped dye lasers was no longer necessary for the treatment of skin diseases, which made the treatment modality much cheaper in respect of costs for equipment and manpower. The first commercially available systems marketed together with a photosensitizer were then low pressure fluorescent lamps ® (Blu-U phototherapy unit, Dusa Pharmaceuticals, Wilmington, USA) emitting blue light at the Soret band in combination with 5® ® ALA (Levulan Kerastick ) for the treatment of actinic keratoses ® ® (AK). Later, the methyl ester of 5-ALA (MAL; Metvix , Metvixia , Galderma S.A., Lausanne, Switzerland) by Norwegian researchers (Peng, Moan, Warloe) was introduced with a red LED light source ® (Aktilite , Galderma) for the treatment of AK, Bowen’s disease and basal cell carcinoma. Due to the relatively low costs of these systems, PDT became relatively successful and is meanwhile a mainstay of treatment in the field of non-melanoma skin cancer worldwide. Over the years, a variety of other light sources have been investigated for the use in porphyrin based PDT in Dermatology. Since pain is a major side effect of cutaneous PDT, the use of pulsed laser systems matching one of the Q-bands of the porphyrin absorption spectrum have been successfully used. The relatively short pulses (<20 ms) do not alert the pain perception. Even longer pulses by the use of intense pulsed light sources frequently used for dermatological condition like removal of unwanted hair and wrinkle treatments or ectatic vessels were successful for pain reduction. However, again those devices are costly and application is not that easy especially when treating large areas. Therefore, the most recent developments in the field of light delivery for PDT in Dermatology were either dealing with sophis® ticated LED or OLED-devices (AKderm , Dermoscan, Regensburg, ® Germany; Ambulight , Ambicare Health, Livingston, Scotland) where light delivery is provided via direct contact of the light source to the sensitized skin area, or textile fabrics made from knitted optical fibers which are very flexible and able to cover easily curved surfaces. Those optical garments are for example able to cover a full scalp so that illumination of this curved surface can be done at once. Recent research projects run by Serge Mordon (INSERM, Lille, France) (Flexitheralight, PHOS-ISTOS) have proven that this technology is capable to treat successfully field cancerized areas of multiple AK at the scalp with PDT in one session. A very recent development which just hit the market is the use of natural daylight for PDT. MAL has received marketing authorization in July 2015 in combination with daylight and will be marketed soon for self-administration by the patient, followed by a 2 h light exposure to daylight immediately after application of the photosensitizer at home for the field-directed treatment of AK. http://dx.doi.org/10.1016/j.pdpdt.2017.01.034
A15
Oral ODe-029 Daylight PDT in the UK: An algorithm for accurate dosimetry, and when and where can we do it? P. O’Mahoney 1,∗ , K. Timmins 2 , M. Khazova 3 , M. Higlett 3 , T. Lister 4 , S. Ibbotson 1,5 , E. Eadie 5 1
University of Dundee, Dundee, UK University of St. Andrews, St. Andrews, UK 3 Public Health England, Didcot, UK 4 Salisbury NHS, Salisbury, UK 5 Photobiology Unit, NHS Tayside, Dundee, UK 2
Daylight photodynamic therapy (dPDT) is a convenient, virtually pain-free treatment for superficial pre-cancerous lesions (actinic keratosis; AK) [1]. Treatment efficacy is dependent on the patient receiving a minimum PpIX-weighted effective dose from visible wavelengths in daylight [2,3], which will be affected by weather conditions and a number of atmospheric factors. To quantify effective light dose, a method of conveniently and accurately measuring personal daylight exposure is required. There may then exist a need to convert this measurement to effective dose, if direct measurement of PpIX-effective irradiance is not possible. The conversion must consider multiple factors such as spectral changes in daylight, time of day and year, and location. As most centres who offer dPDT do not undertake daylight dosimetry, there is a need to understand the optimal times of the year and conditions in which to carry out dPDT in order to be able to offer guidance and confidence to dPDT practitioners. At the Photobiology Unit in Dundee, we accurately calibrate cheap, personal light meters, which are given to patients during dPDT, enabling the incident light, measured in illuminance, to be determined. Our work highlights the importance of calibration in a range of weather conditions, e.g. whether it is sunny, and if there is mild or heavy cloud cover, in order to obtain the most reliable readings. An algorithm, based on spectral irradiance measurements from sites in the UK, can then convert daylight illuminance to PpIXweighted light dose. To enable this conversion, knowledge of the illuminance recorded during treatment and the duration, date, time and location of treatment are required. This method is verified against true light dose values derived from measured spectral irradiance, and is found to give accurate values with a precision of ±6.8%. Applying the above analysis to historic illuminance data from several sites across the UK paints a picture of PpIX-weighted light dose, and gives an indication of when viable treatment can be expected. These data can be used as guidance for other clinics considering dPDT as a treatment option. Through this work we have gained a deeper understanding of the dosimetry associated with dPDT and we are now able to accurately calculate the light dose that a patient receives during treatment. References [1] S.R. Wiegell, et al., Br. J. Dermatol. 158 (2008) 740–746. [2] S.R. Wiegell, et al., J. Eur. Acad. Dermatol. Venereol. 26 (2012) 673–679. [3] S.M. O’Gorman, et al., JAMA Dermatol. (2016) 1–7.
http://dx.doi.org/10.1016/j.pdpdt.2017.01.035