Glioblastoma multiforme (GBM) is the most frequent and aggressive brain tumor, and which harbors not only rapidly dividing cells but also small populations of slowly dividing and dormant cells with tumorigenesity-, self-renewal-, and multi-lineage differentiation capabilities. GBM stem cells (GSCs), which are resistant to conventional chemo -radiotherapy and may be a cause of local recurrence and dissemination. Additionally, heterogeneity of GSCs in the same tumor had been shown by the innovation of microarray and sequencing technology. However, outcome in patients with GBM remains unsatisfactory. Accumulation of the clinical evidence and basic research findings targeting for GSCs and their specific microenvironments (GSC niches) raise the possibility of new treatments to overcome GBM.

The existence of cancer stem cells in solid tumors was first reported in 2003 based on the analyses of human breast cancers. Analyses of clinical specimens are especially important for the advancement of human cancer stem cell research. For example, the analyses of breast cancer stem cells directly isolated from human breast cancer specimens identified the microRNAs that are involved in the regulation of human breast cancer stem cells. In addition, human breast cancer xenograft is an attractive model to analyze cancer stem cells, as well as cancer metastases that have profound effect on the long-term survival of breast cancer patients. We will present the current status of human breast cancer stem cell research that utilizes clinical specimens.

Cancer is generally developed through accumulation of multiple genetic mutations. Epigenetic abnormalities of DNA methylation and histone modification patterns were also found in most cancer cells. Although induced pluripotent stem cells (iPSCs) can be generated through epigenetic reorganization without affecting the underlying genomic sequencing, they have some shared characteristics with cancer cells, which include unlimited growth potential. Taking advantages of such properties of iPSC derivation, the reprogramming technology is applicable not only for regenerative medicine but also for cancer research. Here, we introduce the potential application of iPSC technology for better understandings of cancer biology. Especially, we would like to propose the role of cellular identity in cancer development.

Technological advances such as the high-throughput sequencing are providing us novel aspects and perspectives of cancer stem cells (CSCs). Current evidences support a model where multiple subclones persist, rather than a simple hierarchical model with CSCs. The presence of multiple subclones contributes to increase in fitness and robustness of a cancer, which is reminiscent of the stability in ecosystems. The latest report describing the sequencing of peripheral-blood cells from unselected persons revealed that clonal hematopoiesis with somatic mutations already exists in a fair percentage of elderly persons. The analysis also shed light on some epigenetic modifiers as the driver genes of clonal hematopoiesis. In this article, we review the recent evolution of CSC model in hematology.

A 52-year-old man with bilateral swelling in the scrotum was referred to the department of urology in our hospital in January 2013. Pathological examination of the scrotum revealed diffuse large B-cell lymphoma(DLBCL). Immunohistochemical staining revealed p53 overexpression, and polymerase chain reaction-single strand conformation polymorphism(PCRSSCP) revealed a point mutation in exon 7 of the p53 gene. Rituximab plus cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone(R-CHOP)therapy and intrathecal prophylaxis were initiated. After three courses of R-CHOP therapy, high-dose cytarabine was administered, followed by peripheral blood stem cell harvesting. Busulfan, etoposide, and Ara-C(BEA)therapy was then administered, followed by autologous peripheral blood stem cell transplantation(auto- PBSCT). Primary testicular lymphoma(PTL)is a rare, clinically aggressive form of extranodal lymphoma, and there is a high incidence rate of relapse in the central nervous system(CNS). The vast majority of cases are histologically DLBCL. The p53 mutation is an independent marker of poor prognosis in patients with DLBCL treated with R-CHOP therapy. Our patient has been disease free for 17 months after auto-PBSCT with high-dose chemotherapy, which results in a greater level of penetration into the CNS.

Irinotecan is an effective drug in the treatment of colorectal cancer. However, there are reports of an association between certain UGT1A1 genetic polymorphisms and the development of adverse reactions(such as neutropenia)related to irinotecan metabolism. We retrospectively investigated UGT1A1 genetic polymorphisms and the occurrences of irinotecan-induced neutropenia in 25 patients of colorectal cancer at our hospital. Analysis of UGT1A1 genetic polymorphisms in these patients yielded the following classifications: a wild-type group( *1/*1)comprising 13 patients(52%), a heterozygous group(*1/ *28, *1/*6)of 10 patients(40%), and a homozygous group(*28/*28, *6/*6)of 2 patients(8%). The frequency of neutropenia was 15.4%(2/13)in the wild-type group, 30%(3/10)in the heterozygous group, and 100%(2/2)in the homozygous group. Grade 4 neutropenia only occurred in the homozygous group. These results suggest that a dose reduction of irinotecan should be considered for patients who fall into the homozygous group upon analysis of their UGT1A1 genetic polymorphisms, as such patients might be susceptible to grade 4 neutropenia.

Afatinib is an epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI). In a randomized phase III study(Lux- Lung 3 study)employing patients harboring EGFR mutations, patients administered afatinib show a significantly longer progression free survival time(PFS)than those administeredcombination chemotherapy comprising cisplatin andpemetrexed . However, most of the patients(95.2%)treatedwith afatinib experiencedd iarrhea. In the present report, 16 patients with EGFR mutations were treatedby afatinib at our institution from May 2014 to December 2014. Twelve patients were administered a diarrhea prevention herbal medicine, Hange-shashin-to. Seven of 12 patients(58%)had no diarrhea during the 28 days of therapy. All 4 of the patients who did not receive Hange-shashin-to experienced diarrhea above Grade 1 within 6 days of starting therapy. The rate of diarrhea differed significantly between the patients receiving and not receiving Hangeshashin- to. In conclusion, preventive administration of Hange-shashin-to may reduce the occurrence of diarrhea during afatinib treatment.

One of the most important roles of molecular epidemiology is to investigate gene-environment interactions in order to provide data for personalized risk modification. A case-control study conducted in Aichi showed that an aldehyde dehydrogenase- 2(ALDH2)polymorphism together with cigarette smoking significantly affects the risk of lung cancer. The main purpose of this large-scale genome-cohort study of healthy individuals is to confirm that these factors are associated with the development of diseases and to set optimal thresholds for the environmental factors. The Japan Multi-Institutional Collaborative Cohort(J-MICC)Study was launched in 2005. It has recruited 100,600 healthy participants up to the end of 2014, and plans to follow them until 2025. Although Japanese genome-cohort studies, including the J-MICC Study, the Japan Public Health Center-based Prospective(JPHC)Study, and the Tohoku Medical Megabank Organization Study, consist of different research teams with different financial resources, collaboration to standardize the data collection format for successful pooled analysis is being discussed.

Acute myeloid leukemia (AML) with high ecotropic viral integration site-1 (EVI1) expression (EVI1high AML) is classified as a refractory leukemia with a poor prognosis. We identified G protein-coupled receptor 56 (GPR56) as a novel marker for EVI1high AML, which is an orphan adhesion G protein-coupled receptor (GPCR). GPR56 was found to be associated with high cell adhesion and anti-apoptotic activities in EVI1high AML through activation of RhoA signaling. Moreover, in Gpr56-/- mice, the number of hematopoietic stem cells (HSCs) in bone marrow was significantly decreased with proportional increases in the spleen and peripheral blood, reflecting extramedullary hematopoiesis. The number of Gpr56-/- HSC progenitor cells in the G0 phase was significantly reduced with impaired adhesion and the loss of GPR56 function, which diminished the in vivo repopulating ability of HSCs. In conclusion, GPR56 may represent an important GPCR for the maintenance of quiescence and cellular adhesion of EVI1high AML and HSCs in the bone marrow niche. Moreover, given that GPR56 expression in leukemia stem cells is much higher than that in HSCs, GPR56 is a candidate therapeutic target for leukemia stem cells in EVI1high AML.

Constitutive activation of mTOR is associated with acceleration of leukemia development. However, mTORC1 functions in established leukemia are unclear. We evaluated the role of mTORC1 in mouse acute myeloid leukemia (AML) cells using a murine model of conditional deletion of Raptor, an essential component of mTORC1, and an MLL-AF9-driven leukemia model. mTORC1 is essential for leukemia initiation, but a subset of AML cells with undifferentiated phenotypes survived long-term in the absence of mTORC1 activity. Our study demonstrated AML cells lacking mTORC1 activity to be capable of self-renewal as AML stem cells. This review will summarize our study on the roles of mTORC1 in AML, and discuss potential benefits and risks of mTORC2 inhibition and the potential use of mTOR inhibitors as AML therapy.

Second-line chemotherapy has been established for non-small-cell lung cancer(NSCLC)and sensitive relapsed small cell lung cancer(SCLC).Molecular targeted drugs, such as EGFR- and ALK-inhibitors, have improved survival outcome remarkably in patients with NSCLC harboring EGFR mutations or EML4-ALK fusion proteins.In addition, targeted drugs that may overcome T790M-mediated EGFR-TKI resistance have been developed, and the development of future therapeutic strategies is anticipated.On the other hand, molecular targeted drugs against SCLC have not yet been developed.

Chronic lymphocytic leukemia (CLL) is a mature lymphoid malignancy that has a variable clinical course. Recent genomic studies using next-generation sequencers have revealed recurrent genetic alterations implicated in CLL pathogenesis. Clonal evolution by stepwise acquisition of genetic mutations may result in CLL progression. Among these abnormalities, alteration of B cell receptor (BCR) signaling is critical during CLL development. In addition, signals from the microenvironment support the proliferation and survival of CLL cells. Novel molecular targeted drugs that influence these signals are now becoming clinically available.

Acute lymphoblastic leukemia (ALL), a clonal expansion of hematopoietic blasts, is a highly heterogeneous disease comprising many entities for which distinct treatment strategies are pursued. Recurrent defects including chromosomal translocations, aneuploidies, and gene-specific alterations generate molecular subgroups of B- and T-ALL with differing clinical courses and distinct responses to therapy. Herein, we review the spectrum of genetic aberrations that promote acute B- and T-ALL, as well as the currently-revealed mechanisms of cell transformation and malignant progression. Although 5-year overall survival of childhood ALL patients has improved to as much as 90% due to progress in chemotherapy and other supporting therapeutic modalities, including allo-HSCT, the prognosis is still poor for the remaining 10% of cases, which consist mainly of MLL-AF4-positive ALL and bcr-abl positive ALL. The prognosis of adults with ALL is not satisfactory and adult ALL remains a challenging disease. The development of novel methodologies, including new molecular therapeutic targets, is also needed to improve the prognosis of ALL.

Angioimmunoblastic T-cell lymphoma (AITL) is a distinct subtype of peripheral T-cell lymphoma. The origins of AITL tumor cells were thought to be follicular helper T (TFH) cells based on the common features of these two cell types. Recent findings suggest a multistep model for the development of AITL. The immature blood cells evolve into premalignant (prelymphoma) cells by acquisition of premalignant mutations including TET2 and/or DNMT3A mutations. The premalignant cells finally develop into full-blown tumor cells by accumulation of tumor-specific RHOA mutations. Combinations of premalignant and tumor-specific mutations may induce development of AITL.