Publications by authors named "Chang-Tsu Yuan"

32 Publications

Association between risk factors, molecular features and CpG island methylator phenotype colorectal cancer among different age groups in a Taiwanese cohort.

Br J Cancer 2021 Apr 12. Epub 2021 Apr 12.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Background: CpG island methylator phenotype (CIMP) represents a carcinogenesis pathway of colorectal cancer (CRC) and the association between CIMP CRC, molecular features and risk factors in East Asian population is less studied.

Methods: We prospectively enrolled newly diagnosed CRC patients at the National Taiwan University Hospital. Clinicopathological data and risk factors for CRC were collected during interview. The tumour samples were subjected to CIMP, RAS/BRAF mutation and microsatellite instability tests. CIMP-high was determined when ≧3 methylated loci of p16, MINT1, MINT2, MINT31 and MLH1 were identified. Multivariate logistic regression was used to evaluate the association between risk factors and CIMP-high CRC.

Results: Compared with CIMP-low/negative CRC, CIMP-high CRC was associated with more stage IV disease, BRAF V600E mutation and high body mass index (BMI ≧ 27.5 kg/m) in younger patients (age < 50 y), and more right-sided tumour, BRAF V600E mutation, MSI-high and colorectal polyp in elder patients (age ≧ 50 y). Multivariate analyses showed that BMI ≧27.5 kg/m was significantly associated with CIMP-high CRC in younger patients.

Conclusions: We identified distinct clinicopathological features for CIMP-high CRC among different age groups in Taiwan. Our data suggest the association between BMI ≧27.5 kg/m and CIMP-high CRC in patients younger than 50 years.
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http://dx.doi.org/10.1038/s41416-021-01300-5DOI Listing
April 2021

PspC domain-containing protein (PCP) determines Streptococcus mutans biofilm formation through bacterial extracellular DNA release and platelet adhesion in experimental endocarditis.

PLoS Pathog 2021 Feb 12;17(2):e1009289. Epub 2021 Feb 12.

Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan.

Bacterial extracellular DNA (eDNA) and activated platelets have been found to contribute to biofilm formation by Streptococcus mutans on injured heart valves to induce infective endocarditis (IE), yet the bacterial component directly responsible for biofilm formation or platelet adhesion remains unclear. Using in vivo survival assays coupled with microarray analysis, the present study identified a LiaR-regulated PspC domain-containing protein (PCP) in S. mutans that mediates bacterial biofilm formation in vivo. Reverse transcriptase- and chromatin immunoprecipitation-polymerase chain reaction assays confirmed the regulation of pcp by LiaR, while PCP is well-preserved among streptococcal pathogens. Deficiency of pcp reduced in vitro and in vivo biofilm formation and released the eDNA inside bacteria floe along with reduced bacterial platelet adhesion capacity in a fibrinogen-dependent manner. Therefore, LiaR-regulated PCP alone could determine release of bacterial eDNA and binding to platelets, thus contributing to biofilm formation in S. mutans-induced IE.
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http://dx.doi.org/10.1371/journal.ppat.1009289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906467PMC
February 2021

Solitary tibial lesion as the initial presentation of Langerhans cell histiocytosis: report of two cases and literature review.

J Int Med Res 2021 Jan;49(1):300060520982826

Department of Orthopaedic Surgery, National Taiwan University Hospital, Taipei, Taiwan.

The various presentations of osseous Langerhans cell histiocytosis (LCH) make it difficult to distinguish from other bone diseases. In addition, there is no universally accepted protocol for managing osseous LCH for single non-central nervous system-risk lesions. Here, the rare cases of two paediatric patients, aged 1 and 2 years, who presented with a solitary tibial lesion at time of LCH diagnosis, are reported. One patient progressed to multiple lesions after curettage of the original lesion. Subsequently, both patients received preventive chemotherapy using the Taiwan Paediatric Oncology Group (TPOG) revised protocol for treating low risk patients with LCH, namely, TPOG LCH2002-LR. After receiving this treatment, which included a schedule of prednisolone and vincristine for 6 weeks, followed by prednisolone, vincristine and 6-mercaptopurine for a further 48 weeks, both patients are free from recurrence or progression.
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http://dx.doi.org/10.1177/0300060520982826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829610PMC
January 2021

Mucosa-associated lymphoid tissue lymphoma with isolated endobronchial involvement.

Respirol Case Rep 2020 Nov 16;8(8):e00672. Epub 2020 Oct 16.

Division of Pulmonary Medicine, Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan.

Primary pulmonary lymphoma is an uncommon disease, and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is the most common type of pulmonary lymphoma. The most frequent pattern observed in chest computed tomography (CT) is consolidation, followed by nodules and mass. The differentiation of pulmonary MALT lymphoma from other lung diseases is critical for disease management and treatment. However, pulmonary MALT lymphoma with isolated endobronchial manifestation has seldomly been reported. Here, we report a case of an elderly woman who presented with a four-month history of cough, dyspnoea, and haemoptysis. Chest CT scan revealed left main bronchus narrowing without lung parenchymal lesion. Bronchoscopic examination was performed, and the diagnosis of primary pulmonary MALT lymphoma with isolated endobronchial involvement was made. She has been successfully treated with rituximab.
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http://dx.doi.org/10.1002/rcr2.672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565112PMC
November 2020

An Integrative Morphomolecular Classification System of Gastric Carcinoma With Distinct Clinical Outcomes.

Am J Surg Pathol 2020 08;44(8):1017-1030

Departments of Pathology.

A robust morphomolecular classification system for gastric carcinoma is required. A 4-tier morphologic classification is proposed, including diffuse, intestinal, tubular, and lymphoid types. A tissue microarray for mismatch repair immunohistochemistry and Epstein-Barr virus (EBV) in situ hybridization were performed in 329 gastric carcinomas. DNA flow cytometry was used to detect aneuploidy in formalin-fixed paraffin-embedded samples. Lymphoid histology was the third most common histologic pattern at our institute and strongly associated with EBV infection and PMS2/MLH1-deficiency (both P<0.001). HER2 overexpression and SATB2 expression more frequently occurred in intestinal histology (both P<0.001). Loss of ARID1A expression was strikingly associated with lymphoid histology (P<0.001) and negative E-cadherin expression was correlated with diffuse histology (P=0.001). Programmed death-ligand 1 expression was most frequently present in lymphoid-type gastric carcinoma than other histologic subtypes and correlated with the molecular features of PMS2/MLH1-deficiency and EBV infection (all P<0.001). Aneuploidy was detected in 53% of gastric carcinomas and was highly correlated with intestinal type and the least with the lymphoid type (P<0.001). Notably, lymphoid-type gastric carcinoma showed the best outcome, whereas tubular type showed the worst survival rate (P<0.001). We integrated aneuploidy with morphologic patterns to propose a morphomolecular classification scheme, which served as a successful and independent prognostic factor in multivariate 5-year disease-free survival analysis (P<0.001). Overall, we describe an integrated morphomolecular classification system for gastric carcinomas to effectively predict patient outcomes. This system is cost-effective and reliable and can help select target therapeutics and facilitate clinical management.
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http://dx.doi.org/10.1097/PAS.0000000000001521DOI Listing
August 2020

Knock-out of Hopx disrupts stemness and quiescence of hematopoietic stem cells in mice.

Oncogene 2020 07 12;39(28):5112-5123. Epub 2020 Jun 12.

Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

HOPX is a stem cell marker in hair follicles and intestines. It was shown critical for primitive hematopoiesis. We previously showed an association between higher HOPX expression and clinical characteristics related to stemness and quiescence of leukemic cells in acute myeloid leukemia (AML) patients. To further explore its physiologic functions in hematopoietic system, we generated a mouse model with hematopoietic cell-specific knockout of Hopx (Hopx). In young Hopx mice, the hematopoietic stem cells (HSC) showed decreased reconstitution ability after serial transplantation. Further transcriptomic study revealed decreased HSC signatures in long-term HSCs from the Hopx mice. At 18 months of age, half of the Hopx mice developed cytopenia and splenomegaly. Bone marrow (BM) from the sick mice showed myeloid hyperplasia with predominant mature neutrophils, and decreased progenitor cells and lymphocytes. These phenotypes suggested critical functions of Hopx in maintaining HSC quiescence. Transcriptomic study of the Hopx marrow cells showed significant downregulation of the Cxcl12-Cxcr4 axis, which is critical for maintenance of HSC quiescence. We next examined the role of Hopx in AML by using the MN1 overexpression murine leukemia model. Mice transplanted with MN1-overexpressed Hopx BM cells developed AML with more aggressive phenotypes compared with those transplanted with MN1-overexpressed Hopx-wild cells. Hopx MN1-overexpressed leukemia cells showed higher proliferation rate and downregulation of Cxcl12 and Cxcr4. Furthermore, in human AML, BM plasma CXCL12 levels were lower in patients with lower HOPX expression. In conclusion, our study highlights the roles of Hopx in maintenance of quiescence of the hematopoietic stem cells through CXCL12 pathway in vivo and provides implication of this protein in normal and malignant hematopoiesis.
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http://dx.doi.org/10.1038/s41388-020-1340-2DOI Listing
July 2020

A Newborn Girl with a Huge Abdominal Multicystic Tumor.

Gastroenterology 2021 Jan 1;160(1):e4-e5. Epub 2020 May 1.

Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.04.065DOI Listing
January 2021

Hepatitis B Surface Antigen Positivity Is an Independent Unfavorable Prognostic Factor in Diffuse Large B-Cell Lymphoma in the Rituximab Era.

Oncologist 2020 09 27;25(9):793-802. Epub 2020 Apr 27.

Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.

Background: Patients with diffuse large B-cell lymphoma (DLBCL) with concurrent hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection have distinct clinical features. Nevertheless, the prognostic value of HBsAg in DLBCL in the rituximab era remains unclear.

Materials And Methods: We conducted a retrospective cohort study to investigate the clinical relevance of HBsAg in immunocompetent patients with DLBCL treated with homogeneous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone between 2002 and 2016.

Results: Among 416 analyzed patients, 98 (23.6%) were HBsAg positive. HBsAg positivity was associated with a younger age and more advanced stage at diagnosis, more frequent hepatic impairment during perichemotherapy, and a trend of higher National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score at diagnosis. Compared with the HBsAg-negative patients, the HBsAg-positive patients had a lower overall response rate (76.5% vs. 85.5%, p = .043), poorer 5-year overall survival (OS) rate (57.2% vs. 73.5%, p < .001), and shorter 5-year progression-free survival (PFS) rate (47.2% vs. 60.7%, p = .013). Multivariate analyses showed that HBsAg positivity was an independent unfavorable prognostic indicator for OS and PFS. A scoring system incorporating HBsAg positivity, the NCCN-IPI score, and serum albumin levels proved to be useful for stratifying prognostically relevant subgroups of patients with DLBCL.

Conclusion: This study demonstrated that HBV infection is uniquely relevant to DLBCL. HBsAg might serve as a novel biomarker to improve clinical risk stratification of patients with DLBCL in areas with high prevalence of HBV infection. Further research investigating the etiopathogenesis of HBV infection in DLBCL is imperative.

Implications For Practice: A considerable disparity exists regarding the prognostic relevance of hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection in patients with diffuse large B-cell lymphoma (DLBCL). In this large, retrospective cohort study from an area with high prevalence of HBV infection, the authors demonstrated that HBsAg was an independent unfavorable factor significantly associated with survival, highlighting its potential as a novel prognostic indicator to improve the risk stratification of patients with DLBCL in the rituximab era.
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http://dx.doi.org/10.1634/theoncologist.2019-0756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485358PMC
September 2020

Synthesis, Anticancer Activity, and Preliminary Pharmacokinetic Evaluation of 4,4-Disubstituted Curcuminoid 2,2-bis(Hydroxymethyl)Propionate Derivatives.

Molecules 2020 Jan 22;25(3). Epub 2020 Jan 22.

School of Pharmacy, China Medical University, Taichung 40402, Taiwan.

Compound is a curcumin di--2,2-bis(hydroxymethyl)propionate that shows significant in vitro and in vivo inhibitory activity against MDA-MB-231 cells with eight to ten-fold higher potency than curcumin. Here, we modified the α-position (C-4 position) of the central 1,3-diketone moiety of with polar or nonpolar functional groups to afford a series of 4,4-disubstituted curcuminoid 2,2-bis(hydroxymethyl)propionate derivatives and evaluated their anticancer activities. A clear structure-activity relationship of compound 1 derivatives focusing on the functional groups at the C-4 position was established based on their anti-proliferative effects against the MDA-MB-231 and HCT-116 cell lines. Compounds - are 4,4-dimethylated, 4,4-diethylated, 4,4-dibenzylated, 4,4-dipropargylated and 4,4-diallylated compound , respectively. Compounds 2m-6m, the ester hydrolysis products of compounds -, respectively, were synthesized and assessed for anticancer activity. Among all compound derivatives, compound emerged as a potential chemotherapeutic agent for colon cancer due to the promising in vivo anti-proliferative activities of (IC = 3.10 ± 0.29 μM) and its ester hydrolysis product (IC = 2.17 ± 0.16 μM) against HCT-116. The preliminary pharmacokinetic evaluation of implied that and are main contributors to the in vivo efficacy. Compound 2 was further evaluated in an animal study using HCT-116 colon tumor xenograft bearing nude mice. The results revealed a dose-dependent efficacy that led to tumor volume reductions of 27%, 45%, and 60% at 50, 100, and 150 mg/kg doses, respectively. The established structure-activity relationship and pharmacokinetic outcomes of is the guidance for future development of 4,4-disubstituted curcuminoid 2,2-bis(hydroxymethyl)- propionate derivatives as anticancer drug candidates.
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http://dx.doi.org/10.3390/molecules25030479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037731PMC
January 2020

Identification of CD5/Cyclin D1 Double-negative Pleomorphic Mantle Cell Lymphoma: A Clinicopathologic, Genetic, and Gene Expression Study.

Am J Surg Pathol 2020 02;44(2):232-240

Department of Pathology.

Pleomorphic mantle cell lymphoma (PMCL) can closely mimic diffuse large B-cell lymphoma (DLBCL) morphologically, and expression of CD5 and cyclin D1 is helpful for differential diagnosis. To date, no cases of CD5/cyclin D1 double-negative PMCL have been reported. Four cases of B-cell lymphoma with an immunophenotype of CD5(-) cyclin D1(-) SOX11(+) and morphologic features compatible with DLBCL were included. Two were previously identified, and the other 2 were screened from 500 cases of B-cell lymphoma. We analyzed their clinicopathologic, immunophenotypic, genetic, and gene expression features. Cases of cyclin D1-positive PMCL, cyclin D1-negative PMCL, germinal center B-cell (GCB) DLBCL, and activated B cell (ABC) DLBCL were also studied for comparison. Similar to other PMCL cases, these 4 patients were mainly elderly male individuals with an aggressive clinical course. None of these tumors had detectable translocations involving CCND1, CCND2, CCND3, CCNE1, CCNE2, MYC, BCL2, or BCL6. The genome-wide copy number profile of these 4 cases was similar to that of cyclin D1-negative PMCL. None of these tumors had high expression of cyclin D1, cyclin D2, or cyclin D3. Similar to cyclin D1-negative PMCL, these cases had higher expression of cyclin E1 and cyclin E2 compared with cyclin D1-positive PMCL. The gene expression pattern of these tumors was also similar to that of cyclin D1-negative PMCL. Here we report for the first time 4 cases of CD5/cyclin D1 double-negative PMCL. SOX11 positivity is useful to identify these rare tumors, and further genetic and gene expression analysis can be used to confirm the diagnosis.
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http://dx.doi.org/10.1097/PAS.0000000000001390DOI Listing
February 2020

Phf6-null hematopoietic stem cells have enhanced self-renewal capacity and oncogenic potentials.

Blood Adv 2019 08;3(15):2355-2367

Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

() encodes a 365-amino-acid protein containing 2 plant homology domain fingers. Germline mutations of human cause Börjeson-Forssman-Lehmann syndrome, a congenital neurodevelopmental disorder. Loss-of-function mutations of are detected in patients with acute leukemia, mainly of T-cell lineage and in a small proportion of myeloid lineage. The functions of PHF6 in physiological hematopoiesis and leukemogenesis remain incompletely defined. To address this question, we generated a conditional knockout mouse model and investigated the impact of loss on the hematopoietic system. We found that knockout mice at 8 weeks of age had reduced numbers of CD4 and CD8 T cells in the peripheral blood compared with the wild-type littermates. There were decreased granulocyte-monocytic progenitors but increased Linc-KitSca-1 cells in the marrow of young knockout mice. Functional studies, including competitive repopulation unit and serial transplantation assays, revealed an enhanced reconstitution and self-renewal capacity in knockout hematopoietic stem cells (HSCs). Aged knockout mice had myelodysplasia-like presentations, including decreased platelet counts, megakaryocyte dysplasia, and enlarged spleen related to extramedullary hematopoiesis. Moreover, we found that loss lowered the threshold of -induced leukemic transformation at least partially through increased leukemia-initiating cells. Transcriptome analysis on the restrictive rare HSC subpopulations revealed upregulated cell cycling and oncogenic functions, with alteration of key gene expression in those pathways. In summary, our studies show the in vivo crucial roles of Phf6 in physiological and malignant hematopoiesis.
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http://dx.doi.org/10.1182/bloodadvances.2019000391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693005PMC
August 2019

Traditional Serrated Pathway-associated Colorectal Carcinoma: Morphologic Reappraisal of Serrated Morphology, Tumor Budding, and Identification of Frequent PTEN Alterations.

Am J Surg Pathol 2019 08;43(8):1042-1051

Departments of Pathology.

The phenotypic characteristics of traditional serrated adenoma (TSA)-associated malignancies remain obscure. This study was a morphologic reappraisal of 27 colorectal carcinomas arising from TSA (TSA-CRCs) and 53 BRAF-mutated/microsatellite-stable colorectal carcinomas (BRAF-mut/MSS CRCs). Makinen's criteria for serrated adenocarcinoma were applied to assess the morphologic similarity of the 2 entities. Tumor budding, another histologic feature of serrated adenocarcinoma, was also evaluated. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a commonly mutated gene in the serrated pathway, was assessed with immunohistochemistry. Tumors with aberrant PTEN expression were subjected to molecular analysis using quantitative methylation assay, exon sequencing, and fluorescence in situ hybridization. Most cases (>90%) of TSA-CRCs and BRAF-mut/MSS CRCs exhibited a constellation of serrated morphology, including epithelial serrations, abundant eosinophilic cytoplasm, and discernible/vesicular nuclei. A majority (65%) of them qualified for the diagnosis of serrated adenocarcinoma. High-grade tumor budding was closely associated with serrated morphology and was a significant independent factor for poor patient survival in multivariate analysis (P=0.008). Aberrant PTEN expression was detected in nearly half of the cases of both entities (P=0.501). Among the 44 samples with aberrant PTEN expression, 8 harbored PTEN somatic mutations, which were characterized by random distribution without hotspot clustering, 12 had promoter hypermethylation, and 14 had deleted alleles. These findings support a unique model of colorectal carcinogenesis that is similar between TSA-CRCs and BRAF-mut/MSS CRCs. Both entities exhibited common histologic patterns and similar molecular alterations and may well constitute the TSA pathway.
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http://dx.doi.org/10.1097/PAS.0000000000001274DOI Listing
August 2019

Neutrophil Extracellular Traps Enhance Staphylococcus Aureus Vegetation Formation through Interaction with Platelets in Infective Endocarditis.

Thromb Haemost 2019 May 7;119(5):786-796. Epub 2019 Feb 7.

Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.

The mechanisms or host factors involved in septic thrombus or vegetation formation in -induced infective endocarditis (IE) are unclear. Using an experimental endocarditis rat model, here we demonstrated that HG001-induced vegetation was composed of bacterial floes encased in aggregated platelets and surrounded by neutrophil extracellular traps (NETs). In vitro data demonstrated that platelets contribute to both biofilm and NET formation. Prophylactic administration of DNase I significantly reduced the size of vegetation induced by methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) strains, even though MRSA and MSSA isolates express different biofilm phenotypes and NET-induction abilities in the presence of platelets. Moreover, delivery of both DNase I and daptomycin prophylactically and therapeutically produced synergistic effects by reducing vegetation size and bacterial numbers on damaged valve tissues in MRSA-induced IE. Together, these data suggest that NETs contribute to vegetation formation in endocarditis and DNase I has the potential to control -induced IE in the clinic.
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http://dx.doi.org/10.1055/s-0039-1678665DOI Listing
May 2019

Clinicopathologic correlation of ocular surface squamous neoplasia from a university hospital in North Taiwan 1994 to 2014.

J Formos Med Assoc 2019 Apr 25;118(4):776-782. Epub 2018 Sep 25.

Department of Ophthalmology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taiwan; Department of Ophthalmology, Cathay General Hospital, Taipei, Taiwan; Department of Ophthalmology, College of Medicine, Fu Jen Catholic University, Taiwan. Electronic address:

Background/purpose: To describe the clinical and histologic characteristics of ocular surface squamous neoplasia (OSSN) and evaluate factors significant in recurrence at a university hospital in North Taiwan.

Methods: Patient charts, clinical features, and pathology records were retrospectively reviewed in patients with pathology-proved OSSN from January, 1994 to December, 2014. Clinicopathologic correlation was analyzed.

Results: Thirty-six patients were recruited. Mean age was 63.4 ± 13.0 (ranging from 23 to 87) years old. OSSN was predominant in men (21/36). Clinical appearances included papilliform in 17 eyes, gelatinous in 11 eyes, leukoplakic in 3 eyes, and 5 eyes in corneal intraepithelial neoplasia (CIN). Of 31 conjunctival OSSN, there were 4 in CIN I, 11 in CIN II, 13 in CIN III, and 3 in squamous cell carcinoma. Superior location was associated with higher-grade OSSN. Although statistical analysis was not significant, papilliform and multifocal lesions showed a trend of high-grade OSSN. The stages of tumor were 4, 5, 26, and 1 eye(s) in T1 to T4, respectively. Recurrence of disease occurred in 9 cases (25%) with mean recurrence time of 20.6 (range: 4 to 65) months. Multifocal lesion has a higher tendency for recurrence.

Conclusion: Superior location was associated with high-grade OSSN, and papilliform OSSN might have a tendency of severe and invasive lesions. Multifocal lesions might be associated with higher-grade OSSN and higher recurrence rates.
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http://dx.doi.org/10.1016/j.jfma.2018.09.001DOI Listing
April 2019

Prognostic factors and treatment outcomes of malignant pleural mesothelioma in Eastern Asian patients - A Taiwanese study.

J Formos Med Assoc 2019 Jan 27;118(1 Pt 2):230-236. Epub 2018 Apr 27.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; National Taiwan University Cancer Center, Taipei, Taiwan; Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.

Background/purpose: There are scarce reports on the prognostic factors and treatment outcomes of patients with malignant pleural mesothelioma (MPM) in Asia. This study aimed to address these matters in a real-world setting.

Methods: Medical records of patients with histologically proven MPM diagnosed between 1977 and 2016 at the National Taiwan University Hospital were reviewed. Variables including age, gender, performance status, asbestos exposure, smoking history, histology subtype, staging, and treatment received were recorded. All patients were followed until death or March 1st, 2017. Survival and prognostic factors were analyzed by the Kaplan-Meir method and the Cox proportional hazard model.

Results: A total of 93 patients was identified, including 65 men and 28 women. An increasing trend of MPM cases diagnosed was observed in the past 40 years. Stage I/II disease (HR 0.24, 95% CI 0.13-0.46) and epithelioid histology (HR 0.42, 95% CI 0.23-0.75) were associated with favorable prognosis, whereas age ≥70 years (HR 2.66, 95% CI 1.36-5.22) and ECOG ≥2 (HR 5.03, 95% CI 2.69-9.4) were poor prognostic factors. After adjustment for prognostic factors, surgery in stage I-III MPM (HR 0.36, 95% CI 0.15-0.83) and systemic therapy in stage III/IV disease (HR 0.42, 95% CI 0.19-0.94) conferred a survival benefit.

Conclusion: This is one of the largest case series of MPM reported in Asia outside of Japan. Prognostic factors in the study population included age, performance status, stage, and histology subtype. Surgery in potentially resectable disease and systemic therapy in advanced MPM confer a survival benefit in Asian patients.
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http://dx.doi.org/10.1016/j.jfma.2018.04.001DOI Listing
January 2019

BRAF and KRAS mutations in tubular apocrine adenoma and papillary eccrine adenoma of the skin.

Hum Pathol 2018 03 12;73:59-65. Epub 2017 Dec 12.

Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10051, Taiwan.

Tubular apocrine adenoma (TAA) and papillary eccrine adenoma (PEA) are benign sweat gland tumors. Their names imply that they exhibit apocrine and eccrine differentiation, respectively. However, morphologically they are very similar and are often indistinguishable. The molecular pathogenesis of either tumor is poorly understood at present. On the basis of an index case of nipple adenoma that was morphologically reminiscent of cutaneous TAA/PEA and harbored a BRAF mutation, we investigated whether a similar genetic change is also present in TAA/PEA. BRAF, RAS, and PIK3CA mutation analyses, and BRAF-specific immunohistochemistry were performed for 24 TAAs/PEAs, 10 eccrine poromas, 7 apocrine cystadenomas, 2 TAA-like adenomas associated with nevus sebaceus, and one apocrine adenoma probably arising in anogenital mammary-like glands (AGMLGs). The results demonstrated that BRAF mutations were present in TAAs (9/15, 60%) and PEAs (7/9, 78%), but not in other neoplasms. Two additional TAAs harbored KRAS mutations. In addition, a KRAS mutation was identified in one nevus sebaceus-associated TAA-like adenoma. The speculated AGMLG-related apocrine adenoma had a PIK3CA mutation. We concluded that activating BRAF and KRAS mutations were commonly present in TAAs/PEAs, indicating that in addition to a morphological resemblance, they are closely related genetically. Therefore, they could be considered to be united as a single entity. By contrast, the apocrine adenoma probably arising in AGMLG harbored a PIK3CA mutation, which is also commonly present in hidradenoma papilliferum. Further studies are necessary to determine whether the pathogenesis of AGMLG-related tumors is similar to breast tumors.
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http://dx.doi.org/10.1016/j.humpath.2017.12.002DOI Listing
March 2018

Primary effusion lymphoma in Taiwan shows two distinctive clinicopathological subtypes with rare human immunodeficiency virus association.

Histopathology 2018 May 14;72(6):930-944. Epub 2018 Feb 14.

Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.

Aims: To investigate the clinicopathological and molecular features of primary effusion lymphoma (PEL) in Taiwan and the association with human immunodeficiency virus (HIV), human herpesvirus 8 (HHV8) and Epstein-Barr virus (EBV).

Methods And Results: We investigated retrospectively 26 cases with a median age of 76.5. Only one (4%) patient was infected with HIV. Cytologically, all lymphoma cells revealed typical immunoblastic to plasmablastic morphology. Immunohistochemically, HHV8 was positive in eight (32%) tumours and negative in 17 (68%) cases. All 23 tested cases examined were of the non-germinal-centre B cell phenotype. MYC proto-oncogene (MYC) and Epstein-Barr encoding mRNA (EBER) were positive in 43% (nine of 21) and 17% (four of 23) cases, respectively. Immunoglobulin heavy chain (IGH), B cell lymphoma (BCL)2, BCL6 and MYC were rearranged in 71%, 11%, 12% and 18% cases, respectively. By univariate analysis, the overall survival (OS) was associated statistically with MYC expression (P = 0.012) and BCL2 rearrangement (P = 0.035), but not with the others. By multivariate analysis, no factor was statistically significant. Compared to the HHV8-negative cases, the HHV8-positive cases were mainly of the plasmablastic immunophenotype expressing CD30 and CD138, and with a less frequent expression of pan-B cell markers.

Conclusions: Apart from the phenotypical difference, our HHV8-positive neoplasms were not distinct from the HHV8-negative group. Literature review of 256 cases, including our cases, revealed that HHV8-positive cases were associated more frequently with HIV and EBV infection, with rare MYC rearrangement, and a poorer prognosis than HHV8-negative cases. We propose to name the HHV8-positive cases as 'classical' or 'type I PEL' and the HHV8-negative cases as 'type II PEL', stressing the similarities and the distinctive features between these two groups.
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http://dx.doi.org/10.1111/his.13449DOI Listing
May 2018

NRASQ61R immunohistochemistry detects both NRASQ61R and KRASQ61R mutations in colorectal cancer.

Pathology 2017 Jun 19;49(4):387-390. Epub 2017 Apr 19.

Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

The NRASQ61R monoclonal antibody (clone sp174) is a mutation-specific antibody that is increasingly being used to detect the NRAS mutation in melanomas. This antibody has been reported to be highly correlated with the NRAS mutation status in melanomas and follicular neoplasms of the thyroid gland. However, its utility in colorectal carcinoma (CRC) has remained largely unknown. In this study, we assessed the sensitivity, specificity, and diagnostic utility of NRASQ61R immunohistochemistry in a cohort consisting of tissue sections of 113 CRCs, which were molecularly profiled for the KRAS, NRAS, and BRAF mutations. Five CRCs tested positive for NRASQ61R immunohistochemistry. Four of these CRCs exhibited the NRAS mutation and one exhibited the KRAS mutation. All of the other 108 colorectal carcinomas lacking the NRAS or KRAS mutation tested negative for NRASQ61R immunohistochemistry. In the positively stained cases, we observed a diffuse staining pattern in >90% of the tumour cells with a moderate-to-strong intensity. By contrast, the staining was essentially entirely negative in cases negative for the NRAS or KRAS mutations. We concluded that although it cross-reacts with the mutant KRAS protein, the NRASQ61R antibody is a useful diagnostic tool that assists in the molecular testing of CRCs and facilitates patient management.
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http://dx.doi.org/10.1016/j.pathol.2017.01.008DOI Listing
June 2017

Comprehensive screening for MED12 mutations in gynaecological mesenchymal tumours identified morphologically distinctive mixed epithelial and stromal tumours.

Histopathology 2017 May 16;70(6):954-965. Epub 2017 Feb 16.

Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.

Aims: MED12 exon 2 mutations have been identified in most uterine leiomyomas and mammary fibroepithelial tumours. MED12 has not been genotyped in most other gynaecological mesenchymal tumours. The purpose of this study was to determine the prevalence of MED12 mutations in uncommon gynaecological mesenchymal tumours.

Methods And Results: Sixty-eight uncommon gynaecological mesenchymal tumours were genotyped for MED12 exon 2, including 27 Müllerian adenosarcomas (including three tentatively diagnosed as 'variant adenosarcomas'), six cellular angiofibromas, six aggressive angiomyxomas, five angiomyofibroblastomas, five superficial myofibroblastomas, five atypical polypoid adenomyomas, and 14 endometrial stromal sarcomas. Immunohistochemistry for CD10, myogenic markers, hormone receptors, MDM2, and CDK4, and fluorescence in-situ hybridization (FISH) for JAZF1, PHF1 and YWHAE rearrangement, were performed on selected cases. The three 'variant adenosarcomas' harboured MED12 exon 2 mutations (including p.L36R hotspot mutation, recurrent p.L39_A50del, and a novel splice site mutation). Three endometrial stromal sarcomas with JAZF1-SUZ12 or JAZF1-PHF1 fusion harboured unprecedented mutations (p.D54G in two, and p.Q48* in one). All remaining tumours were wild-type. The three MED12-mutated 'variant adenosarcomas' showed distinctive morphological features, including 'fibromyomatous' cytomorphology, a close association with adenomyosis, clustered thick-walled vessels, focal conspicuous hyalinization, and intralymphovascular tumour growth. Features of conventional adenosarcomas, including nuclear atypia, mitotic activity, periglandular condensation, and phyllodes-like architecture, were inconspicuous. All three cases showed immunoreactivity for desmin and hormone receptors, while being negative for MDM2 and CDK4; they showed no JAZF1, PHF1 or YWHAE rearrangement. Despite deep myoinvasion, these tumours followed an indolent clinical course.

Conclusions: These MED12-mutated adenosarcoma-like tumours might represent a distinct entity that requires more studies for its identification. MED12 exon 2 mutations seemed to have no significant role in other uncommon gynaecological mesenchymal tumours.
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http://dx.doi.org/10.1111/his.13156DOI Listing
May 2017

RNF43 mutation frequently occurs with GNAS mutation and mucin hypersecretion in intraductal papillary neoplasms of the bile duct.

Histopathology 2017 Apr 10;70(5):756-765. Epub 2017 Jan 10.

Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.

Aims: RNF43 is a tumour suppressor gene that suppresses the Wnt-β-catenin signalling pathway. We investigated the role of RNF43 in intraductal papillary neoplasm of the bile duct (IPNB).

Methods And Results: We conducted mutation analysis of RNF43 in 50 IPNBs, and identified six (12%) RNF43 mutations. RNF43 mutation was more frequent in the intestinal subtype of IPNB (17%) than in the gastric/pancreatobiliary subtype (5%). There was a strong association of RNF43 mutation with GNAS (P = 0.007) mutation, and a borderline correlation with KRAS (P = 0.074) mutation. The presence of macroscopic mucin hypersecretion was closely related to RNF43 (P = 0.024) and GNAS (P < 0.001) mutations. A two-step clustering analysis algorithm successfully categorized IPNBs into two subgroups by using the clinicopathological and molecular features of IPNBs. One subgroup of IPNB represented the 'biliary counterpart of intraductal papillary mucinous neoplasm of the pancreas' (biliary-IPMN), and showed unique features reminiscent of IPMN, such as macroscopic and microscopic mucin hypersecretion, an intestinal cell lineage, GNAS mutation, and RNF43 mutation. Biliary-IPMNs were significantly associated with high expression of cytokeratin (CK) 20, mucin 2 (MUC2), and CDX2, as shown by immunostaining (P = 0.032, P = 0.001, and P = 0.026, respectively), and had a borderline association with low expression of CK7 (P = 0.063). With the use of this splitting algorithm, RNF43 mutations were identified in 36% of the biliary-IPMNs.

Conclusions: The identification of RNF43 mutations in a distinct subset of IPNBs revealed a new molecular role in the pathogenesis of IPNB, and provided a potential application for cancer therapeutics by the use of Wnt pathway inhibitors.
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http://dx.doi.org/10.1111/his.13125DOI Listing
April 2017

Frequent PIK3CA activating mutations in nipple adenomas.

Histopathology 2017 Jan 29;70(2):195-202. Epub 2016 Sep 29.

Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Aims: Nipple adenoma (NA) is a rare benign epithelial tumour occurring in the nipple. Histologically, it exhibits variable and often mixed adenosis-like and usual ductal hyperplasia-like growth patterns. Morphologically, it is similar to other benign proliferative breast lesions occurring in the breast parenchyma, which have been shown to harbour activating mutations in PIK3CA, AKT1 or, less frequently, in RAS in more than 50% of cases. In this study, we aimed to analyse the mutation status of PIK3CA, AKT1, RAS and BRAF in NAs and correlated the mutation status with the histological features.

Methods And Results: Mutation analysis of PIK3CA, AKT1, RAS and BRAF was performed in 24 NAs by Sanger sequencing. Our results showed that activating PIK3CA mutations were identified in eight of the 15 NAs (53%) with a predominantly adenosis-like pattern and four of the nine NAs (44%) with a predominantly usual ductal hyperplasia-like pattern. One tumour with a PIK3CA H1047R mutation also had a KRAS Q61H mutation. Two tumours with an adenosis-like pattern had BRAF V600E mutations. Overall, half of the NAs (12 of 24, 50%) in our series had PIK3CA mutations and 58% (14 of 24) had PIK3CA, RAS or BRAF mutations.

Conclusions: Our data indicate that, similar to other benign proliferative lesions occurring in the breast parenchyma, activating PIK3CA mutations are very common in NAs, and KRAS mutation may occur concurrently with PIK3CA mutation. In addition, as BRAF mutation has not been identified in benign proliferative lesions in previous studies, BRAF-mutated NAs appear to have distinct pathogenesis.
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http://dx.doi.org/10.1111/his.13043DOI Listing
January 2017

Gastric-type adenocarcinoma in situ of uterine cervix: cytological and histopathological features of two cases.

Virchows Arch 2016 Sep 22;469(3):351-6. Epub 2016 Jun 22.

Department of Pathology, National Taiwan University Hospital, No. 7 Chung-Shan S. Rd., Taipei, 100, Taiwan.

Benign, premalignant, and malignant endocervical glandular lesions occasionally show a gastric phenotype. We report 2 cases of gastric-type adenocarcinoma in situ (AIS) of the endocervix, not associated with lobular endocervical glandular hyperplasia or gastric-type adenocarcinoma. Cytologically, both showed endocervical glands with slightly enlarged nuclei, distinctive nucleoli, pseudostratified strips, and intracytoplasmic golden yellow mucin. Histologically, both lesions were situated in preexisting endocervical glands and presented columnar cells with voluminous pale eosinophilic cytoplasm and evident nuclear atypia. In case 1, the lesion was located at the mid-zone of the endocervical canal and, in case 2, at the outer endocervical canal with extension to the transformation zone and prominent intestinal metaplasia. In both, the cells showed voluminous cytoplasm containing gastric-type mucin, stained red by combined alcian blue/periodic acid-Schiff stain. Immunohistochemically, both lesions were positive for HIK1083 and p53, while negative for p16 and ER. Human papilloma virus (HPV) DNA was not detected by polymerase chain reaction. Our cases illustrate that gastric-type AIS can occur without lobular endocervical glandular hyperplasia. The lesions can occur in the outer cervical canal and present extensive intestinal differentiation. Awareness of this rare type of endocervical glandular lesion is important since they are pathogenetically different from the more common HPV-associated lesions and may become more prevalent in the HPV-eradicating era.
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http://dx.doi.org/10.1007/s00428-016-1978-xDOI Listing
September 2016

RNF43 Is an Early and Specific Mutated Gene in the Serrated Pathway, With Increased Frequency in Traditional Serrated Adenoma and Its Associated Malignancy.

Am J Surg Pathol 2016 10;40(10):1352-9

Departments of *Pathology ‡Oncology ∥Medical Genetics, National Taiwan University Hospital †Graduate Institute of Pathology §Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

RNF43 is an E3 ligase that suppresses the Wnt/β-catenin signaling pathway and is frequently mutated in microsatellite-unstable colorectal carcinoma. To investigate the pathogenetic role of RNF43 in the serrated pathway, we conducted mutation analysis of RNF43 in several types of colorectal neoplasms. RNF43 mutation was found in 2 of 20 (10%) sessile serrated adenomas, 10 of 36 (28%) traditional serrated adenomas, 7 of 37 (19%) traditional serrated adenomas with cytologic dysplasia, and 9 of 31 (29%) BRAF-mutated/microsatellite-stable colorectal carcinomas; however, no mutation was found in 30 tubulovillous/villous adenomas. All mutations were located upstream of the ring finger domain of RNF43 without clustering, which is distinct from the pattern described for microsatellite-unstable colorectal carcinoma. RNF43 mutation was closely associated with BRAF mutation but inversely associated with KRAS mutation in traditional serrated adenoma with or without cytologic dysplasia (P=0.018 and 0.045, respectively). The finding of RNF43 mutation in sessile serrated adenoma and traditional serrated adenoma, but not in tubulovillous/villous adenoma, indicated that RNF43 mutation is an early and specific molecular aberration in the serrated pathway. The frequency of RNF43 mutation was significantly higher in traditional serrated adenoma with or without cytologic dysplasia and BRAF-mutated/microsatellite-stable colorectal carcinoma than sessile serrated adenoma. The unique molecular spectrum of these tumors suggests a stepwise neoplastic progression from sessile serrated adenoma to traditional serrated adenoma and BRAF-mutated/microsatellite-stable colorectal carcinoma, which should be recognized as the traditional serrated pathway to distinguish from the sessile serrated pathway.
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http://dx.doi.org/10.1097/PAS.0000000000000664DOI Listing
October 2016

Case report: mismatch repair proficiency and microsatellite stability in gastric cancer may not predict programmed death-1 blockade resistance.

J Hematol Oncol 2016 Mar 24;9:29. Epub 2016 Mar 24.

Department of Oncology, National Taiwan University Hospital, 7, Chun-Shan S Rd, Taipei, 10002, Taiwan.

Background: Anti-programmed death-1 therapy has poor efficacy in mismatch repair-proficient (pMMR) colorectal cancers; however, its efficacy in pMMR gastric cancers remains undetermined. Here, we report the case of a patient with pMMR and microsatellite-stable gastric cancer who exhibited a partial response to salvage anti-programmed death-1 therapy with pembrolizumab.

Case Presentation: Initially, the patient underwent subtotal gastrectomy 4 years ago for early-stage gastric cancer (pT1bN2M0, stage IIA). Immunohistochemical analysis of the tumor revealed strongly positive for HER2/neu. He had received trastuzumab plus pertuzumab, cisplatin, and capecitabine for recurrent tumors since September 2014 for 15 cycles. Disease progression of gastric cancer was found in August 2015. Since September 2015, the patient has received pembrolizumab monotherapy (200 mg as a fixed dose, every 3 weeks) for 3 months and the repeat computed tomography demonstrated a confirmed partial response. The plasma carcinoembryonic antigen also decreased dramatically. Both immunohistochemistry and a polymerase chain reaction-based method revealed that the patient had pMMR gastric cancer.

Conclusions: This case report provides the first report that mismatch repair-proficient and microsatellite-stable gastric cancers can respond well to anti-PD-1 monotherapy and indicates both markers may not sufficiently be predictive of anti-PD-1 therapy resistance in gastric cancer.
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http://dx.doi.org/10.1186/s13045-016-0259-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806434PMC
March 2016

Tigroid background in cytology of hyalinizing clear cell carcinoma of the salivary gland.

Diagn Cytopathol 2016 Apr 30;44(4):338-41. Epub 2015 Dec 30.

Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.

Hyalinizing clear cell carcinoma (HCCC) is a rare and low grade salivary gland carcinoma with a unique recurrent EWSR1 gene translocation. HCCC most commonly arises from intraoral minor salivary glands and its cytological features have not been well evaluated. We report a 28-year-old man with palatal HCCC and emphasize the "tigroid background" and metachromatic matrix observed in scrape cytology. This "tigroid background," usually associated with glycogen-rich clear cell tumors, is an important cytological feature of HCCC. Awareness of this feature can do great help in pathological research and diagnosis.
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http://dx.doi.org/10.1002/dc.23423DOI Listing
April 2016

Intestinal tuberculosis previously mistreated as Crohn's disease and complicated with perforation: a case report and literature review.

Springerplus 2015 7;4:326. Epub 2015 Jul 7.

Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.

Introduction: Tuberculosis is known as a notorious mimicker and distinguishing between intestinal tuberculosis and Crohn's disease is a huge diagnostic challenge.

Case Description: Here, we report a case of hollow organ perforation due to intestinal tuberculosis that was previously mistreated as Crohn's disease. Staged operation with emergency resection of the diseased small bowel and temporary ileostomy was performed for the perforation, followed by 6-month standard treatment for miliary tuberculosis, which was diagnosed on the basis of the presence of acid-fast bacilli in the diseased bowel and positive culture of Mycobacterium tuberculosis from sputum, ascites, and stool samples. Ileostomy takedown was performed, and the continuity of the gastrointestinal tract was restored 6 months after the first surgery. The patient recovered well thereafter.

Conclusion: Timely surgical intervention can help establish the finial diagnosis of tuberculosis, rescue the patient from abdominal emergency, and provide a chance for cure.
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http://dx.doi.org/10.1186/s40064-015-1129-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493258PMC
July 2015

Parathyroidectomy improves cardiovascular outcome in nondiabetic dialysis patients with secondary hyperparathyroidism.

Clin Endocrinol (Oxf) 2014 Apr 18;80(4):508-15. Epub 2013 Oct 18.

Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, Kaohsiung Armed Force General Hospital, Kaohsiung, Taiwan.

Objective: Secondary hyperparathyroidism and its associated abnormalities in mineral metabolism and haemodynamic changes increase the cardiovascular risk in patients with end-stage renal disease (ESRD). Our objective was to determine the association of parathyroidectomy (PTX) with major cardiovascular events in nondiabetic dialysis patients with severe secondary hyperparathyroidism (SHPTH).

Design And Patients: We performed a cohort study with fifty-three nondiabetic ESRD patients who were treated with maintenance haemodialysis and who had intact parathyroid hormone (PTH) levels > 800 pg/ml. Participants received either only medical therapy or medical therapy and total PTX with autotransplantation for SHPTH.

Measurements: We evaluated the associations between PTX and major cardiovascular events including death, cerebrovascular accident and myocardial infarction. The biochemical and haemodynamic changes associated with PTX were measured.

Results: During the mean follow-up of 72 months, twenty-three patients received only medical treatment (medical group) while thirty patients underwent PTX in addition to medical treatment (PTX group). The two groups were comparable in respect of baseline characteristics. PTX group was found to be associated with a reduced incidence of major cardiovascular events (P = 0·021). A multiple Cox regression analysis showed that the variable significantly associated with major cardiovascular events was treatment modality (medical therapy vs medical therapy and parathyroidectomy, hazard ratio = 26·12, 95% CI = 1·30-526·27, P = 0·033). Blood pressure, haemoglobin, alkaline phosphatase, calcium, phosphate and calcium × phosphate product significantly improved after PTX.

Conclusions: PTX was associated with better cardiovascular outcome in nondiabetic dialysis patients with severe SHPTH.
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http://dx.doi.org/10.1111/cen.12333DOI Listing
April 2014

Low-dose heparin retention in temporary hemodialysis double-lumen catheter does not increase catheter occlusion and might reduce risk of bleeding.

Blood Purif 2011 9;32(3):232-7. Epub 2011 Aug 9.

Division of Nephrology, Department of Medicine, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Rd., Kaohsiung, Taiwan, ROC.

Background: The objective of this study was to assess the impact of heparin concentration retained in temporary double-lumen catheters on bleeding risk.

Methods: Activated partial thromboplastin time (aPTT) was measured in patients hemodialyzed via double-lumen catheters. Heparin solutions of 5,000 U/ml (group 1, n = 95) and 1,000 U/ml (group 2, n = 89) were randomly retained in catheters after placement and each hemodialysis (HD) session. Blood transfusion, bleeding episodes, and changes of hematocrit were recorded.

Results: The aPTT at the beginning of HD or 10 min after heparin lock was significantly prolonged, which was more prominent in the 5,000 U/ml group, whereas the aPTT declined to baseline values at the end of HD or before the next dialysis session in both groups. Infection and occlusion rates were similar in both groups. More patients suffered from major bleeding and prominent decline of hematocrit in the 5,000 U/ml group.

Conclusions: Low-dose heparin (1,000 U/ml) retention in double-lumen catheters for temporary HD maintains comparable catheter patency and might reduce the bleeding risk.
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http://dx.doi.org/10.1159/000328743DOI Listing
January 2012

Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC-PK1) cell lines.

Exp Cell Res 2010 Apr 2;316(7):1109-18. Epub 2010 Mar 2.

Division of Nephrology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Purpose: Tumor growth factor-beta1 (TGF-beta1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-beta1-mediated EMT and fibrosis in kidney injury.

Methods: We examined apoptosis and EMT in TGF-beta1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-beta1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-beta1 signal pathway proteins and EMT markers.

Results: We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-beta1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-beta1-mediated apoptosis and also partially inhibited TGF-beta1-mediated EMT. We showed that EPO treatment suppressed TGF-beta1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-beta1-treated cells.

Conclusions: EPO inhibited apoptosis and EMT in TGF-beta1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction.
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http://dx.doi.org/10.1016/j.yexcr.2010.02.022DOI Listing
April 2010