Antiangiogenic photodynamic therapy (PDT) using Visudyne causes effective suppression of tumor growth

We previously observed that antiangiogenic photodynamic therapy (PDT), namely, laser irradiation at 15 min after administration of photosensitizer, by using stable liposomal benzoporphyrin derivative monoacid ring A (BPD-MA), in which the liposomes were composed of dipalmitoylphosphatidylcholine, palmitoyloleoylphosphatidylcholine, cholesterol, and dipalmitoylphosphatidylglycerol (10:10:10:2.5 as a molar ratio), was quite effective for cancer treatment. On the other hand, Visudyne, a commercialized liposomal formulation of BPD-MA, is based on more fluid lipids, namely, dimyristoylphosphatidylcholine and egg yolk phosphatidylglycerol, and is thought to be less stable in the presence of serum. The data of spin column chromatography indicated a little faster transfer of BPD-MA from Visudyne to lipoprotein fraction when Visudyne was incubated with serum than when the stable liposomal BPD-MA was used. The phototoxicity of Visudyne against a human endothelial cell line, ECV304, was almost the same as that of stable liposomal BPD-MA after PDT treatment. Therefore, we examined the antiangiogenic scheduling of PDT with Visudyne. Tumor growth of Meth-A sarcoma-bearing mice was strongly suppressed when the antiangiogenic scheduling was performed with Visudyne, namely, irradiation at 15 min after injection of the drug, in comparison with the conventional scheduling in which laser irradiation is done at 3 h post-injection. This greater effectiveness of PDT at 15 min was suggested to be caused by hemostasis, based on observations made in a dorsal air sac angiogenesis model. Visudyne-mediated antiangiogenic PDT cured 40 or 60% of Meth-A-bearing mice completely when 0.25 or 0.5 mg/kg BPD-MA, respectively, was used. These data suggest that the antiangiogenic scheduling is effective in Visudyne-mediated cancer PDT despite the transferring of BPD-MA from the liposomal fraction to lipoproteins in the bloodstream.     

Recurrent ovarian cancer with cancer peritonitis treated with weekly paclitaxel infusion--a clinicopharmacological study

We treated a patient with recurrent ovarian cancer with cancerous peritonitis by weekly paclitaxel (w-TXL) therapy (65 mg/m2). Abdominocentesis was not performed to eliminate ascites, in order to maintain higher quality of life (QOL), and critical adverse reaction was not seen for 12 months. We measured the TXL concentration in blood plasma and ascites after TXL infusion by HPLC method. The TXL titer in plasma was 427 ng/ml after infusion, 23 ng/ml after 24 hours and under 10 ng/ml after 48 hours. The TXL titer in ascites was 41 ng/ml after infusion, 37 ng/ml after 6 hours, 18 ng/ml after 12 hours, 10 ng/ml after 24 hours and under 10 ng/ml after 48 hours. TXL transportation from blood to ascites was good. This result suggested that intravenous infusion of TXL was effective for cancerous peritonitis treatment.     

Evaluation for reliability and feasibility of the draft protocol for the enhanced rat 28-day subacute study (OECD Guideline 407) using androgen antagonist flutamide

As part of an international validation project to establish a test protocol for the 'Enhanced OECD Test Guideline no. 407', a 28-day repeated dose study of flutamide was performed (1) to examine which of the current and/or additional parameters can detect endocrine effects of test chemicals most reliably and sensitively, (2) to investigate whether it is actually feasible to routinely include all additional parameters into the testing routine, and (3) to assess intra-laboratory variability by performing two identical studies (experiments A and B) in parallel using groups of five animals each per dose and sex. Groups of five male and five female CD(SD)IGS rats were treated by oral gavage with 0, 1, 10 and 100 mg flutamide/kg body weight for at least 28 days. The dose level considered to be around the MTD (100 mg/kg) exerted the expected antiandrogenic effects on androgen related tissues: significant decrease of the weights of androgen dependent organs and the sperm count and increase in histopathological lesions. At the middle dose (10 mg/kg), significant decrease of prostate weight (ventral and dorso-lateral parts combined) was observed and it was suggested that weight measurement of androgen dependent organs provides the most reliable and sensitive endpoint with this protocol. As for the feasibility, because of many items in this protocol, selection should be based on the sensitivity. From our data, addition of weight measurement of androgen dependent organs to the items of the existing OECD 407 guideline might allow accurate screening for endocrine disruptors. At the dose level considered to be around the MTD, the findings achieving statistical significance in one experiment with five animals/dose/sex could be reproduced in the second experiment, and evaluation with the small groups was consistent with findings using the combined groups of 10 animals/dose/sex. The results demonstrate that the protocol can reliably detect antiandrogenic effects of flutamide.     

Surgery combined with radiosurgery of large acoustic neuromas

The treatment of acoustic neuromas has been improved by advancements in microsurgical techniques and in radiosurgery. To further elucidate the degree of clinical improvement, we evaluated the treatment results of a combination of surgery and radiosurgery for large acoustic neuromas. METHODS: From January 1994 through December 2000, we treated 14 patients with large acoustic neuromas using a combination of surgery and radiosurgery. Of these, 8 were male and 6 were female patients, with an average age of 47 years (range, 18-64). The average maximum diameter of the tumor was 42 mm (range, 30-58 mm). All patients underwent operations using the retrosigmoid approach, and one patient was retreated using the transpetrosal transtentorial approach. The tumors were removed subtotally in thirteen patients and partially in one who had a very large hypervascular acoustic neuroma. There were no mortality and no surgical complications, such as hemorrhage or CSF leakage. Postoperative facial palsy was avoided in 10 patients (71%). Radiosurgery was performed 1 to 6 months (mean, 2.9 months) after surgery. At the time of radiosurgery, the treatment size (mean diameter) became 19.2 mm (range, 9.8-36.1 mm). The average tumor marginal dose was 12.1Gy (range, from 10-14 Gy). The mean follow-up period was 32 months after radiosurgery. RESULTS: The tumor size decreased in 6 patients, unchanged in 5 patients, and increased in 3 patients. Only 1 patient (7%) with extra large tumor needed surgical resection 1 year after radiosurgery. Excellent facial nerve function (House & Brackmann Grade I or II) was preserved in 12 patients (85.7%) in the final follow-up. CONCLUSIONS: In the case of large acoustic neuromas, subtotal removal and subsequent radiosurgery is one option for maintaining cranial nerve function and long-term tumor growth control.     

Optimal temperature for the management of severe traumatic brain injury: effect of hypothermia on intracranial pressure,systemic and intracranial hemodynamics,and metabolism

OBJECTIVE: We studied the effect of hypothermia on intracranial pressure, systemic and intracranial hemodynamics, and metabolism in patients with severe traumatic brain injury to clarify the optimal temperature for hypothermia, with a view toward establishing the proper management techniques for such patients. METHODS: The study was performed in 31 patients with severe head injury (Glasgow Coma Scale score as high as 5). All patients were sedated, paralyzed, ventilated, and cooled to 33 degrees C. Brain temperature, core temperature, intracranial pressure, cerebral perfusion pressure, jugular venous oxygen saturation, mixed venous oxygen saturation, cardiac output, oxygen delivery, oxygen consumption, and resting energy expenditure were monitored continuously. RESULTS: Intracranial pressure decreased significantly at brain temperatures below 37 degrees C and decreased more sharply at temperatures 35 to 36 degrees C, but no differences were observed at temperatures below 35 degrees C. Cerebral perfusion pressure peaked at 35.0 to 35.9 degrees C and decreased with further decreases in temperature. Jugular venous oxygen saturation and mixed venous oxygen saturation remained in the normal range during hypothermia. Resting energy expenditure and cardiac output decreased progressively with hypothermia. Oxygen delivery and oxygen consumption decreased to abnormally low levels at rectal temperatures below 35 degrees C, and the correlation between them became less significant at less than 35 degrees C than that when temperatures were 35 degrees C or higher. Brain temperature was consistently higher than rectal temperature by 0.5 +/- 0.3 degrees C. CONCLUSION: These results suggest that, after traumatic brain injury, decreasing body temperature to 35 to 35.5 degrees C can reduce intracranial hypertension while maintaining sufficient cerebral perfusion pressure without cardiac dysfunction or oxygen debt. Thus, 35 to 35.5 degrees C seems to be the optimal temperature at which to treat patients with severe traumatic brain injury.     

Optimal lymphadenectomy for squamous cell carcinoma in the thoracic esophagus: comparing the short- and long-term outcome among the four types of lymphadenectomy

Abstract Controversy continues over the optimal extent of lymphadenectomy (regional versus three-field) for a potentially resectable squamous cell carcinoma in the thoracic esophagus. In the Consensus Conference of the International Society for Diseases of the Esophagus (ISDE), held in Munich in 1994, the types of lymphadenectomy were classified as standard, extended, total, or three-field lymphadenectomy. The objective of the present study was to determine the optimal procedure among these four types of lymphadenectomy. The mortality and morbidity rates, postoperative course, and survival rates were compared among 302 patients who underwent curative (R0) transthoracic esophagectomy with one of these four types of lymphadenectomy at Kurume University Hospital, Fukuoka, Japan, from 1986 to 1998. Three-field lymphadenectomy resulted in better survival than any other type of lymphadenectomy for patients with positive lymph node metastasis from a cancer in the upper or middle thoracic esophagus. A postoperative complication, such as recurrent laryngeal nerve paralysis, anastomotic leakage, and tracheal ischemic lesion, was significantly more common after three-field lymphadenectomy. However, the mortality rate was the same among the four procedures. Three-field lymphadenectomy was optimal for an upper or middle thoracic esophageal cancer with metastasis in the lymph node(s) based on improved long-term survival, whereas there was not a large difference in short-term and long-term outcomes after the four types of lymphadenectomy for a lower thoracic esophageal cancer. Electronic Publication     

Lack of estrogenic or (anti-)androgenic effects of d-phenothrin in the uterotrophic and Hershberger assays

Synthetic pyrethroids are among the most common insecticides and pesticides currently in use worldwide. Recently, d-phenothrin, a synthetic pyrethroid, is suspected to have endocrine activities through the estrogen and androgen receptors. However, no study has been conducted to evaluate its potential for hormonal activity using an in vivo test specifically focused on estrogenic and androgenic activities. In this study, we evaluated the interaction of d-phenothrin (0, 100, 300 or 1000 mg/kg per day, p.o.) with estrogen- or androgen-mediated mechanisms using in vivo short-term assays. While internationally standardized protocols for the uterotrophic and Hershberger assays have not yet been fully developed, both are widely used and are being considered by the OECD as short-term screening assays for hormonal activity. The highest dose level tested for d-phenothrin was a limit dose (1000 mg/kg per day) designated in the current draft protocol by the OECD, and in fact there was no excessive systemic toxicity in both assays; slightly increased liver weight but no change of serum androgen levels in accessing anti-androgenicity. Potential estrogenic effect of d-phenothrin was evaluated by means of 3-day uterotrophic assay using immature Crj:CD(SD)IGS rats (20 days of age). No increase in uterine weight (wet or blotted) was observed following oral exposure to d-phenothrin. Reference control ethynyl estradiol (0.001 mg/kg per day) showed a significant effect in this assay protocol. A 10-day Hershberger assay using castrated peripubertal male rats measures the androgenic or anti-androgenic effects of the test chemicals on several accessory glands/tissues (the ventral prostate, dorso-lateral prostate, seminal vesicles with coagulating glands, levator ani plus bulbocavernosus muscles, glans penis and Cowper's glands). d-Phenothrin was administered by oral gavage for 10 days to castrated male Crj:CD(SD)IGS rats (7 weeks of age, rats were castrated at 6 weeks of age) with or without co-administration of 0.2 mg/kg per day testosterone propionate (subcutaneous injection on the dorsal surface). Reference controls of methyltestosterone and p,p'-DDE (100 mg/kg per day) provided significant effects in this assay protocol, whereas d-phenothrin did not show any androgenic or anti-androgenic effects. It is concluded that, based on the results of these two reliable in vivo assays, d-phenothrin exhibits no potential to cause adverse estrogenic or (anti-)androgenic effects even at dose of 1000 mg/kg per day, the limit dose designated in the current draft protocol by the OECD.     

Laryngeal preservation with definitive radiotherapy in radiosensitive hypopharyngeal cancer

Fifty-seven patients with hypopharyngeal cancer treated by irradiation at Kyushu University Hospital between 1985 and 1992 were analyzed retrospectively. They included 53 men and 4 women, and their ages ranged from 39 to 83 years (mean, 63 years). Two patients had stage I, 7 had stage II, 13 had stage III, and 35 had stage IV disease according to the UICC (1997) classification. Initially, they were irradiated in the conventional way with a dose of 30 Gy, and 17 patients with good response were irradiated to curative dose (more than 60 Gy), and 32 patients with poor response were operated immediately. Medically inoperable or unresectable patients were treated in a semiradical way (n = 8). The 5-year overall and cause-specific survival rates were 46% and 51%, respectively. Five-year cause-specific survival rates were 88% for stages I and II (n = 9), 67% for stage III(n = 13), and 35% for stage IV (n = 35). Five-year cause-specific survival according to treatment method was 58% for surgery and 51% for curative radiotherapy. There was no statistically significant difference between the two rates. These results suggest that initial radiation response is an important factor in deciding on the following treatment method. Curative radiotherapy for hypopharyngeal cancer according to initial radiation response is a desirable treatment strategy.     

Enhanced antitumor effects of a bicistronic adenovirus vector expressing both herpes simplex virus thymidine kinase and monocyte chemoattractant protein-1 against hepatocellular carcinoma

The efficacy of the suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system for the treatment of cancer is limited because of the insufficient gene transfer and the low killing activity. To enhance the antitumor activity, we determined whether recombinant adenovirus vector (rAd)s expressing both HSV-tk and monocyte chemoattractant protein-1 (MCP-1) genes could potentiate the destruction of hepatocellular carcinoma (HCC). The rAd Ad-tk-MCP1 harboring HSV-tk and MCP-1 genes in sequence under the universal CAG promoter was constructed with a bicistronic unit including the encephalomyocarditis virus-internal ribosomal entry site. The levels of HSV-tk expression and GCV-sensitive tumoricidal activity of Ad-tk-MCP1 were comparable to those of rAd expressing HSV-tk alone. The growth of subcutaneous tumors in athymic nude mice was markedly suppressed when tumors were treated with Ad-tk-MCP1 as opposed to another bicistronic vector Ad-MCP1-tk, rAd expressing either HSV-tk or MCP-1, or both of these vectors. The antitumor effects of Ad-tkMCP1 may be dependent on the activation of macrophages, since the recruitment of macrophages was observed tumor necrosis factor-alpha production was enhanced in the tumor tissue. Furthermore, the enhanced antitumor effect was abolished by inactivating macrophages with carrageenan treatment. These results demonstrated that a bicistronic rAd harboring both suicide and chemokine genes in sequence exerted the enhanced, macrophage-dependent, antitumor effects in a model of HCC and support the use of this strategy for the treatment of HCC.