In contrast to pilocytic astrocytomas(PAs), pilomyxoid astrocytomas(PMAs)demonstrate monophasic piloid cells with angiocentric distribution and a more aggressive clinical course. Recently, several reports have described combined histological features of both subtypes;accordingly, these were termed intermediate pilomyxoid tumors(IPTs). The KIAA1549-BRAF fusion gene has been found in approximately 70% of PAs, but is reportedly rare in PMAs. We describe a clinicopathological study of two patients with pilomyxoid-spectrum astrocytoma(PMSA). Case 1 was of a 29-year-old man who presented with a generalized seizure. Gadolinium-magnetic resonance imaging(Gd-MRI)demonstrated a less enhanced tumor in the left temporal lobe. Case 2 was of a 9-year-old boy who presented with headache. Gd-MRI revealed an irregularly enhanced tumor in the left cerebellum. In Case 1, the tumor showed monomorphous bipolar cells in a myxoid background and angiocentric arrangement;therefore, the diagnosis was PMA. In Case 2, part of the tumor had a myxoid, angiocentric pattern characteristic of PMA;the other part had a biphasic pattern characteristic of PA. PMA and PA were mixed in a 7:3 ratio;therefore, IPT was diagnosed. No BRAF V600E mutations were found by immunohistochemistry and sequencing in either case. Three major KIAA1549-BRAF fusion subtypes were analyzed by quantitative reverse transcription polymerase chain reaction(RT-PCR)and sequencing. No fusions were found in Case 1. However, K16-B9 fusion was identified in Case 2, and this fusion was more prevalent in the PA component than in the PMA component. In summary, no BRAF V600E mutations were found in PMSAs, but KIAA1549-BRAF fusion was identified in IPT, particularly in the PA component.

The majority of cancer incidences and deaths occur in the elderly. Elderly patients are a heterogeneous population in terms of physical reserve, comorbidity, polypharmacy, and other geriatric conditions. The elderly has been under-represented in clinical trials of cancer therapy, even in the era of targeted therapy. It is widely believed that targeted therapy, which interferes with specific pathways required for tumor development and growth, is more effective and less toxic than cytotoxic chemotherapy. However, some toxicities are concerned in the elderly such as arterial thromboembolism associated with the use of bevacizumab and cardiotoxicity with trastuzumab. This article reviews the available evidence on the efficiency and toxicity of targeted therapy for solid tumors in the elderly.

Malignant neoplasm preferentially occurs in the elderly. Common cancers in the elderly are gastric, colorectal, lung and prostate cancers in men whereas colorectal, lung, gastric and pancreatic cancers in women. There are several characteristic features such as tumor location, histology, biological behavior and pathway of carcinogenesis in malignant neoplasms occurring in the elderly. Multiple cancers increase with aging. Although it is generally believed that carcinoma in the elderly shows well differentiation, slow growth, low incidence of metastasis and favorable prognosis, the tumor does not always show such features. Regarding biological behavior of malignant tumor in the elderly, age-related alterations of the host such as stromal weakness and decreased immune response against cancer cell invasion should be considered as well as characteristics of tumor cell itself. Thus, we need a specific strategy for treatment for malignant neoplasms in the elderly.

Both the soft tissue sarcomas and the neuroendocrine tumors are rare diseases. Therefore the recruiting of these patients was more difficult than other cancer species, and the development of the new therapy for these diseases did not readily advance. However, the identification of driver molecules for each sub-type enabled us to the development of the molecular targeted drugs. As for the GIST, several TKIs are used, but in late years it is found that susceptibility of TKIs varies according to difference in second mutation. In this chapter, the molecular target drug for the soft tissue sarcoma and the neuroendocrine tumor is reviewed.

Over the three decades, advances in the fields of cancer genetics and immunology have elucidated mechanisms that cause the growth of cutaneous malignancies. This has contributed to the rational design of molecular target therapies. In this review, the molecular pathways and cancer immunology critical to the development of cutaneous malignancies are discussed. Included is a review of the following novel pharmacologic agents; BRAF inhibitors, MEK inhibitors, anti-CTLA-4 antibody and anti-PD-1 antibodies for melanoma, cetuximab and gefitinib for squamous cell carcinoma, vismodegib for basal cell carcinoma and nevoid basal cell carcinoma syndrome, imiquimod for extramammary Paget's disease, imatinib for dermatofibrosarcoma protuberans and vorinostat and mogamulizumab for cutaneous T-cell lymphoma.

Targeted therapies against vascular endothelial growth factor (VEGF), VEGF receptor and epidermal growth factor receptor (EGFR) have improved survival in patients with metastatic colorectal cancer (mCRC). Clinical studies have demonstrated that the following 6 targeted agents showed antitumor activity in patients with mCRC: bevacizumab, aflibercept, ramucirumab, cetuximab, panitumumab and regorafenib. KRAS exon 2 (codons 12 and 13) mutations were negative predictive biomarkers for efficacy of anti-EGFR antibody therapy. Expanded RAS mutations (including KRAS exon 2, exon 3 and exon 4 mutations as well as NRAS mutations) can further predict the therapeutic effects of this therapy. It seems to be necessary to identify new predictive biomarkers and develop new targeted agents for personalized treatment for mCRC.

Several driver oncogenes, including EGFR mutations and ALK rearrangement, have been identified in lung cancer. The EGFR tyrosine kinase inhibitors (TKIs) and ALK-TKIs show dramatic effects against lung cancer with EGFR activating mutations and ALK rearrangements, respectively. However, 20% of EGFR mutant lung cancer patients show intrinsic resistance, and the responders almost invariably acquire resistance to EGFR-TKIs within several years. Several mechanisms, including secondary mutations in EGFR or ALK, activation of alternative pathway, have been reported to contribute to resistance to EGFR-TKIs and ALK-TKIs. New generation TKIs for overcoming resistance to EGFR-TKI or ALK-TKI are being evaluated in clinical trials. Further investigations to develop optimal therapy based on accurate diagnosis of resistant mechanism are warranted to improve the success of treatment with targeted drugs in lung cancer.

Up to the present, several genes have been identified as drivers for lung carcinogenesis, and their aberrations have been shown to be linked with differential response to therapy. Optimized treatments are, therefore, important in the situation that we have options for treatments by driver gene aberrations. Recently, comprehensive analyses of DNA and RNA from lung tumor tissues have been actively performed and have been pushing the lung cancer medicine forwards. In addition, circulating cell-free tumor DNA in plasma as a "liquid biopsy" opens a great hope for noninvasive molecular diagnosis. This article will highlight findings of recent comprehensive genome analysis to improve precision lung cancer medicine.

Owing to development of next generation sequencer (NGS), deep biological insights of breast cancer have been provided. Information of genomic mutations and rearrangements in patients' tumors is required to understand the mechanism in resistance of molecular targeted medicine. To date, NGS analyses illustrated not only base substitution patterns and lists of driver mutations and key rearrangements, but also a manner of tumor evolution. Breast cancer genome is dynamically changing and evolving during cancer development course and treatment procedures. Liquid biopsy is a non-invasive method to detect the genomic evolution of breast cancer, which is now under development for future application to clinical practice of cancer treatment. In this article, latest knowledge regarding breast cancer genome, especially in terms of 'evolution', is summarized.

Efficacy of cancer pharmacotherapy depends upon drug exposure to the body and responsiveness of the tumor to the drug treatment. Drug exposure is determined by pharmacokinetics and dose, whereas responsiveness is intrinsically variable by tumor heterogeneity. Molecular targeting drugs are used as promising therapy for cancers, and most of them are coupled with particular diagnostics which can predict responders and non-responders before treatment. On the other hand, lower drug exposure to the body can lead to insufficient efficacy. A number of important evidences have been published recently on exposure-response relationships for molecular targeting drugs including monoclonal antibodies and small molecules. In this chapter, two examples are presented; anti-HER2 antibody and tyrosine kinase inhibitor. Patients with the lowest trough concentrations of trastuzumab in cycle 1 showed shorter overall survival in metastatic gastric cancer study. Efficacy of imatinib in chronic myelogenous leukemia depended on plasma concentration of imatinib, and therapeutic drug monitoring (TDM) of imatinib is expected to improve the therapeutic outcome in CML.

Emerging evidence has been unveiled that major oncogenic pathways, which serve as a main focus for the molecular targeting therapies, play a pivotal role in establishing immunosuppressive tumor microenvironments. The modulation of various immune modulatory pathways, such as upregulation of PD-L1 by various oncogenic mutations such as EGFR, BRAF, activation of PI3K and JAK-Stat3 on tumor cells, may be critical in modulating tumor immune responses. Given the potential clinical impact of immune checkpoint blockade and other immunotherapeutic regimens as a future anticancer regimen, it is critical to clarify the mechanisms by which molecularly targetable oncogenes and tumor microenvironments influence quality of tumor immunosurveillance, which should provide a new strategy for suitable combinatorial approaches composing of molecular targeting and immunotherapies.

Aberrant activation of the Wnt, Notch and Hedgehog pathways via mutations or ligand overexpression has been implicated in a large number of cancer types where they are involved in functions ranging from tumor initiation to cancer stem cell (CSC) maintenance and angiogenesis. Agents targeting each one of these three pathways have now reached clinical trials, and the first one of these, Vismodegib, a hedgehog pathway inhibitor, was approved in 2012 by US FDA for the treatment of advanced basal cell carcinoma. Development of agents that target critical steps in these pathways as novel signal transduction pathways will be complicated by signaling cross-talk. The role that embryonic signaling pathways play in the function of CSCs, the development of new anti-CSC therapeutic agents, and the complexity of potential CSC signaling cross-talk are being explored coupled with early phase I clinical studies.

Poly(ADP-ribose) polymerases(PARP) synthesize the ADP-ribose polymers onto proteins and play a role in DNA repair. PARP inhibitors block the repair of single-strand breaks, which in turn gives rise to double-strand breaks during DNA replication. Thus, PARP inhibitors elicit synthetic lethality in cancer with BRCA1/2 loss-of-function mutations that hamper homologous recombination repair of double-strand breaks. Olaparib, the first-in-class PARP inhibitor, was approved for treatment of BRCA-mutated ovarian cancer in Europe and the United States in 2014. Other PARP inhibitors under clinical trials include rucaparib, niraparib, veliparib, and the "PARP-trapping" BMN-673. BRCA1/2 sequencing is an FDA-approved companion diagnostics, which predicts the cancer vulnerability to PARP inhibition. Together, synthetic lethal PARP inhibition is a novel promising strategy for cancer intervention even in cases without prominent driver oncogenes.

Kinase cascades are involved in all stages of tumorigenesis through modulation of transformation and differentiation, cell-cycle progression, and motility. Advances in molecular targeted drug development allow the design and synthesis of inhibitors targeting cancer-associated signal transduction pathways. Potent selective inhibitors with low toxicity can benefit patients especially with several malignancies harboring an oncogenic driver addictive signal. This article evaluates information on solid tumor-related kinase signals and inhibitors, including receptor tyrosine kinase or serine/threonine kinase signals that lead to successful application in clinical settings. In addition, the resistant mechanisms to the inhibitors is summarized.

Molecular alteration of PI3K and mTOR pathways is frequently detected in various types of cancers. PIK3CA mutations are the predictive markers for anti-EGFR antibodies, trastuzumab, and lapatinib. The p110 isoform selective PI3K inhibitors has been developed in the clinical settings to reduced off-target induced adverse events. Feedback loop for PI3K signal leads the resistance to PI3K inhibitors. Dual PI3K/mTOR inhibitors and mutation selective PI3K inhibitors are under evaluation to circumvent the resistance.

Apoptosis and autophagy usually function to eliminate damaged cells and damaged proteins, respectively. Dysfunction of these events induces oncogenesis and cancer development. Therefore, small compounds that activate apoptosis and autophagy are good candidates for anti-cancer chemotherapeutics to combat cancers. This review focuses on recent advances in apoptosis/autophagy and their relationship with tumorigenesis.

Basic, clinical and translational metabolic researches in cancer area have been extensively tried to discover and develop novel cancer metabolism drugs. Since tumor cells have metabolic dependencies that distinguish them from their normal counterparts, targeted inhibition of these metabolic dependencies is considered a promising therapeutic strategy against cancer. For example the representative cancer metabolism is that cancer cells exhibit profound metabolic alterations by choosing aerobic glycolysis to metabolize glucose to lactate regardless of the presence of adequate oxygen, although normal cells which mainly utilize glucose by using mitochondrial oxidative phosphorylation to generate ATP. In this review, we focus on several important oncogenes and enzymes, whose alterations have contributed extensively to the metabolic phenotype of cancer cells, with an emphasis on the therapeutic targets.

A common strategy to identify tumor suppressor genes has been positional cloning, taking advantages of chromosomal abnormalities, linkage to polymorphic markers, etc. We have been taking another approach, based on shotgun cloning with cDNA-expression library, to isolate genes suppressing an aspect of transformed phenotypes. Genes identified in such an artificial system, however, require subsequent validation for their clinical relevance through independent approaches, such as finding mutations and altered expression in human cancers. Whether the parental genes act as oncogenes or tumor suppressors needs to be deduced from available annotations and/or new experimental data. Once validated, such genes, being isolated by virtue of their biological activities, are likely to be useful in developing new strategies for tumor prognosis, tumor stratification, and drug discovery.

Target-based screening and cell-based screening are major approaches to identify anticancer drug candidates. Cell-based screening often contributes to the discovery of first-in-class drugs, but identification of the cellular targets of obtained compounds is a time-consuming step. To overcome this problem, affinity purification with small-molecule probes, which is a classic, but still the most common approach, has become more sophisticated and diversified. In addition, recent advances in omics studies and imaging analyses have allowed us to profile the biological effects of small molecules globally and quantitatively. Consequently, new therapeutic targets/drug leads involved in cancer cell cycle, transcription and redox regulation have been discovered.

Cancer is known to be a genetic disease, which is caused by abnormalities of oncogenes and/or tumor-suppressor genes. Genetic abnormalities include mutation, deletion or amplification of DNA sequences. Based on the findings of the genetic abnormalities in malignant tumors, many molecular-targeting agents, e.g. Bcr-Abl kinase inhibitors and EGFR kinase inhibitors, have been developed and approved. In addition to genetic abnormalities, epigenetic abnormalities, e.g. DNA methylation, histone methylation and histone acetylation, are also involved in carcinogenesis and tumor development. Based on the findings of the epigenetic abnormalities in malignant tumors, the novel epigenetic molecular-targeting agents, e.g. DNA(DNMT) methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors, have also been developed and approved. Moreover, histone methyltransferase(HMT) inhibitors and histone demethylase(HDM) inhibitors have been also discovered and some agents are in clinical trials.