Junichi Hiratsuka

Gadolinium neutron-capture therapy using novel gadopentetic acid–chitosan complex nanoparticles: in vivo growth suppression of experimental melanoma solid tumor

The potential of gadolinium neutron-capture therapy (Gd-NCT) for cancer was evaluated using chitosan nanoparticles as a novel gadolinium device. The nanoparticles, incorporating 1200 microg of natural gadolinium, were administered intratumorally twice in mice bearing subcutaneous B16F10 melanoma. The thermal neutron irradiation was performed for the tumor site, with the fluence of 6. 32x10(12) neutrons/cm(2), 8 h after the second gadolinium administration. After the irradiation, the tumor growth in the nanoparticle-administered group was significantly suppressed compared to that in the gadopentetate solution-administered group, despite radioresistance of melanoma and the smaller Gd dose than that administered in past Gd-NCT trials. This study demonstrated the potential usefulness of Gd-NCT using gadolinium-loaded nanoparticles.

First clinical case of boron neutron capture therapy for head and neck malignancies using 18F-BPA PET

We investigated the application of boron neutron capture therapy (BNCT) to suitable cancers other than glioblastoma and melanoma. Head and neck malignancies were consequently selected as adaptable cancers. We reported the clinical results of our first case treated and discussed several advantages to the application of BNCT to head and neck tumors.

Asbestos-Induced Cellular and Molecular Alteration of Immunocompetent Cells and Their Relationship with Chronic Inflammation and Carcinogenesis

Asbestos causes lung fibrosis known as asbestosis as well as cancers such as malignant mesothelioma and lung cancer. Asbestos is a mineral silicate containing iron, magnesium, and calcium with a core of SiO2. The immunological effect of silica, SiO2, involves the dysregulation of autoimmunity because of the complications of autoimmune diseases found in silicosis. Asbestos can therefore cause alteration of immunocompetent cells to result in a decline of tumor immunity. Additionally, due to its physical characteristics, asbestos fibers remain in the lung, regional lymph nodes, and the pleural cavity, particularly at the opening sites of lymphatic vessels. Asbestos can induce chronic inflammation in these areas due to the production of reactive oxygen/nitrogen species. As a consequence, immunocompetent cells can have their cellular and molecular features altered by chronic and recurrent encounters with asbestos fibers, and there may be modification by the surrounding inflammation, all of which eventually lead to decreased tumor immunity. In this paper, the brief results of our investigation regarding reduction of tumor immunity of immunocompetent cells exposed to asbestos in vitro are discussed, as are our findings concerned with an investigation of chronic inflammation and analyses of peripheral blood samples derived from patients with pleural plaque and mesothelioma that have been exposed to asbestos.

Locally Recurrent Prostate Cancer After High-Dose-Rate Brachytherapy: The Value of Diffusion-Weighted Imaging, Dynamic Contrast-Enhanced MRI, and T2-Weighted Imaging in Localizing Tumors

OBJECTIVE The purpose of this article is to retrospectively evaluate the utility of prostate MRI for detecting locally recurrent prostate cancer after high-dose-rate (HDR) brachytherapy. MATERIALS AND METHODS Sixteen men with biochemical failure after HDR brachytherapy for prostate cancer underwent prostate MRI, including T2-weighted imaging, dynamic contrast-enhanced MRI (DCE-MRI), and diffusion-weighted imaging (DWI), using a 1.5-T MRI unit before 12-core-specimen biopsy. Two radiologists in consensus assessed the presence of tumor on each sequence within eight regions of the prostate (six from the peripheral zone [PZ] and two from the transition zone [TZ]) on the basis of biopsy. RESULTS Biopsy revealed locally recurrent prostate cancer in 22 (17 in PZ and five in TZ) of 128 regions (17.2%). The sensitivity, specificity, and accuracy of each MRI method in the detection of recurrent tumor were 27%, 99%, and 87%, respectively, for T2-weighted imaging; 50%, 98%, and 90%, respectively, for DCE-MRI; and 68%, 95%, and 91%, respectively, for DWI. The sensitivity of DWI in detecting recurrent tumor was significantly higher than that of T2-weighted imaging (p = 0.004). Multiparametric MRI achieved the highest sensitivity (77%) but with slightly decreased specificity (92%). CONCLUSION These results indicate that a multiparametric MRI protocol that includes DWI provides a sensitive method to detect local recurrence after HDR brachytherapy.

Boron neutron capture therapy outcomes for advanced or recurrent head and neck cancer

We retrospectively review outcomes of applying boron neutron capture therapy (BNCT) to unresectable advanced or recurrent head and neck cancers. Patients who were treated with BNCT for either local recurrent or newly diagnosed unresectable head or neck cancers between December 2001 and September 2007 were included. Clinicopathological characteristics and clinical outcomes were retrieved from hospital records. Either a combination of borocaptate sodium and boronophenylalanine (BPA) or BPA alone were used as boron compounds. In all the treatment cases, the dose constraint was set to deliver a dose <10–12 Gy-eq to the skin or oral mucosa. There was a patient cohort of 62, with a median follow-up of 18.7 months (range, 0.7–40.8). A total of 87 BNCT procedures were performed. The overall response rate was 58% within 6 months after BNCT. The median survival time was 10.1 months from the time of BNCT. The 1- and 2-year overall survival (OS) rates were 43.1% and 24.2%, respectively. The major acute Grade 3 or 4 toxicities were hyperamylasemia (38.6%), fatigue (6.5%), mucositis/stomatitis (9.7%) and pain (9.7%), all of which were manageable. Three patients died of treatment-related toxicity. Three patients experienced carotid artery hemorrhage, two of whom had coexistent infection of the carotid artery. This study confirmed the feasibility of our dose-estimation method and that controlled trials are warranted.

In vivo diagnosis of human malignant melanoma with positron emission tomography using specific melanoma-seeking 18F-DOPA analogue.

Detection and diagnosis of human malignant melanoma byPositron Emission Tomography (PET) using 18F-10B-L-BPA, a specificmelanogenesis-seeking compound synthesized for use in Boron NeutronCapture Therapy for malignant melanoma (NCT), has beendeveloped. This resulted in a novel, highly effectivemethodology for the selective three dimensional imaging ofmetastatic malignant melanomas, and for accurate determination of10B concentration in the tumor and surrounding tissue,providing almost all diagnostic information necessary for completenon-invasive radiation dose planning in the treatment ofmalignant melanoma both for NCT as well asother therapeutic modalities.

Salvage high-dose-rate brachytherapy for local prostate cancer recurrence after radiotherapy – preliminary results

Study Type – Prognostic (case series)

Anti-HER2-antibody enhances irradiation-induced growth inhibition in head and neck carcinoma.

To explore the antiproliferative effects of rhumAbHER2 on head and neck squamous carcinoma cell (HNSCC) lines and breast cancer cell lines (BCCLs) and to evaluate the combined effects with irradiation, 2 human HNSCC lines and 2 BCCLs were exposed to rhumAbHER2 with or without irradiation. The results showed that combined treatment enhanced the growth and colonization inhibitory effects of rhumAbHER2 or irradiation. Interestingly, the apoptotic cell fraction produced by irradiation disappeared on combined treatment. This disappearance was associated with repression of p53 and Bax upregulation induced by irradiation, but conservation of the upregulation of p27. Based on these results, rhumAbHER2 and irradiation may be a new strategy for treating HNSCC and breast cancers. In addition, the upregulation of cyclin‐dependent kinase inhibitors by rhumAbHER2 may occur upstream of irradiation‐induced p53 upregulation.

Asbestos Induces Reduction of Tumor Immunity

Asbestos-related cancers such as malignant mesothelioma and lung cancer are an important issue in the world. There are many conflicts concerning economical considerations and medical evidence for these cancers and much confusion regarding details of the pathological mechanisms of asbestos-induced cancers. For example, there is uncertainty concerning the degree of danger of the iron-absent chrysotile compared with iron-containing crocidolite and amosite. However, regarding bad prognosis of mesothelioma, medical approaches to ensure the recognition of the biological effects of asbestos and the pathological mechanisms of asbestos-induced carcinogenesis, as well as clinical trials to detect the early stage of mesothelioma, should result in better preventions and the cure of these malignancies. We have been investigating the immunological effects of asbestos in relation to the reduction of tumor immunity. In this paper, cellular and molecular approaches to clarify the immunological effects of asbestos are described, and all the findings indicate that the reduction of tumor immunity is caused by asbestos exposure and involvement in asbestos-induced cancers. These investigations may not only allow the clear recognition of the biological effects of asbestos, but also present a novel procedure for early detection of previous asbestos exposure and the presence of mesothelioma as well as the chemoprevention of asbestos-related cancers.

The relative biological effectiveness of 10B-neutron capture therapy for early skin reaction in the hamster.

The relative biological effectiveness (RBE) of 10B-neutron capture therapy (BNCT) on skin was analyzed using hamsters. The Kyoto University Research Reactor, which has a very low contamination of gamma rays and fast neutrons, was used as a thermal neutron source. Boron-10-para-boronophenylalanine hydrochloride ([10B]BPA.HCl) was administered to the hamsters. The evolution and time course of early skin reactions were assessed. These reactions were compared with those produced by electron beams. The maximum safe skin doses (no more than moist desquamation) of BNCT and electron beams were established to be 11 and 21 Gy, respectively. The RBE at this single dose with BNCT was found to be 1.94, assuming that the RBE of the gamma rays was 1.0 and each component of BNCT (mixed radiations) was simply additive.