Der case report berichtet über den Fall eines 65 Jahre alten Mann mit einem fulminatem Verlauf einer Pemetrexed induzierte Pneumonitis. Der Patient, mit einem malignen Pleuramesotheliom (MPM), UICC: III, wurde in die Notaufnahme 6 Tage nach dem vierten Zyklus Pemetrexed (500mg/m2) mit Atemnot, Husten und Fieber aufgenommen. Eine empirische antimikrobielle Therapie wurde initiiert und für drei Wochen ohne wesentliche klinische Besserung fortgeführt. Im Verlauf entwickelte der Patient ein acute respiratory distress syndrome (ARDS) mit schwerer respiratorischer Insuffizienz und eine nicht-invasive Beatmung wurde eingeleitet. Das HR-CT zeigte eine bilaterale, basal betonte Milchglastrübung und begleitende Bereiche mit Verdichtungen. Bei unauffälligem intensiven mikrobiologischem Work-up und dem charakteristischen Bild einer diffusen alveolären Schädigung im HR-CT wurde die Diagnose einer Pemetrexed induzierte Pneumonitis gestellt und eine hochdosierte Kortikosteroid-Therapie eingeleitet. Unter dieser Therapie verbesserte sich der klinische Zustand des Patienten bei signifikant verbessertem Gasaustausch und rückläufiger Milchglastrübung/Verdichtungen im HR-CT. Nach 7 Wochen im Krankenhaus wurde der Patient in stabilem Zustand in die pulmonale Rehabilitation entlassen, eine Follow-Up Untersuchung wurde nach 4 Monaten durchgeführt.

Background Photodynamic therapy (PDT) uses the combination of photosensitizing drugs and harmless light to cause selective damage to tumor cells. PDT is therefore an option for focal therapy of localized disease or for otherwise unresectable tumors. In addition, there is increasing evidence that PDT can induce systemic anti-tumor immunity, supporting control of tumor cells, which were not eliminated by the primary treatment. However, the effect of non-lethal PDT on the behavior and malignant potential of tumor cells surviving PDT is molecularly not well defined. Methodology/Principal Findings Here we have evaluated changes in the transcriptome of human glioblastoma (U87, U373) and human (PC-3, DU145) and murine prostate cancer cells (TRAMP-C1, TRAMP-C2) after non-lethal PDT in vitro and in vivo using oligonucleotide microarray analyses. We found that the overall response was similar between the different cell lines and photosensitizers both in vitro and in vivo. The most prominently upregulated genes encoded proteins that belong to pathways activated by cellular stress or are involved in cell cycle arrest. This response was similar to the rescue response of tumor cells following high-dose PDT. In contrast, tumor cells dealing with non-lethal PDT were found to significantly upregulate a number of immune genes, which included the chemokine genes CXCL2, CXCL3 and IL8/CXCL8 as well as the genes for IL6 and its receptor IL6R, which can stimulate proinflammatory reactions, while IL6 and IL6R can also enhance tumor growth. Conclusions Our results indicate that PDT can support anti-tumor immune responses and is, therefore, a rational therapy even if tumor cells cannot be completely eliminated by primary phototoxic mechanisms alone. However, non-lethal PDT can also stimulate tumor growth-promoting autocrine loops, as seen by the upregulation of IL6 and its receptor. Thus the efficacy of PDT to treat tumors may be improved by controlling unwanted and potentially deleterious growth-stimulatory pathways.

Objective: Photodynamic therapy (PDT) uses the combination of a photosensitizing drug and light to cause selective damage to solid tumors. For early or localized disease, PDT can be a curative therapy with many advantages over available alternatives. For more advanced or metastatic disease curative therapy is usually not possible. However, there is increasing evidence that PDT can also induce systemic anti-tumor immunity, indicating that PDT can become a rational therapeutic option, even if not all tumor cells are primarily eliminated by PDT. One prerequisite to minimize tumor relapse in these settings is to counteract repair mechanisms of PDT-induced damage and to aid PDT-triggered immune stimulation.

A summary of clinical trials employing photodynamic diagnosis (PDD) and photodynamic therapy (PDT) for the diagnosis and treatment of brain malignancies is presented. Intra-cavity PDT has been performed within the surgical cavity following FGR, employing oral administration of 5-aminolevulinic acid (5-ALA), either targeting fluorescing tissue regions that were not removed during FGR due to safety reasons (referred to as focal PDT, n=20) or illuminating the entire resection cavity (referred to as integral PDT, n=9). Both approaches proved technically feasible and safe. Spectroscopic measurements performed pre-, during and post-PDT revealed Protoporphyrin IX (PpIX)-photobleaching of more than 95% after the delivery of 200 J/cm(2). This light dose did not induce any side effects. Furthermore, interstitial PDT (iPDT) has been employed within one feasibility trial (n=10) and one Phase I/II trial (n=15). Here, three to six cylindrical light diffusors (20-30 mm length, 200 mW/cm, 720 J/cm) were positioned within the target tissue under stereotactic guidance. Pre-treatment planning was performed with the intent to target the entire tumour volume with a sufficient light dose while also minimising the risk of any light-induced temperature increase. For the feasibility trial patients with small, recurrent gliomas were included, resulting in a median survival of 15 months as well as some unexpected long-term survivals (up to 5 years). The Phase I/II trial employed the same clinical procedures. Here, the 12-month survival was 35% and the median progression-free survival was 6 months. In summary, stereotactic iPDT in combination with treatment-planning could be shown to be a safe and feasible treatment modality. These trials are presently being extended to also include on-line monitoring of PpIX fluorescence and photobleaching kinetics. Preliminary data has revealed dramatically different PpIX levels and photobleaching kinetics. Such data could possibly be employed for realtime treatment monitoring and as an early prognostic marker for the PDT response.

Photodynamic therapy (PDT) uses the combination of a photosensitizing drug and light to cause selective damage to solid tumors. For early or localized disease, PDT can be a curative therapy with many advantages over available alternatives. For more advanced or disseminated disease, curative therapy is usually not possible with current technologies of light application, nevertheless it can improve quality of life and lengthen survival. More recently, there has been increasing evidence that PDT can also induce systemic anti-tumor immunity, indicating that PDT can become a rational therapeutic option, even if not all tumor cells are primarily eliminated by PDT. One prerequisite to minimize tumor relapse in these settings is to elucidate how tumor cells can cope with the PDT-induced damage. Here we have characterized the rescue response of human PC-3 prostate cancer cells exposed in vitro to sublethal PDT after 5-aminolevulinic acid-induced protoporphyrin IX sensitization at the transcriptome level using Affymetrix HG U133 Plus 2.0 oligonucleotide microarrays. Cells were irradiated with laser light at a wavelength of 635 nm adjusted to an irradiance of 100 mW/cm2 with irradiations of 1.5 and 3 J/cm2. The early response was characterized by the up-regulation of early response genes like FOS, JUN, EGR1, ATF3, DUSP, heat shock protein genes as well as histone genes, therefore resembling the early response of tumor cells to high dose PDT but without signs of irreversible cell damage. Twenty-four hours after PDT the cells still express high level of early response genes but 235 additional probe sets/genes were now significantly up-regulated (≥3x) that were not up-regulated 4 h after PDT. The most prominently up-regulated genes belong to gene families encoding the aldo-keto reductases, fibroblast growth factors, and HSP40-related proteins. In terms of a possible anti-tumor immune response it is noteworthy that also a multitude of chemokine and interleukin genes were up-regulated by the tumor cells upon PDT. Most of them are involved in granulocyte attraction and activation and some are also important for angiogenesis. In conclusion, the global molecular characterization of the rescue response to PDT of tumor cells indicates that PDT rather favors an anti-tumor immune response than tumor immune escape reactions. Therefore, combining PDT and immunotherapy seem to be an attractive direction for the establishment of novel multimodal tumor therapies. Bei der photodynamischen Therapie (PDT) von soliden Tumoren wird eine Kombination aus einer photosensibilisierenden Substanz und Licht benutzt, um eine selektive Zerstürung der Tumorzellen zu erzielen. Für Tumore im Frühstadium oder lokalisierte Tumorerkrankungen, kann die PDT eine kurative Therapie darstellen, die viele Vorteile gegenüber bestehenden Behandlungsmethoden hat. Bei fortgeschrittenen oder disseminierten Erkrankungen ist eine kurative Therapie in der Regel nicht müglich, es kann aber durchaus eine Verbesserung der Lebensqualität bzw. eine Lebensverlängerung erreicht werden. In jüngster Zeit häufen sich Hinweise, dass durch PDT auch systemische Tumorimmunität induziert werden kann. Deshalb kann PDT durchaus eine sinnvolle Therapieoption darstellen, auch wenn es zunächst nicht gelingt, die Tumorzellen vollständig zu eliminieren. Um bei einem solchen Vorgehen die Gefahr einer Rezidivbildung zu minimieren, sollte bekannt sein, wie Tumorzellen mit einer durch PDT verursachten Schädigung umgehen. Wir haben die Antwort von humanen PC-3 Prostatakarzinomzellen auf eine sublethale Bestrahlung nach 5-Aminolävulinsäure-induzierter Sensibilisierung mittels Protoporphyrin-IX auf Transkriptionsebene mit Affymetrix HG U133 Plus 2.0 Oligonukleotid-Mikroarrays charakterisiert. Die Zellen wurden mit Laserlicht einer Wellenlänge von 635 nm und einer Bestrahlungsstärke von 100 mW/cm2 und einer Lichtdosis von 1,5 bzw. 3 J/cm2 bestrahlt. Die frühe Antwort 4 h nach PDT war durch die Hochregulation von early response-Genen wie FOS, JUN, EGR1, ATF3, DUSP, sowie Hitzeschock- und Histongenen bestimmt, wie dies in ähnlicher Weise auch für die Hochdosis-PDT bekannt ist. Allerdings blieben dabei irreversible Zellschäden aus. 24 Stunden nach der PDT exprimierten die Zellen immer noch große Mengen der early response-Gene, aber zusätzlich waren 235 weitere probe sets-Gene signifikant hochreguliert (≥3x). Die am stärksten hochregulierten Gene gehürten zu Genfamilien, die für Aldo-keto-Reduktasen, Fibroblasten-Wachstumsfaktoren und HSP40-verwandte Proteine kodieren. Im Hinblick auf eine mügliche Anti-Tumorimmunreaktion ist es bemerkenswert, dass die Expression einer Vielzahl von Chemokin- und Zytokingenen durch PDT gesteigert wurde, die meisten davon spielen eine Rolle bei der Granulozyten-Rekrutierung und -Aktivierung und einige sind für die Angiogenese wichtig. Zusammenfassend kann man sagen, dass die umfassende molekulare Charakterisierung der Tumorzellreaktion auf PDT andeutet, dass PDT eher eine Anti-Tumorimmunantwort als Tumor-Escape-Mechanismen unterstützt. Deshalb künnte die Kombination von PDT und Immuntherapie eine vielversprechende multimodale Tumortherapie werden.

Photodynamic therapy (PDT) uses a combination of a photosensitizing drug and light to cause selective damage to solid tumors. For early or localized disease, PDT can be a curative therapy with many advantages over available alternatives. For more advanced or disseminated disease curative therapy is usually not possible with current technologies of light application, however it can improve quality of life and lengthen survival. More recently there is increasing evidence that PDT can also induce systemic anti-tumor immunity, indicating that PDT could become a rational therapeutic option, even if not all tumor cells are primarily eliminated by PDT. One prerequisite to minimize tumor relapse in these settings is to elucidate how tumor cells can cope with the PDT-induced damage. Here we have characterized the rescue response of human prostate cancer and glioblastoma cells exposed in vitro to sub-lethal PDT after 5-aminolevulinic acid-induced protoporphyrin IX sensitization at the transcriptome level using Affymetrix U133 2.0 oligonucleotide microarrays. Cells were irradiated with laser light at a wavelength of 635 nm adjusted to an irradiance of 100 mW/cm2 with fluences varying between 0.5 and 3 J/cm2. The early response was characterized by the up-regulation of early response genes like FOS, JUN, EGR1, ATF3, DUSP, heat-shock protein genes as well as histone and metallothionein genes, therefore resembling the early response of tumor cells to high-dose PDT but without signs of irreversible cell damage. Twenty-four hours after PDT the cells still expressed high level of early response genes but 241 additional probe sets/genes were significantly up-regulated (5x) compared to those that were not up-regulated (⩽2x) 4 h after PDT. The most prominently up-regulated genes belong to gene families encoding the aldo-keto reductases, fibroblast growth factors and Hsp40-related proteins. In terms of a possible anti-tumor immune response it is noteworthy that also a multitude of chemokines and interleukins were up-regulated by the tumor cells upon PDT. Most of them are involved in granulocyte attraction and activation and some are also important for angiogenesis. In conclusion, the global molecular characterization of the rescue response to PDT of tumor cells indicated that PDT rather favors an anti-tumor immune response than tumor immune escape reactions. Therefore combining PDT and immunotherapy seem to be an attractive direction for the establishment of novel multimodal tumor therapies.

fluoreszierende Porphyrinderivate zur Markierung von stark proliferierendem Gewebe und Karzinomen im Frühstadium, gewinnen zunehmend an klinischer Bedeutung bei der Diagnose prämaligner Veränderungen /3/. Häufig scheitert jedoch eine eindeutige Lokalisierung des Fluorochroms an der gewebespezifischen Eigenfluoreszenz, die sich im beobachteten Spektralbereich der Fluoreszenz des Markers überlagert. Während eine örtliche Diskriminierung beider Anteile bei vergleichbaren optischen Anregungseigenschaften versagt, können bei deutlich unterschiedlichen Anregungsspektren von Fluorochrom und gewebeeigenen Farbstoffen mit Hilfe der Zweiwellenlängen-Laseranregung diese Anteile getrennt und damit eine Fluoreszenz-Kontrastverstärkung erreicht werden. Die Methode wurde in tierexperimentellen Studien zum Nachweis von chemisch induzierten Blasenturr-oren eingesetzt /!/. Die Anfärbung der Karzinome erfolgt durch intravenöse Injektion eines Gemisches aus Dihämatoporphyrinäther und -ester ( D H E ) . Wenige Tage nach systemischer Verabreichung liegt die fluoreszierende Komponente von DHE in Tumoren in höherer Konzentration als im gesunden Nachbargewebe vor 121. Nach Anregung mit vorzugsweise violettem Licht um 400 nm kann diese Substanz durch ihre charakteristische Fluoreszenz im roten Spektralbereich mit Emissionsbanden bei 630 und 690 nm nachgewiesen werden (Abb. l, oben rechts). Dieser Fluoreszenz ist der Eigenfluoreszenzanteil überlagert (schwarz in Abb. l, oben rechts), dessen spektraler Verlauf aus Messungen an DHE-freiem Ge.webe bekannt ist. Abb. l Fluoreszenzbilder und korrespondierende Fluoreszenzspektren einer mit DHE behandelten Hundeblase bei Violettanregung (oben), Blauanregung (Mitte) und nach Bildbzw. Spek' trensubtraktion (violett minus blau, unten).

Bladder cancer (BC) is among the most expensive oncological diseases. Any improvement in diagnosis or therapy carries a high potential for reducing costs. Fluorescence cystoscopy relies on a selective formation of Protoporphyrin IX (PpIX) or more general photoactive porphyrins (PAP) in malignant urothelium upon instillation of 5-aminolevulinic acid (5-ALA) or its hexyl-derivative h-ALA. Fluorescence cystoscopy equipment has been developed with the aim to compensate for the undesired distortion caused by the tissue optical properties by displaying the red fluorescence simultaneously with the backscattered blue light. Many clinical studies proved a high sensitivity in detecting flat carcinoma in situ and small papillary malignant tumours. As a result, recurrence rates were significantly decreased in most studies. The limitation lies in a low specificity, caused by false positive findings at inflamed bladder wall. Optical coherence tomography (OCT) is currently being investigated as a promising tool to overcome this limitation.H-ALA-PDT (8 or 16 mM h-ALA in 50 ml instillation for 1-2 h, white light source, catheter applicator) has recently been investigated in a phase I study. 17 patients were applied 100 J/cm(2) (3 patients received incrementing doses of 25 - 50 - 100 J/cm(2)) during approx. 1 hour irradiation time in 3 sessions, 6 weeks apart. PDT was performed without any technical complications. Complete photobleaching of the PpIX-fluorescence, as intended, could be achieved in 43 of 45 PDT-sessions receiving 100 J/cm(2). The most prominent side effects were postoperative urgency and bladder pain, all symptoms being more severe after 16 mM h-ALA. Preliminary evaluation shows complete response assessed at 3 months after the third PDT-session (i.e. 6 months after first treatment) in 9 of 12 patients. 2 of these patients were free of recurrence until final follow-up at 84 weeks.

Glioblastoma multiforme continues to be a devastating disease despite modest improvements in survival achieved at present, and there is an urgent need for innovative treatment concepts. Five-aminolevulinic acid (ALA) is a drug which induces protoporphyrin IX accumulation in malignant gliomas and has been explored for fluorescence-guided resections of these tumors. ALA is also under investigation as a photosensitizer. We report a case of a patient with prior left frontal glioblastoma multiforme treated by surgery, radiation and chemotherapy, who developed a remote lesion in the left insula, which was refractory to secondary treatments. In a compassionate use setting she was treated by oral application of ALA (20 mg/kg bodyweight), and stereotactic phototherapy achieved by positioning four laser diffusors using 3-dimensional irradiation planning, and a 633 nm diode laser. The lesion disappeared 24 h after therapy. Circumferential contrast enhancement was observed at 72 h, which disappeared in the course of subsequential months. Edema resolved completely. The patient is still free of recurrence 56 months after treatment, demonstrating an impressive and long-lasting response to this novel mode of therapy.

OBJECTIVES To study the feasibility of 5-aminolevulinic-acid (5-ALA)-induced photodynamic diagnosis (PDD) for the evaluation of the surgical margins (SMs) during radical prostatectomy (RP) in patients with prostate cancer (PCa).METHODS A total of 18 patients with histologically confirmed PCa (Gleason score 4 to 8, prostate-specific antigen 1 to 20 ng/mL) underwent RP. Of the 18 patients, 16 received 5-ALA (20 mg/kg) orally 2 hours before RP, and 2 served as controls without any application of 5-ALA. To study the protoporphyrin IX (PPIX) accumulation after application of 5-ALA, all harvested specimens were investigated by fluorescence microscopy and spectroscopy. In 10 of 16 patients, PDD of the SMs and the prostate was performed during RP using an incoherent light source filtered for efficient fluorescence excitation.RESULTS In all 16 patients, who had received 5-ALA fluorescence microscopy showed a selective accumulation of PPIX in the PCa cells, and only weak PPIX fluorescence could be detected in benign epithelial cells and none in the adjacent stroma. The 2 patients, who had not received 5-ALA had no PPIX fluorescence in the prostate. Of 10 patients, 8 demonstrated fluorescence-negative and histologically confirmed negative margins during PDD, and 1 each demonstrated a fluorescence-positive SM that was also confirmed by histologic examination and a positive SM that was not confirmed by PPD.CONCLUSIONS This is the first report of PDD for PCa using 5-ALA. These initial results have demonstrated that PPIX is selectively enhanced in malignant tissue, an essential prerequisite of PDD. Additional studies are warranted to validate these preliminary data and the efficacy of PDD for PCa during RP.

Photodynamic therapy (PDT) has received increased attention as a treatment modality for malignant tumors as well as non-oncologic diseases such as age-related macular degeneration (AMD). An alternative to excite the photosensitizer by the common one-photon absorption is the method of two-photon excitation (TPE). This two-photon photodynamic therapy has the potential of improving the therapeutic outcome due to a highly localized photodynamic effect. The present study investigated the two-photon excited PDT performing in vitro experiments where C6 rat glioma cells were irradiated with a pulsed and focused fs Ti:sapphire laser emitting light at 800 nm. The irradiance distribution of the laser beam was carefully analyzed before the experiment and the applied irradiance was known for each position within the irradiated cell layer. Cells were divided into four groups and one group was incubated with 5-ALA and irradiated 4-5h later. The survival of this group was tested after irradiation by means of ethidium bromide and acridine orange staining and compared to a control group, which was irradiated under the same conditions, but not incubated with 5-ALA before. Both groups showed necrotic areas depending on the applied irradiance, the value of which at the margin of the necrotic area could be deduced from its size. 5-ALA incubated cells became necrotic after irradiation with a mean irradiance above 6.1 x 10(10) W/cm(2), while non-incubated cells remained viable. Cells of both groups became necrotic when treated with an irradiance above 10.9 x 10(10) W/cm(2). The observed affected area of the cell layers was between 0.13 mm(2) and 1.10 mm(2). Since the irradiation of non-incubated cells below the mean power density of 10.9 x 10(10) W/cm(2) induced no necrosis, apparently no thermal damage was induced in the cells and necrosis of the 5-ALA incubated cells can be ascribed to the photodynamic effect induced by two-photon excitation. The successful photodynamic treatment of a large area of a monolayer cell culture induced by two-photon excitation offers new perspectives for photodynamic treatment modalities.

The pharmacokineties of 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) in lesions of urethral condylomata acuminata were investigated. Sixty patients (20 to 60 years old, 48 male and 12 female) were divided randomly into five groups and received topic application of different concentrations of ALA solution (0.5%, 1%, 3%, 5% or 10%). Biopsy was performed between I and 7 h and specimens were subjected to histological, PpIX fluorescence and human papillomavirus (HPV) DNA typing analyses. Fluorescence examination confirmed that ALA-induced PpIX fluorescence was dominantly distributed in the HPV-infected epidermis. In contrast, only a minimal amount of PpIX fluorescence was detected in the dermis. The maximal fluorescence intensity was detected at 5 h incubation. Higher ALA concentration (e.g. 5% and 10%) produced a stronger intensity. These results suggest that the topical application of 5-10% ALA solution for 3-5 h is the optimal condition for the photodynamic therapy of urethral condylomata acuminata. The selective damage of the condylomata acuminata lesions in the epidermis without damaging the dermis ensures a better control of recurrence and side effects such as ulceration or scarring. DNA typing showed that all patients were positive for low risk-HPV DNA and among them 18.3% of patients harbored high risk-HPV DNA.

Aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) may represent a treatment option for malignant brain tumors. We used a three-dimensional cell culture system, the C6 glioma spheroid model, to study acute effects of PDT and how they might be influenced by treatment conditions.

Background and Objective: Limited knowledge of the light and temperature distribution within the target volume in combination with non-selective accumulation of the applied photosensitizers (PS) has hampered the clinical relevance of interstitial photodynamic therapy (iPDT) for treatment of malignant glioma patients. The current pilot study focused on the development and the clinical implementation of an accurate and reproducible irradiation scheme for iPDT using 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) as a selectively working PS.Study Design/Materials and Methods: Monte Carlo simulations of fluence rate and heat transport simulations were performed using the optical properties of normal brain tissue infiltrated by tumor cells (absorption coefficient mu(a) = 0.2 cm(-1), reduced scattering coefficient: mu'(s) = 20 cm(-1)). A modified 3-D treatment-planning software was used to calculate both, the treatment-volume and the exact position of the light diffusers within the lesion. The feasibility and the risk of iPDT were tested in 10 patients with small and circumscribed recurrent malignant gliomas.Results: The optimum distance between the implanted light diffusers was determined to be 9 mm with regard to both fluence rate and temperature distribution. For this distance a temperature increase above 42 degrees C was not expected to occur. Up to six cylindrical light diffusers were stereotactically implanted to achieve a complete irradiation of the tumor volume, which was possible in every single patient (mean tumor volume: 5.9 cm(3)). The total applied light fluence was between 4,320 J and 11,520 J. Side effectsof iPDT were not observed. Median survival was 15 months.Conclusion: 5-ALA iPDT in combination with a 3-D treatment-planning (which was based on optical and thermal simulations) is a safe and feasible treatment modality. The clinical impact of these findings deserves further prospective evaluation.

BACKGROUND:In the diagnosis of early-stage lung cancer photosensitizer-enhanced fluorescence bronchoscopy with inhaled 5-aminolevolinic acid (5-ALA) increases sensitivity when compared to white-light bronchoscopy. This investigation was to evaluate the in vivo tissue pharmacokinetics of inhaled 5-ALA within the bronchial mucosa in order to define the time optimum for its application prior to bronchoscopy.METHODS:Patients with known or suspected bronchial carcinoma were randomized to receive 200 mg 5-ALA via inhalation 1, 2, 3, 4 or 6 hours before flexible fluorescence bronchoscopy was performed. Macroscopically suspicious areas as well as areas with visually detected porphyrin fluorescence and normal control sites were measured spectroscopically. Biopsies for histopathology were obtained from suspicious areas as well as from adjacent normal areas.RESULTS:Fluorescence bronchoscopy performed in 19 patients reveals a sensitivity for malignant and premalignant changes (moderate dysplasia) which is almost twice as high as that of white-light bronchoscopy, whereas specificity is reduced. This is due to false-positive inflammatory lesions which also frequently show increased porphyrin fluorescence. Malignant and premalignant alterations produced fluorescence values that are up to 5 times higher than those of normal tissue. According to the pharmacokinetics of porphyrin fluorescence measured by spectroscopy, the optimum time range for 5-ALA application is 80-270 min prior to fluorescence bronchoscopy, with an optimum at 160 min.CONCLUSION:According to our results we propose inhalation of 5-ALA 160 min prior to fluorescence bronchoscopy, suggesting that this time difference provides the best tumor/normal tissue fluorescence ratio.

Objectives: To investigate the pharmacokinetics of ALA induced protoporphyrin IX (PpIX) in lesions of urethral condylomata acuminata. Methods: Sixty patients (20 - 60 years old, 48 male and 12 female) with urethral condylomata acuminata were divided randomly into 5 groups to receive different concentrations of ALA solution (0.5, 1, 3, 5 or 10%). The ALA solution was applied topically to the lesion for a different length of time (1, 3, 5 or 7 h). Biopsy was performed at the end of incubation and specimens were subjected to histological and PpIX fluorescence analyses. Results: ALA-induced PpIX fluorescence was dominantly distributed in the epidermis. The maximal fluorescence intensity was detected at the 5 h of incubation. Higher ALA concentration (e.g. 5 and 10%) produced stronger intensity. In contrast, only the minimal amount of PpIX fluorescence was detected in the dermis. Conclusions: The results suggest that the topical application of 5 - 10% ALA solution for 3-5 h are the optimal conditions for ALA/PpIX-mediated photodynamic therapy for the treatment of urethral condylomata acuminata.

Motivation: Photodynamic Therapy (PDT) with interstitial light delivery by multiple fibers for the treatment of large tissue volumes requires measurement of sensitizer distribution for dosimetric considerations. For stereotactic interstitial PDT of malignant glioma, for instance, a pre-irradiation comparison of the contrast enhancing tissue volume in MR-imaging with the photosensitized volume as assessed by fluorescence detection is desirable. For PDT of prostate cancer, the quantitative measurement of the selectivity of sensitizer uptake in cancer versus normal prostate parenchyma is important.Methods: It has previously been shown by others that the fluorescence intensity measured by a thin single optical fiber for excitation and detection is largely independent on optical parameters of the tissue that contains the fluorochrome. However, the investigators assumed similar values for excitation and emission wavelengths. This study concerned liquid phantom measurements (absorber: ink or hemoglobin, fluorochrome: Na-fluorescein) and Monte Carlo calculations, with extended conditions, where the absorption differs by a factor of 10 between excitation (426 nm) and emission (530 nm) wavelengths. The absorption coefficient (mu(a)') was varied between 0.01 - 0.3 mm(-1) (@ 426 nm), the effective scattering coefficient (mu(s)') between 0.6 - 2.5 mm(-1). A 200 gm and a 1000 larn core fiber were used.Results: Fluorescence intensity measured at 530 nm via a thin optical fiber (core diameter small compared to light penetration depth) depends minimally on optical tissue parameters. This result is valid for ink as absorber (mu(a) identical at excitation and emission) as well as for hemoglobin (mu(a) different). Fluorochrome concentration measurements seem possible with a 200 mu m core fiber, but not with the 1000 mu m core fiber.

Surgical management of malignant gliomas remains a major challenge to neurosurgeons. Prognosis of these locally highly invasive tumors is linked to the completeness of their resection. In the brain, however, highly proliferative, marginal tumor tissue is difficult to distinguish, and resections with safety margins are not an option. Five-aminolevulinic acid (ALA) induces specific porphyrin fluorescence within malignant glioma tissue. These porphyrins, being highly fluorescent and photosensitizing, have proven useful for fluorescence-guided resections of malignant gliomas, which has evolved into a practical method for routine use. The potential of ALA as a photosensitizer for adjunctive photodynamic therapy (PDT) is currently under investigation. This article focuses on background and implementation of fluorescence-guided resections of malignant gliomas. It summarizes the rationale for, and present status of PDT using ALA.