Publications by authors named "Kazuya Ishiguro"

18 Publications

  • Page 1 of 1

Activated macrophages promote invasion by early colorectal cancer via an interleukin 1β-serum amyloid A1 axis.

Cancer Sci 2021 Jul 22. Epub 2021 Jul 22.

Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA-sequencing (RNA-seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues and detected significant upregulation of serum amyloid A1 (SAA1) in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Coculture experiments using CRC cell lines and THP-1 cells suggested that interleukin 1β (IL-1β) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL-1β. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1-like/M2-like macrophages at SAA1-positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of matrix metalloproteinase-9 in macrophages. Our data suggest that tumor-associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1 and that SAA1 may be a predictive biomarker and a useful therapeutic target.
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http://dx.doi.org/10.1111/cas.15080DOI Listing
July 2021

An Integrated Epigenome and Transcriptome Analysis to Clarify the Effect of Epigenetic Inhibitors on GIST.

Anticancer Res 2021 Jun;41(6):2817-2828

Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan;

Background/aim: Epigenetic alterations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). To obtain further insight into the GIST epigenome, we analyzed genome-wide histone modification and DNA methylation in GIST cells.

Materials And Methods: To reverse epigenetic silencing, GIST-T1 cells were treated with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor, and subsequently H3K4me3 levels, the DNA methylome, and the transcriptome were analyzed.

Results: Treatment with epigenetic inhibitors not only up-regulated genes with DNA methylation, but also genes related to interferon signaling. ChIP-seq analysis revealed that drug treatment up-regulated H3K4me3 levels in retrotransposons, including endogenous retroviruses (ERV). Finally, utilizing the omics data, we found that hypermethylation of MEG3 is a frequent event and an indicator of poorer prognosis in GIST patients.

Conclusion: Epigenetic inhibitors may activate interferon signaling via viral mimicry in GIST cells. Moreover, epigenome data could be a useful resource to identify novel GIST-related genes.
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http://dx.doi.org/10.21873/anticanres.15062DOI Listing
June 2021

Dual EZH2 and G9a inhibition suppresses multiple myeloma cell proliferation by regulating the interferon signal and IRF4-MYC axis.

Cell Death Discov 2021 Jan 12;7(1). Epub 2021 Jan 12.

Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Epigenetic mechanisms such as histone modification play key roles in the pathogenesis of multiple myeloma (MM). We previously showed that EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, and G9, a H3K9 methyltransferase, are potential therapeutic targets in MM. Moreover, recent studies suggest EZH2 and G9a cooperate to regulate gene expression. We therefore evaluated the antitumor effect of dual EZH2 and G9a inhibition in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed MM cell proliferation in vitro by inducing cell cycle arrest and apoptosis. Dual EZH2/G9a inhibition also suppressed xenograft formation by MM cells in vivo. In datasets from the Gene Expression Omnibus, higher EZH2 and EHMT2 (encoding G9a) expression was significantly associated with poorer prognoses in MM patients. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in MM cells. Notably, dual EZH2/G9a inhibition reduced H3K27/H3K9 methylation levels in MM cells and increased expression of endogenous retrovirus (ERV) genes, which suggests that activation of ERV genes may induce the IFN response. These results suggest that dual targeting of EZH2 and G9a may be an effective therapeutic strategy for MM.
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http://dx.doi.org/10.1038/s41420-020-00400-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803977PMC
January 2021

[Primary diffuse large B-cell lymphoma of the breast in a male patient with Sjögren's syndrome].

Rinsho Ketsueki 2020 ;61(11):1584-1589

Department of Gastrointestinal medicine, Tenshi Hospital.

When a 74-year-old male patient visited our hospital for the treatment of herpes zoster, his computed tomography (CT) revealed a mass in his right breast, axillary lymph node enlargement, and multiple lung nodules. A histological examination of the breast and lymph node biopsies revealed diffuse large B-cell lymphoma (DLBCL) while the bronchial and salivary gland biopsies showed secondary amyloidosis and Sjögren's syndrome (SjS). According to the Ann Arbor staging, the clinical stage of the lymphoma was evaluated as IIE. The patient achieved a complete remission after six cycles of rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone (R-THP-COP) combined with intrathecal chemotherapy to prevent meningeal infiltration and irradiation after chemotherapy. Primary breast lymphoma was diagnosed within 2% of the breast tumor. Only sixteen male cases of breast lymphoma have been previously reported. In those reports, gynecomastia and hormonal therapy accounted for nine cases, but none of the cases coexisted with SjS. The present case is suggestive of the need to investigate possible autoimmune involvement in the development of lymphoma.
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http://dx.doi.org/10.11406/rinketsu.61.1584DOI Listing
February 2021

Aggressive variant of splenic marginal zone lymphoma characterized using a cancer panel test and treated with rituximab-containing chemotherapy: A case report.

Medicine (Baltimore) 2020 Aug;99(35):e21938

Department of Surgical Pathology, Hokkaido University Hospital.

Rationale: Aggressive variant of splenic marginal zone lymphoma (AV-SMZL) is a very rare disease that is often associated with TP53 mutations and has a poor prognosis. On the other hand, recent advances in genome sequencing techniques enable us to understand the molecular characteristics of rare cancers such as AV-SMZL. Here we present a case of AV-SMZL analyzed using a genetic test.

Patient Concerns: A 66-year-old woman was admitted with splenomegaly and lymphocytosis. Computed tomography revealed marked splenomegaly without lymphadenopathy in any other areas. The serum soluble interleukin-2 receptor (sIL-2R) level was significantly elevated. Peripheral and bone marrow blood tests showed an increase in abnormal lymphocytes.

Diagnosis: A splenectomy revealed an SMZL pattern with increased numbers of large cells and mitotic cells and a high Ki-67 positivity rate, which led to a diagnosis of AV-SMZL. Although TP53 mutation was not detected, mutations in NOTCH2, NCOA4, PTEN, EPHA3, and KMT2D were identified. Among these, the mutations in NCOA4, PTEN, and EPHA3 were novel pathogenic mutations in SMZL, which suggests they may be related to the aggressiveness and persistence of the disease.

Interventions: The patient was administered a rituximab-containing regimen and rituximab-maintenance therapy.

Outcomes: The patient continues to exhibit a complete response.

Lessons: This is a case of AV-SMZL in which a cancer panel test successfully detected genetic alterations that are potentially associated with its pathogenesis. These findings suggest that genetic analysis is useful for making diagnoses as well as for determining treatment strategies in AV-SMZL.
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http://dx.doi.org/10.1097/MD.0000000000021938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458248PMC
August 2020

UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells.

Clin Epigenetics 2019 05 7;11(1):70. Epub 2019 May 7.

Department of Molecular Biology, Sapporo Medical University School of Medicine, S1, W17, Chuo-ku, Sapporo, 060-8556, Japan.

Background: Ubiquitin-like protein containing PHD and RING finger domains 1 (UHRF1) is a major regulator of epigenetic mechanisms and is overexpressed in various human malignancies. In this study, we examined the involvement of UHRF1 in aberrant DNA methylation and gene silencing in colorectal cancer (CRC).

Results: CRC cell lines were transiently transfected with siRNAs targeting UHRF1, after which DNA methylation was analyzed using dot blots, bisulfite pyrosequencing, and Infinium HumanMethylation450 BeadChip assays. Gene expression was analyzed using RT-PCR and gene expression microarrays. Depletion of UHRF1 rapidly induced genome-wide DNA demethylation in CRC cells. Infinium BeadChip assays and bisulfite pyrosequencing revealed significant demethylation across entire genomic regions, including CpG islands, gene bodies, intergenic regions, and repetitive elements. Despite the substantial demethylation, however, UHRF1 depletion only minimally reversed CpG island hypermethylation-associated gene silencing. By contrast, the combination of UHRF1 depletion and histone deacetylase (HDAC) inhibition reactivated the silenced genes and strongly suppressed CRC cell proliferation. The combination of UHRF1 depletion and HDAC inhibition also induced marked changes in the gene expression profiles such that cell cycle-related genes were strikingly downregulated.

Conclusions: Our results suggest that (i) maintenance of DNA methylation in CRC cells is highly dependent on UHRF1; (ii) UHRF1 depletion rapidly induces DNA demethylation, though it is insufficient to fully reactivate the silenced genes; and (iii) dual targeting of UHRF1 and HDAC may be an effective new therapeutic strategy.
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http://dx.doi.org/10.1186/s13148-019-0668-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505222PMC
May 2019

Isolated Orbital Myeloid Sarcoma as a Therapy-related Myeloid Neoplasm.

Intern Med 2019 04 19;58(7):1045-1046. Epub 2018 Nov 19.

Department of Hematology, Tenshi Hospital, Japan.

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http://dx.doi.org/10.2169/internalmedicine.2105-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478994PMC
April 2019

Gastric adenocarcinoma of fundic gland mucosa type localized in the submucosa: A case report.

Medicine (Baltimore) 2018 Sep;97(37):e12341

Department of Pathology Department of Laboratory Department of Digestive Endoscopy Department of Gastroenterological Surgery, Tsukuba Medical Center Hospital, Tsukuba, Ibaraki, Japan.

Rationale: Gastric adenocarcinoma of fundic gland type (GA-FG) is a new histological type of gastric cancer manifesting with differentiation into a fundic gland. Furthermore, gastric adenocarcinoma of fundic gland mucosa type (GA-FGM) is a tumor that shows differentiation into not only a fundic gland but also foveolar epithelium and a mucous gland. These tumors tend to invade the submucosal layer. However, no cases of these tumors being localized only in the submucosa have been reported. Here, we present a case of GA-FGM localized in the submucosa and describe the cytological features of this tumor. To our knowledge, this is the first reported case of GA-FGM localized in the submucosa.

Patient Concerns: A man in his early 70s was referred to our institution because of the detection of a gastric submucosal tumor during a health checkup.

Diagnoses: Gastric adenocarcinoma of fundic gland mucosa type.

Interventions: Endoscopic ultrasound-guided fine-needle aspiration (FNA), endoscopic submucosal dissection (ESD), and total gastrectomy with lymph node dissection were performed.

Outcomes: The FNA specimen showed epithelial cells with low-grade atypia. In the ESD specimen, adenocarcinoma showing a gastric fundic gland mucosa-like morphology was observed. Immunohistochemical analysis showed positive staining for pepsinogen I, H+/K+-adenosine triphosphatase, MUC6, and MUC5AC and negative staining for MUC2 and CD10, indicating tumor differentiation into fundic gland mucosa. Therefore, the tumor was diagnosed as GA-FGM, with localization in the submucosal layer. Total gastrectomy and lymph node dissection were performed because of the positive margins of the ESD specimen. Neither residual tumor nor lymph node metastasis was detected; however, many foci of heterotopic gastric glands (HGGs) were observed in the gastric wall, suggesting that GA-FGM arose from an HGG. After treatment, no recurrence was observed during a 1-year follow-up period.

Lessons: Various tumors may arise from HGGs. Furthermore, when an FNA specimen shows gastric fundic gland mucosa-like epithelial cells with weak atypia, the possibility of GA-FG and GA-FGM should be considered.
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http://dx.doi.org/10.1097/MD.0000000000012341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156021PMC
September 2018

DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling.

Haematologica 2019 01 31;104(1):155-165. Epub 2018 Aug 31.

Department of Molecular Biology, Sapporo Medical University School of Medicine

Epigenetic alterations play an important role in the pathogenesis in multiple myeloma, but their biological and clinical relevance is not fully understood. Here, we show that DOT1L, which catalyzes methylation of histone H3 lysine 79, is required for myeloma cell survival. expression levels were higher in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma than in normal plasma cells. Treatment with a DOT1L inhibitor induced cell cycle arrest and apoptosis in myeloma cells, and strongly suppressed cell proliferation The anti-myeloma effect of DOT1L inhibition was confirmed in a mouse xenograft model. Chromatin immunoprecipitation-sequencing and microarray analysis revealed that DOT1L inhibition downregulated histone H3 lysine 79 dimethylation and expression of IRF4-MYC signaling genes in myeloma cells. In addition, DOT1L inhibition upregulated genes associated with immune responses and interferon signaling. Myeloma cells with histone modifier mutations or lower expression were less sensitive to DOT1L inhibition, but with prolonged treatment, anti-proliferative effects were achieved in these cells. Our data suggest that DOT1L plays an essential role in the development of multiple myeloma and that DOT1L inhibition may provide new therapies for myeloma treatment.
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http://dx.doi.org/10.3324/haematol.2018.191262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312027PMC
January 2019

Near Tetraploidy Acute Myeloid Leukemia in Long-term Remission with Persistent Clonal Hematopoiesis with del(20)(q12q13).

Intern Med 2017 Nov 1. Epub 2017 Nov 1.

Department of Surgery, Tenshi Hospital, Japan.

Patients with near tetraploidy/tetraploidy (NT/T)-acute myeloid leukemia (AML) are rare and generally show poor survival. A 62-year-old man was referred to our hospital with pancytopenia. A bone marrow examination revealed the proliferation of extremely large blasts, and led to the diagnosis of AML M0. A cytogenetic analysis showed an NT-karyotype of 91, XXYY, -5, add(18)(p21),del(20)(q12q13) ×2. Complete remission was achieved with single remission induction chemotherapy. Although consolidation chemotherapies were not available because of his critical condition, he remained in remission and survived for more than 40 months without cytopenia. However, repeated bone marrow examinations showed persistent clonal hematopoiesis with del(20)(q12q13) without apparent myelodysplasia.
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http://dx.doi.org/10.2169/internalmedicine.9122-17DOI Listing
November 2017

Elevation of Plasmin-α2-plasmin Inhibitor Complex Predicts the Diagnosis of Systemic AL Amyloidosis in Patients with Monoclonal Protein.

Intern Med 2018 Mar 11;57(6):783-788. Epub 2017 Oct 11.

Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Japan.

Objective The complication of systemic immunoglobulin light chain (AL) amyloidosis in patients with monoclonal immunoglobulin affects the prognosis, but amyloid deposition in tissues is sometimes difficult to detect due to bleeding tendencies and preferential distributions. However, fibrinolysis is known to be exacerbated in patients with systemic AL amyloidosis specifically. We therefore explored new biomarkers for predicting a diagnosis of systemic AL amyloidosis focusing on coagulation and fibrinolysis markers. Methods We reviewed the clinical features and treatment outcomes of patients with serum monoclonal protein, including primary systemic AL amyloidosis and multiple myeloma (MM), treated at our hospital between January 2008 and December 2014. Results Among several biomarkers, only the serum level of plasmin-α2-plasmin inhibitor complex (PIC) in patients with systemic AL amyloidosis (n=26) at the diagnosis was significantly higher than in patients with MM without AL amyloidosis (n=26) (mean±standard deviation, 3.69±2.82 μg/mL vs. 1.23±0.97 μg/mL, p<0.01). The cut-off for predicting a diagnosis of systemic AL amyloidosis in patients with serum monoclonal protein was 1.72 μg/mL with 84.6% sensitivity and 80.8% specificity. Hepatic involvement resulted in a significantly higher PIC level than no involvement in patients with systemic AL amyloidosis. The serum PIC level was also associated with the hematological response of systemic AL amyloidosis. Conclusion PIC is a useful biomarker for the diagnosis and management of patients with systemic AL amyloidosis.
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http://dx.doi.org/10.2169/internalmedicine.8999-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891514PMC
March 2018

EZH2 expression is a prognostic biomarker in patients with colorectal cancer treated with anti-EGFR therapeutics.

Oncotarget 2017 Mar;8(11):17810-17818

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan.

The polycomb group protein enhancer of zeste homolog 2 (EZH2) is a methyltransferase that suppresses microRNA-31 (miR-31) in various human malignancies including colorectal cancer. We recently suggested that miR-31 regulates the signaling pathway downstream of epidermal growth factor receptor (EGFR) in colorectal cancer. Therefore, we conducted this study for assessing the relationship between EZH2 expression and clinical outcomes in patients with colorectal cancer treated with anti-EGFR therapeutics. We immunohistochemically evaluated EZH2 expression and assessed miR-31 and gene mutations [KRAS (codon 61/146), NRAS (codon 12/13/61), and BRAF (codon 600)] in 109 patients with colorectal cancer harboring KRAS (codon 12/13) wild-type. We also evaluated the progression-free survival (PFS) and overall survival (OS). In the result, low EZH2 expression was significantly associated with shorter PFS (log-rank test: P = 0.023) and OS (P = 0.036) in patients with colorectal cancer. In the low-miR-31-expression group and the KRAS (codon 61/146), NRAS, and BRAF wild-type groups, a significantly shorter PFS (P = 0.022, P = 0.039, P = 0.021, and P = 0.036, respectively) was observed in the EZH2 low-expression groups than in the high-expression groups. In the multivariate analysis, low EZH2 expression was associated with a shorter PFS (P = 0.046), independent of the mutational status and miR-31. In conclusion, EZH2 expression was associated with survival in patients with colorectal cancer who were treated with anti-EGFR therapeutics. Moreover, low EZH2 expression was independently associated with shorter PFS in patients with cancer, suggesting that EZH2 expression is a useful additional prognostic biomarker for anti-EGFR therapy.
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http://dx.doi.org/10.18632/oncotarget.14863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392288PMC
March 2017

Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorder Presenting as Primary Bone Lymphoma in a Patient with Rheumatoid Arthritis.

Intern Med 2016 15;55(16):2259-64. Epub 2016 Aug 15.

Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Japan.

Primary bone lymphoma (PBL) is a rare disorder. We herein present a case of other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD) presenting as PBL. A 63-year-old woman was diagnosed with rheumatoid arthritis and had been treated with methotrexate for seven years. Two months before admission, she suffered from pain in the limbs. Magnetic resonance imaging revealed multiple irregular lesions in the bones of the limbs, which showed an uptake of (18)F-FDG on positron emission tomography. A biopsy of the right radius revealed diffuse large B-cell lymphoma, leading to the diagnosis of OIIA-LPD. She received rituximab-containing regimens resulting in a complete response.
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http://dx.doi.org/10.2169/internalmedicine.55.6684DOI Listing
March 2017

IgG4-producing lymphoma arising in a patient with IgG4-related disease.

Med Mol Morphol 2016 Dec 11;49(4):243-249. Epub 2016 Apr 11.

Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

We herein report a case in which an IgG4-producing lymphoma arose in a patient with a previous diagnosis consistent with an IgG4-related disease. A 43-year-old man presented with enlarged cervical lymph nodes and was treated with steroids and radiation for what was initially assumed to be Kimura's disease, although the lesions were later histologically re-diagnosed as IgG4-related lymphadenopathy. Fourteen years later, when the patient was 58-years-old, he presented with retroperitoneal fibrosis and swollen lymph nodes. The suspicious lesions were not histologically examined as the patient did not give consent. However, the serum IgG4 concentration was high (1400 mg/dL) and he was clinically diagnosed with systemic IgG4-related disease. Although steroid administration reduced the size of the lesions, tapering the dose finally resulted in systemic, prominently enlarged lymph nodes. Analysis of the biopsy specimen revealed that these multiple lymph node lesions were marginal zone B cell lymphomas that themselves expressed IgG4. Complete remission was achieved after a total of six courses of chemotherapy including rituximab. This case suggests that the infiltrating IgG4-expressing cells observed in IgG4-related disease can clonally expand to malignant lymphomas.
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http://dx.doi.org/10.1007/s00795-016-0139-2DOI Listing
December 2016

The relationship between EZH2 expression and microRNA-31 in colorectal cancer and the role in evolution of the serrated pathway.

Oncotarget 2016 Mar;7(11):12704-17

Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Polycomb group protein enhancer of zeste homolog 2 (EZH2) is a methyltransferase that correlates with the regulation of invasion and metastasis and is overexpressed in human cancers such as colorectal cancer. MicroRNA-31 (miR-31) plays an oncogenic role and is associated with BRAF mutation and poor prognosis in colorectal cancer. EZH2 is functionally considered to suppress miR-31 expression in human cancers; however, no study has reported its relationship with colon cancer. We therefore evaluated EZH2 expression using immunohistochemistry and assessed miR-31 and epigenetic alterations using 301 colorectal carcinomas and 207 premalignant lesions. Functional analysis was performed to identify the association between EZH2 and miR-31 using cancer cell lines. In the current study, negative, weak, moderate, and strong EZH2 expressions were observed in 15%, 19%, 25%, and 41% of colorectal cancers, respectively. EZH2 was inversely associated with miR-31 (P < 0.0001), independent of clinicopathological and molecular features. In a multivariate stage-stratified analysis, high EZH2 expression was related to favorable prognosis (P = 0.0022). Regarding premalignant lesions, negative EZH2 expression was frequently detected in sessile serrated adenomas/polyps (SSA/Ps) (76%; P < 0.0001) compared with hyperplastic polyps, traditional serrated adenomas, and non-serrated adenomas (25-36%). Functional analysis demonstrated that the knockdown of EZH2 increased miR-31 expression. In conclusion, an inverse association was identified between EZH2 and miR-31 in colorectal cancers. Our data also showed that upregulation of EZH2 expression may be rare in SSA/Ps. These results suggest that EZH2 suppresses miR-31 in colorectal cancer and may correlate with differentiation and evolution of serrated pathway.
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http://dx.doi.org/10.18632/oncotarget.7260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914316PMC
March 2016

Molecular diagnostics of a single drug-resistant multiple myeloma case using targeted next-generation sequencing.

Onco Targets Ther 2015 5;8:2805-15. Epub 2015 Oct 5.

Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.

A 69-year-old man was diagnosed with IgG λ-type multiple myeloma (MM), Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients.
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http://dx.doi.org/10.2147/OTT.S86515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599646PMC
October 2015

Decrease of B-type natriuretic peptide to less than 200 pg/mL predicts longer survival in cardiac immunoglobulin light chain amyloidosis.

Int J Hematol 2015 Aug 28;102(2):200-4. Epub 2015 May 28.

Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, South 1, West 16, Chuou-ku, Sapporo, Hokkaido, Japan.

Immunoglobulin light chain (AL) amyloidosis is a systemic disorder caused by depositions of insoluble amyloid fibrils that are composed of fragments of monoclonal light chains produced by abnormal plasma cells. The prognosis is reported to be poor; median survival time (MST) is 1-2 years overall, and is 6 months in patients with cardiac involvement. We here report the treatment outcomes of 24 patients with AL amyloidosis at our hospital between January 2008 and December 2012, including 11 patients with cardiac involvement. MST from the diagnosis was significantly shorter (9.8 months) in patients with cardiac involvement. Of these, patients who achieved a decrease of B-type natriuretic peptide (BNP) to <200 pg/mL after treatment survived longer than patients who did not (MST: not reached vs. 6.1 months; p = 0.003, log-rank test). The median time to decrease BNP to <200 pg/mL was 6.3 months. The decline of BNP to 200 pg/mL or less during treatment predicts longer survival in patients with cardiac AL amyloidosis.
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http://dx.doi.org/10.1007/s12185-015-1814-0DOI Listing
August 2015

Allogeneic bone marrow transplantation in a patient with primary hepatic diffuse large B-cell lymphoma that relapsed after autologous stem cell transplantation.

Nihon Shokakibyo Gakkai Zasshi 2014 Sep;111(9):1798-804

Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine.

A 64-year-old woman was admitted to our hospital due to a relapse of primary hepatic lymphoma (PHL). Three years previously, she had been referred to our hospital with a history of chronic hepatitis B for further examination of severe liver dysfunction, at which point a liver biopsy revealed PHL. She received conventional chemotherapy resulting in complete response (CR). An autologous stem cell transplantation was subsequently performed. However, 25 months after the transplantation, she suffered a relapse of PHL and was readmitted to our hospital. She achieved CR after treatment with salvage chemotherapy and then received an allogeneic bone marrow transplantation. CR has since been maintained for more than one year. This case provides insight about treatment choices in PHL.
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September 2014
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