The heterogeneity of acute myeloid leukemia (AML) has been established by many new insights from molecular biological studies. In AML with favorable cytogenetic changes, KIT gene mutation has been known as a worse prognostic marker. Even in AML with normal cytogenetics, numerous molecular genetic alterations have been identified including internal tandem duplication of the FLT3 gene (FLT3-ITD), mutations in the NPM1 gene, mutations in the CEBPA gene, and partial tandem duplication of the MLL gene. Of these, FLT3-ITD has the most important prognostic implication. Insights into the molecular pathogenesis of AML have led to the development of more specific targeted agents. Currently, a number of agents have been explored in AML, including immunoconjugate of anti-CD33 antibody and cytotoxic agent (gemtuzumab ozogamicin: GO), tyrosine kinase inhibitors and farnesyl transferase inhibitor. These agents have shown promise in small studies. Large phase III studies will reveal whether these are effective in inducing complete remission and prolonging survival. Combining targeted agents with each other or with chemotherapy may improve the response rates. GO is the most promising drug, which has been evaluated in randomized trials by several major cooperative groups to determine whether the addition of GO improves the complete remission rate and overall survival. In the near future AML may be classified and treated by their molecular biological alterations.

Conventionally advanced-non-small cell lung cancer have been treatment platinum and 90S new drug (paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan). However survival benefit is several months and treatment outcome have arrives at plateau. One molecule target drug have been attract attention. In this chapter mainly on gefitinib that refer that have been to data that clinical trial and EGFR gene mutation and resistance to EGFR-TKI. EGFR mutation with an initial dramatic response acquired resistance to the EGFR-TKI. Until the present that stracture have been participate T790M for acquired resistance and amplification of the MET gene is another mechanism of acquired resistance to EGFR-TKI.

The most important point of the translational research for oncology is clinical application. The excellent research will clarify the molecular pathogenesis of cancer and develop a beneficial intervention in the clinic. The laboratory science done on patient material is a critical part of the translational research. However, there are several problems to expand the translational research in Japan. Developing excellent basic researches and arranging systems to support the translational research will be necessary.

Multiple myeloma(MM) is a neoplasia of plasma cells in bone marrow. High dose chemotherapy followed by stem cell transplantation and new drugs such as thalidomide and bortezomib have improved the survival in MM. However, most of patients with myeloma are incurable so there is a need for the new therapeutic approaches that have been developed against molecular targets and pathway. It has been reported that activation of NF-kappaB pathway was required to survival of myeloma cells and this pathway was the potential target for anti -MM therapy. Recently we reported diverse genetic aberrations that activated NF-kappaB signaling in MM. In this section, the molecular pathogenesis of myeloma, especially the new findings related with NF-kappaB activation, will be reviewed in Japanese.

Accumulating evidences suggest that many molecules are working as inhibitors of proliferation in myeloma cells e.g., PTEN, mTOR(PI3-kinase signal molecules), p53, RB1, INK4 family and KIP/CIP family (cell cycle check point molecules), PF4 (inhibitor of angiogenesis). In this review, significance of these molecules in myeloma is summarized. Additionally, our finding of growth inhibitory effect by PU.1 is explained.

Cellular biology of primary myeloma cells from myeloma patients, has been rapidly developing by using DNA analysis, gene expression profiling (GEP) and surface marker analysis. These studies reveal that human myeloma cells specifically lose the expression of B cell master gene, PAX-5, and express multi-lineage markers, and XBP-1 transgenic mice showed the late onset of human myeloma-like monoclonal plasmacytosis in the bone marrow of aged mice. GEP reveals that primary myeloma cells are subdivided into 7 groups: among these subgroups, PR (proliferation) group predicts poor prognosis. With regard to molecular mechanism of myeloma oncogenesis, the importance of primary IgH translocation followed by the second IgH translocation is proposed, but it is also noted that human myeloma cells show the marked heterogeneity.

Multiple myeloma(MM) originating from plasma cells is characterized by complex chromosomal aberrations. The most prominent chromosomal abnormalities of MM are aneuploidy and translocations affecting the immunoglobulin heavy chain locus on chromosome 14q32. Additionally, a variety of genetic aberrations such as ras mutations have been found in MM. Because these chromosomal and genetic abnormalities are closely associated with clinical behavior including prognosis, cytogenetic findings have a great impact on planning treatment strategy. Furthermore, studies of signal transductions and mechanisms of oncogenesis in association with these abnormalities will provide targets to develop novel therapeutic agents. Here we summarize the chromosomal and genetic abnormalities of MM and their clinical implications.

Neoadjuvant chemotherapy for breast cancer has achieved a higher response rate with the combination of anthracycline and taxane. Molecular targeted agents, such as trastuzumab, are expected to enhance the effectiveness of treatment. The main objectives of neoadjuvant chemotherapy are to reduce tumor size, increase breast conserving rate, identify treatment response, adjust the following treatment strategy, and develop a new treatment using biological specimens. Recently, there has been an increasing demand to provide a tailored treatment in neoadjuvant chemotherapy with establishment of genetic testing for biological markers and adjustment of therapeutic strategy following identification of the early treatment response. We reviewed recent advances in neoadjuvant chemotherapy for breast cancer.

Recently it is considered that there is a small population of cells with stem cell property not only in leukemia but also in solid cancer.These cells show the ability of self-renewal and multi-potential differentiation, and can initiate and maintain a tumor. The origin of cancer stem cells might be their normal stem cells, progenitor cells, or bone marrow-derived cells. It is still difficult to isolate cancer stem cells in solid cancer. There are three possible methodologies to isolate or identify cancer stem cells; the use of a surface marker, use of cells cultured in a specific condition (sphere), or the use of side population cells identified by FACS. The gold standard assay that fulfills the definition of cancer stem cell may be serial transplantation in animal models. Cancer stem cells are likely to be responsible for disease relapse or metastasis, and also for resistance to radiation or conventional chemotherapy. The stem cell niche plays an important role on maintaining cancer stem cells. The novel promising therapies against cancer stem cells are considered, including antibody-based therapy, signal inhibitors, overcoming radiation and drug resistance, or differentiation therapy. Another interesting therapy targeting the niche may also be considered.

Among 4 major traditional groups of thyroid carcinoma, papillary and follicular carcinomas are most common, and other forms, anaplastic and medullary carcinomas, are relatively rare. The 2003 WHO histological classification of thyroid tumor separated 7 other malignant thyroid tumors into distinct pathological entities, such as poorly differentiated, squamous cell, mucinous carcinomas, carcinoma showing thymus-like differentiation (CASTLE), etc. Although they are also extremely rare, recognition of their clinicopathologic features are very important. In this review, not only diagnostic and therapeutic strategies for the rare forms of thyroid carcinomas, specifically focussed on medullary carcinoma and CASTLE, but also their histogenetic abnormalities were discussed.

A number of genetic abnormalities in oncogenes or anti-oncogenes have been identified in association with thyroid carcinogenesis. Especially, oncogenes such as ras mutation, ret/PTC and Braf mutation that constitutively activate MAP kinase pathway a refrequently found in papillary thyroid cancer. The p53 mutation aggravates differentiated thyroid cancers to anaplastic thyroid cancer. These gene alterations are studied not only to understand basically the mechanisms of oncogenesis but also to develop clinically genetic diagnosis or molecular target therapy. In this article, we review the genetic diagnostic methods and phenotype-genotype relationship of human thyroid cancers.

Molecular mechanism of thyroid carcinogenesis has been well studied through the discovery of genetic abnormalities such as RET/PTC rearrangement and BRAF mutation, both of which constitutively activate MAP kinase pathway and are frequently found in papillary thyroid cancer. The TP53 mutation is thought to play a critical role in transformation of differentiated thyroid cancer into anaplastic thyroid cancer. Besides these genetic alterations, cancer stem cell theory has recently been applied to thyroid field. A better understanding of thyroid cancer stem cell may not only ameliorate our comprehension of thyroid cancer biology, but also open the possibility of innovative diagnostic procedures and development of novel targeted therapies. In this article, we mainly review thyroid carcinogenesis based on the evidence of radiation-induced cancer and cancer stem cell hypothesis.