After the year 2000, the treatment of cancer remarkably changed, including the development of outpatient cancer chemotherapy. Meanwhile, we have encountered many clinical problems related to cancer patient pharmacy services. To resolve these problems, I have tried to establish the individualized and optimal cancer pharmacotherapy utilizing the findings of basic research. In this review, three topics of my research will be introduced. 1) In 2005, information regarding the genetic polymorphism of UGT1A1*28 was described in the package insert of the drug irinotecan in the United States. At that time, however, there was little similar information for Japanese patients. Through clinical research, we demonstrated that UGT1A1*6 was a significant factor for neutropenia, as induced by irinotecan. 2) Tyrosine kinase inhibitors are mainly used at a fixed dose, but wide interpatient variability has been observed relative to their pharmacokinetics and/or pharmacodynamics. To overcome these variations, clinical and basic pharmacological research on erlotinib, sorafenib and sunitinib was carried out. Especially, in sunitinib therapy, we demonstrated that the breast cancer resistant protein in the intestine functions as a limiting factor for oral absorption, and that therapeutic drug monitoring could be helpful for avoiding severe toxicities, resulting in prolonged progression-free survival. 3) We quantitatively assessed side effect management by pharmacist intervention for outpatient chemotherapy. We calculated the improvement ratio between before and after pharmacist intervention, and found that 135 suggestions (50.8%) led to significant improvements, indicating that pharmacist intervention could be useful for attenuating the side effects of cancer chemotherapies.

Implementation of screening programs aimed at early detection of colorectal cancer is essen- tial to reduce incidence and mortality rates. Current screening and diagnostic methods range from semi-invasive procedures such as colonoscopy to noninvasive stool-based tests. On the other hands, with the development of new sensitive molecular techniques, colorectal cancer initiation and progression have been known to control by both genetic and epigenetic events, which can be used for the development of novel, minimally invasive molecular bio- markers. The purpose of this review is to discuss the commercially available colorectal cancer molecular diagnostic methods as well as to highlight some of the new candidate molecular markers for stool, and blood samples.

Irinotecan is a camptothecin analog used worldwide for a broad range of solid tumors, including colorectal cancer. It can cause severe adverse drug reactions, such as neutropenia or diarrhea. Recent pharmacogenetic studies on irinotecan have revealed the impact of UGT1A1 polymorphisms on severe adverse effects. The concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, markedly alters the disposition of irinotecan, potentially increasing toxicity. For patients showing homozygosity for UGT1A1*28, *6 or compound heterozygosity for UGT1A1*6 and *28, dose reduction of irinotecan is strongly recommended. But dose reduction criteria or effect of dose reduction have not been clarified. If prediction accuracy of expression risk of adverse reaction improve, It is expected to be possible to appro- priate therapeutic indications and drug selection, dose setting.

Nowadays immune checkpoint inhibitors such as anti-CTLA-4, PD-1 and PD -L1 anti- bodies, are most striking among the clinical development of immunotherapy. These mono- clonal antibodies restore and augment the anti-tumor immune activities of cytotoxic T cells by mainly blocking immune checkpoint molecules on T cells or their ligands on antigen presenting and tumor cells. Based on preclinical data, many clinical trials have demonstrated the acceptable safety profiles and efficacies in a variety of cancers. Early phase clinical of mono therapies of immune checkpoint inhibitors had failed for colorectal cancer (CRC). How- ever, some pilot studies suggested anti -PD-1 antibody was very effective in CRC patients with microsatellite instability (MSI) -high. Now several clinical trials are investigating new agents, alone and in combination, for colorectal cancer patients with microsatellite stable (MSS). The current clinical development and TR research and future challenges in utilizing immune checkpoint inhibitors in CRC will be described.

In recent years, the cancer therapy based on the biomarker has been clinically introduced in colorectal cancer. Furthermore, the therapeutic development for the colorectal cancer patients corresponding to gene alteration, such as BRAF gene mutation and microsatellite instability(MSI), are underway. Although the development of the novel treatments according to biomarkers is urgent the fragmentation of the patient population by biomarker have caused various problems in the treatment development. To accelerate the development of therapeutic agents for small population, we conduct a nationwide genome screening project'SCRUM- Japan'.

MicroRNAs(miRNAs) are key regulators involved in various tumors. Recently, it has become clear that aberrant miRNA expression has a functional role in the initiation and progression of colorectal cancer (CRC). Distinct miRNA expression profiles have cancer- specific patterns and are associated with diagnosis, prognosis and therapeutic outcome in CRC. Many studies have shown that the miRNA play an important role in carcinogenesis, invasion and metastasis by regulating multiple target gene expressions and should be early detection biomarkers and therapeutic targets for CRC. Here we review the mechanisms and clinical uses of representative miRNAs in colorectal cancer.

Cancer has a character of heterogeneity, which makes it difficult to determine treatment strategy and predict prognosis. To conquer this problem, comprehensive analyses have been actively performed for gene expression, and molecular subtypes of various types of cancer have been identified by many studies. In colorectal cancer(CRC), there are known to be other subtypes than gene expression, that is, chromosome instability(CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). Classification of molecular subtypes by integrating these multiple biological properties would realize the effective tailor-made treatment, and improve CRC patient's prognosis. In this article, we overview the mechanisms of CRC carcinogenesis, and present the latest biological classification of subtypes in CRC.

Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Although fusion genes generated by chromosomal rearrangements are the most frequent genetic alterations in pediatric ALL, fusions are insufficient for the development of this disease, and thus, cannot serve as therapeutic targets for ALL. Recently, integrated genetic analysis using next generation sequencing technology has revealed the genetic landscapes of pediatric ALL. These studies disclosed that in addition to fusion genes, aberrations of cell proliferation pathways and epigenetic regulations are also involved in the pathogenesis of pediatric ALL. On the other hand, more recently, abnormalities of supper enhancer regions of TAL1 have been detected as a novel oncogenic mechanism of pediatric T cell ALL. Furthermore, germline mutations of ARID5B, PAX5, and GATA3 have been found to be involved in the genetic risk of developing ALL. Therefore, currently, the molecular mechanisms of pediatric ALL have been fully disclosed.

Outcomes of patients with acute lymphoblastic leukemia (ALL) have improved dramatically with conventional chemotherapy consisting of multiple agents. However, considering the major impact of tyrosine kinase inhibitors in the treatment of Philadelphia chromosome-positive ALL, sensitivities to each chemotherapeutic agent must be appreciated in individual cases to further improve therapeutic outcomes of ALL patients. Recent advances in genome-wide association and comprehensive genetic mutation studies with next-generation sequencing enable the involvement of single nucleotide polymorphisms and acquired genetic mutations in the drug resistance of ALL to be evaluated. Herein, we overview recent findings regarding the mechanisms of drug resistance in ALL. Our observations in a large panel of ALL cell lines are also presented.

The current standard treatment for diffuse large B-cell lymphoma (DLBCL) is R-CHOP administration. This therapeutic protocol began in the first decade of the 21st century, based on the results of a randomized trial which compared R-CHOP with a CHOP regimen for elderly patients and showed an approximately 20% survival advantage in the R-CHOP arm. Recent developments of new drugs such as monoclonal antibody and molecularly targeted agents have been remarkable and many such agents have been introduced into clinical practice with high expectations. Nevertheless, the standard regimen for DLBCL has not been renewed for more than 15 years. In this article, we consider the types of investigations which have pointed to the conclusion that the R-CHOP regimen remains the current standard for DLBCL patients. Future perspectives are also discussed.

The loss of mismatch repair(MMR)function as a result of MLH1 promoter methylation is closely correlated with high frequency microsatellite instability, and tumors with such characteristics are resistant to anticancer drugs such as 5-FU. We examined the incidence and characteristics of deficient MMR(dMMR)in elderly gastric cancer patients by performing a comprehensive immunohistochemical screening. The study was conducted in 199 patients diagnosed with gastric cancer, aged 75 years or older, who underwent a gastrectomy between April 2005 and January 2014. dMMR was detected in 23 patients(12%). All the tumors with dMMR were deficient in MLH1 and PMS2. dMMR was significantly more common compared to proficient MMR(pMMR)in patients with a more advanced age(p=0.03), women(p<0.01), and a tumor location corresponding to the lower region(p<0.01). Considering the incidence of dMMR in elderly gastric cancer patients, only a limited proportion of patients are likely to be eligible for immune checkpoint inhibitor therapy, which is expected to become more popular in the near future.

Standard induction chemotherapy regimens achieve complete remission rates of 80% in younger adult patients with acute myeloid leukemia (AML). However, because of disease relapse only 40-50% of patients achieve long-term survival. Five-year survival rates in older patients are only one third of those achieved in younger cases. The adverse prognostic impact of advanced age is attributable to the chemotherapy-resistant nature of the blasts and the limited tolerability these patients have for intensive chemotherapy. For younger patients with relapsed/refractory AML, the therapeutic approach to curing AML is the re-induction of complete remission employing intensive chemotherapy, followed by allogeneic hematopoietic cell transplantation. If this approach is not feasible, less intensive chemotherapy or best supportive care or transplantation without disease remission may be performed. Older patients are unlikely to be candidates for hematopoietic cell transplantation in general. Older patients with newly diagnosed AML of low risk may be treated with intensive chemotherapy, while those with intermediate/high risks may have options including less intensive chemotherapy and best supportive care.

Current treatment of acute myeloid leukemia (AML) still relies on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). AML is a heterogeneous neoplasm characterized by distinct chromosomal and genetic abnormalities. Recent comprehensive gene analyses have highlighted distinct genetic subgroups that are associated with different responses to chemotherapy. Therefore, the molecular landscape of AML is fundamental to the development of novel therapeutic approaches and provides opportunities for individualization of therapy. In addition, the age-related incidence of clonal hematopoiesis is high, affecting nearly 10% of healthy people more than 65 years of age. Clonal hematopoiesis is confirmed by the presence of mutations related to AML including genes involved in DNA methylation, chromatin modification and RNA splicing. In the analysis of gene mutation profiles in secondary AML (s-AML) from myelodysplastic syndromes and myeloproliferative neoplasms, secondary-type gene mutations were identified with >95% specificity in s-AML as compared with de novo AML, including RNA splicing, chromatin modification and cohesion complex genes, and were highly associated with poor responses to chemotherapy as well as TP53 mutation. It is important to identify genetic subgroups at relatively high-risk of relapses who should receive allogeneic HSCT during the first remission. In this review, prognostic stratification for individualized treatment of AML is discussed.

Exosomes are membrane vesicles approximately 100 nm in diameter, present in a wide range of body fluids, including blood, cerebrospinal fluid, urine and saliva. Exosomes reflect the physiological state of their cells of origin and cancer cell-derived exosomes carry pathogenic components, such as proteins, messenger RNA (mRNA), microRNA (miRNA), and DNA. Thus, exosomes in body fluids provide a rich source of potential biomarkers. However, the use of exosomes as biomarkers to improve patient care has been limited by their small size and the extensive sample preparation required for their isolation and measurement. In this review, we describe a new liquid biopsy technique designed to sensitively detect disease specific circulating exosomes. We also provide perspectives in translational medicine from the standpoint of diagnosis and therapy.

Epigenetic marks, such as histone modifications or DNA methylation, regulate tissue specific gene expression by affecting the structures and accessibility of chromatin or DNA. Epigenetics, the molecular mechanisms regulating the epigenome, would therefore be critically involved in development and cell differentiation versus proliferation. Histone modifications include methylation, acetylation, phosphorylation and ubiquitination of specific lysine, arginine or serine residues on histone tails, and each modification has its own specific effect on gene expressions. Modification of histones is accomplished by multimeric protein complexes including polycomb and trithorax group proteins. Regulation of DNA methylation is another mechanism of epigenetic regulation, which is achieved by DNA methyltransferase (DNMT) and TET family proteins. Methylation of cysteine residues on DNA generally leads to transcriptional repression, and oxidation of methylated cysteines provides another type of molecular mark on DNA that regulates gene expression. Next generation sequencing of tumor genomes has uncovered recurrent somatic mutations of epigenetic genes such as DNMT3A, TET2, and ASXL1 in hematologic malignancies, showing that epigenetic dysregulation is a critical step leading to the transformation of hematopoietic cells. Rigorous integrated functional analyses of mutated epigenetic genes are currently underway, and are anticipated to lead to the development of novel molecularly targeted therapies for hematologic malignancies.

"Liquid biopsy" is one of the hottest topics in the cancer molecular diagnostics field because of its potential to replace conventional tissue biopsy. "BEAMing" is one of the digital PCR platform technologies for liquid biopsy samples, and it features a high enough sensitivity to detect a very low concentration of mutation frag- ments in circulating tumor DNA from the plasma of cancer patients. In this article, some of the promising clinical applications of BEAMing technology and its future possibilities as an advanced cancer diagnostic will be briefly summarized. [Review].