Enhanced tumor control following sequential treatments of photodynamic therapy (PDT) and localized microwave hyperthermia in vivo

Photodynamic therapy (PDT), or photoradiation therapy (PRT), utilizing hematoporphyrin derivative (HPD) as photosensitizer and an argon-dye laser system as the light source, was used alone and in combination with localized microwave hyperthermia (2450 MHz) to treat axillary tumors of the SMT-F mammary carcinoma in mice. Thirty-minute heat treatments were applied either immediately before or immediately after a standard PDT treatment of 630 nm light at 75 mW/cm2 for 30 min (135 J/cm2) given 24 hr post-7.5 mg/kg HPD, intraperitoneally (i.p.). Tumor control as judged by lack of tumor regrowth 35 days or longer after the combined treatments was compared to that following each treatment when given alone. Little or no enhancement of tumor control was seen when sublethal temperatures of 37.5, 38.5, and 39.5 degrees C were applied for 30 min immediately following the PDT treatment. However, increasing levels of enhancement were seen when heat treatments of 40.5 and 41.5 degrees C or 44.5 degrees C, given for 30 min, were applied immediately before or after the photodynamic treatment.     

Modulation of hematoporphyrin derivative-sensitized phototherapy with corynebacterium parvum in murine transitional cell carcinoma

The interaction of photodynamic therapy (PDT) with hematoporphyrin derivative (Hpd) and immunotherapy with Corynebacterium parvum (CP) was studied in a murine transitional cell carcinoma (MBT-2) model. C3H/He mice were transplanted subcutaneously in the hind limb with 2.5 X 10(5) tumor cells. One day after transplantation, mice were randomized into groups to receive saline (control), PDT, CP 25 micrograms, CP 250 micrograms, CP 25 micrograms + PDT, and CP 250 micrograms + PDT. PDT was administered by intraperitoneal (IP) injection of Hpd (12.5 micrograms/g body weight), followed twenty-four hours later by photoirradiation. CP was given intralesionally at the same time as IP injection of Hpd (24 hours before photoirradiation). A low dose of CP (25 micrograms) was shown to enhance the effect of PDT while PDT reduced the benefit obtained with high dose of CP (250 micrograms). In a second series of experiments, CP (250 micrograms) treatment after photoirradiation was shown to give significantly greater benefit than CP treatment before photoirradiation. The study thus indicates that the effectiveness of combined immunophototherapy is dependent on the sequence of the combination and its intricate relationship with the dosage of CP. The enhancement of PDT by low dose of CP in this model suggests the usefulness of this combined immunophototherapy in enhancing tumor control and in lessening deleterious side effects.     

Combination studies of hyperthermia induced by the neodymium: yttrium-aluminum-garnet (Nd:YAG) laser as an adjuvant to photodynamic therapy

Photodynamic therapy (PDT) and hyperthermia have been investigated as treatments for several types of tumors. Studies have been done to determine the efficacy of each modality individually and recently in combination with each other. In this study, 630-nm light was delivered by an argon-dye laser and hyperthermia was induced using an Nd:YAG laser. Both lasers offer the ability of delivering the beams through a quartz fiberoptic alone or simultaneously. This study examines the efficacy of the simultaneous administration of PDT and selective hyperthermia at 44.5 degrees C in tumor control in the spontaneous mammary tumor (SMT-F) in DBA mice. Hyperthermia alone (44.5 degrees C, 30 min) resulted in complete destruction of tumors, with no subsequent regrowth in 6.6% of the mice treated. PDT alone (5 mg/kg dihematoporphyrin ether; 135 J/cm) resulted in a cure rate of approximately 10%, and the simultaneous treatment of the modalities resulted in a 32.8% cure rate after 90 days. These values are indicative of a synergistic interaction.     

Intermittent hepatic arterial or portal occlusion reduces liver tumor growth

The effect of repeated, intermittent hepatic vascular occlusion on liver tumor growth was studied in 32 rats. An adenocarcinoma was inoculated in the left liver lobe. After 8 days, the tumor size was measured and then, in three groups, the hepatic artery was occluded intermittently during 5 days for 15 min, 1 hr, or 2 hr daily, respectively. The tumor growth after 6 days in these groups was compared with that in a group where instead the portal vein was occluded intermittently during 5 days for 15 min, and with that in a group of sham-operated control rats. In the control rats, the tumor volume (mean +/- SEM) increased from 0.16 +/- 0.03 to 1.34 +/- 0.15 cm3 during the 6 days of experiment. It was found that repeated, intermittent occlusion of the hepatic artery or the portal vein, retarded the liver tumor growth to 30-60% of the growth rate in sham-operated controls (P less than or equal to 0.015). The 15-min daily hepatic artery or portal vein occlusion was found to reduce the tumor growth rate as much as daily hepatic artery occlusion for 2 hr. It is suggested that short, daily, intermittent hepatic vascular occlusions might be efficient in the palliative treatment of liver malignancy.     

Laser acupuncture-induced analgesic effect and molecular alterations in an incision pain model: a comparison with electroacupuncture-induced effects

Low-level laser acupuncture (LLLA) produces photobiomodulation through acupuncture point and is an alternative to low-level laser therapy. Although the analgesic effect of LLLA on chronic pain has been proven, its effect on acute postincisional pain has yet to be investigated. A plantar incision (PI) model was used to mimic human postsurgical pain. Male adult rats received GaAlAs laser irradiation at the right ST36 acupoint immediately after operation and on the following 4 days. Three laser treatment groups (two red laser groups with a 30- or 15-min treatment duration and one 30-min near-infrared laser group) were compared with sham LLLA and naive groups and an electroacupuncture (EA) group (separate study). Behavioral withdrawal thresholds of both hind paws were measured before and after incision. Expression of mitogen-activated protein kinases (p-ERK and p-p38), inducible nitric oxide synthase (iNOS), and tumor necrosis factor (TNF) in the spinal cord was analyzed. All three LLLA treatments attenuated post-PI tactile allodynia in the ipsilateral paw, but only the 30-min red laser treatment affected the contralateral paw and had similar efficacy to that of EA. All laser treatments barely reduced heat hyperalgesia in both hind paws. At 3 days after PI, the 30-min red laser group showed reversed increases of PI-induced p-ERK, p-p38, and iNOS but not TNF expression in the spinal cord. Repetitive LLLA treatments ameliorated PI-induced mechanical pain. The inhibition of multiple sensitization signals highlights the unique clinical role of LLLA. Thus, LLLA is an alternative to EA as an adjuvant for postoperative pain control.     

Hyperthermic potentiation of photodynamic therapy employing Photofrin I and II: comparison of results using three animal tumor models

Hyperthermia induced by a microwave source (2,450 MHz) was used alone and in combination with photodynamic therapy (PDT) to treat the SMT-F, EMT-6, and RIF animal tumors in vivo. PDT was administered using either Photofrin I or II as the photosensitizer and an argon-pumped tunable dye laser (630 nm) as the light source. Greater than additive increases in long-term tumor control were achieved when hyperthermia was given immediately post-PDT in the SMT-F and RIF tumor systems. Only additive (or independent) increases in tumor control were achieved when hyperthermia was given immediately before PDT in all these tumor systems and when heat was applied post-PDT using the EMT-6 tumor. In a series of experiments using the SMT-F tumor, it was observed that decreases in PDT drug or light doses could be offset (in terms of tumor control) by the addition of a subsequent heat treatment. This result, along with others presented, indicates the clinical potential of PDT and hyperthermia as adjuvant cancer modalities.     

PSD-007介导的光动力疗法治疗小鼠骨肉瘤的实验研究

目的 观察光敏剂PSD-007对小鼠骨肉瘤细胞LM-8的体外及体内光动力效应.方法 PSD-007与LM-8细胞共同孵育后以激光照射,应用MTT法测定光密度(OD540)值,计算抑制率.40只C3H小鼠接种LM-8细胞,皮下瘤块直径7～8 mm时随机分为:(1)对照组,空白对照、生理盐水加光照、注射PSD-007不光照;(2)光动力治疗组,分别注射5mg/kg、10mg/kg PSD-007,6 h后以激光照射.1周后测量瘤体大小、重量,计算抑瘤率并行病理学检查.C3H小鼠30只建立肿瘤模型,肿瘤直径达10～12mm时,分别行肿瘤边缘切除无光动力治疗(对照组)、边缘切除后240 J/cm2光动力治疗及边缘切除后360 J/cm2光动力治疗.4周后比较肿瘤复发率.结果 体外只光照或只注射PSD-007对LM-8细胞均无杀伤作应.PSD-007浓度越高、激光照射强度越大,LM-8细胞OD540值越小.PSD-007浓度>4μg/ml,光照强度>6 J/cm2时,抑制率>50%.光镜下细胞形态呈坏死或凋亡样改变.体内实验显示光动力治疗组的肿瘤体积及瘤重均减小,肿瘤边缘切除高强度激光照射组的复发率较对照组低.结论 PSD-007对LM-8细胞有明确的光动力抑制效应,其作用大小取决于其浓度和激光照射强度.光动力疗法可以降低肿瘤边缘切除后的复发率.

Abstract：

Objective To evaluate the PSD-007-mediated photodynamic effect on mouse osteosarcoma cell line LM-8, both in vitro and in vivo. Methods LM-8 cells were incubated with different concentrations of PSD-007 for 4 hours and then followed different laser irradiations. After photodynamic therapy (PDT), cell viability was measured using MTT assay and the optical density in each experiment was measured at 450 nm with a micro plate reader. The inhibition rate of cell growth was calculated. Four-week-old female C3H mice were used for implantation of LM-8 cells. When the diameter of tumor reached up to 7-8 mm, the mice were randomly divided into following groups: 1) control group, including untreated control, saline with laser irradiation, PSD-007 without laser irradiation; 2) PDT group, PSD-007 (5 and 10 mg/kg) was injected intravenously into the mice, and the tumor site was irradiated with laser light 6 hours after injection. Seven days after PDT, the size and weight of the tumors were measured. The inhibition rate of tumor was calculated, and all tumor specimens were taken for pathologic examination. After the diameter of tumor was 10-12 mm, the tumors were performed a marginal resection and subsequently followed 3 different treatments: without PDT (control), PDT with 240 J/cm2 or 360 J/cm2 laser irradiation. After 4 weeks treatment, the tumor recurrence rates were analyzed. Results MTT assay revealed that the cytotoxic effect of PDT on the LM-8 cells was positively correlated with the concentration of PSD-007 and the level of laser irradiation. When the concentration exceeded 4μg/ml, and the energy exceeded 6 J/cm2, the inhibition ratio was over 50%. No anti-tumor effect was observed in the cells treated with only laser irradiation or PSD-007 injection. Compared with the control group, the size and weight of the tumors were obviously decreased after PDT. PDT performed after marginal resection of the tumor reduced the rate of local recurrence. Conclusion PDT with PSD-007 showed cytotoxic effect on the LM-8 cells, and which performed after marginal resection of the tumor reduced the rate of local recurrence.     

Effect of the Duration of Electrical Stimulation on the Analgesic Response in Patients with Low Back Pain

Background: Electrical stimulation of peripheral nerves produces acute analgesic effects. This randomized, sham-controlled, crossover study was designed to evaluate the effect of differing durations of electrical stimulation on the analgesic response to percutaneous electrical nerve stimulation in 75 consenting patients with low back pain.

Methods: All patients received electrical stimulation for four different time intervals (0, 15, 30, and 45 min) in a random sequence over the course of an 11-week study period. All active percutaneous electrical nerve stimulation treatments were administered using alternating frequencies of 15 and 30 Hz three times per week for 2 consecutive weeks. The prestudy assessments included the health status survey short form questionnaire and 10-cm visual analog scale scores for pain, physical activity, and quality of sleep, with 0 being the best and 10 being the worst. The pain scoring was repeated 5-10 min after each 60-min study session and 24 h after the last treatment session with each of the four methods. The daily oral analgesic requirements were assessed during each of the four treatment blocks. At the end of each 2-week treatment block, the questionnaire was repeated.

Results: Electrical stimulation using percutaneously placed needles produced short-term improvements in the visual analog scale pain, physical activity, and quality of sleep scores, and a reduction in the oral analgesic requirements. The 30-min and 45-min durations of electrical stimulation produced similar hypoalgesic effects (48 +/- 21% and 46 +/- 19%, respectively) and were significantly more effective than either 15 min (21 +/- 17%) or 0 min (10 +/- 11%). The 30- and 45-min treatments were also more effective in improving physical activity and sleep scores over the course of the 2-week treatment period. In contrast to the sham treatment (0 min), the health status survey short form revealed that electrical stimulation for 15 to 45 min three times per week for 2 weeks improved patient function.     

Adriamycin enhanced in vitro and in vivo photodynamic therapy of mesothelioma.

The ability of Adriamycin (AD) to enhance the known in vitro and in vivo tumoricidal effects of photodynamic therapy (PDT) on the H-MESO-1 human malignant mesothelioma cell line was investigated. In vitro cytotoxicity was determined by incubating H-MESO-1 cells in microtiter plates (2 x 10(5) cells/well, 6 wells/group) with the photosensitizer Photofrin II (PF) and varying concentrations of AD (0, 2.5, 5.0, and 10.0 micrograms/ml) for 24 hr followed by exposure to gold vapor laser light (GVL) at a fluence of 6000 J/M2. [3H]Thymidine (1 microCi) was added to each well 24 hr after treatment. Cells were harvested and counted for thymidine incorporation 24 hr later. PDT alone resulted in a decrease in thymidine incorporation of 23% while the addition of AD to PDT at AD concentrations of 2.5, 5.0, and 10.0 micrograms/ml resulted in decreases of 62, 85, and 69%, respectively (P = 0.005) as compared to untreated controls. H-MESO-1 tumor bearing nude mice (n = 5) were injected ip with PF (5 mg/kg) and AD (5 mg/kg) 24 hr prior to illumination of the tumor site with GVL (120 J/cm2). Control groups (n = 5) received PDT, AD, and/or GVL alone. Tumor surface area was measured as the product of the greatest perpendicular dimensions every 5 days for 30 days. Administration of PDT without AD resulted in a decrease in tumor surface area of 50% on Day 10 with regrowth of tumor by Day 30 while AD alone with or without GVL had no impact on tumor growth.(ABSTRACT TRUNCATED AT 250 WORDS)     

Photodynamic therapy for endobronchial metastases from nonbronchogenic primaries

BACKGROUND: Endobronchial metastases (EBM) occur in 2% of nonbronchogenic malignancies and frequently present with hemoptysis or dyspnea. This report summarizes our recent experience with photodynamic therapy (PDT) for EBM. METHODS: All patients who have undergone PDT for the treatment of symptomatic EBM from nonbronchogenic primaries were identified in the Division of Thoracic Surgery database to determine number of treatments, frequency of symptom relief, and patient survival. RESULTS: Endobronchial PDT was administered to 27 patients from April 1997 through December 2000. The predominant primary tumor was renal cell (44%). Endobronchial metastases presented metachronously in 74% of patients. Patients underwent a median of two PDT treatments. Local anesthesia with sedation was used in 76% of treatments. Four patients (15%) developed immediate postoperative respiratory distress. Follow-up bronchoscopy 24 to 48 hours after initial treatment demonstrated tumor necrosis in all cases. Acute relief of hemoptysis and dyspnea was achieved in 85% of patients. Seven patients died within 6 weeks of treatment. Median survival time after PDT was 4 months (range 0.2 to 30 months). CONCLUSIONS: Patients with EBM treated with PDT had a median survival of 4 months and patients with limited metastatic disease survived up to 30 months. Photodynamic therapy was effective in palliating hemoptysis or dyspnea from EBM with an acceptable morbidity, although the 30-day mortality was 22%.     

Sequential whole bladder photodynamic therapy treatments: A preclinical study

We postulated that sequential whole bladder photodynamic therapy (WBPDT) treatments with a low WBPDT dose would result in improved safety profile and good local tumor control. However, the drawback with such a proposal is the potential cumulative effect of sequential WBPDT treatments on bladder function. We designed this preclinical study to determine the safety of sequential WBPDT treatments. Six female dogs underwent a single WBPDT treatment comprising 1.5 mg/kg of Photofrin? and 15 J/cm(2) of light. Four dogs received a second treatment; and three dogs received three treatments. Pre- and post-WBPDT evaluations included cystoscopy and saline cystometry at baseline, 1 week, and 12 weeks. Gross and histopathologic analysis of cystectomy specimens occurred at 1 and 12 weeks. A single photodynamic therapy (PDT) treatment induced average bladder capacity losses of 11% (0-33) and 0% at post-WBPDT weeks 1 and 12, respectively. A second sequential WBPDT treatment caused average bladder capacity losses of 36% (0-57%) and 17% (2-24%) at weeks 1 and 12, respectively. Three sequential WBPDT treatments induced average bladder capacity losses of 22% (0-42) and 0% at weeks 1 and 12, respectively. Full recovery in bladder capacity occurred in all cases except after the second sequential treatment, which induced a persistent bladder capacity loss of 17% at 12 weeks. Histopathologic analysis of cystectomy specimens revealed a focal discernible injury to the superficial muscle in only one of the dogs that received three treatments. We conclude that sequential WBPDT treatments using low dose PDT Photofrin? (1.5 mg/kg and light ≤15 J/cm(2)) is safe, and we recommend using this low WBPDT dose in clinical investigation.     

Effect of the duration of electrical stimulation on the analgesic response in patients with low back pain

BACKGROUND: Electrical stimulation of peripheral nerves produces acute analgesic effects. This randomized, sham-controlled, crossover study was designed to evaluate the effect of differing durations of electrical stimulation on the analgesic response to percutaneous electrical nerve stimulation in 75 consenting patients with low back pain. METHODS: All patients received electrical stimulation for four different time intervals (0, 15, 30, and 45 min) in a random sequence over the course of an 11-week study period. All active percutaneous electrical nerve stimulation treatments were administered using alternating frequencies of 15 and 30 Hz three times per week for 2 consecutive weeks. The prestudy assessments included the health status survey short form questionnaire and 10-cm visual analog scale scores for pain, physical activity, and quality of sleep, with 0 being the best and 10 being the worst. The pain scoring was repeated 5-10 min after each 60-min study session and 24 h after the last treatment session with each of the four methods. The daily oral analgesic requirements were assessed during each of the four treatment blocks. At the end of each 2-week treatment block, the questionnaire was repeated. RESULTS: Electrical stimulation using percutaneously placed needles produced short-term improvements in the visual analog scale pain, physical activity, and quality of sleep scores, and a reduction in the oral analgesic requirements. The 30-min and 45-min durations of electrical stimulation produced similar hypoalgesic effects (48+/-21% and 46+/-19%, respectively) and were significantly more effective than either 15 min (21+/-17%) or 0 min (10+/-11%). The 30- and 45-min treatments were also more effective in improving physical activity and sleep scores over the course of the 2-week treatment period. In contrast to the sham treatment (0 min), the health status survey short form revealed that electrical stimulation for 15 to 45 min three times per week for 2 weeks improved patient function. CONCLUSION: The recommended duration of electrical stimulation with percutaneous electrical nerve stimulation therapy is 30 min.     

Photodynamic therapy for human malignant mesothelioma in the nude mouse

Photodynamic therapy (PDT) utilizes a photoactivatable preparation, Photofrin II, which selectively localizes in cancerous tissue and produces substances toxic to that tissue when activated by light. Whether PDT would be able to selectively destroy human malignant mesothelioma was investigated by using a human-derived malignant mesothelioma tumor subcutaneously implanted in nude mice. Human malignant mesothelioma was grown subcutaneously to a size of 0.2-0.4 cm3. Selective retention of Photofrin II was studied by measuring light-induced inhibition of cytochrome c oxidase activity in tumor, heart, and lung. Photofrin II was retained in greater quantities in tumor than in heart or lung at 24 hr after injection. Using laser light at 630 nm under varying conditions, tumor growth was measured every 2 days following PDT for 18 days. All PDT regimens were successful in destroying malignant mesothelioma. Photofrin II at 5 mg/kg was superior to 2 mg/kg (P less than 0.005), light delivered at 50 mW/cm2 x 2 hr was superior to that delivered at 200 mW/cm2 x 30 min (P less than 0.05), and a total fluence of 180 J/cm2 was equivalent to 360 J/cm2 in affecting tumor growth. Ten of 12 mice treated at 50 mW/cm2 became tumor-free and remained so for 30 days following treatment. We concluded that PDT was effective against human malignant mesothelioma in a nude mouse model without adversely affecting the animal. A role for PDT in treating patients with malignant mesothelioma may exist.     

Surgical and palliative management and outcome in 184 patients with hilar cholangiocarcinoma: palliative photodynamic therapy plus stenting is comparable to r1/r2 resection

OBJECTIVE: First, to analyze the strategy for 184 patients with hilar cholangiocarcinoma seen and treated at a single interdisciplinary hepatobiliary center during a 10-year period. Second, to compare long-term outcome in patients undergoing surgical or palliative treatment, and third to evaluate the role of photodynamic therapy in this concept. SUMMARY BACKGROUND DATA: Tumor resection is attainable in a minority of patients (<30%). When resection is not possible, radiotherapy and/or chemotherapy have been found to be an ineffective palliative option. Recently, photodynamic therapy (PDT) has been evaluated as a palliative and neoadjuvant modality. METHODS: Treatment and outcome data of 184 patients with hilar cholangiocarcinoma were analyzed prospectively between 1994 and 2004. Sixty patients underwent resection (8 after neoadjuvant PDT); 68 had PDT in addition to stenting and 56 had stenting alone. RESULTS: The 30-day death rate after resection was 8.3%. Major complications occurred in 52%. The overall 1-, 3-, and 5-year survival rates were 69%, 30%, and 22%, respectively. R0, R1, and R2 resection resulted in 5-year survival rates of 27%, 10%, and 0%, respectively. Multivariate analysis identified R0 resection (P < 0.01), grading (P < 0.05), and on the limit to significance venous invasion (P = 0.06) as independent prognostic factors for survival. PDT and stenting resulted in longer median survival (12 vs. 6.4 months, P < 0.01), lower serum bilirubin levels (P < 0.05), and higher Karnofsky performance status (P < 0.01) as compared with stenting alone. Median survival after PDT and stenting, but not after stenting alone, did not differ from that after both R1 and R2 resection. CONCLUSION: Only complete tumor resection, including hepatic resection, enables long-term survival for patients with hilar cholangiocarcinoma. Palliative PDT and subsequent stenting resulted in longer survival than stenting alone and has a similar survival time compared with incomplete R1 and R2 resection. However, these improvements in palliative treatment by PDT will not change the concept of an aggressive resectional approach.     

Photodynamic therapy for head and neck cancer xenografts in athymic mice

This study examines efficacy and optimal treatment variables of photodynamic therapy (PDT) for human head and neck squamous cancer (HNSC) xenografts in athymic mice. Two and four days after injection of hematoporphyrin derivative (HPD), tumors were illuminated with red light from an argon-dye laser. Sixty-three tumors were treated. With HPD dose and light intensity constant at 7.5 mg/kg and 100 mW/cm2, respectively, the extent of tumor necrosis was strongly dependent on duration of light exposure. There was no substantial difference in results for 30- and 60-minute treatment durations between animals injected with HPD 2 and 4 days before treatment. After 30 minutes treatment time, responses were seen in 8 of 10 mice (2 days post-HPD) and 11 of 12 mice (4 days post-HPD). After 60 minutes treatment time, toxicity was high. We conclude that, in this model, PDT is effective in selective killing of HNSC. For future comparison studies in this model, if the indicated HPD dose and light intensity are used we recommend a 2-day delay after HPD injection and a light exposure duration of 30 minutes.     

Stereotactic intratumoral photodynamic therapy for recurrent malignant brain tumors.

Photodynamic therapy (PDT) using purified hematoporphyrin derivative and stereotactic intratumorally implanted optical laser fiber(s) was used to treat patients with recurrent malignant gliomas and metastatic melanoma of the brain. Tumor response to PDT was evaluated by recording changes in the volume and pattern of tumor enhancement between computed tomographic and magnetic resonance imaging scans done before and after PDT, metabolic changes in tumor tissue by 31P magnetic resonance spectroscopy, and patient outcome. Toxicity of PDT to brain was evaluated on the basis of changes in the patients' neurological examinations and correlated with changes in brain adjacent to tumor seen on postoperative imaging studies. Dramatic tumor responses to PDT were seen in all gliomas, but no response of tumor to treatment was seen with melanoma. Transient signs and symptoms of increased peritumoral cerebral edema caused by PDT were seen in all patients. Two patients suffered permanent neurological sequelae, monocular blindness and a partial visual field defect, as a result of treatment. Two patients with recurrent anaplastic astrocytomas remain in remission at 45 and 35 weeks after PDT. We conclude that intratumoral photoradiation therapy of hematoporphyrin derivative-photosensitized malignant gliomas effectively produces necrosis of the solid component of malignant gliomas; however, intratumoral photoradiation may not reach the portion of tumor that invades normal brain.     

Effect of photodynamic therapy in a multimodal approach for advanced carcinoma of the gastro-esophageal junction

Background and Objective We wanted to determine the role of additional photodynamic therapy in a multimodal approach for the treatment of patients with advanced cancer of the gastro-esophageal junction. Study Design/Materials and Methods We reviewed 53 patients, after endoluminal palliation, with advanced cancer of the gastro-esophageal junction. Combined dilatation and retrograde tumor disobliteration with Nd-YAG laser before photodynamic therapy (PDT), brachyradiotherapy, or both, became necessary in 12 patients. Brachyradiotherapy was carried out in all patients. PDT before brachyradiotherapy was performed in 25 patients. The endoluminal treatment was completed by external beam irradiation in 30 patients (15 cases with PDT and 15 without PDT) with an at least fair performance status. RESULTS: Photodynamic therapy showed a significant difference regarding the mean opening of the tumor stenosis (mean, 6.4 mm; P = 0.0002), the mean decrease in tumor length (3.1 cm; P = 0.00001) and the increase in median survival (13. 8 months; P = 0.001). The combined multimodal approach by using PDT, brachyradiotherapy and external beam irradiation showed a median survival of 16.8 months. However, additional external beam irradiation showed no significant difference (P = 0.11). The rate of severe complications was 5.7%. The mortality rate was 1.9%. CONCLUSION: Photodynamic therapy has been shown to be an effective treatment for palliation of advanced cancer at the gastro-esophageal junction. The use of PDT combined with irradiation was associated with an acceptable survival rate, low rates of complications and reasonable quality of life.     

Enhancing the antitumoral effect of hypericin-mediated photodynamic therapy by hyperthermia

BACKGROUND AND OBJECTIVES: In the previous study, we have found a synergistic effect on the RIF-1 tumor cell killing when hypericin-mediated photodynamic therapy (PDT) was combined with hyperthermia. The purpose of the present study was to investigate the antitumoral effect of hypericin-PDT in combination with hyperthermia in the RIF-1 mouse tumor model. STUDY DESIGN/MATERIALS AND METHODS: Tumor response to PDT in combination with hyperthermia was compared to the response to PDT or hyperthermia alone. To explore the possible mechanism involved in the interaction of PDT and hyperthermia, we determined the tumor cell survival by in vivo/in vitro cell survival assay and analyzed the functional blood vessels by Hoechst 33342 staining. The mode of cell death was examined by TUNEL assay. RESULTS: Enhanced tumor response was obtained by PDT immediately followed by hyperthermia. Tumor cell survival assay revealed that indirect vascular effect contributed greatly to the overall tumor cell death induced by PDT with hypericin, whereas direct tumor cytotoxicity played a major role in hyperthermia-induced tumor cell killing. Combining PDT with hyperthermia brought about a synergistic interaction on direct tumor cell killing. Even though PDT or hyperthermia alone induced severe blood vessel shutdown and the combined treatments led to significant potentiation of the vascular damage as examined by Hoechst staining, the gain in tumor cell death as a result of this secondary vascular effect was limited after the combined treatments. Following the cellular damage by PDT in combination with hyperthermia, tumor cells were triggered to undergo apoptosis. CONCLUSIONS: Our study demonstrated the possibility of using hyperthermia to potentiate the antitumoral effect of hypericin-mediated PDT.     

Immediate changes in subcellular structures of transplanted tumors following photodynamic and laser hyperthermic therapy

Background and Objective: To further understand the precise process of the tumor cell degeneration after photodynamic therapy (PDT), laser hyperthermic therapy (LH), and combined treatments using an Nd:YAG laser. It is important to examine initial morphological alteration of tumor cells after these treatments. Study Design/Materials and Methods: In this study, nude mice bearing HeLa cell tumors were treated with PDT, LH, and combined treatments of the two. Tumor tissues obtained immediately after these treatments were analyzed using electron microscopy and morphometry. Results: In the combined treatments, which produced more severe effects on tumor cells, morphological features of apoptosis such as cytoplasmic condensation, blebs, and apoptotic bodies appeared in the cells, although the typical alteration in the nuclear chromatin was not seen. Conclusion: Cytoplasmic alterations may proceed more rapidly than nuclear alterations in the cellular degeneration induced by the single or combined treatments of PDT and LH.     

Protective effect of aprotinin on ischemic hepatocellular damage

During hepatic resection, occlusion of the hepatoduodenal ligament has been frequently applied to prevent intraoperative bleeding. To reduce hepatocellular ischemic damage in this procedure, we pretreated animals with Aprotinin. Three hours after an intravenous injection of 40,000 KIU Aprotinin in SD rats, we occluded the afferent hepatic vessels for 50-min and 60-min periods. 92% of occluded animals could sustain life after 60 min. Without premedication only 17 of 25 animals (68%) survived the 50-min occlusion, and 18 of 32 (56%) the 60-min occlusion. Biochemical analysis of sera was carried out 12 hr after a 40- and 60-min occlusion of the hepatoduodenal ligament with Aprotinin pretreatment. Furthermore we induced compensatory cirrhosis by application of CCL4 and biochemical analysis of sera was carried out after a 30-min occlusion. The elevation of SGOT and SGPT values was drastically reduced in the animals with Aprotinin medication in comparison with those without treatment. These observations suggest the highly protective effect of Aprotinin in the case of warm ischemic hepatic damage, especially in the cirrhotic liver. After pretreatment of LEW rats with Aprotinin (40,000 KIU i.v.), we perfused the livers with chilled Ringer solution containing 40,000 KIU Aprotinin/20 ml. We transplanted the livers orthotopically into LEW rats. With the application of Aprotinin liver preservation time increased to 10-15 hr. However, without Aprotinin the livers could be successfully preserved for only 4-6 hr. Our results indicated that premedication with high doses of Aprotinin provided highly protective effects against warm and cold ischemic damage of the liver.