We have experienced 4 cases of therapy-related leukemia (TRL) in 119 patients with multiple myeloma (MM) who had received combination chemotherapy including alkylating agents between 1988 and 1998. All 4 cases were acute myelogenous leukemia, 3 were males and 1 was female. Median age at diagnosis of MM was 60 years, and median time to TRL from diagnosis of MM was 5.5 years. The chromosome abnormalities were found in 3 of those cases. All 4 cases were resistant to antileukemic chemotherapy, and median survival time from TRL was only 5.5 months. The TRL in MM is thought to be a more important problem, because recently the treatment for this disease has become more intensive, including high-dose chemotherapy supported by autologous stem cell transplantation.

We have investigated the relationship between gene expression of Bcl 2 and Bax and the therapeutic effect in oral cancer patients. A significant correlation between Bcl-2/Bax gene expression ratio in the peripheral blood mononuclear cells (PBMCs) from the patients, and the therapeutic effect of radiation therapy in combination with UFT and OK-432, as well as survival rate, was observed. In addition, the statistically significant correlation was also observed between Bcl-2/Bax ratio and IFN-gamma and NK activity induced with OK-432. These findings suggest that Bcl-2 and Bax gene expression in PBMCs may be useful as a prognostic factor in oral cancer patients.

A clinical significance of the aberrant expression of HLA class I molecules including HLA class I and HLA-G was analyzed using tissue array analysis. Our institute has established a two millimeter spot sized tissue array set of 105 clinical cases of resected human non small cell lung cancer tissues. A loss of HLA class I was observed in the 58.3% of cancer tissues. The aberrant expression of HLA G was also observed in the 55.2% of cancer tissues. Statistically significant correlations were observed among HLA class I expression and tumor size, nodal involvement and pathological stage. Survival analyses were shown that the HLA class I loss was correlated to a recurrence free survival time. The HLA-G expression did not correlate with any clinico-pathological parameters. A loss of HLA class I was probably involved due to a cancer progression in human non-small cell lung cancer through the mechanism of immune escape from the host immune system.

Phage display has been utilized for making recombinant antibody fragments (Fab or single chain Fv) of human, mouse, or other origins. After construction of an antibody combinatorial library, antigen-specific recombinant antibody fragments can be easily isolated by biopanning of the phage library displaying antibody fragment fused with viral coat protein III against antigen proteins, antigen-expressing live cells, or fixed cells. Using this technique, a variety of human recombinant antibody fragments can be retrieved from bone marrow cells, lymph node cells, or peripheral blood cells of patients with infectious diseases, autoimmune diseases, and cancer. To develop diagnostically and therapeutically useful human antibody medicines, we should first select recombinant antibody fragments not only with antigen-binding activity but also with bioactivity such as virus or toxin neutralization, or tumor-specific cytotoxicity. To achieve this goal, several steps in antibody phage display may be improved: 1) a larger library should be constructed for possible isolation of minor populations present in the repertoire; 2) the biopanning procedure should be improved for isolation of antibody fragments reactive with immunologically minor epitopes; 3) the screening procedure should be based on the measurement of the bioactivity as well as the antigen-binding activity; 4) if necessary, the affinity and specificity of selected antibody fragments should be improved. In this review, I discuss how to isolate clinically useful recombinant antibody fragments efficiently using a phage display system introducing our achievements.

Carney complex is a rare syndrome which includes cardiac myxoma, hyperactive endocrine neoplasm, spotty pigmented skin, and extracardiac myxomatous tumors. We report a case of a 26-year-old woman with Carney complex in whom recurrent multiple cardiac myxomas were resected 4 years after the first operation for left atrial (LA) myxoma. She had a history of left adrenalectomy in 1997 for Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). In February 2001, she was diagnosed with Carney complex because of evidence of LA myxoma, her spotty pigmented skin lesions, her past history and family history of cardiac myxoma in her mother. Then, LA myxoma was successfully resected through the superior trans-septal approach and has been followed-up by ultrasound cardiography (UCG) every 6-month after discharge. In January 2005, UCG revealed 2 masses in the LA and the right ventricle outflow tract. The 2nd surgery was performed in February 2005. We found the 3rd myxoma during surgery, resembling a flat polyp in the LA just at the inflow of the right upper pulmonary vein. All 3 myxomas were successfully resected. Sixteen months after the 2nd operation, she has been doing well without any sign of recurrence of myxoma.

The World Health Organization (WHO) histologic classification was presented by the international committee to provide a universal system for clinicians and researchers in 1999 and was further modified in 2004. This classification is mainly based on Müller-Hermelink et al.'s system and six distinct types were defined. Thymomas were classified into type A, AB, B1, B2, and B3 tumors, according to the shape and atypia of epithelial cells and also the abundance of lymphocytes. Another type of tumor is thymic carcinomas, which have apparent atypia of neoplastic cells. Neuroendocrine tumor (carcinoid) of the thymus was categorized as thymic carcinoma because of the resemblance of genetic aberrations. Several studies have shown that the WHO histologic type is correlated with the proportion of invasive tumors and is an independent prognostic factor along with Masaoka stage. Furthermore, association with myasthenia gravis, ability to induce CD4+CD8+T cells and express HLA-DR molecules, and chromosomal imbalances such as loss of heterogeneity were found to be correlated with the WHO histologic type. Thus, the WHO histologic classification system reflects the oncologic, immunologic, and genetic characteristics of thymic epithelial tumors. The clinical application of this classification system is expected.

Recent progress in molecular biology introduced a concept of molecular targeting therapy against many diseases including neurosurgical disorders. Molecular targeting therapy is promising, because targeting a disease-specific molecule it may provide cure without inducing unfavorable side effects. Focusing mainly on CNS (central nervous system) malignancies, authors discuss the current development of molecular targeting therapy with a special concern to strategies using DNA, RNA, immunotoxin, and molecular selective inhibitors. Strategies using DNA include gene therapy and DNA vaccine. RNA interference (RNAi) is one of the promising molecular targeting strategies using RNA. Immunotoxins such as recombinant chimeric cytotoxin consisting of interleukin-13 and a truncated exotoxin produced by the Pseudomonas aeruginosa bacterium is now under clinical investigation. Many molecular targeted agents such as selective inhibitors for protein kinases are now in preclinical and clinical development for patients with malignant glioma. Additionally, authors introduce their attempts to visualize the local drug delivery using real-time MRI monitoring. Visualization of drug delivery, while achieving effective drug distribution using convection-enhanced delivery (CED), may also contribute to the disease targeting. These strategies together should help us develop the effective 'disease-targeting therapy' for CNS disorders.

Cell proliferation is regulated through a transition between the G0 phase and cell cycle. We isolated a mammalian temperature-sensitive mutant cell line defective in the function from the G0 phase to cell cycle. Senescent human somatic cells fail to enter into the cell cycle from the G0 phase with stimulation by any growth factor. Telomere shortening was found to be a cause of cellular senescence, and reexpression of telomerase immortalized human somatic cells. Immortalized human somatic cells showed normal phenotypes and were useful not only for basic research but also for clinical and applied fields. The importance of p53 and p21 activation/induction i now well accepted in the signal transduction process from telomere shortening to growth arrest, but the precise mechanism is largely unknown as yet. We found that the MAP kinase cascade and histone acetylase have an important role in the signaling process to express p21. Tumor tissues and cells were found to have strong telomerase activity, while most normal somatic human tissues showed very weak or no activity. Telomerase activity was shown to be a good marker for early tumor diagnosis because significant telomerase activity was detected in very early tumors or even in some precancerous tissues compared with adjacent normal tissues. Telomere/telomerase is a candidate target for cancer chemotherapeutics, and an agent that abrogated telomere functions was found to kill tumor cells effectively by inducing apoptosis whereas it showed no effect on the viability of normal cells.