Masako Uno

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.

Superselective angiographic embolization for intractable epistaxis

Conclusions. Routine embolization of the ipsilateral facial artery (FA) is effective because of the high success rate. The use of different embolic materials for the internal maxillary artery (IMA) and the FA was considered safe because of the absence of major complications. Objective. To evaluate outcomes of routine embolization of the FA as well as the IMA ipsilateral to the bleeding site for intractable epistaxis, and outcomes using different embolic materials for the FA and the IMA. Patients and methods. Twenty-two patients with intractable epistaxis who underwent superselective embolization were retrospectively analyzed with a mean follow-up of 7 months. The FA and the IMA ipsilateral to the bleeding site were embolized. Two embolic materials, gelatin sponge and microcoils, were used for the IMA and the FA, respectively. Results. The short-term success rate within the first 7 days was 77.3% (17/22). The long-term success rate was 95.5% (21/22). There were no major complications in 22 cases. Minor complications occurred in 13 cases (59%). These minor complications usually did not last more than a week and most resolved within a day.

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.

IL-10 in myeloma cells.

In addition to interleukin (IL)-6, IL-10 is considered as one of the most important cytokines regulating the proliferation and cellular characteristics of myeloma cells. It is still unclear from the clinical data how serum IL-10 levels of various stages of myeloma, are related to clinical manifestations of this disease. Several studies have reported that IL-10 affects myeloma cells by stimulating secondary signals for cell proliferation through oncostatin M (OSM) and IL-11. In experiments using human myeloma cell lines established at our laboratory, IL-10 seemed to be expressed in half of myelomas simultaneously with OSM, and to be correlated with c-maf, a transcription factor, which has been known to be overexpressed in myelomas with t(14;16)(q32;q23). In addition, IL-10 abolishes all trans retinoic acid (ATRA)-induced growth inhibition of myeloma cells. The expression and production of IL-10 in myeloma patients may be important for sub-categorization and the establishment of a case-oriented therapy.

Esophageal motor dysfunction plays a key role in GERD with globus sensation--analysis of factors promoting resistance to PPI therapy.

Abstract Objective. Patients with gastroesophageal reflux disease (GERD) also have various extra-esophageal symptoms. Laryngopharyngeal reflux disease (LPRD) is a subtype of GERD associated with globus sensation, but proton pump inhibitor (PPI) therapy achieves disappointing results. This study investigated esophageal motility in GERD patients with globus sensation who were resistant to PPI therapy. Design. The subjects were 350 patients with globus sensation. All patients underwent both laryngoscopy and upper gastrointestinal endoscopy to exclude organic disease. After 4 weeks of treatment with rabeprazole sodium (20 mg daily), the patients were divided into PPI-responsive and PPI-resistant groups. Then we investigated esophageal motility in the PPI-resistant group by a multichannel intraluminal impedance and manometry study. Results. A total of 119 patients (55.6%) were resistant to PPI therapy, among whom 57 patients (47.9%) had abnormal esophageal motility. They included 36 patients (66.4%) with ineffective esophageal motility, 9 patients (14.4%) with achalasia, 6 patients (9.6%) with diffuse esophageal spasm, 5 patients (8%) with nutcracker esophagus, and 1 patient (1.6%) with hypertensive lower esophageal sphincter. There were significant differences of upper esophageal sphincter pressure and esophageal body peristalsis between the patients with PPI-resistant LPRD and healthy controls matched for age and sex. Conclusion. Among patients with PPI-resistant LPRD, 47.9% had abnormal esophageal motility.

Expression and in vitro modification of parathyroid hormone-related protein (PTHrP) and PTH/PTHrP-receptor in human myeloma cells.

To elucidate the role of PTHrP in myeloma, we examined the expression levels of PTHrP and its receptor in human myeloma cell lines and clinical specimens from 13 myeloma cases. In vitro modification of PTHrP expression and production induced by TGF-β and PMA in PTHrP expressing myeloma cell lines was also investigated. PTHrP expression was detected in six out of seven myeloma cell lines with an inverse correlation with the expression of its receptor, and in 10 out of 13 clinical specimens in varying degrees. The PTHrP expression and secretion into culture medium were enhanced by supplemental TGF-β and PMA. PMA also seemed to affect PTHrP upregulation via TGF-β activation. The fundamental role of PTHrP in bone lesions and hypercalcemia in myeloma may be important to consider even during the initial phase of the disease and particularly in the progression of bone complications with hypercalcemia.

Cell cycle analysis and expression of cell cycle regulator genes in myeloma cells overexpressing cyclin D1.

Among the recently discovered myeloma‐specific gene alterations associated with chromosomal translocations, cyclin D1/PRAD1/Bcl‐1 overexpression caused by t(11;14)(q13;q32) is considered to be the most frequent in myeloma patients and cell lines, and may be a prognostic factor clinically. To elucidate the cellular biological role of overexpressed cyclin D1 in myeloma cells, we examined the mRNA expression levels of cell cycle regulators including three cyclin Ds, cyclin‐dependent kinase inhibitors (CDK‐Is) and accelerators. Cyclin D1 overexpression was clearly demonstrated in the lines with abnormal 11q13 and associated with overexpression of S and G2 accelerator genes. The cyclin D1‐overexpressing lines tended to have a shortened G1 phase compared with the non‐expressing lines. In addition, artificial silencing using antisense oligonucleotides for cyclin D1 suppressed the growth rate of some but not all cyclin D1‐overexpressing cells. These results indicate that overexpression of cyclin D1 caused by cytogenetic abnormalities may make cells progress through the cell cycle rapidly, but it seems that other factors such as cyclin D2 and translocation‐related genes affect the cell cycle progression in myeloma cells.

Interleukin 10 abolishes the growth inhibitory effects of all‐trans retinoic acid on human myeloma cells

Summary. Recently, it was disclosed that all‐trans retinoic acid (ATRA) inhibits myeloma cell growth by downregulating the interleukin 6 (IL‐6)/IL‐6 receptor (IL‐6R) auto/paracrine loop, and upregulating p21/Cip1 cyclin‐dependent kinase inhibitor (CDK‐I), thereby inducing apoptosis with a decrease in Bcl‐2 protein expression. To elucidate and generalize the effects of ATRA on the proliferation and cellular biology of myeloma cells, 12 human myeloma cell lines established in our laboratory were utilized. Two out of the 12 lines showed enhanced growth on supplementation of ATRA and were characterized by IL‐10 production, downregulation of membrane Fas and reduced upregulation of p21/Cip1 CDK‐I message. These characteristics may prove important for the clinical use of ATRA and should be considered before starting ATRA therapy for myeloma.

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.

BNCT of Nasal Melanoma: A Case Report

Malignant melanoma developing in the mucosa of the nasal cavity and paranasal sinuses is rare and has an unfavorable prognosis. We report the clinical course of the first case treated by boron neutron capture therapy (BNCT) for nasal malignant melanoma and discuss several advantages of BNCT. The patient was a 55-year-old man with nasal malignant melanoma complaining of right nasal bleeding. He underwent a pre-irradiation CT scan for treatment planning that was performed with the “JCDS” software program. The tumor was irradiated at the Japan Atomic Energy Agency Research Reactor No. 4 (JRR4) with epithermal neutrons at 3.5MW for 44 minutes. The tumor dose and normal tissue dose calculated ranged from 16.0 to 21.2Gy and from 6.8 to 9.5Gy, respectively. There has been continuous complete regression in the tumor and no acute and chronic complications for 8 months up to the present. Although only one patient has shown a complete regression and additional long-term follow-up should be performed to assess this treatment, we believe that nasal malignant melanoma is suitable for BNCT and that such excellent results will have a great impact on patients in the near future.