Where is PDT observed all year round?

Photodynamic therapy represents a new minimally invasive therapy method. It uses the principle of semi-selective, light-induced tissue destruction while maintaining the anatomical and physiological integrity. For this purpose, a photosensitizing substance is administered prior to therapy, the concentration of which accumulates in malignant transformed tissue in a higher concentration than in normal tissue. The subsequent light irradiation leads to cell death via oxygen radicals. Photodynamic therapy is currently used in various specialist areas for palliative and curative tumor therapy. Due to the limited depth of penetration of the therapeutic light, the future of the method lies in the curative therapy of early malignant tissue changes in the skin and the hollow organs that are accessible endoscopically. In addition, a new area of ​​application can open up for photodynamic therapy in the field of non-oncological disease patterns.

Keywords: photodynamic therapy, photosensitizer, laser

Photodynamic Therapy
Photodynamic therapy represents a new minimally invasive therapeutic modality. This treatment takes advantage of the principle of semiselective, light-induced tissue destruction while maintaining the anatomic and physiologic integrity. For this purpose a photosensitizing substance is administered which accumulates in malignantly transformed tissue in a higher concentration than in normal tissue. The following light irradiation causes cell death by means of oxygen radicals. For the time photodynamic therapy is applied in various specialties for palliative and curative tumor treatment. Due to the limited penetration depth of the therapeutic light the future of the method will concentrate on the curative therapy of early malignant tissue alterations of the skin and the hollow organs within endoscopical reach. Furthermore, photodynamic therapy will open a new field of application in the area of ​​non-oncologic diseases.

Key words: photodynamic therapy, photosensitizer, laser

The term “photodynamic effect” was first introduced in 1904 by Hermann von Tappeiner, then director of the pharmacological institute of the University of Munich. He defined it as a “light-induced reaction in biological systems involving oxygen”. After basic research with different dyes, he recognized the high therapeutic potential back then. The method was revived around 1960 and consistently brought up to date through the development of new substances and light sources (5, 11, 38).
Photodynamic effect
The basic principle of the photodynamic effect is based on the tumor-selective accumulation of light-sensitive substances, so-called photosensitizers, after usually intravenous administration (Figure 1). The reasons for this preferred accumulation are complex and conditioned by the tumor-specific morphology and its receptor-specific properties.
At the cellular level, the photodynamic effect unfolds through the absorption of light. It leads to excited energy states of the sensitizer. The relaxation to a metastable intermediate level is the starting point for an energy transfer to molecular oxygen, which is thereby converted into singlet oxygen (type 2 reaction). These radicals are able to destroy vital structures such as cell membranes through photo-oxidation (Figure 2). In addition to the cellular damage, a breakdown in tumor vascularization occurs just a few minutes after exposure to light. The interaction of both effects is suitable for destroying the tumor. A known side effect is the skin's transient sensitivity to light, which can last for up to several weeks.
The photodynamic method is a form of therapy that is currently preferred for the local treatment of flat, superficial carcinomas on the skin or in hollow organs accessible endoscopically. The extent of the necrosis is determined by the depth of penetration of the light, which, depending on the substance, lies in the red spectral range.
The most common photosensitizers and their absorption wavelengths are listed in Table 1. All of these substances are currently in clinical studies and are on the way to industrial implementation.
The efficiency of the photodynamic effect is determined not only by the phototherapeutic potential of the sensitizer but also by the quality of the light application systems. Lamp systems and diode lasers are used as powerful light sources in the red spectral range. They are suitable to provide non-thermal power densities of 100 to 200 mW / cm². Glass fiber-supported light applicators are designed depending on the geometry of the organ to be irradiated. A homogeneous illumination of circular surfaces is achieved by fiber-coupled microlenses. Cylinder emitters are used for tubular organs (for example in the bronchial and gastrointestinal areas). Spherical hollow organs, such as the urinary bladder, can be illuminated largely homogeneously by spherical radiators. On the way to the further clinical dissemination of the method, an application set consisting of a light source, emitter and photosensitizer will be available in the future, which will enable each specialist area to carry out this minimally invasive form of therapy safely and easily according to the specific requirements.
Clinical application
Even though there are reports on more than 500 documented photodynamic therapies (PDT) for gastrointestinal tumors in the specialist literature and the method is approved by the American health authority (FDA) for the palliative therapy of gastrointestinal tumors, PDT is still an experimental therapeutic method in gastroenterology It should therefore only be carried out in designated centers under study conditions. The use of PDT is currently primarily focused on the destruction of early carcinomas limited to the mucosa or premalignant changes in the esophagus. In these situations, radical resection of the esophagus is currently the treatment method of choice. The method-related relatively high morbidity and mortality of surgical resection and the drastic increase in adenocarcinoma at the esophago-cardiac junction (beret carcinoma) explain the search for less invasive local therapy methods with a curative approach. Here, endoscopic mucosal resection (EMR) competes with PDT (8, 9). The largest study published to date on PDT in Barrett's carcinoma or severe dysplasia (HGD) was able to demonstrate complete treatment success in over 80 percent of 100 treated patients. However, due to the porphyrin derivatives used as photosensitizers in this study, stenoses or strictures requiring treatment were observed in around 30 percent of the patients treated after PDT (33). In our own patient collective, which now includes more than 150 patients with Barrett's carcinoma, HGD or severe dysplasia, 5-aminolevulinic acid (ALA) is primarily used as a precursor of an endogenous photosensitizer (protoporphyrin IX). The high mucosal specificity of ALA induces a sole ablation of the mucosa without destroying deeper wall layers. Post-therapeutic stenoses as well as phototoxic reactions of the skin have not been observed so far. In a first published series in 32 patients, a complete remission was achieved in all patients with HGD and those with Barrett's carcinoma and a tumor thickness of less than 2 mm. With tissue layers of more than 2 mm, complete remission could not be achieved with this procedure (7). To irradiate the esophagus, irradiation applicators are used, which induce homogeneous tissue irradiation in a therapy session with a length of 2 to 8 cm, depending on the laser power (8).
In comparison to Barrett's carcinoma, there are only two reports on PDT in early squamous cell carcinoma or HGD of the squamous epithelium of the esophagus on 24 and 29 patients, respectively (17, 35). As in the treatment of Barrett's early lesions, the authors' working group used 5-aminolevulinic acid and was able to achieve a complete remission in all patients with squamous cell HGD without any relevant side effects (Figure 1 a – c). In contrast, with ALA this was only possible in 50 percent of carcinoma cases. In contrast, the working group in Lausanne achieved local tumor-free status in 84 percent of all carcinoma patients using protoporphyrin derivatives or chlorins. However, one third of the patients had relevant complications that required treatment.
The use of PDT for endoscopically difficult to approach early gastric cancer, in which endoscopic mucosal resection (EMR) cannot be carried out or only incompletely for technical and anatomical reasons, also appears to be very promising. Here, the use of a more effective chlorin photosensitizer has proven itself in our own patient collective. Without relevant morbidity, a complete remission was achieved in 80 percent of all early cancers, and if criteria were favorable according to the Japanese classification even in 100 percent of all cases (7). Especially when treating small, non-localizable premalignant or malignant lesions (so-called biopsy carcinomas), PDT allows large-area homogeneous irradiation and is fundamentally different from EMR and thermoablative procedures.
With regard to palliative therapy using PDT, investigations are available for inoperable large-volume esophageal carcinomas that are partially
aspects show that the method is superior to conventional laser therapy (29). For methodological reasons (limited penetration depth of the therapeutic laser light in PDT) and in view of the good and economical therapy alternatives (conventional laser therapy, self-expanding metal endoprostheses), PDT is unlikely to play an essential role in the future in the palliative treatment of stenosing inoperable tumors of the upper and lower gastrointestinal tract. A potentially sensible palliative indication could arise for PDT in stenosing bile duct carcinoma. An initial report to patients with advanced cholangiocellular carcinoma who could no longer be treated surgically or conventionally endoscopically reported a drastic decrease in laboratory parameters after PDT with a subsequent improvement in quality of life. The 30-day mortality was zero and the median survival was 440 days (32). If these results are confirmed in controlled prospective studies, PDT would represent a serious improvement in the palliative treatment of inoperable bile duct carcinomas.
In pulmonology, PDT is used for the selective endoscopic treatment of bronchial carcinoma with both palliative and curative objectives.
Porphyrin derivatives (Photofrin) are used as sensitizers; after being approved in Japan, they have also been approved for clinical use in the USA and various European countries since the beginning of 1998 (34). Photofrin is administered intravenously at a dose of 2 mg / kg body weight. 48 hours later, the tumor is irradiated with an absorbed dose of 200 J / cm2 tumor surface or 200 J / cm tumor length. The output power is 100 to 150 mW, the irradiation time about eight minutes. A flexible plastic fiber with a diameter of 1 mm is used as the light guide. The irradiation can take place superficially or interstitially, that is, by piercing the irradiation probe into the tumor. The bronchoscopy can be performed with flexible instruments under local anesthesia and light sedation.
The palliative use of PDT aims to widen or remove tumor-related stenoses or occlusions of the central airways in patients with dyspnoea, retention pneumonia and respiratory insufficiency. Studies have shown a slightly longer lasting recanalization effect after PDT compared to the Nd-YAG laser (40). However, due to the delayed rejection of the necrotic tumor tissue, this effect only occurs after days; the necrotic tissue must be removed mechanically by a second bronchoscopy. PDT is therefore not suitable for the treatment of emergencies and is unlikely to establish itself in routine clinical practice because of the long-term skin sensitization in patients whose prognosis is usually only a few months.
The clinical focus of PDT is the curative treatment of so-called early endobronchial carcinoma. PDT is indicated for patients with carcinoma in situ and those who have a high operational risk functionally or who are inoperable for functional or technical reasons. The prerequisite for curative treatment is that the tumor growth in the area is limited to a few square centimeters and the bronchial wall is only a few millimeters deep infiltrated. The clinical criterion is that the tumor growth is not (yet) manifested radiologically / computed tomography. Recently, autofluorescence bronchoscopy and endosonography can be used to detect the extent of the area and to determine the depth of infiltration.
PDT of early cancer with curative intent initially leads to complete remissions of 80 to 90 percent after PDT and 50 to 70 percent in the long term (13, 20, 27). PDT is the only endobronchial treatment form proven by studies with curative results that come close to the operative treatment results (Figure 2 a-d). Its superiority over other endobronchial therapy methods, such as Nd-Yag laser, electrocoagulation, cryotherapy and endobronchial brachytherapy, is primarily due to its tumor selectivity. In addition, as a result of the thin irradiation probe, tumor localizations down to the subsegments can also be reached, while the range of the other methods mentioned is limited to the area of ​​lobe bronchi.
Contraindications to photodynamic therapy are rare. Edema formation can occasionally occur immediately after treatment. PDT should therefore not be used in the area of ​​the trachea or in singular airways in a condition after pneumonectomy. Two to three days after irradiation, fibrin deposits appear, which can be removed as part of a control bronchoscopy. Scarred stenoses are rare complications, which are mainly observed after higher radiation doses or after repeated radiation treatments.
The treatment of early tumor stages is also the domain of PDT in urology. PDT can be considered established for the treatment of otherwise refractory or recurrent superficial and multifocal urothelial carcinomas of the urinary bladder and multifocal carcinoma in situ of the urinary bladder. In selected cases, it even represents an alternative to radical cystectomy. In previous studies, in treatment-refractory carcinoma in situ after PDT, a sustained remission was observed in around 60 percent, at least temporarily, and in over 30 percent, which in view of the selected patient population is a high one Shows the effectiveness of PDT (3, 4, 23, 31). In a prospective randomized study, patients received adjuvant PDT after transurethral resection of bladder tumors. It was found that the average time to recurrence after PDT was 394 days, which was significantly longer than in the non-adjuvant control group with 94 days (6).
In the future, the assessment of PDT in the urology department will be based more on the comparison of side effects, the frequency of repeat treatments and the cost factor.
PDT with 5-aminolevulinic acid (ALA) instilled into the bladder is an interesting prospect (30, personal communication from Dr. Jichlinski, Urological Clinic, University of Lausanne). A major advantage of this
This “topical” PDT is based on the fact that the local application of the photosensitizer prevents systemic effects (for example photosensitization of the skin). Another future aspect is the interstitial PDT of solid organ tumors, particularly the prostate. Interstitial PDT results in a type of thermal hemorrhagic necrosis. Damage to the urethra, as occurs with transurethral laser treatment of benign prostatic hyperplasia, could not be determined (28).
Ear, nose and throat medicine
The main area of ​​application of PDT in ENT medicine is also the treatment of early and superficial squamous cell carcinomas of the mucosa of the upper aerodigestive tract. These tumors are predominantly of exogenous origin (alcohol and / or tobacco abuse) and therefore tend to multiply or become cancerous in the sense of a so-called field cancerization flat appearance. In the latter cases, surgical therapy often causes considerable functional and possibly also aesthetic impairment.This is because a complete resection of the tumor or multiple tumors often involves extensive surgery with the necessity of a consecutive reconstruction using a near or far flap. For such cases, PDT offers itself as a therapy option. A decisive advantage of PDT is certainly that previous or planned therapeutic measures such as surgery, radiation therapy and / or chemotherapy do not represent any restriction. The effectiveness of PDT in early cancers of the oral cavity, pharynx, and larynx has been demonstrated in several clinical studies (Table 1) (2, 10, 12, 14, 18, 19, 25, 36, 39, 41). A special indication are laryngeal carcinomas that have grown over a large area (so-called wallpaper carcinomas), which occasionally cannot be surgically treated with partial resection procedures that preserve the larynx, but only with a laryngectomy, which is significant for the loss of voice.
As a rule, photosensitizers of the first generation (hematoporphyrin derivatives) are used for PDT by means of intravenous administration. There is little clinical experience with the newer photosensitizers, including topical mucosal application, so that the value of these therapeutic modalities still needs to be evaluated (21).
More extensive tumors, i.e. tumors with greater depth of infiltration or higher volume, are only accessible to a curative PDT to a limited extent due to the limited penetration depth of the laser light that initiates the photoreaction (2). Future developments are aimed at newer laser applicators with the possibility of homogeneous light distribution and improved dosimetry. Tong et al. were able to achieve impressive, sometimes longer-lasting remissions in recurrent nasopharyngeal carcinomas (24). The use of PDT as a palliative therapy method is nevertheless controversial with reference to the impairment of quality of life due to the need for light protection measures. Encouraging pilot results on the use of PDT as an adjuvant therapy measure after surgical treatment of extensive primary tumors or cervical lymph node metastases (2), however, open prospects for further studies. This particularly applies to patients with a high risk of recurrence, as appears to be the case, for example, with marginal resection or growth of cervical lymph node metastases beyond the capsule.
In adenoid cystic carcinomas, mucosal melanomas, and AIDS-associated Kaposi's sarcomas, PDT has been used with good success in some cases (14). In HPV-associated laryngeal papillomatosis, PDT seems to lengthen the intervals between therapy sessions (10). A final assessment of this disease, which has been recurring over many years - triggered by the persistence of human papillomaviruses - is currently not possible, even if there have been isolated reports that there has been no recurrence in mostly relatively short observation periods.
In dermatology, the above-described mode of action of PDT results in a wide range of indications both with regard to effective cell destruction in the context of oncology (24) and with regard to the induction of immunomodulatory effects in inflammatory dermatoses.
From an oncological point of view, systemic PDT with porphyrin derivatives is only used for large or multiple basal cell carcinomas or initial spinocellular carcinomas in patients who can no longer be operated on or with other methods in the case of changes that can no longer be treated due to the long-lasting generalized photosensitization. Here, too, 24 to 48 hours after intravenous injection of 2 mg / kg body weight Photofrin, irradiation with red light (intensity 100 to 150 mW / cm², light dose 100 to 150 J / cm²) takes place. Post-therapeutic necrosis in the treatment area is restricted to the tumor and heals with almost no scarring in the course of the treatment (37).
Cutaneous Kaposi's sarcomas or skin metastases of colorectal carcinomas can also be effectively treated with Photofrin after systemic sensitization. More promising in this indication, however, is indocyanine green (ICG), a dye that has been approved for diagnostic purposes since the 1950s. The lack of cutaneous photosensitization of the patient is an advantage due to the rapid elimination. Since ICG absorbs in the near infrared, the irradiation takes place with a diode laser at 805 nm, which enables an increased depth of penetration into the tissue (1).
On the other hand, topical PDT with ALA or one of its derivatives (ester compounds) will probably be approved as a therapeutic method in dermatology this year (ALA-PDT) for the treatment of actinic keratoses in the USA. The clear advantages of topical PDT with ALA such as the lack of invasiveness and carcinogenicity of the procedure as well as the excellent cosmetic results
These have meanwhile been proven in numerous studies (26). Based on the studies available to date on over 10,000 patients with superficial skin tumors, in our opinion, only actinic keratoses, Bowen's disease and superficial basal cell carcinomas (smaller than 2 to 3 mm) are indications for curative PDT as part of a single treatment (100 to 150 mW) / cm²; 100 to 150 J / cm²) after topically applied ALA (20 percent preparation, occlusive for 4 to 6 h). An incoherent light source is also suitable for irradiation without loss of therapeutic effectiveness. The only known side effect of ALA-PDT is the sunburn-like pain that occurs during the illumination (37).
Summary and Outlook
PDT with its principle of semi-selective, light-induced tissue destruction while maintaining anatomical and physiological integrity is a fascinating minimally invasive therapy concept. However, this status report makes it clear from the individual sub-areas that PDT is currently (still) of a scientific-experimental nature and can only be used clinically in patients after careful examination and comparison with the current therapeutic standards.
In the future, the remaining methodological problems (e.g. photosensitizers, dosimetry, tissue interaction, application techniques in hollow organs) must be solved, and the procedure should be standardized and economized on a sub-area basis. Furthermore, a critical clinical examination in the sense of controlled studies under valid quality standards (Good Clinical Practice, GCP) is required.
The future of PDT clearly lies in the local therapy of early malignant lesions and not in palliative treatment. This future perspective complements well with the general tendency to detect malignant lesions earlier through better knowledge of risk groups. This also applies to other specialties, such as gynecology, ophthalmology and even neurosurgery.
A completely new field may open up for PDT in the area of ​​non-oncological disease patterns in the next few years. After the immunomodulatory and antibacterial effects of PDT have also been shown in experimental studies, areas of application are opening up in rheumatological diseases, dermatological clinical pictures such as psoriasis vulgaris, ophthalmological issues (e.g. macular degeneration) and even in targeted localized or systemic infection control. Even the therapeutic use of PDT for stenosing vascular diseases is currently being tested experimentally (22).

How this article is cited:
Dt Ärztebl 2000; 97: A 3337-3343 [Issue 49]

The numbers in brackets refer to the bibliography, which is available from the author in an offprint and on the Internet (www.aerzteblatt.de).

Address for the authors:
Prof. Dr. med. Christian Ell
Internal Medicine Clinic II
Dr. Horst Schmidt Clinics
Clinic of the state capital Wiesbaden
Ludwig-Erhard-Strasse 100
65199 Wiesbaden
Email: [email protected]

1 Clinic for Internal Medicine II, (Director: Prof. Dr. med.
Christian Ell), Dr. Horst Schmidt Clinics, Wiesbaden
2 Laser research laboratory (Director: Prof. Dr. med. Alfons Hofstetter) of the Urological Clinic of the Ludwig Maximilians University, Munich
3 Lung Clinic (Director: Prof. Dr. med. Karl Häußinger) of the LVA Upper Bavaria
4 Clinic and Polyclinic for ENT (Director: Prof. Dr. med. Heiner Iro) of the University Clinic Erlangen-Nuremberg
5 Clinic and Polyclinic for Urology (Director: Prof. Dr. med. Dieter Jocham) of the Medical University of Lübeck
6 Clinic and Polyclinic for Dermatology, (Director: Prof.
Dr. med. Michael Landthaler) Clinic of the University of Regensburg

Potential indications for photodynamic therapy in ENT medicine
- Superficial mucosal carcinomas and precancerous changes in the upper aerodigestive tract, especially with extensive tumor growth
- Superficial skin tumors on the face
- Adjuvant therapy after surgical and / or radiotherapy treatment of advanced or relapsed carcinomas
- Adenoid cystic carcinomas, especially in the case of relapses or residues after surgical therapy
- AIDS-associated Kaposi's sarcomas of the oropharyngeal mucosa
- Malignant melanoma of the mucous membrane of the upper aerodigestive tract
- Laryngeal papillomatosis (to extend the therapy intervals)

Principle of photodynamic diagnosis and therapy. After selective enrichment of the photosensitizer (S), fluorescence emission can be observed after excitation with violet light. This makes it possible to find tumors that are difficult to identify. The phototoxic effect with tissue necrosis unfolds after exposure to red light.

Energy level diagram of a sensitizer with energy transfer to molecular oxygen.

Table 1
Photosensitizers currently in use
Substance absorption wavelength (nm)
Porphyrin derivative (Photofrin) 630
5-ALA induced protoporphyrin IX 635
Chlorin (Foscan) 652
Purpurin (Purlytin) 665
Phthalocyanine (Zn-Pc) 675
Benzoporphyrin derivative (verteporfin) 695
Texaphyrin (Antrin) 730
Indocyanine Green (ICG Pulsion) 805
ALA, 5-aminolevulinic acid

Figure 1: Multifocal early squamous cell carcinoma a) before PDT, b) after vital staining with Lugol's solution, c) after PDT complete remission.

´Table 2
Photodynamic therapy of early cancers of the upper aerodigestive tract
Study Year Number of Tumor Location T- Photo- Dosage CR PR NR
Patient categories sensitizer (mg / kg)%%%
Keller et al. (19) 1985 3 oral cavity T1-2 Photofrin 1.5-2 100 0 0
Grossweiner et al. (20) 1987 9 oral cavity and pharynx "Früh- Photofrin 2 89 11 0
carcinomas "
Wenig et al. (21) 1990 26 recurrences of various T1 Photofrin 2 77 23 0
Freche et al. (22) 1990 32 Glottis T1 Photofrin 2 78 22 0
HpD 3
Schweitzer (23) 1990 6 Oral cavity and larynx T1 Photofrin 2 83 17 0
Gluckman (24) 1991 13 oral cavity T1 Photofrin 2 85 15 0
2 Larynx T1 Photofrin 2 100 0 0
8 Field cancerization Tis Photofrin 2 87.5 12.5 0
Feyh et al. (25) 1993 8 oral cavity, Tis, T1 Photosan 2 87.5 12.5 0
12 Oropharynx Tis, T1 – T2 III 2 92 8 0
Larynx Photosan
Grant et al. (26) 1994 12 oral cavity T1 Photofrin 2 92 8 0
Zhao et al. (27) 1986 50 Lippe - HpD - 100 0 0
Biel (28) 1998 34 Oral cavity, nose, Tis, T1–3 Photofrin 2 100 0 0
33 Larynx Tis, T1-4 Photofrin 2 94 6 0
Total 248 90.6 9.4 0
modified and supplemented from Biel 1998 (28); Release included until 1998
CR, complete remission; PR, partial remission; NR, no remission or progression; HpD, hematoporphyrin derivative; Tis, tumor in situ

Figure 2: Radiologically occult squamous cell carcinoma a) at the right tracheobronchial angle, b) during photodynamic irradiation, c) after PDT: normal mucosa, histologically no evidence of tumor, d) normal findings five years after PDT.

´Table 3
Photodynamic Therapy in Dermatology
Indication photosensitizer treatment parameters complete
(Sensitization, dosage remission
Incubation time, light dose) guess (5)
Actinic keratoses ALA 10–20%, 3–8 h 71–100
60-150 J / cm2
Bowen's disease Photofrin 2.0 mg / kg body weight, 98–100
50-100 J / cm2
ALA 20%, 4-8 hours, 90-100
80-180 J / cm2
Basal cell carcinoma Photofrin 2.0 mg / kg body weight, 60–90
60-220 J / cm2
- superficial ALA 20%, 4–8 h 80–95
100-180 J / cm2
- nodular ALA 20%, 4-8 h 20-60
80-180 J / cm2
Squamous cell carcinoma Photofrin 2.0 mg / kg body weight, 80–90
(Carcinoma in situ, 100-150 J / cm2
Early cancer) ALA 20%, 3–8 h, 85
60-150 J / cm2
Kaposi's sarcoma Photofrin 2.0 mg / kg body weight, 60–70
70-120 J / cm2
ICG 2 x 2 mg / kg body weight 94
100 J / cm2
Comparison of the complete remission rates depending on the diseases and the selected treatment parameters; Compilation of the results in the literature, according to Szeimies et al., 1997 (37)
ALA, 5-aminolevulinic acid; ICG, indocyanine green

Figure 3: a) Bowen's disease (carcinoma in situ) on the lower leg of a 76-year-old patient; b) Condition three months after a single topical ALA-PDT, only residual erythema and a delicate atrophic scar.
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