葡萄酒色斑光动力学疗法的研究进展

上世纪90年代,我国首先开始将光动力学疗法(Photodynamic Therapy,PDT)用于葡萄酒色斑(Port Wine Stain,PWS)的治疗。PDT由两大重要因素构成:光敏剂、激发光源。光动力学疗法通过直接杀伤细胞,破坏病灶血管,引发细胞凋亡,免疫调节等来发挥作用。因其对靶组织具有高敏感性,可减少正常组织的损伤。目前,PDT主要用于皮肤外生性疾病和眼、鼻腔、口腔及呼吸道、消化道、泌尿生殖道等腔道内肿瘤的治疗。本文就PDT在治疗葡萄酒色斑上的应用及研究进展进行综述。     

Photodynamische Therapie im Gastrointestinaltrakt Möglichkeiten und Grenzen

Background. Photodynamic therapy (PDT) is characterized by the extensive selective accumulation of a photoactive agent, the photosensitizer, in malignant or precancerous tumour cells. The photoactive compound is activated by light beam of a specific wavelength and causes cell death. A significant proportion of patients with gastrointestinal malignancies cannot undergo curative treatment, as either the cancer is too advanced or the patient's general constitution is too poor to allow invasive strategies. In such cases, PDT has already proven to be a promising therapeutic modality for selected dysplasias and malignancies in the gastrointestinal tract. Material and methods. A retrospective review of the literature was performed in order to determine the experience gained with PDT and to assess its clinical value in the curative and palliative management of gastrointestinal neoplasms. Results. PDT seems to be an adequate treatment for selected forms of early cancer and small lesions of the GI tract or for small residual areas after the tumour has been debulked by other techniques (e. g. limited surgical resection, thermal ablation). Especially for patients who refuse or are ineligible for conventional surgery, PDT offers promising results compared to currently accepted clinical approaches. Conclusions. As a primary or adjuvant mode for either curative or palliative treatment of gastrointestinal neoplasms, PDT is a potentially effective, minimally invasive therapeutic modality. However, further clinical assessment by means of comparative, standardized studies is essential to the definition of its role in oncology.     

Photodynamic therapy for the treatment of advanced gastrointestinal tumours

In the study, 120 patients with advanced gastrointestinal tumours were treated by PDT; 5 mg/kg of HpD was intravenously given 48–72 h prior to PDT. The light source was an argon dye laser with an output beam of 630 nm. The irradiation time varied from 15–25 min with a power of 100–350 mW cm^–2. The entire tumour was irradiated with a light dose of 100–250 J cm^–2. Of the 120 patients, 20 had cancer of esophagus, 72 had cancer of the gastric cardia, 18 had cancer of the stomach and 10 had cancer of the rectum. Eighty-eight patients (73.3%) had a response to PDT. Twelve patients with CR were followed up for one to five years, two patients died during the two years after PDT.     

Current Concepts in Gastrointestinal Photodynamic Therapy

OBJECTIVE: To review current concepts of photodynamic therapy (PDT) applied to the treatment of tumors of the gastrointestinal tract. SUMMARY BACKGROUND DATA: PDT initially involves the uptake or production of a photosensitive compound by tumor cells. Subsequent activation of the photoreactive compound by a specific wavelength of light results in cell death, either directly or as a result of vascular compromise and/or apoptosis. METHODS: The authors selectively review current concepts relating to photosensitization, photoactivation, time of PDT application, tissue selectivity, sites of photodynamic action, PDT effects on normal tissue, limitations of PDT, toxicity of photosensitizers, application of principles of PDT to tumor detection, and current applications of PDT to tumors of the gastrointestinal tract. RESULTS: PDT is clearly effective for small cancers, but it is not yet clear in which cases such treatment is more effective than other currently acceptable approaches. The major side effect of PDT is cutaneous photosensitization. The major limitation of PDT is depth of tumor kill. As data from current and future clinical trials become available, a clearer perspective of where PDT fits in the treatment of cancers will be gained. Many issues regarding pharmacokinetic data of photosensitizers, newer technology involved in light sources, optimal treatment regimens that take advantage of the pharmacophysiology of photoablation, and light dosimetry still require solution. One can foresee application of differing sensitizers and light sources depending on the specific clinical situation. As technologic advances occur, interstitial PDT may have significant application. CONCLUSIONS: PDT has a potentially important role either as a primary or adjuvant mode of treatment of tumors of the gastrointestinal tract.     

Photodynamic therapy in gastrointestinal cancer.

Six patients with an early stage of gastrointestinal (GI) cancer (T1N0M0, stage I) were successfully treated by photodynamic therapy (PDT) as follows: esophagus-1, stomach-2, rectum-3. The patients were photosensitized 72 hrs prior to treatment with pure hematoporphyrin at a dose of 5.10(-6) kg/kg b.w. in a slow intravenous infusion. Argon-pumped dye laser light at 0.630 microns wavelength was used in single and multiple treatment sessions with the power density ranging from 0.015 to 0.192 W.m-2 and a dose varying from 0.320 to 1.600 kJ.m-2. Tumor eradication (complete response) was obtained in each of the patients. No early or late treatment related complications were recorded. The patients were followed-up in the course of 7-16 months after treatment and no local recurrence or general development of disease (metastases) were reported. PDT in the early stage of GI carcinoma was recognized as a radical therapeutic method in clinical oncology.     

Application of hematoporphyrin derivative and laser-induced photodynamical reaction in the treatment of lung cancer: a preliminary report on 21 cases

This paper reports results of hematoporphyrin derivative based on photodynamic therapy (PDT) of 24 lung cancer lesions in 21 patients that were followed at least three months. Three of 24 lesions exhibited complete remission and 20 of 24 lesions exhibited a response to PDT. Tumors in twenty of twenty-one patients exhibited visually discernible hematoporphyrin derivative fluorescence upon irradiation with the 514-nm line from an argon ion laser. There were no severe complications due to PDT. The hematoporphyrin derivative, argon iin laser pumped dye laser (rhodamine B) system,and quartz fiber we used in this clinical series were all made in the People's Republic of China.     

Phase II Trial of Debulking Surgery and Photodynamic Therapy for Disseminated Intraperitoneal Tumors

Background: Photodynamic therapy (PDT) combines photosensitizer drug, oxygen, and laser light to kill tumor cells on surfaces. This is the initial report of our phase II trial, designed to evaluate the effectiveness of surgical debulking and PDT in carcinomatosis and sarcomatosis.Methods: Fifty-six patients were enrolled between April 1997 and January 2000. Patients were given Photofrin (2.5 mg/kg) intravenously 2 days before tumor-debulking surgery. Laser light was delivered to all peritoneal surfaces. Patients were followed with CT scans and laparoscopy to evaluate responses to treatment.Results: Forty-two patients were adequately debulked at surgery; these comprise the treatment group. There were 14 GI malignancies, 12 ovarian cancers and 15 sarcomas. Actuarial median survival was 21 months. Median time to recurrence was 3 months (range, 1–21 months). The most common serious toxicities were anemia (38%), liver function test (LFT) abnormalities (26%), and gastrointestinal toxicities(19%), and one patient died. Conclusions: Photofrin PDT for carcinomatosis has been successfully administered to 42 patients, with acceptable toxicity. The median survival of 21 months exceeds our expectations; however, the relative contribution of surgical resection versus PDT is unknown. Deficiencies in photosensitizer delivery, tissue oxygenation, or laser light distribution leading to recurrences may be addressed through the future use of new photosensitizers.Presented at the 53rd Annual Meeting of the Society of Surgical Oncology, New Orleans, Louisiana, March 16-19, 2000.     

Photodynamic treatment of neoplastic lesions of the gastrointestinal tract

Photodynamic therapy (PDT) is a form of cancer treatment based on the selective accumulation of a photosensitizer (by exogenous or endogenous means) in neoplastic tissue. Subsequent activation of the photosensitizer by a specific wavelength of light results in tumor cell death. Activation of a photosensitizer to the appropriate energy state results in the production of singlet oxygen, a powerful oxidizing agent. PDT can kill cells by three mechanisms: direct cell death by photooxidation, apoptosis, or as a consequence of vascular shutdown. The toxicity of PDT is site specific and dependent on the organ being irradiated and the selectivity of the photosensitizer for target tissue over normal tissue. However, there are also reactions related to the sensitizer per se that are independent of those related to the treatment site. Such reactions include cutaneous photosensitization, nausea, vomiting, hypotension, and altered liver 'function' tests. Excitation of photosensitizer by an incident photon produces reemission of a fluorescent photon, which can be used to detect a tumor that is not ordinarily evident. The major limiting factor in using PDT is the depth of tumor kill. The majority of clinical experience involving PDT of the gastrointestinal tract involves patients who are considered to be poor operative risks, and reported follow-ups after treatment are not only limited but also variable.     

An ultrastructural study of human bladder cancer treated by photodynamic therapy

An electron microscopic study has been carried out biopsy material of transitional cell carcinoma of human bladder, taken before and after photodynamic therapy (PDT), from 14 patients. It has been demonstrated that bladder cancer is highly sensitive to PDT using haematoporphyrin derivative (HPD, made in China) and laser irradiation. It was found that vascular endothelium within the tumour tissue was very sensitive to PDT, showing distinct changes as early as immediately after completion of a 20-min irradiation. Twenty-four hours after PDT, almost all the capillaries examined were necrotic and broken down into small fragments. The cancer cells were less sensitive to PDT, being damaged later and less seriously than the blood vessels. It has been concluded that in PDT-treated tumours the vascular endothelium is damaged primarily while the cancer cells are destroyed, to a considerable extent, secondarily as the consequence of structural damage to capillaries and functional disturbance in the microcirculation. We would speculate that the main factor influencing the final response is the actual concentration of HPD in various types of cell in the tumours.     

Photodynamic therapy for treatment of malignant dysphagia

Photodynamic therapy (PDT) was recently approved by the Food and Drug Administration for palliating obstructing esophageal cancer. This report reviews our initial experience using PDT to treat malignant dysphagia. Patients with inoperable, obstructing esophageal cancer were considered for PDT. Photofrin was injected 48 hours before endoscopic laser activation. Dysphagia score was assessed. Thirty patients underwent 53 PDT courses. Improvement in dysphagia occurred in 83%. Mean dysphagia score decreased from 2.8 to 1.8 (p < 0.05). Complications included esophageal stricture (9.4%), candida esophagitis (5.7%), symptomatic pleural effusion (5.7%), contained esophageal perforation (1.9%), aspiration pneumonia (1.9%), and sunburn (13.2%). Seventeen patients (57%) required more than one PDT treatment, and in 10 an expandable metal stent was used as an adjunct. The 30-day mortality rate was 7%. PDT is effective in palliating patients with malignant dysphagia. The ideal patient for PDT has an obstructing, primarily endoluminal esophageal tumor with minimal extrinsic compression.     

Photodynamic Therapy Provides Local Control of Cholangiocarcinoma in Patients Awaiting Liver Transplantation

Many transplant centers use endoscopically directed brachytherapy to provide locoregional control in patients with otherwise incurable cholangiocarcinoma (CCA) who are awaiting liver transplantation (LT). The use of endoscopic retrograde cholangiopancreatography (ERCP)‐directed photodynamic therapy (PDT) as an alternative to brachytherapy for providing locoregional control in this patient population has not been studied. The aim of this study was to report on our initial experience using ERCP‐directed PDT to provide local control in patients with unresectable CCA who were awaiting LT. Patients with unresectable CCA who underwent protocol‐driven neoadjuvant chemoradiation and ERCP‐directed PDT with the intent of undergoing LT were reviewed. Four patients with confirmed or suspected CCA met the inclusion criteria for protocol LT. All four patients (100%) successfully underwent ERCP‐directed PDT. All patients had chemoradiation dose delays, and two patients had recurrent cholangitis despite PDT. None of these patients had progressive locoregional disease or distant metastasis following PDT. All four patients (100%) underwent LT. Intention‐to‐treat disease‐free survival was 75% at mean follow‐up of 28.1 months. In summary, ERCP‐directed PDT is a reasonably well tolerated and safe procedure that may have benefit by maintaining locoregional tumor control in patients with CCA who are awaiting LT.     

Percutaneous dilatational tracheostomy

BACKGROUND: The aim of this study was to investigate the rate, timing, the incidence of complications of percutaneous dilatational tracheostomy (PDT) and its effects by on nosocomial pneumonia. METHODS: The study is a retrospective analysis of 104 patients (56 males, 48 females) > or = 18 years (54 +/- 19) who had undergone a PDT for respiratory failure during the five years 1998-2003. RESULTS: Among 238 patients requiring mechanical ventilation > or = 48 hours, 104 (43.7%) required PDT. PDT was performed after 4.3 +/- 2.3 days of ventilation and the disconnection from mechanical ventilation was 13.6 +/- 8.5 days. Lower airway tract infection was detected in 88 patients: 55 patients (62.5%) before PDT and in 33 patients (37.5%) after PDT. The nosocomial pneumonia was observed after 5.9 +/- 1.67 days of ventilation. CONCLUSIONS: Our results suggest that PDT was performed relatively early, with an acceptable complication rate and that our post-PDT nosocomial pneumonia incidence is low.     

Percutaneous dilatational tracheostomy is as safe as open tracheostomy

Although percutaneous dilatational tracheostomy (PDT) has been advocated as an alternative to open tracheostomy (OT) its relative safety has been questioned repeatedly. This study prospectively compared the safety and complications of PDT and OT. Ninety-four patients underwent PDT and 252 patients underwent OT at this institution from December 1998 through April 2000 with the choice of procedure left to the operator. OT was performed in the operating room whereas PDT was performed in intensive care units (ICUs). PDT was performed by surgeons and medical intensivists under a strict institutional policy and procedure governing patient selection and conduct of the procedure. Complications were defined as bleeding, loss of airway, hypotension, hypoxia, tracheostomy tube malposition, subcutaneous emphysema, infection, and conversion of PDT to OT. All patients survived the operation. PDT and OT had similar complication rates: 2.1 per cent for PDT versus 2.8 per cent for OT (P = not significant). Postoperative bleeding, which was the most frequent complication, occurred in one PDT patient and four OT patients. One PDT patient required conversion to OT as a result of extensive tracheal fibrosis. Subcutaneous emphysema, soft-tissue infection, and a malpositioned tracheostomy tube were the remaining complications in the OT patients. We conclude that the complication rates of PDT and OT are comparable. The choice of PDT or OT should be dictated by the surgeon's training and experience, the patient's condition, neck anatomy, and stability for transfer to the operating room.     

Photodynamic therapy of superficial bladder tumors

Photodynamic therapy (PDT), using hematoporphyrin derivative (HPD) and the red light (wavelength 630 nm) of an argon-dye laser as the source of excitation energy was performed on 46 patients with superficial bladder tumors. Two methods of laser irradiation, (1) focal PDT using a 400 micron quartz fiber through a cystourethroscope in 22 patients with superficial bladder tumors and (2) whole bladder wall total PDT using a motor-driven laser light scattering device in 24 patients with multifocal carcinoma in situ and/or dysplasia of bladder mucosa associated with multicentric concurrent superficial tumors, were used. The patients in (2) had been referred for total cystectomy, and 19 of these 24 patients had a history of several transurethral resections, hyperthermia and/or instillation therapy. HPD 2-4 mg/kg was i.v. injected 48 to 72 hours before PDT. Judging from the results of 60 protrusions treated by focal PDT, the light power should be 200 mW/cm2 for 5-10 minutes or more and the total light energy should be 100 J/cm2 or more in tumors up to 2 cm in size. With focal PDT, 4 of the 22 patients had no recurrence with the mean tumor free time of 20.8 months. In 6 of the 24 patients treated with total PDT using 10, 20 or 30 J/cm2 of light energy, there was no recurrence with a mean tumor-free time of 7.5 months and there was no significant relationship between the recurrence rate and total light energy used.     

Photodynamic therapy of malignant brain tumours: a phase I/II trial

Twenty patients bearing malignant brain tumours (18 glioblastoma multiforme, one malignant meningioma, one melanoma metastasis) were treated 25 times with photodynamic therapy (PDT)--the combination of Hematoporophyrin derivative and light at 630 nm (40-120 J/cm2). Sixteen times the PDT was followed immediately by a single dose radiation of 4 Gy of fast electrons. Conventional radiotherapy following PDT was performed in eight patients. The median survival of three patients with multiple recurrences of glioblastoma grade IV and various chemo- and radiotherapy was 5 months. Four out of 10 patients with one recurrence and prior treatment died with a median survival of 5 months, six are still living up to 12 months. Six patients with a primary glioblastoma are surviving now up to 22 months. Phototoxicity to the skin, the only side effect of PDT, was noted in five cases, but did not pose any threat to the patients. The treatment did not affect the quality of life of the patients. Our preliminary results with the photodynamic treatment of malignant gliomas indicate that PDT might be a valuable addition to our armament in the treatment of such tumours.     

Photodynamic therapy of human colorectal carcinoma cell line

Colorectal cancer is one of the most common cancers in Europe and North America and it is the most common gastrointestinal carcinoma. The population in the Czech Republic has a higher incidence of colorectal carcinoma compared to other countries. Efforts are underway to develop better screening strategies and novel therapies to improve patient survival rates. Despite all efforts, colorectal cancer remains one of the leading causes of death from cancer. Photodynamic therapy (PDT) is an established modality for the treatment of various diseases. The PDT procedure involves the administration of a photosensitizer followed by illumination. The anti-tumor effects result from direct killing of malignant cells, shutting down of the tumor's vasculature, and the promotion of an immune response. In our experiment, we examined the effects of phototherapy with disulfonated hydroxyaluminum phthalocyanine (Al(OH)S2Pc) on the growth of colorectal carcinoma cells, in an effort to offer a new treatment modality for patients with this disease.     

Hyperbaric oxygen and photodynamic therapy in the treatment of advanced carcinoma of the cardia and the esophagus

BACKGROUND AND OBJECTIVE: The photochemical reaction of photodynamic therapy (PDT) depends on the presence of molecular oxygen. Because of anoxic regions in tumor tissue and vascular shutdown during PDT, the efficiency is limited. Therefore, the use of hyperbaric oxygen, which increases the oxygen in tumor tissue, as well as the amount of singlet oxygen, may enhance the efficiency of PDT. STUDY DESIGN/MATERIALS AND METHODS: After diagnostic work-up, photosensitization was carried out with a hematoporphyrin-derivate 2 mg/kg body weight 48 hours before PDT. The light dose was calculated as 300 J/cm of fiber tip. Twenty-three patients were treated by PDT alone and 29 patients received PDT under hyperbaric oxygen at a level of two absolute atmospheric pressures. RESULTS: Improvement regarding dysphagia and stenosis-diameter could be obtained in both treatment arms with no significant difference (P = 0.43 and P = 0. 065, respectively). The tumor length also decreased in both groups and showed a significant difference in favour of the PDT/HBO group (P = 0.002). The mean overall survival was 11.3 months. The mean survival time for the PDT group was 8.7 months and for the PDT/HBO group 13.8 months (P = 0.021). CONCLUSION: According to this pilot study, combined PDT/HBO represents a new approach in the treatment of esophageal and cardia cancer, which appears to have enhanced the efficiency of PDT.     

Weaning from ventilator after cardiac operation using the Ciaglia percutaneous tracheostomy.

OBJECTIVE: To determine the predictors of weaning from mechanical ventilation after cardiac operation with the Ciaglia percutaneous dilatational tracheostomy (PDT) in our preliminary experience in the use of this technique. METHODS: We prospectively analysed 33 consecutive patients (mean age 70.9+/-12.7 years) who underwent PDT in our intensive care unit after cardiac operation. The investigation involved preoperative and postoperative clinical status, operative procedure, indication and timing for PDT. RESULTS: PDT was performed after a mean time of 7.7+/-5.0 consecutive days of translaryngeal intubation. Twenty-four (73%) patients were weaned from ventilator after a mean time of mechanical ventilation of 15.8+/-9.1 days. Time point of PDT was the only predictor of ventilator weaning (P=0.0029): there was significant association between PDT performed before the seventh consecutive day of translaryngeal intubation (early PDT) and successful weaning from ventilator (P=0.01; odds ratio=11.2, 95% confidence interval=1.2-104.3). Among the patients weaned from ventilator, those who underwent early PDT had significantly shorter times of mechanical ventilation, and intensive care unit and hospital stays than patients with later PDT (P=0.035, 0.011 and 0.0073, respectively). Nine (27%) patients died of their underlying disease while still being mechanically ventilated; another six (18%) spontaneously breathing but still incannulated patients died afterward. No major PDT-related complications were observed. Two minor peristomal bleedings and one self-resolving subcutaneous emphysema were recorded. CONCLUSIONS: Early PDT was a safe and effective method to wean from mechanical ventilation the cardiosurgical patients of this series.     

Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma

Background: Patients with malignant pleural mesothelioma (MPM) usually die of progressive local disease. This report describes the results of a Phase III trial comparing maximum debulking surgery and postoperative cisplatin, interferon α-2b, and tamoxifen (CIT) immunochemotherapy with and without intraoperative photodynamic therapy (PDT) to determine (1) whether such a multimodal approach can be performed with minimum morbidity and mortality in malignant pleural mesothelioma (MPM), and (2) whether first-generation (i.e., 630-nm laser light, Photofrin II) intrapleural PDT impacts on local recurrence or survival. Methods: From July 1993 to June 1996, 63 patients with localized MPM were randomized to either PDT or no PDT. The tumors of 15 patients could not be debulked to 5 mm. Patients assigned to PDT (n=25) and no PDT (n=23) were similar with respect to age, sex, tumor volume, and histology. Results: The type of resection (11 pleurectomies and 14 pneumonectomies vs. 12 pleurectomies and 11 pneumonectomies), length postoperative stay, and ICU time were comparable (PDT vs. no PDT). There was one operative death (hemorrhage), and each group had two bronchopleural fistulas. Postoperative staging divided patients into the following categories: stage I: PDT, 2, no PDT, 2; stage II: PDT, 2, no PDT, 2; stage III, PDT, 21; no PDT, 17; stage IV, PDT, 0; 0; no PDT, 2. Comparable numbers of CIT cycles were delivered. Median survival for the 15 non-debulked patients was 7.2 months, compared to 14 months for the 48 patients on protocol. There were no differences in median survival (14.4 vs. 14.1 months) or median progression-free time (8.5 vs. 7.7 months), and sites of first recurrence were similar. Conclusions: Aggressive multimodal therapy can be delivered for patients with higher stage MPM. First-generation PDT does not prolong survival or increase local control for MPM. Presented at the 50th Annual Cancer Symposium of The Society of Surgical Oncology, Chicago, Illinois, March 20–23, 1997.     

Combined photodynamic therapy and hyperbaric oxygenation in carcinoma of the esophagus and the esophago-gastric junction

Objectives: The photochemical reaction of photodynamic therapy (PDT) depends on the presence of molecular oxygen. Due to anoxic regions in tumor tissue and vascular shutdown during PDT the efficiency is limited. Therefore, the use of hyperbaric oxygen which increases the oxygen in tumor tissue, as well as the amount of singlet oxygen, may enhance the efficiency of PDT. Patients and methods: After diagnostic work-up, photosensitization was carried out with a hematoporphyrin-derivate 2 mg/kg BW 48 h prior to PDT. The light dose was calculated as 300 J/cm fiber tip. Thirty-one patients were treated by PDT alone and 44 patients received PDT under hyperbaric oxygen at a level of two absolute atmospheric pressure. Results: Improvement regarding stenosis-diameter could be obtained in both treatment arms with no significant difference (P=0.82). The dysphagia-score and tumor-length also decreased in both groups and showed a significant difference in favour of the PDT/HBO-group (P=0.0064 and P=0.0002, respectively). The median overall survival for the PDT-group was 7 months and for the PDT/HBO-group 12 months (P=0.0098). Conclusion: According to this prospective non-randomized study, combined PDT/HBO represents a new approach in the treatment of esophageal and cardia cancer which appears to have enhanced the efficiency of PDT.