Improvement of the tumor-suppressive effect of boron neutron capture therapy for amelanotic melanoma by intratumoral injection of the tyrosinase gene.

Boron neutron capture therapy (BNCT) is successful when there is a sufficient (10)B concentration in tumor cells. In melanoma, (10)B-para-boronophenylalanine (BPA) accumulation is proportional to melanin-producing activity. This study was done to confirm enhancement of the tumor-suppressive effect of BNCT on amelanotic melanoma by intratumoral injection of the tyrosinase gene. D178 or FF amelanotic melanomas were implanted s.c. in Syrian hamsters. One group of D178- or FF-bearing hamsters (TD178 or TFF group) received intratumoral injections of pcDNA-Tyrs constructed as a tyrosinase expression plasmid. The other hamsters (pD178 and pFF groups) were injected with pUC119, and control hamsters (D178 and FF groups) only with transfection reagents. All the groups underwent immunofluorescence analysis of tyrosinase expression and BPA biodistribution studies. BNCT experiments were done at the Kyoto University Research Reactor. Tyrosinase expression increased in the tumors of the TD178 and TFF groups but remained the same in the pD178 and pFF groups. Tumor boron concentrations in the TD178 and TFF groups increased significantly (TD178: 49.7 +/- 12.6 versus D178: 27.2 +/- 4.9 microg/g, P < 0.0001; TFF: 30.7 +/- 6.6 versus FF: 13.0 +/- 4.7 microg/g, P < 0.0001). The BNCT tumor-suppressive effect was marked in the TD178 and TFF groups. In vivo transfection with the tyrosinase gene increased BPA accumulation in the tumors, the BNCT tumor-suppressive effect on amelanotic melanoma being significantly enhanced. These findings suggest a potential new clinical strategy for the treatment of amelanotic melanoma with BNCT.

[A dose escalation study of concurrent chemoradiation therapy with nedaplatin for cervical cancer].

Doses of nedaplatin (CDGP) were established for concurrent chemoradiation therapy (CCRT) for cervical cancer, and a collaborative dose escalation study involving 8 hospitals was conducted to investigate the safety and efficacy of this therapy. Radiotherapy was performed according to the standard treatment described in the Regulations of Cervical Carcinoma Treatment. CDGP at 80 mg/m2 as Level 1 or at 90 mg/m2 as Level 2 was administered on Days 1 and 29 of treatment. Dose-limiting toxicity (DLT) was observed in 1 of 6.patients receiving 80 mg/m2 of CDGP and in all 2 patients receiving 90 mg/m2 of CDGP; therefore, Level 2 was regarded as the maximum tolerated dose (MTD), and Level 1 as the recommended dose. DLT signs consisted of delayed improvement in the leukocyte count in 2 patients and anorexia in 1 patient, suggesting that delayed improvement in the leukocyte count is the main DLT of this combination therapy. The main side effects were digestive disorders such as nausea and anorexia and bone marrow suppression, such as leukopenia, neutropenia, and thrombopenia. Side effects in the Level 1 group were more mild than in the Level 2 group. The efficacy was PR or better in all patients. The CR rates were 60% (6/10) in the Level 1 group and 50% (1/2) in the Level 2 group; there was no marked difference between the two groups. These results suggest that CCRT involving administration of CDGP at 80 mg/m2 on Days 1 and 29 is safe and effective.

Evaluation of serum KL-6 as a predictive marker of radiation pneumonitis in patients with breast-conservation therapy.

BACKGROUND: Although radiation pneumonitis in radiotherapy following breast-conservation surgery is rare, it may lead to severe pneumonitis as well as to other types of pulmonary dysfunction. This study examined the usefulness of the serum KL-6 level as a new marker for the early detection of radiation pneumonitis. METHODS: Twenty-nine consenting patients served as subjects (age range, 32-78 years; mean age, 51 years) between 2001 and 2002. A total tangential irradiation dose of 50 Gy/25 fractions (fr) was administered for 5 weeks, using a 4-MV X-ray, and an additional 10 Gy/5 fr for 1 week of 6-MeV electron-beam irradiation was performed for patients with pathological tumor cell findings in the excised tumor margins. Levels of serum KL-6 were measured before and after radiotherapy. RESULTS: Four patients developed radiation pneumonitis, all of whom had elevated post-therapy KL-6 levels. Patients with lower or unchanged KL-6 levels did not develop radiation pneumonitis. There was a significant difference in serum KL-6 levels between patients with and without radiation pneumonitis (P = 0.0421). KL-6 levels remained below the threshold value of 465 U/ml in all patients. CONCLUSION: For the early detection of radiation pneumonitis following breast-conservation surgery, and to assess the efficacy of therapy, the monitoring and measuring of changes in KL-6 levels before and after radiotherapy is more important than comparing KL-6 levels against the threshold value. Measuring KL-6 serum levels is also useful in assessing the efficacy of therapy for radiation pneumonitis.

Observation of microvasculatures in athymic nude rat transplanted tumor using synchrotron radiation microangiography system.

RATIONALE AND OBJECTIVES: The diagnostic potential of tumor microvasculatures with the monochromatic synchrotron radiation microangiography (MSRA) system was examined in an experimental model using athymic nude rats. MATERIALS AND METHODS: In the lower abdominal wall in athymic nude rats (male, 120-150 g, 6 weeks old), 1 x 10(7) cells of N-nitrosomethylurea-induced rat mammary adenocarcinoma was transplanted to prepare a lower abdominal wall tumor transplanted model. A microcatheter was inserted in the abdominal aorta in a rat under anesthesia, and microangiographic images of the normal inferior epigastric artery and vein were obtained using an MSRA system. Changes in the tumor microvasculatures were observed using an MSRA system on the day 7 (n = 3), day 14 (n = 3), day 21 (n = 3), and day 28 (n = 3) after transplant. In addition, we measured the microvessel density (MVD) with a computer using the binarization method. These results were compared among the histologic MVDs. RESULTS: The microvasculatures of tumors measuring 20-30 microm were observable by the MSRA system in the transplanted tumor model using the inferior epigastric artery and vein as the feeding vessels. The tumor microvasculatures were observed for 7-28 days after transplantation. The tumor MVD obtained by the binarization method increased as the tumor volume increased. When histologic MVD was compared with the fixed quantitative results of angiographic MVD, a significant correlation (r = 0.933, P <.01) was observed. CONCLUSION: These preliminary investigations indicate that MSRA proved to be suitable for quantification and appears to be a simple method for clearly imaging tumor microvasculatures.

Clinical results of combined treatment conformal high-dose-rate iridium-192 brachytherapy and external beam radiotherapy using staging lymphadenectomy for localized prostate cancer.

PURPOSE: To report the first long-term biochemical control rate of patients treated with two protocols using a combination of external beam radiotherapy (EBRT) and high-dose-rate (HDR) brachytherapy for localized prostate cancer in Japan. METHODS AND MATERIALS: Between October 1997 and July 2001, 71 patients with localized prostatic adenocarcinoma were treated with a combination of EBRT and HDR brachytherapy. Patient age ranged from 58 to 81 years (mean 70.5). Of the 71 patients, 12, 41, and 18 had Stage T1c, T2, and T3, respectively, according to the International Union Against Cancer classification system (1997). The mean initial prostate-specific antigen (PSA) level was 24.2 ng/mL (median, 11.9 ng/mL); 30% of the patients had an initial PSA level >20 ng/mL. Of the 71 patients, 31 had received neoadjuvant hormonal therapy. Hormonal therapy before treatment was stopped at the beginning of RT in all cases. Patients in this series were treated on two protocols. In the initial protocol, patients were treated with whole pelvis EBRT to 45.0 Gy in 25 fractions and three HDR fractions of 5.5 Gy each (35 patients). In the second protocol, patients were treated with prostatic EBRT to 41.8 Gy in 19 fractions, with an added staging lymphadenectomy to rule out lymph node metastasis for patients with high-risk factors, and four HDR fractions of 5.5 Gy each (36 patients). The American Society for Therapeutic Radiology and Oncology consensus definition for biochemical failure was used. Acute and chronic toxicities were scored using the Radiation Therapy Oncology Group guidelines. Follow-up ranged from 24 to 65 months (median, 44 months). RESULTS: Of the 71 patients, 69 were alive at the last follow-up. Two patients had died of hepatocellular carcinoma and gastric cancer at 3.5 and 4.0 years after treatment with no biochemical failure. Sixty-six patients (93%), including the two who had died of intercurrent disease, showed a tendency for a PSA decline after treatment and had no biochemical or clinical evidence of disease at the last follow-up visit. Sixty patients (85%) achieved PSA nadir levels of < or =1.0 ng/mL. The biochemical/clinical failure-free control rate at 3 and at 5 years was 93% and 93%, respectively. The bladder and rectal complications were minimal. CONCLUSION: Despite the high frequency of high-risk patients in the present patient population, the actuarial biochemical control rate was 93% at 5 years. Acute and chronic toxicity with this method was acceptable. Additional long-term follow-up is required to assess this treatment, because the median survival is not likely to be reached for several years.

Angiosarcoma treated with radiotherapy: impact of tumor type and size on outcome.

PURPOSE: Angiosarcoma is a rare and highly malignant vascular neoplasm. The purpose of this study was to elucidate the tumor characteristics and evaluate the efficacy of radiotherapy (RT) for angiosarcoma. MATERIALS AND METHODS: Thirty patients with angiosarcoma (20 males and 10 females, age range 4-89 years, median 66) who received RT from 1986 to 1999 were enrolled in the study. Twenty-four patients had angiosarcoma of the face and scalp (AFS), and 6 patients had angiosarcomas at other sites. AFS was classified into two categories (according to the macroscopic features): nodular AFS (14 patients) and endophytic AFS (10 patients). The median prescribed irradiation dose was 68 Gy. Surgery had been previously performed in 9 patients, and adjuvant immunotherapy using recombinant interleukin-2 (rIL-2) was combined during and after RT in 20 patients. Univariate analyses and calculation of survival by Kaplan-Meier methods were performed. RESULTS: Local tumor control was obtained in 17 patients (57%). However, 7 (47%) of them developed distant metastases. The median survival time for all patients was 8 months (7 months for AFS), and the 13-year overall survival rate was 25% (20% for AFS). Twenty-one patients died of angiosarcoma, with the cause of death local failure in 7 patients, distant failure in 7, and both in 7. Tumor type and size were found to be significant prognostic factors (p = 0.004 and p = 0.007, respectively), and age, total amount of rIL-2, gender, radiation dose, and surgery were not. Six patients (4 with nodular AFS and 2 with angiosarcoma in other parts) survived >2 years. No patient with endophytic AFS survived >2 years. Ten patients (33%) died of respiratory failure secondary to pulmonary metastases. High-dose rIL-2 administration suppressed the occurrence of distant metastases (p = 0.006). Two patients developed radiation dermatitis (Radiation Therapy Oncology Group Grade 4). CONCLUSION: RT, combined with complete resection or adjuvant rIL-2 immunotherapy, could be a promising treatment strategy, leading to prolonged survival in patients with angiosarcoma.

A long-term survivor of leiomyosarcoma around the right side of the base of the skull: effective radiotherapy combined with intra-arterial chemotherapy.

We report a rare case of a leiomyosarcoma that developed around the right side of the base of the skull in a 51-year-old woman. The patient consulted our hospital complaining of pain in the right side of her neck and upper right arm in August 1994. A leiomyosarcoma, originating around the right side of the neck and base of the skull was diagnosed. Initially, surgery was planned, but invasion into the spinal canal was discovered. Curative resection of the leiomyosarcoma around the right side of the base of the skull was not possible. Therefore, external beam radiotherapy (EBRT) combined with intra-arterial chemotherapy and hyperthermia was employed. After the treatment, the tumor decreased in size to 45% of its initial volume, and, simultaneously, her symptoms completely disappeared. The patient initially remained clinically free of the disease, but showed reaggravations at the primary tumor site 3 years and 3 months, and 4 years and 11 months, after the first treatment. The reaggravations were treated with EBRT combined with intra-arterial chemotherapy. As a result, she survived for 5 years and 7 months after the first treatment.

[A case of advanced hypopharyngeal carcinoma successfully treated with superselective intra-arterial infusion of docetaxel].

Docetaxel is an excellent agent with a high antitumor effect for advanced/recurrent head and neck cancer. A 67-year-old male with advanced hypopharyngeal cancer (T3N2bM1: Stage IV) underwent two courses of superselective intra-arterial infusion of docetaxel and intravenous administration of CDDP and 5-FU. Using a coaxial technique, a microcatheter was placed in the feeding artery. Using imaging techniques docetaxel (60 mg/body and 30 mg/body) was infused into the vessels. During chemotherapy the patient received concomitant radiotherapy (50 Gy). MRI after chemoradiation showed a complete response for the primary tumor and a partial response for the neck metastasis. Grade 4 leukopenia and neutropenia and grade 3 pharyngitis/esophagitis were observed during chemoradiotherapy, but these adverse effects abated immediately and were not critical. We conclude that this superselective intra-arterial infusion of docetaxel will be useful and safe for head and neck cancer.

Participation of Fas-mediated apoptotic pathway in KB, a human head and neck squamous cell carcinoma cell line, after irradiation.

In head and neck clinical oncology, recurrent cancer after initial irradiation therapy is no longer sensitive to irradiation. To explore the irradiation resistance in head and neck squamous cell carcinoma, a human cell line, KB, derived from the floor of the oral cavity was used. The participation of the Fas-mediated apoptotic pathway was suggested by the upregulation of the surface Fas molecule, the reduction of the apoptotic cell fraction after inhibition of caspase 8 which is a Fas-related initiator caspase, and the changes in Fas-related genes after irradiation. Therefore, it is suggested that disruption of the Fas-mediated apoptotic pathway participates in the acquisition of irradiation-resistance in HNSCC.