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Purpose: EML4-ALK is a lung cancer oncogene, and ALK inhibitors show marked therapeutic efficacy for tumors harboring this fusion gene. It remains unsettled, however, how the fusion gene should be detected in specimens other than... more
Purpose: EML4-ALK is a lung cancer oncogene, and ALK inhibitors show marked therapeutic efficacy for tumors harboring this fusion gene. It remains unsettled, however, how the fusion gene should be detected in specimens other than formalin-fixed, paraffin-embedded tissue. We here tested whether reverse transcription PCR (RT-PCR)-based detection of EML4-ALK is a sensitive and reliable approach. Experimental Design: We developed a multiplex RT-PCR system to capture ALK fusion transcripts and applied this technique to our prospective, nationwide cohort of non–small cell lung cancer (NSCLC) in Japan. Results: During February to December 2009, we collected 916 specimens from 853 patients, quality filtering of which yielded 808 specimens of primary NSCLC from 754 individuals. Screening for EML4-ALK and KIF5B-ALK with our RT-PCR system identified EML4-ALK transcripts in 36 samples (4.46%) from 32 individuals (4.24%). The RT-PCR products were detected in specimens including bronchial washing...
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Purpose: EML4-ALK is a transforming fusion tyrosine kinase, several isoforms of which have been identified in lung cancer. Immunohistochemical detection of EML4-ALK has proved difficult, however, likely as a result of low transcriptional... more
Purpose: EML4-ALK is a transforming fusion tyrosine kinase, several isoforms of which have been identified in lung cancer. Immunohistochemical detection of EML4-ALK has proved difficult, however, likely as a result of low transcriptional activity conferred by the promoter-enhancer region of EML4. The sensitivity of EML4-ALK detection by immunohistochemistry should be increased adequately. Experimental Design: We developed an intercalated antibody-enhanced polymer (iAEP) method that incorporates an intercalating antibody between the primary antibody to ALK and the dextran polymer-based detection reagents. Results: Our iAEP method discriminated between tumors positive or negative for EML4-ALK in a test set of specimens. Four tumors were also found to be positive for ALK in an archive of lung adenocarcinoma (n = 130) and another 4 among fresh cases analyzed in a diagnostic laboratory. These 8 tumors were found to include 1 with EML4-ALK variant 1, 1 with variant 2, 3 with variant 3, an...
Research Interests: Immunohistochemistry, Polymers, Medicine, Lung Cancer, Humans, and 14 moreMice, Animals, Monoclonal Antibodies, T cells, Kinesin, Prognosis, Anaplastic Lymphoma Kinase (ALK), Genetic variation, Adenocarcinoma, Molecular Sequence Data, fibroblasts, reverse transcriptase polymerase chain reaction, Protein tyrosine kinases, and lung neoplasms
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype characterized by both biological and clinical heterogeneity. In refractory cases, complete response/complete response unconfirmed rates in salvage therapy remain... more
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype characterized by both biological and clinical heterogeneity. In refractory cases, complete response/complete response unconfirmed rates in salvage therapy remain low. We performed whole-exome sequencing of DLBCL in a discovery cohort comprising 26 good and nine poor prognosis cases. After candidate genes were identified, prognoses were examined in 85 individuals in the DLBCL validation cohort. In the discovery cohort, five patients in the poor prognosis group harbored both a mutation and 17p deletion. Sixteen mutations were identified in in nine patients in the good prognosis group, but none in the poor prognosis group. In the validation cohort, mutations and deletions were confirmed to be poor prognostic factors for overall survival (OS) (P = 0.016) and progression-free survival (PFS) (P = 0.023) only when both aberrations co-existed. mutations were validated as prognostic markers for excellent OS (P = 0.037)...
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Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma type. The immunophenotypic and genetic features of DLBCL in Taiwan have not been characterized. In this study, we performed immunohistochemical analysis and interphase... more
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma type. The immunophenotypic and genetic features of DLBCL in Taiwan have not been characterized. In this study, we performed immunohistochemical analysis and interphase fluorescence in situ hybridization (FISH) using tissue microarray sections to investigate a cohort of unselected DLBCL cases in a single institution in Taiwan from 1990 to 2010. Of the 153 cases investigated, CD10, bcl-6, and MUM1 were expressed in 16.3%, 71.2%, and 71.9% cases, respectively, with 27.5% (n = 42) of cases being classified as having a germinal center B-cell (GCB) origin by the Hans algorithm. By FISH analysis, 19.6%, 4.6%, 26.1%, and 3.9% cases showed rearrangement at IGH, BCL2, BCL6, and MYC loci, respectively, including three (2.0%) cases of double-hit lymphoma. As compared with the non-GCB tumors, GCB tumors more frequently expressed CD10 (p < 0.001) and bcl-6 (p = 0.001) with less frequent expression of MUM1 (p = 0.007). Moreover, ...
Research Interests: Immunohistochemistry, Adolescent, Medicine, Humans, Fluorescence in situ hybridization, and 13 moreTaiwan, Female, Male, Young Adult, Aged, Middle Aged, Adult, Survival Rate, Diffuse Large B-Cell Lymphoma, B Lymphocytes, Germinal Center, Diffuse large B cell lymphoma, and Medical and Health Sciences
Central nervous system (CNS) involvement is a serious complication in patients with diffuse large B-cell lymphoma (DLBCL) and evaluating CNS risk is an important issue. Using the standard international prognostic index (IPI) and CNS-IPI,... more
Central nervous system (CNS) involvement is a serious complication in patients with diffuse large B-cell lymphoma (DLBCL) and evaluating CNS risk is an important issue. Using the standard international prognostic index (IPI) and CNS-IPI, a recently proposed model including IPI risk factors and adrenal/kidney involvement, we assessed CNS risk in 1220 untreated DLBCL patients who received R-CHOP without prophylaxis. According to the standard IPI, the cumulative incidences of CNS involvement at 2 years were 1.3, 4.6, 8.8, and 12.7% in the low-, low-intermediate-, high-intermediate-, and high-risk groups, respectively (p <.001). This result is comparable with that of the CNS-IPI. Patients with breast involvement tended to have lower risk according to the standard IPI but showed frequent CNS involvement, similar to patients with testis involvement. The standard IPI is also a useful predictor of CNS involvement. Patients with breast/testis involvement would be candidates for prophylaxi...
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Overexpression of the BCL2 is associated with a poor prognosis in diffuse large B-cell lymphoma (DLBCL). The assessment of MYC immunohistochemistry (IHC) is becoming optimized, whereas the criteria for BCL2 positivity are highly variable.... more
Overexpression of the BCL2 is associated with a poor prognosis in diffuse large B-cell lymphoma (DLBCL). The assessment of MYC immunohistochemistry (IHC) is becoming optimized, whereas the criteria for BCL2 positivity are highly variable. Furthermore, data on the frequency and prognostic value of BCL2 positivity are conflicting. We aimed to evaluate BCL2 expression by IHC and assess the prognostic significance of the histopathologically-scored BCL2 expression in 456 patients with DLBCL uniformly treated with standard immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP). We initially designed four-grade BCL2 scoring criteria, from 0 to 3+, and found that approximately 40% of DLBCL showed strong BCL2 expression (score 3+). The scores from the pathologist's visual estimation were confirmed to be reliable using a digital image analysis. A retrospective survival analysis revealed that BCL2 score 3+ was a significant prognostic factor ...
Research Interests: Immunohistochemistry, Medicine, Humans, Female, Blood, and 15 moreMale, Clinical Sciences, Aged, Middle Aged, Doxorubicin, Survival Rate, Retrospective Studies, Diffuse Large B-Cell Lymphoma, Cyclophosphamide, Disease Free Survival, Diffuse large B cell lymphoma, Vincristine, Prednisone, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
Expression of T-cell markers, generally investigated for immunophenotyping of T-cell lymphomas, is also observed in several types of B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). We previously reported that CD5... more
Expression of T-cell markers, generally investigated for immunophenotyping of T-cell lymphomas, is also observed in several types of B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). We previously reported that CD5 expression in DLBCL is an inferior prognostic factor in the era of rituximab. However, data regarding the frequencies, histological relevance, and prognostic importance of T-cell markers other than CD5 are currently unavailable. In the present study, we comprehensively evaluated the expression of T-cell markers (CD2, CD3, CD4, CD5, CD7, and CD8) in 501 B-cell lymphomas, including 225 DLBCLs, by flow cytometry and subsequent immunohistochemistry. T-cell markers other than CD5, such as CD2, CD4, CD7, and CD8, were expressed in 27 (5%) patients, and notably, all of these cases were classified as large B-cell lymphoma subtypes: 25 DLBCLs and 2 intravascular large B-cell lymphomas. CD5 and other T-cell markers were expressed in 15% (31/225) and 10% (25/225) of...
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Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we... more
Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.
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EML4-ALK is a fusion-type protein tyrosine kinase that is generated in human non-small-cell lung cancer (NSCLC) as a result of a recurrent chromosome inversion, inv ( 2 )(p21p23). Although mouse 3T3 fibroblasts expressing human EML4-ALK... more
EML4-ALK is a fusion-type protein tyrosine kinase that is generated in human non-small-cell lung cancer (NSCLC) as a result of a recurrent chromosome inversion, inv ( 2 )(p21p23). Although mouse 3T3 fibroblasts expressing human EML4-ALK form transformed foci in culture and s.c. tumors in nude mice, it has remained unclear whether this fusion protein plays an essential role in the carcinogenesis of NSCLC. To address this issue, we have now established transgenic mouse lines that express EML4-ALK specifically in lung alveolar epithelial cells. All of the transgenic mice examined developed hundreds of adenocarcinoma nodules in both lungs within a few weeks after birth, confirming the potent oncogenic activity of the fusion kinase. Although such tumors underwent progressive enlargement in control animals, oral administration of a small-molecule inhibitor of the kinase activity of ALK resulted in their rapid disappearance. Similarly, whereas i.v. injection of 3T3 cells expressing EML4-AL...
Research Interests: Biology, Cancer Research, Medicine, Multidisciplinary, Transgenic Mice, and 15 moreLung Cancer, Humans, Mice, Animals, Protein Tyrosine Kinase, T cells, Respiratory Failure, Mouse Model, Targeted Therapy, Transgenic Mouse Technology, Fusion Protein, Protein Kinase Inhibitors, Non small Cell Lung Cancer, Nude mice, and lung neoplasms
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Research Interests: Pathology, Biology, Immunohistochemistry, Medicine, Low Frequency, and 15 moreLung Cancer, Humans, Mutation, Polymerase Chain Reaction, Modern, Transcription Factor, Middle Aged, DNA binding proteins, Age of Onset, Adenocarcinoma, Tyrosine Kinase, Reverse transcription polymerase chain reaction, Medical and Health Sciences, Modern Pathology, and lung neoplasms
Research Interests: Survival Analysis, Immunohistochemistry, Cancer Research, Medicine, Lung Cancer, and 15 moreHumans, Female, Male, Clinical Sciences, Oral Squamous Cell Carcinoma (OSCC), Anaplastic Lymphoma Kinase (ALK), Thoracic Oncology, Cell Cycle Proteins, Thoracic, Adenocarcinoma, DNA mutational analysis, reverse transcriptase polymerase chain reaction, Protein tyrosine kinases, Cardiovascular medicine and haematology, and lung neoplasms
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Research Interests: Microcirculation, Stem Cell, Medicine, Complication, Humans, and 12 moreInternal Medicine, Intestinal Mucosa, Male, Differential Diagnosis, Hemolytic Uremic Syndrome, Clinical Sciences, Bone Marrow Transplantation, Adult, Public health systems and services research, Thrombosis, Thrombotic Microangiopathy, and Fatal outcome
Research Interests: Survival Analysis, Treatment Outcome, Adolescent, Medicine, Humans, and 15 moreInternal Medicine, Young Adult, Anemia, Aged, Middle Aged, Doxorubicin, ALOPECIA, Adult, Prognosis, Cyclophosphamide, neutropenia, leukopenia, Hematological Oncology, Vincristine, and Cardiovascular medicine and haematology
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Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Adenocarcinoma is the most common form of lung cancer worldwide. In Japan, female adenocarcinomas are increasing, and more than two-thirds of them are... more
Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Adenocarcinoma is the most common form of lung cancer worldwide. In Japan, female adenocarcinomas are increasing, and more than two-thirds of them are non-smokers. EGFR mutation and EML4-ALK fusion, both of which are important for choice of molecular-targeted therapies, have been reported to be mutually exclusive. However, both genetic changes tend to occur in the similar populations, i.e; younger, non-smoking subjects. To examine the global allelic profiles to pursue specific genes for both the groups, SNP-chip-based high-resolution molecular allelo-karyotyping analysis was performed. Methods: 51 female cases, 31 with EGFR mutation and 20 with EML4-ALK translocation, were enrolled in this study. All tumors were surgically resected at the Cancer Institute Hospital, Tokyo. Clinicopathological parameters including, age, pathological stage, differentiation grade of the tumor, tumor size were examined and microscopic lymphatic- and blood-vessel invasions were described. DNA was extracted from snap-frozen specimen. They were analyzed using Affymetrix GeneChip and our robust algorithm, CNAG/AsCNAR, to perform sensitive analysis of copy number alteration and allelic composition. Results: EGFR mutation and EML4-ALK fusion were mutually exclusive. Tumors with EML4-ALK fusion conferred less-differentiated histology and smaller tumor size (P<0.0001, P=0.0017, respectively). No statistical differences were found in age, pathological stage, and microscopic lymphatic/blood vessel invasions. With SNP-chip allelo-karyotyping analysis, among selected 23 amplified and 5 deleted regions, EML4-ALK tumors had significantly lower frequencies of allelic changes than EGFR tumors. For amplification, there were four regions (7p11.2, 16p13.3, 17q12, and 17q25.1) detected more frequently in EGFR tumors than in EML4-ALK tumors, and no regions found more in tumor with EGFR mutations than in those with EML-ALK translocation. For deletion, one region (9p24.1-p23) was again more often deleted in EGFR-mutated than in ALK-translocated tumors. Homozygous deletion was detected only at 9p21.3, including CDKN2A/p16, found in both groups. Conclusions: Allelo-karyotyping analysis using high-resolution array technology revealed that EGFR-mutated tumors had more frequent amplifcations and deletions than ALK-translocated tumors at the particular 5 regions. Among them, 7p11.2 harbors EGFR, 17q12 contains ERBB2, and 9p24.1-p23 includes PTPRD. This study clearly demonstrated that gene dosage alterations were less prevalent in tumors with ALK fusion than those with EGFR mutations, implying two distinct carcinogenesis pathways in non-smokers’ lung cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3902. doi:10.1158/1538-7445.AM2011-3902
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Background Lung cancer is the leading cause of cancer death in Japan. Adenocarcinoma is the most common form of lung cancer with poor-prognosis due to late-stage detection and resistance to conventional treatment. The complexity of the... more
Background Lung cancer is the leading cause of cancer death in Japan. Adenocarcinoma is the most common form of lung cancer with poor-prognosis due to late-stage detection and resistance to conventional treatment. The complexity of the genetic alterations confer pulmonary adenocarcinomas with marked patterns of gene expression. It is now critical to unravel the mechanisms which underlie a subset of tumor and they should have a significant impact in selecting patients for targeted therapy. Novel SNP-chip high resolution molecular allelo-karyotyping analysis allows us to examine global DNA copy number changes and allelic loss to evaluate allele-specific gene dosage in cancer cells. Methods A series of consecutive 111 lung adenocarcinomas, including 10 cases harboring EML4-ALK fusion, were analyzed using Affymetrix GeneChip and our robust algorithm, CNAG/AsCNAR, to perform sensitive analysis of copy number alteration and allelic composition. This robust algorithm also enabled sensitive...
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Background The TNFAIP3 gene, which encodes a ubiquitin-modifying enzyme (A20) involved in the negative regulation of NF-κB signaling, is frequently inactivated by gene deletions/mutations in a variety of B-cell malignancies. However, the... more
Background The TNFAIP3 gene, which encodes a ubiquitin-modifying enzyme (A20) involved in the negative regulation of NF-κB signaling, is frequently inactivated by gene deletions/mutations in a variety of B-cell malignancies. However, the detection of this in primary Hodgkin lymphoma (HL) specimens is hampered by the scarcity of Hodgkin Reed-Sternberg (HR-S) cells even after enrichment by micro-dissection. Methods We used anti-CD30 immunofluorescence with fluorescence in-situ hybridization (FISH) to evaluate the relative number of TNFAIP3/CEP6 double-positive signals in CD30-positive cells. Results From a total of 47 primary classical Hodgkin lymphoma (cHL) specimens, 44 were evaluable. We found that the relative numbers of TNFAIP3/CD30 cells were distributed among three groups, corresponding to those having homozygous (11%), heterozygous (32%), and no (57%) deletions in TNFAIP3. This shows that TNFAIP3 deletions could be sensitively detected using our chosen methods. Conclusions Com...
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ABSTRACT
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Late-onset neutropenia (LON) has been reported following rituximab-containing chemotherapy. Its incidence and risk factors, however, have not been extensively studied. We retrospectively reviewed the medical records of 107 patients... more
Late-onset neutropenia (LON) has been reported following rituximab-containing chemotherapy. Its incidence and risk factors, however, have not been extensively studied. We retrospectively reviewed the medical records of 107 patients treated with rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphomas and identified cases with LON as defined by the neutrophil count of &amp;amp;lt;or=1.0 x 10(9)/l without an apparent cause after the recovery of neutrophil count following completion of the intended chemotherapy. With a median follow-up of 411 days, 23 patients developed LON out of the 107 at a median of 106 days after the last chemotherapy. Cumulative incidence of LON among the total patients was 24.9%. The median neutrophil count nadir was 0.61 x 10(9)/l. The LON episodes were generally self-limited, and filgrastim was administered in one patient. Including this patient, there were no serious infectious episodes in the cases with LON. In multivariate analysis, intensive chemotherapy regimens including high-dose therapy followed by autologous hematopoietic stem cell transplantation (ASCT) and high-dose methotrexate-containing regimens without ASCT were a risk factor for LON. This study suggests that LON is a frequent complication of rituximab-containing intensive chemotherapy.
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Loss of human leukocyte antigen (HLA)-DR expression may be related to a poor prognosis of diffuse large B-cell lymphoma (DLBCL), and tumor-associated macrophages (TAMs) may influence tumor progression. We retrospectively reviewed 36... more
Loss of human leukocyte antigen (HLA)-DR expression may be related to a poor prognosis of diffuse large B-cell lymphoma (DLBCL), and tumor-associated macrophages (TAMs) may influence tumor progression. We retrospectively reviewed 36 patients with newly diagnosed DLBCL who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy at Kanagawa Cancer Center in Japan from 2004 to 2010. HLA-DR expression by lymphoma cells was evaluated using flow cytometry, and TAMs in lymphoma tissue were detected by immunohistochemistry for CD68 as a marker of macrophages and CD163 as a marker of M2 TAMs. Three-year overall survival was, respectively, 100% versus 69.6% in the HLA-DR &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;bright&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;not bright&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; groups (p = 0.012). Patients from the HLA-DR &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;not bright&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; group with strong CD163 expression had a much worse prognosis than other patients. The HLA-DR status shown by flow cytometry can be used to predict the prognosis of patients with DLBCL receiving R-CHOP therapy and prognostic accuracy can be increased by also assessing TAMs.
Research Interests: Immunohistochemistry, Treatment Outcome, Macrophages, Humans, Female, and 15 moreMale, Phenotype, Clinical Sciences, Aged, Middle Aged, Doxorubicin, Adult, Retrospective Studies, Prognosis, Immunophenotyping, Cyclophosphamide, Neoplasm staging, Diffuse large B cell lymphoma, Vincristine, and Prednisone
The AML1 gene encodes a DNA-binding protein that contains the runt domain and is the most frequent target of transloca- tions associated with human leukemias. Here, point mutations of the AML1 gene, V105ter (single-letter amino acid code)... more
The AML1 gene encodes a DNA-binding protein that contains the runt domain and is the most frequent target of transloca- tions associated with human leukemias. Here, point mutations of the AML1 gene, V105ter (single-letter amino acid code) and R139G, (single-letter amino acid codes) were identified in 2 cases of myelo- dysplastic syndrome (MDS) by means of the reverse transcriptase-polymerase chain
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Recently, elevated peripheral blood monocyte counts at diagnosis have been shown to be an independent marker associated with poor prognosis in patients with both non-Hodgkin and Hodgkin lymphoma. In this study, we retrospectively analyzed... more
Recently, elevated peripheral blood monocyte counts at diagnosis have been shown to be an independent marker associated with poor prognosis in patients with both non-Hodgkin and Hodgkin lymphoma. In this study, we retrospectively analyzed the data from a total of 550 patients with diffuse large B-cell lymphoma and evaluated the relationship between central nervous system relapse and absolute monocyte counts at diagnosis. Twenty-six patients developed central nervous system relapse. The central nervous system relapse-free survival rate was significantly lower in patients with the absolute monocyte counts ≥ 0.51 × 10(9)/L (87.8% versus 96.4%; P<0.001). This association was independently significant after adjusting for other significant factors, including systemic relapse as a time-dependent covariate by multivariate analysis (hazard ratio 2.46; 95% confidence intervals 1.05-5.75; P=0.039). These results suggest that the absolute monocyte count at diagnosis is an independent signifi...
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The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non-small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown... more
The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non-small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance. We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity relationships of ALK mutations, we performed computational therm...
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EML4-ALK fusion gene is found in only a small subset (2-6%) of non-small cell lung cancer. There is an urgent need to establish a rational diagnostic algorithm to identify this rare but important fusion in lung cancer. We performed a... more
EML4-ALK fusion gene is found in only a small subset (2-6%) of non-small cell lung cancer. There is an urgent need to establish a rational diagnostic algorithm to identify this rare but important fusion in lung cancer. We performed a comprehensive analysis of EGFR/KRAS mutation and ALK rearrangement in a total of 360 surgically resected lung cancers. ALK rearrangement was examined by 3 analyses: multiplex reverse transcription-PCR, fluorescent in situ hybridization (FISH), and immunohistochemistry (IHC) with the intercalated antibody-enhanced polymer method. A scoring system was used for IHC (iScore). A test set (202 patients with unselected lung cancer) was used for proposing a diagnostic algorithm. This diagnostic algorithm was validated in 158 patients with EGFR and KRAS mutation-negative adenocarcinoma. ALK rearrangement was identified in 2 patients (1.0%) from the test set and both adenocarcinomas were negative for EGFR and KRAS mutations. The results of FISH and RT-PCR were co...
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Members of the RAS superfamily of small guanosine triphosphatases (GTPases) transition between GDP-bound, inactive and GTP-bound, active states and thereby function as binary switches in the regulation of various cellular activities.... more
Members of the RAS superfamily of small guanosine triphosphatases (GTPases) transition between GDP-bound, inactive and GTP-bound, active states and thereby function as binary switches in the regulation of various cellular activities. Whereas HRAS, NRAS, and KRAS frequently acquire transforming missense mutations in human cancer, little is known of the oncogenic roles of other small GTPases, including Ras-related C3 botulinum toxin substrate (RAC) proteins. We show that the human sarcoma cell line HT1080 harbors both NRAS(Q61K) and RAC1(N92I) mutant proteins. Whereas both of these mutants were able to transform fibroblasts, knockdown experiments indicated that RAC1(N92I) may be the essential growth driver for this cell line. Screening for RAC1, RAC2, or RAC3 mutations in cell lines and public databases identified several missense mutations for RAC1 and RAC2, with some of the mutant proteins, including RAC1(P29S), RAC1(C157Y), RAC2(P29L), and RAC2(P29Q), being found to be activated and transforming. P29S, N92I, and C157Y mutants of RAC1 were shown to exist preferentially in the GTP-bound state as a result of a rapid transition from the GDP-bound state, rather than as a result of a reduced intrinsic GTPase activity. Activating mutations of RAC GTPases were thus found in a wide variety of human cancers at a low frequency; however, given their marked transforming ability, the mutant proteins are potential targets for the development of new therapeutic agents.
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To assess the prognostic value of matrix Gla protein (MGP) expression in cases of breast cancer, 9 samples from patients diagnosed with breast cancer who were followed up for more than 10 years were microdissected and then analyzed using... more
To assess the prognostic value of matrix Gla protein (MGP) expression in cases of breast cancer, 9 samples from patients diagnosed with breast cancer who were followed up for more than 10 years were microdissected and then analyzed using Affymetrix U133 Plus 2.0 Arrays. Genes that exhibited significant differences in expression between patients with a good prognosis and those with a poor prognosis were identified. The MGP gene was among the genes up-regulated in cases where the prognosis was poor, indicating that the mRNA levels of MGP are a potential prognostic indicator of breast cancer. However, immunohistostaining of breast tissue microarrays (n=207) did not reveal a correlation between the protein expression of MGP and overall survival, neither was there a correlation between the protein expression of MGP and ER status or bone metastasis. In breast cancer cases, the mRNA level of MGP may be a marker indicating poor prognosis; however, protein expression determined by immunohistostaining is not.
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Members of the RAS superfamily of small guanosine triphosphatases (GTPases) transition between GDP-bound, inactive and GTP-bound, active states and thereby function as binary switches in the regulation of various cellular activities.... more
Members of the RAS superfamily of small guanosine triphosphatases (GTPases) transition between GDP-bound, inactive and GTP-bound, active states and thereby function as binary switches in the regulation of various cellular activities. Whereas HRAS, NRAS, and KRAS frequently acquire transforming missense mutations in human cancer, little is known of the oncogenic roles of other small GTPases, including Ras-related C3 botulinum toxin substrate (RAC) proteins. We show that the human sarcoma cell line HT1080 harbors both NRAS(Q61K) and RAC1(N92I) mutant proteins. Whereas both of these mutants were able to transform fibroblasts, knockdown experiments indicated that RAC1(N92I) may be the essential growth driver for this cell line. Screening for RAC1, RAC2, or RAC3 mutations in cell lines and public databases identified several missense mutations for RAC1 and RAC2, with some of the mutant proteins, including RAC1(P29S), RAC1(C157Y), RAC2(P29L), and RAC2(P29Q), being found to be activated and transforming. P29S, N92I, and C157Y mutants of RAC1 were shown to exist preferentially in the GTP-bound state as a result of a rapid transition from the GDP-bound state, rather than as a result of a reduced intrinsic GTPase activity. Activating mutations of RAC GTPases were thus found in a wide variety of human cancers at a low frequency; however, given their marked transforming ability, the mutant proteins are potential targets for the development of new therapeutic agents.