A 21-year-old woman who underwent laparoscopic total colectomy for familial adenomatous polyposis (FAP) 1 year 3 months previously presented with a mass larger than 10 cm around the ileostomy. Multiple tumors in the mesentery around the ileostomy and anterior to the sacrum, accompanied by bilateral hydronephrosis, were detected by computed tomography. The patient was diagnosed with intraabdominal desmoid tumors, stage Ⅳ according to the Church's classification. The desmoid tumor (15×9 cm) around the ileostomy was completely resected surgically, whereas another desmoid tumor (5×4 cm) was incompletely resected. We found a desmoid tumor of more than 10 cm in size and many fibromatous plaques in the mesentery. We then performed 4 courses of systemic chemotherapy with dacarbazine and doxorubicin in for the residual desmoid tumors after surgery. There was no growth of the residual desmoid tumors for 12 months after chemotherapy. Genetic tests detected a pathogenic germline mutation of the APC gene in the high-risk region of the desmoid tumor. We also confirmed somatic mutations in the resected specimens.

The aim of this study was to evaluate the outcome of surgical treatment for recurrence after curative pancreatectomy for pancreatic ductal cancer. Ten cases were enrolled, and the time from initial pancreatectomy to recurrence, location of recurrence, and outcome after surgical treatment for recurrence was evaluated. The time to recurrence was more than 1 year in 4 cases, and the locations of recurrence in these cases were the remnant pancreas and lung in 3 and 1 patients, respectively. Among these 4 cases, a second recurrence was observed in only 1 case, and survival after surgical treatment of the first recurrent site was more than 3 years in the other 3 cases. For the remaining 6 cases, the time to recurrence was less than 1 year and the recurrences were located in the abdomen but not in the remnant pancreas. A second recurrence was observed in all cases, and the survival time was less than 2 years in 4 out of 6 cases. Based on the results of this study, recurrence in the remnant pancreas and lung after curative resection for pancreatic ductal cancer could be a potential indication for surgical treatment.

Recently, new generation androgen receptor (AK) targeted agents enzautamide or abiraterone etc.) has been clinically utilized in patients with castration-resistant prostate cancer (CRPC). However, metastatic CRPC has also AR-independent survival pathway which leads to lethal phenotype by either adaptation or clonal selection resistant mechanism after AR targeted therapy. There are many studies regarding the progression mechanisms without AR signal transduction, such as growth factor, anti-apoptotic factor, and PTEN/mTOR pathway and so on. Also, cancer microenvironment and cancer stem cell is a hot research area for CRPC. It is very important to repress both AR-dependent and -independent signaling pathway to improve the clinical outcome in CRPC patients. Application of the new technology, such as next generation sequencing, would be developing for the prostate cancer research, providing pre-clinical proof-of-principle as a promising approach in CRPC.

Androgen receptor(AR) has a critical role in prostate cancer(PCa) progression and targeting AR axis signaling by androgen deprivation therapy is a standard treatment for advanced PCa. Recently, the role of AR even in castration-resistant PCa(CRPC) is well recognized and emerging evidence suggests survival advantages of treatment by targeting AR in CRPC. This review outlines AR functions that contribute to PCa progression, AR structural alterations and AR activation via intracrine, co-factors, and kinase pathways in CRPC. Finally, we describe about recently reported bipolar androgen therapy as a novel treatment for CRPC targeting AR.

Recently, new drugs including abiraterone and enzalutamide have been able to be used for castration resistant prostate cancer(CRPC) patients. However, a subset of these patients who receive the new drugs does not response to the therapies. Furthermore, most patients who initially response to the drugs, progress to secondary resistance eventually. Therefore, it is important to investigate a novel therapeutic target and a novel treatment-selection marker for CRPC. In this review, we focused on AR-V7, TMPRSS2-ERG fusion gene and EP4 antagonist as representative translational researches.

It is evident that genetic factors play critical roles in prostate cancer development. GWAS (genome-wide association studies) in multiple ethnic groups have been identifying more than 100 loci or genes which was significantly associated with prostate cancer susceptibility. They include several loci at 8q24, prostate-specific gene, inflammation gene, and metabolism-related genes. Risk prediction for prostate cancer by combining multiple SNPs is still primitive and not sufficiently accurate for clinical use, but this model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA or very high risk of prostate cancer.

Understanding mechanisms of transition to castration-resistant prostate cancer(PCa) through results of various basic researches in PCa field has introduced two new hormonal reagents (abiraterone acetate and enzalutamide) in our clinical fields. Moreover, recent advancements in technologies such as next-generation sequencing (NGS) have improved our understanding of the biology of PCa and helping to move PCa toward the personalized treatment paradigm. Herein, we review some of our current knowledge of the PCa mutational landscape through NGS and also discuss about the evolution of more sensitive modern mass spectrometric analytical techniques such as imaging mass spectrometry. Additionally, we summarized our understanding of some mechanisms of resistance against the new hormonal reagents.

Biomarkers are defined as characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers obtained by PCR or flow cytometry are used for the diagnosis and subtyping of hematopoietic tumor cases. They are also used to predict the effectiveness of molecular-targeted therapies and detect minimal residual leukemia cells. In order to cure leukemia, it is necessary to eradicate leukemia stem cells. For that purpose, biomarkers to identify and characterize the leukemia stem cells in each case are needed. Therefore, we examined molecules involved in various stemness-related signaling pathways, especially NOTCH signaling in acute leukemia cells. In T-lymphoblastic leukemia cells, which often have activating NOTCH1 mutations, NOTCH works in oncogenic signaling. Although acute myeloid leukemia (AML) cells express NOTCH and NOTCH ligands, it is still controversial whether NOTCH is oncogenic or tumor-suppressive. To utilize the expression and activation of NOTCH as a leukemia stem cell biomarker, further investigation is required. Other stemness-related signaling molecules such as WNT, HEDGEHOG, HIF, and mTOR are also under investigation to assess whether they can be used as stem cell biomarkers in a clinical setting.

Alternative splicing is an important mechanism that links to transcription and contributes to protein diversity. Disturbed alternative splicing is frequently observed in cancers, but its precise mechanism remains largely unknown. FUSE-binding protein (FBP) -interacting repressor (FIR) is a transcriptional repressor of the c-myc gene. Previous studies indicated that a splice variant of FIR, FIRΔexon2, that lacks exon2 in the transcriptional repressor domain, was increased in colorectal cancers, hepatocellular carcinomas, and leukemia cells. Furthermore, FIRΔexon2 activated c-myc transcription by disabling wild-type FIR as a dominant-negative form of FIR. Recently, somatic mutations of the SF3B1 (SAP155) gene, a subunit of the SF3B spliceosome complex, were found in myelodysplastic leukemia. In this study, FIR heterozygous knockout (FIR(+/-)) was established as a dominant-negative model of FIR in the C57BL/6 mouse. FIR(+/-) mice showed an increased c-myc mRNA expression level, particularly in peripheral blood, although FIR(+/-) mice had no apparent pathogenic phenotype. Therefore, an increased c-myc mRNA expression level alone is not enough for leukemogenesis. Nevertheless, FIR(+/-)TP53(-/-) mice generated acute T-cell lymphoblastic leukemia (T-ALL) with increased organ and/or bone marrow invasion. In conclusion, alternative splicing of FIR, generating FIRΔexon2, contributes to not only colorectal carcinogenesis but also leukemogenesis independent of the c-Myc activation pathway. Finally, we will discuss our hypothesis that FIRΔexon2 interferes with FBW7, that FIRΔexon2 inhibits PP1 in the EGFR pathway, and that FIR haploinsufficiency is potentially associated with protein expression through transcriptional and post-transcriptional mechanisms.

Leukemia arises through an evolutionary process of somatic mutation and selection. Transient abnormal myelopoiesis (TAM) is a clonal pre-leukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism underlying leukemogenesis, a xenograft model of TAM was established using NOG mice. Serial engraftment after cell transplantation from a TAM patient who developed ML-DS a year later showed the self-renewal capacity of these cells. We detected a GATA1 mutation but no copy number alterations (CNAs) in the primary patient sample by conventional genomic sequencing and CNA profiling. However, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, both of which are clinically associated with ML-DS. Detailed genetic analysis identified minor subclones with a 16q deletion or this distinct GATA1 mutation in the primary patient sample. These results suggest that genetically heterogeneous subclones with various leukemia-initiating potentials already exist in the neonatal TAM phase, and that ML-DS may develop from a pool of such minor clones through clonal selection. Our xenograft model could be a valuable tool for gaining insight into the processes underlying leukemogenesis.

A new class of gene mutations, identified in the pathogenesis of adult acute myeloid leukemia (AML), includes DNMT3A, IDH1/2, TET2 and EZH2. However, these mutations are rare in pediatric AML cases, indicating that pathogeneses differ between adult and pediatric forms of AML. Meanwhile, the recent development of massively parallel sequencing technologies has provided a new opportunity to discover genetic changes across entire genomes or proteincoding sequences. In order to reveal a complete registry of gene mutations, we performed whole exome resequencing of paired tumor-normal specimens from 19 pediatric AML cases using Illumina HiSeq 2000. In total, 80 somatic mutations or 4.2 mutations per sample were identified. Many of the recurrent mutations identified in this study involved previously reported targets in AML, such as FLT3, CEBPA, KIT, CBL, NRAS, WT1 and EZH2. On the other hand, several genes were newly identified in the current study, including BCORL1 and major cohesin components such as SMC3 and RAD21. Whole exome resequencing revealed a complex array of gene mutations in pediatric AML genomes. Our results indicate that a subset of pediatric AML represents a discrete entity that could be discriminated from its adult counterpart, in terms of the spectrum of gene mutations.

The rare central nervous system (CNS) infiltration of Waldenström macroglobulinemia (WM) is known as Bing-Neel syndrome (BNS). Furthermore, the transformation of WM into diffuse large B-cell lymphoma (DLBCL) is also unusual. Herein, we report a 69-year-old male with DLBCL transformed from BNS. In November 2008, the patient visited a prior hospital because of anemia and was diagnosed with WM. After receiving chemotherapy (R-CHOP), his serum immunoglobulin M (IgM) level decreased and then remained at approximately 2000 mg/dl for 3 years. In November 2011, he complained of visual impairment and photophobia in his left eye. Magnetic resonance imaging showed enlargement of the left optic nerve and cerebrospinal fluid examination indicated CNS infiltration of WM cells. Consequently, he was diagnosed with BNS. He thus received CNS targeted chemotherapy (R-MPV) and achieved a partial response. In May 2014, IgM was elevated and swelling of systemic lymph nodes was detected. Inguinal lymph node biopsy yielded a pathological diagnosis of DLBCL and the clonality of tumor cells between WM and DLBCL was confirmed by the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR).

Recent genome studies have identified recurrent somatic mutations in various myeloid malignancies, including acute myeloid leukemia, myelodysplastic syndrome and myeloproliferative neoplasm. These mutations frequently occur in epigenetic regulator genes, and functions of the proteins encoded by these genes in hematopoietic cells have been extensively analyzed, as reported recently. It is noteworthy that several epigenetic regulator genes, such as DNMT3A, TET2 and ASXL1, have also been identified in pre-leukemic stem cells. As targeting pre-leukemic stem cells would be a promising therapeutic approach, further investigations of epigenetic abnormalities in hematopoietic cells are anticipated to lead to the development of novel epigenetic therapies. In this review, we discuss recent genetic and functional data regarding epigenetic regulator genes and the future landscape of this new research field.

Predicting and monitoring the treatment response of patients with esophageal carcinoma are important. Molecular analyses of biopsy specimens are useful; however, the characteristics of the biopsy specimen are not similar to those of whole tumors, including metastatic tumors. Therefore, liquid biopsy using blood samples has been applied for the prediction of the tumor stage, sensitivity to radiotherapy, sensitivity to chemotherapy, and recurrent disease. Liquid biopsy is advantageous for monitoring the treatment response and as an objective diagnostic tool; it is cost effective.