Victor V. Sokolov

Photodynamic therapy of early esophageal cancer

In 1992-2006 at P.A. Hertsen Moscow Oncology Research Institute photodynamic therapy (PDT) was performed in 48 esophageal cancer patients (total 48 lesions). For PDT we used Russian photosensitizers (Photogem, Photosens, Radachlorin, Alasens), Russian diode lasers (Crystall) and endoscopic equipment. As a result of PDT complete regression was in 77% of esophageal cancer lesions, partial regression was in 23%. The follow-up period was 3-11 years. Median of survival was in 4.59 years of esophageal cancer patient.

Photodynamic therapy (PDT) of malignant tumors by photosensitzer photosens: results of 45 clinical cases

Photosensitizer Photosens is a mixture of sulphonated Al-phthalocyanines with a different number of substituents per phthalocyanine molecule. In the beginning of 1994, this photosensitizer was approved for clinical trials. Since that time till May 1995, 45 patients with 120 tumors were treated by PDT-Photosens. The main tumor localizations were lung (5/6), head and neck (4/4), esophagus (8/8), stomach (2/2), vulva (2/2), bladder (1/1), breast cancer (3/3), skin (basalioma, melanoma, sarcoma Kaposi, mts breast cancer) (20 patients/94 tumors). The lesions were photoirradiated 48-72 h after intravenous injection of Photosens in doses from 0.5 to 2.0 mg/kg b.w. (1.0 mg/kg b.w., on average). PDT was performed by laser power density from 20 to 1400 mW/sq cm (300 mW/sq.cm, on average), energy density varying from 15 to 200 J/sq cm (100 J/sq.cm, on average). The therapeutical effect of PDT was evaluated histologically, endoscopically, roentgenologically and sonographically 3 - 4 weeks after the treatment. Complete regression of tumors was reached in 56%, significant remission was reached in 34%, and partial remission was observed in 10% of cases. The follow-up of patients with complete tumor regression was to 15 months.

Fluorescence observations of patients in the course of photodynamic therapy of cancer with the photosensitizer PHOTOSENS

In the course of clinical trials of Photosens (Al-sulphonated phthalocyanine) as a new drug for PDT of cancer fluorescence observations of patients with injected photosensitizer are performed. The aim of current investigations is to develop the clinical method of cancer diagnostics with Photosens, to study the pharmaco-kinetics of the drug in the human body and its retention in tumors.

First clinical results with a new drug for PDT

After experimental investigation clinical trials of photodynamic therapy (PDT) with the new photosensitizer Photosens -- (AL-sulphonated phthalocyanine) -- have been started. Four patients (with basal cell carcinoma, sarcoma Kaposi and early stage lung cancer) were treated by PDT. After an intravenous injection of drug in dose 2.0 mg/kg b.w. tumors were exposed to frequency-doubled radiation of Nd:yttrium aluminate laser (670 nm) with power densities from 80 to 200 mW/sq cm and total energies up to 2144 J. Immunological and clinical observations of patients are performed. First results indicate the high efficacy of the new drug as a tumor photosensitizer.

Photodynamic therapy of cancer with the photosensitizer PHOTOGEM

The first clinical trials of photodynamic therapy (PDT) in Russia were started in P. A. Hertzen Moscow Research Oncology Institute in October of 1992. Up to now, 61 patients with primary or recurrent malignant tumors of the larynx (3), trachea (1), bronchus (11), nose (1), mouth (3), esophagus (12), vagina and uterine cervix (3), bladder (2), skin (6), and cutaneous and subcutaneous metastases of breast cancer and melanomas (6) have been treated by PDT with the photosensitizer Photogem. At least partial tumor response was observed in all of the cases, but complete remission indicating no evident tumors has been reached in 51% of the cases. Among 29 patients with early and first stage cancer 14 patients had multifocal tumors. Complete remission of tumors in this group reached 86%.

Pharmocokinetical study of Al- and Zn-sulphonated phthalocyanines

The comparative pharmacokinetical study of Al- and Zn- sulphonated phthalocyanines (AlPcS and ZnPcS, respectively) is the aim of the present work. Mice bearing solid Ehrlich tumor were used in this study. AlPcS (sodium salt) and ZnPcS (ammonium and sodium salts were used as photosensitizers. The photosensitizers were injected i/v in various doses. The exogenous fluorescence of tissues (tumor, liver, spleen, kidneys, muscles, skin) was measured dynamically after sensitization. It was shown that all of the photosensitizers under study had similar distribution pattern in organisms of mice and were selectively accumulated in the Ehrlich tumor tissue. The exogenous fluorescence intensity of tissues and it tumor:normal muscle ratio (Cs) depended on the dosage of the preparation, on the time, which had passed after drug injection, and on the stage of tumor growth. It was also shown that the kinetics of the tissue uptake of the studied sensitizers varied to some extent. Thus, the obtained data may be interesting for deeper understanding of the interaction of the dye with malignant tissues.

Multi-course PDT of malignant tumors: the influence on primary tumor, metastatic spreading and homeostasis of cancer patients

The first clinical trials of photodynamic therapy (PDT) of cancer with two photosensitizers, PHOTOHEME and PHOTOSENS, were started in P.A. Hertzen Research Oncological Institute (Moscow, Russia) in 1992 and 1994. Up to now, 208 patients with primary, recurrent and metastatic malignant tumors (469) of skin (34 patients/185 tumors), breast cancer (24/101), head and neck (30/31), trachea and bronchus (31/42), esophagus (35/35), stomach (31/32), rectum (4/4), vagina and uterine cervix (7/8) and bladder (12/31) have been treated by PDT. One-hundred-thirty patients were injected with PHOTOHEME, 64 patients were injected with PHOTOSENS, 14 patients were injected with PHOTOHEME and PHOTOSENS. Totally, 302 courses of treatment were performed: 155 patients had one course and 53 patients were subjected to two to nine PDT sources with intervals from 1 to 18 months. A therapeutic effect of a one-course and multi- course PDT of malignant tumors (respiratory, digestive and urogenital systems) was evaluated clinically, histologically, roentgenologically, sonographically and endoscopically. The biochemical, hematological and immunological investigations were performed for all the patients in dynamics. Results of our study showed that a multi-course PDT method seems to be perspective in treatment of malignant tumors of basic localizations.

Clinical fluorescence diagnostics in the course of photodynamic therapy of cancer with the photosensitizer PHOTOGEM

The results are described of the first clinical fluorescence diagnostic observations of tumors, carried out in P. A. Hertzen Moscow Research Oncology Institute in the course of clinical trials of a new HpD-type photosensitizer Photogem, developed for cancer treatment by photodynamic therapy. The method of tumor diagnostics using fluorescence spectra of photogem has been developed and a designed spectrometric system has been tested.

Study of laser-induced autofluorescence emission spectra from normal and malignant bronchial epithelium/Untersuchung der laser-induzierten Autofluoreszenz-Emissionsspektren von normalem und malignem Bronchialepithel

Abstract Objective: Autofluorescence bronchoscopy (AFB) is currently considered the most promising diagnosis modality for the detection of early stage lung cancer with a sensitivity which normally exceeds 90%, although its specificity is rather low. The number of false positive results can be reduced by the combination of autofluorescence (AF) imaging with quantitative spectroscopy. The aim of this study was to reveal additional spectral characteristics of AF emission which may have the potential to maximize the endogenous contrast between normal mucosa and bronchial malignancy in vivo. Material and method: AF emission spectra were recorded at 532 nm laser excitation in the course of AFB of totally 20 patients with central-type X-ray negative lung cancer. According to the results of histopathological analysis, two sets were made up of the spectral data corresponding to normal bronchial epithelium and malignant lesions. Results: Comparative studies of nine basic spectral characteristics of in vivo AF spectra recorded from normal and malignant bronchial epithelium were performed. Statistical analysis and probabilistic estimations revealed that endogenous contrast between normal bronchial epithelium and early stage lung cancer in the 550–800 nm spectral range includes at least five spectral characteristics. The following characteristics were found to be considered as diagnostically informative at 532 nm excitation: i) the maximum spectral intensity, ii) the integral intensity within the range of 550–800 nm, iii) the position of the maximum spectral intensity, iv) the center of gravity and v) the relative shape parameter. Conclusion: Real time measurements and estimation of all important spectral information on the basis of the probabilistic approach is assumed to be useful for real time recommendations for biopsies and for minimizing the number of false positive results during the course of AFB. For the realization of this approach, further trials are necessary to collect a large number of AF spectra samples, corresponding to different tissue pathologies such as inflammation, metaplasia, and dysplasia. Zusammenfassung Ziel: Die Autofluoreszenz-Bronchoskopie (AFB) gilt derzeit als das vielversprechendste Diagnoseverfahren für die Früherkennung von Lungenkrebs mit einer Sensitivität, die normalerweise bei über 90% liegt, allerdings bei gleichzeitiger geringer Spezifität. Die Zahl falsch-positiver Befunde lässt sich durch eine Kombination der Fluoreszenzbildgebung mit quantitativen spektroskopischen Messungen reduzieren. Ziel dieser Studie war es, zusätzliche spektrale Eigenschaften der emittierten Autofluoreszenz (AF) zu identifizieren, die das Potenzial haben, den endogenen Kontrast zwischen normaler und maligner Bronchialschleimhaut in vivo zu maximieren. Material und Methode: Während der AFB von 20 Patienten mit zentral lokalisiertem Lungenkrebs (bei unauffälligem Röntgenbefund) wurden unter Laser-Anregung (532 nm) AF-Emissionsspektren aufgezeichnet. Gemäß der Ergebnisse der histopathologischen Analyse wurden zwei spektrale Datensätze (normales Bronchialepithel vs. malignes Gewebe) gewonnen. Ergebnisse: Es wurden vergleichende Untersuchungen der neun grundlegenden spektralen Eigenschaften der in vivo gewonnenen AF-Spektren von normalem und malignem Bronchialepithel durchgeführt. Die statistische Analyse und Wahrscheinlichkeitsbetrachtungen ergaben, dass der endogene Kontrast zwischen normalem Bronchialepithel und frühem Lungenkrebs im Spektralbereich 550–800 nm durch mindestens fünf spektrale Eigenschaften beschrieben werden kann. Folgende Eigenschaften wurden als diagnostisch informativ eingestuft: i) die maximale spektrale Intensität, ii) die integrale Intensität im Bereich von 550 bis 800 nm, iii) die Position der maximalen spektralen Intensität, iv) der Schwerpunkt und v) der relative Formparameter. Fazit: Echtzeit-Messungen und die Abschätzung aller auf dem Wahrscheinlichkeitsansatz basierenden spektralen Informationen könnten die Empfehlung zu einer Biopsie unterstützen und zur Minimierung falsch-positiver Ergebnisse im Verlauf der AFB beitragen. Für die Verwirklichung dieses Ansatzes sind weitere Versuche notwendig, um eine größere Anzahl von AF-Spektren entsprechend der unterschiedlichen Gewebepathologien wie Entzündungen, Metaplasien und Dysplasien zu sammeln.

Fluorescence examinations of patients with tumors of diferent localizations in the course of photodynamic therapy with photosensitizer photosens

In the course of the clinical trials of Photosens (Al-sulphonated phthalocyanine) as a drug for PDT of cancer fluorescence examinations of 45 patients with injected photosensitizer (0.5 - 2.0 mg/kg b.w.) were performed. The aim of these investigations was to study the drug accumulation in normal, inflammatory tissues and tumors of different localizations. The data concerning kinetics of photosensitizer accumulation and its removal from normal skin and lip mucosa are also presented.