Graduate Institute of Pathology

Taipei, Taiwan

Graduate Institute of Pathology

Taipei, Taiwan
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Tsai J.-H.,National Taiwan University Hospital | Huang W.-C.,Far Eastern Memorial Hospital | Kuo K.-T.,National Taiwan University Hospital | Chen Y.-L.,National Taiwan University Hospital | And 2 more authors.
Histopathology | Year: 2012

Aims: S100P is a calcium-binding protein that is frequently expressed in pancreatic adenocarcinoma and perihilar cholangiocarcinoma. The aim of this study was to investigate the pathological significance of the expression of S100P in peripheral intrahepatic cholangiocarcinoma (ICC). Methods and results: Immunohistochemical staining was used to investigate S100P expression in 112 cases of peripheral ICC. The results were compared with those for perihilar and extrahepatic cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have elevated serum levels of carcinoembryonic antigen (CEA) and CA19-9 than those with S100P-negative peripheral ICCs. All cases of peripheral ICC associated with intrahepatic lithiasis and all cases with intraductal/periductal growth patterns were positive for S100P. S100P-positive peripheral ICCs were highly associated with 'bile duct' morphology rather than cholangiolar differentiation. Nearly all cases of perihilar and extrahepatic cholangiocarcinoma were positive for S100P. Similarly to perihilar and extrahepatic cholangiocarcinomas, S100P-positive peripheral ICCs showed more frequent expression of CEA and MUC2, and were more likely to be N-cadherin-negative, than S100P-negative cases. Notably, K-RAS mutations were only detected in S100P-positive peripheral ICCs, with a frequency similar to that in perihilar and extrahepatic cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have poor prognoses than those with S100P-negative tumours. Conclusions: S100P immunostaining identifies a subset of peripheral ICC that probably originates from larger bile ducts. This subset of peripheral ICCs shares common morphological and molecular features with perihilar and extrahepatic cholangiocarcinomas. © 2012 Blackwell Publishing Limited.


Lin Y.-C.,National Defense Medical Center and Tri Service General Hospital | Lin Y.-C.,Taoyuan Armed Forces General Hospital | Perng C.-L.,Tri Service General Hospital | Perng C.-L.,Graduate Institute of Pathology | And 5 more authors.
Taiwanese Journal of Obstetrics and Gynecology | Year: 2013

Objective: Adenoid basal carcinoma (ABC) is an uncommon neoplasm of the uterine cervix. ABC can be accompanied by carcinoma in situ or invasive carcinoma. Most cases are discovered accidentally during radical hysterectomy. ABC is associated with a high risk of human papillomavirus infection (HPV), most often HPV 16 infection. Case report: We present a rare case of an 86-year-old Taiwanese married woman who suffered from bloody vaginal discharge and occasional lower abdominal pain and received cervical biopsy. The pathological report revealed squamous cell carcinoma (SCC) of the uterine cervix. After radical hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymph node dissection, the final pathological report revealed SCC coexisting with ABC, and both of the components were infected by HPV 31. After receiving radiotherapy, she maintained outpatient department follow-up. Conclusion: A literature review revealed that this was a rare case of combined ABC-SCC associated with HPV 31 infection. In this case, the ABC component did not affect the tumor stage because it was confined to the cervix. However, we must avoid overestimating the clinical stage because the ABC component is thought to be a benign lesion. © 2013 .


Wu C.-L.,Graduate Institute of Pathology | Ping S.-Y.,A-Life Medical | Yu C.-P.,Graduate Institute of Pathology | Yu D.-S.,Tri Service General Hospital
Kaohsiung Journal of Medical Sciences | Year: 2012

Overexpression of hypoxia-inducible factor-1 alpha is noted during the invasive and metastatic process of transitional cell carcinoma. It will upregulate vascular endothelial growth factor (VEGF) and drive proliferation, invasiveness, metastasis, and antiapoptotic ability of cancer cells. We proposed that tyrosine kinase receptor inhibitor, sunitinib malate - (Sutent; Pfizer Inc., Taiwan), combined with chemotherapeutic drug may present synergistic cytotoxic enhancement to transitional cell carcinoma cells with subsequent inhibition of their cellular behaviors, including proliferation, invasiveness, and metastatic activity. The contents of VEGF-A in mouse bladder tumor cells (MBT-2) and culture medium were detected by quantification-polymerase chain reaction and Western blot individually. The inhibitory concentrations of various chemotherapeutic drugs, sunitinib, and their combination treatment in MBT-2 were determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Microchamber transmembrane migration assay was applied in evaluation of the inhibitory effects of different dosages of sunitinib and combination treatment on tumor cells. The cell cycle and apoptosis were analyzed after combination therapy by flow cytometry. Variation in apoptotic pathway was elucidated by Western blot using specific antibodies with cleaved PARP and caspase-3. Metastatic animal model mimicked by tail vein injection of MBT-2 cells was used to evaluate the treatment efficiency in tumor weight and survival rate. The mRNA and protein level of VEGF-A in MBT-2 cells increased by 70% at 48 hours interval under hypoxia stress condition. In MTT assay, MBT-2 cells had shown the highest sensitivity to epirubicin. Sunitinib combined with epirubicin had shown a synergistic cytotoxic effect to MBT-2 cells. Sunitinib and its combination with epirubicin showed significant inhibition on MBT-2 cells migration in microchambers. G2/M phase arrest and increased subG1 in cell cycle was seen in the epirubicin and sunitinib combination treatment group. The activation of apoptosis pathway was confirmed by increased cleaved caspase-3 and cleaved PARP in MBT-2 cells. In tail vein tumor inoculation C3H mice model, epirubicin alone and sunitinib combination therapy decreased tumor growth in lungs with marginal effect. Sunitinib and epirubicin combination had shown a synergistic cytotoxic effect and inhibited cell migration ability in MBT-2 cells. The combination can induce cell cycle arrest at G2/M phase and increase subG1 cells. Metastatic animal study also showed that sunitinib combined with epirubicin has a marginal effect on inhibition of tumor growth of lungs. The tyrosine kinase receptor inhibitor-targeted combined chemotherapy regimen may provide as a new treatment modality for advanced bladder cancer in the future. Copyright © 2012, Elsevier Taiwan LLC. All rights reserved.


Sun J.-R.,Tri Service General Hospital | Jeng W.-Y.,National Cheng Kung University | Perng C.-L.,Tri Service General Hospital | Perng C.-L.,Graduate Institute of Pathology | And 4 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2016

Objectives: Amino acid substitutions within the AdeRS two-component system are believed to result in overexpression of the AdeABC efflux pump and extensive resistance to antibiotics in clinical Acinetobacter baumannii isolates. However, the exact amino acid substitutions in AdeRS that cause overexpression of the AdeABC efflux pump remain unclear.We elucidated the role of amino acid substitutions in AdeRS by a complementation assay in an adeRS knockout strain of A. baumannii. Methods: Five types of adeRS operon from tigecycline-resistant XDR A. baumannii (XDRAB) were cloned and introduced into the adeRS knockout strain to reverse its tigecycline susceptibility. Results: Through shuffling gene segments among those five adeRS operons and performing site-directed mutagenesis, we found that the specific amino acid substitution Gly186Val in AdeS is crucial for reducing tigecycline susceptibility of A. baumannii. Conclusions: Our result demonstrates that a critical amino acid substitution in AdeS alters the AdeABC efflux pump-mediated tigecycline resistance of A. baumannii. © The Author 2016.


Sun J.-R.,Graduate Institute of Medical Science | Sun J.-R.,Tri Service General Hospital | Perng C.-L.,Tri Service General Hospital | Perng C.-L.,Graduate Institute of Pathology | And 8 more authors.
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2014

Tigecycline (TGC)-resistant extensively drug-resistant Acinetobacter baumannii (XDRAB) is an increasing threat in regard to nosocomial infections. The resistance–nodulation–cell division (RND) efflux pump has played an important role in TGC resistance. In this study, total 81 TGC-resistant XDRAB isolates were analyzed for their responses to the efflux pump inhibitor 1-(1-naphthylmethyl)-piperazine (NMP). We found that NMP could reduce by 4-fold or greater than 4-fold the minimum inhibitory concentration (MIC) of TGC in 45 isolates (55.6 %). After typing with pulsed-field gel electrophoresis (PFGE), group A appeared to be the major cluster with good synergistic response to NMP. Transcripts of the AdeABC efflux pump gene were consistently more correlated with TGC resistance than transcripts of the AdeFGJ or AdeIJK efflux pump genes in these isolates. Of the 81 isolates, the amino acid sequences of AdeR and AdeS were further classified and combined into 31 different codes. Although the dissemination of TGC-resistant XDRAB isolates was genetically diverse in our hospital, their responses to NMP conversion were still strain-dependent. We found that AdeRS combination codes were better than PFGE typing in separating groups of isolates with different sensitivity to NMP conversion. © 2014, Springer-Verlag Berlin Heidelberg.


PubMed | Tri Service General Hospital, National Cheng Kung University, Graduate Institute of Pathology and Tzu Chi University
Type: Journal Article | Journal: The Journal of antimicrobial chemotherapy | Year: 2016

Amino acid substitutions within the AdeRS two-component system are believed to result in overexpression of the AdeABC efflux pump and extensive resistance to antibiotics in clinical Acinetobacter baumannii isolates. However, the exact amino acid substitutions in AdeRS that cause overexpression of the AdeABC efflux pump remain unclear. We elucidated the role of amino acid substitutions in AdeRS by a complementation assay in an adeRS knockout strain of A. baumannii.Five types of adeRS operon from tigecycline-resistant XDR A. baumannii (XDRAB) were cloned and introduced into the adeRS knockout strain to reverse its tigecycline susceptibility.Through shuffling gene segments among those five adeRS operons and performing site-directed mutagenesis, we found that the specific amino acid substitution Gly186Val in AdeS is crucial for reducing tigecycline susceptibility of A. baumannii.Our result demonstrates that a critical amino acid substitution in AdeS alters the AdeABC efflux pump-mediated tigecycline resistance of A. baumannii.


Perng C.-L.,Tri Service General Hospital | Perng C.-L.,Graduate Institute of Pathology | Chang L.-F.,Yuanpei University | Chien W.-C.,Noustem Biotech. Inc. | And 3 more authors.
Clinical Biochemistry | Year: 2012

Objectives: The aim was to evaluate the use of combination of SBT (sequence based typing) and HARP (heterozygous ambiguity resolving primer) in HLA typing to acquire high resolution typing results. Design and methods: 167 DNA samples were analyzed by SBT. The web site HARPs Finder provided by Conexio Genomics, the developer of HARPs (http://www.harpsfinder.conexio-genomics.com/index.html) was then used to search for appropriate HARPs. Results: HARPs can resolve 95% of ambiguities for locus A; 86% for B and 60% for DRB1 locus. However, there are still limitations. Practically PCR products of un-separated alleles are used as templates for sequencing by HARP; sometimes, it is still impossible to get unambiguous typing. Conclusions: We outlined the advantages and disadvantages of SBT/HARP. A list of HARPs for choice to resolve ambiguity of SBT in Taiwanese population is concluded. © 2012 The Canadian Society of Clinical Chemists.


Sun J.-R.,Graduate Institute of Medical Science | Sun J.-R.,Tri Service General Hospital | Perng C.-L.,Tri Service General Hospital | Perng C.-L.,Graduate Institute of Pathology | And 10 more authors.
PLoS ONE | Year: 2012

Over-expression of AdeABC efflux pump stimulated continuously by the mutated AdeRS two component system has been found to result in antimicrobial resistance, even tigecycline (TGC) resistance, in multidrug-resistant Acinetobacter baumannii (MRAB). Although the insertion sequence, ISAba1, contributes to one of the AdeRS mutations, the detail mechanism remains unclear. In the present study we collected 130 TGC-resistant isolates from 317 carbapenem resistant MRAB (MRAB-C) isolates, and 38 of them were characterized with ISAba1 insertion in the adeS gene. The relationship between the expression of AdeABC efflux pump and TGC resistant was verified indirectly by successfully reducing TGC resistance with NMP, an efflux pump inhibitor. Further analysis showed that the remaining gene following the ISAba1 insertion was still transcribed to generate a truncated AdeS protein by the Pout promoter on ISAba1 instead of frame shift or pre-termination. Through introducing a series of recombinant adeRS constructs into a adeRS knockout strain, we demonstrated the truncated AdeS protein was constitutively produced and stimulating the expression of AdeABC efflux pump via interaction with AdeR. Our findings suggest a mechanism of antimicrobial resistance induced by an aberrant cytoplasmic sensor derived from an insertion element. © 2012 Sun et al.


Liu C.-H.,Tri Service General Hospital | Wang H.-H.,Tri Service General Hospital | Perng C.-L.,Tri Service General Hospital | Perng C.-L.,Graduate Institute of Pathology | And 3 more authors.
Thoracic Cancer | Year: 2014

Primary extranodal natural killer/T- cell lymphoma, nasal type (NK/TCL) in the lung is extremely rare and associated with Epstein-Barr virus (EBV) infection. An 80-year-old male presented with hemoptysis, which had lasted three days. Physical examination revealed inspiratory crackles at the left lung base and massive splenomegaly. Chest radiograph shows a mass-like lesion in the left lower lung but no active lesion six months earlier. Computed tomography demonstrated a soft tissue mass (size: 6.6 × 5.1cm) with increased ground-glass opacities in the left lower lobe, several pulmonary nodules, and mediastinal lymphadenopathy. Transthoracic needle biopsy of the left-lower-lobe lung mass was performed. The pathology revealed atypical lymphoid cell infiltration, which is immunoreactive for cytoplasmic CD3, CD30 and CD56, but not reactive for CK and CD20. EBV-encoded RNA (EBER) was also detected in these atypical lymphoid cells. The serum EBV DNA level was 7.03 × 106copies/mL and subtype 1 EBV was identified. No evidence of lymphoma involvement was found in the extrathoracic site. Primary pulmonary lymphoma showing nasal-type NK/T-cell subtype was diagnosed. Chemotherapy with cyclophosphamide and prednisolone was initiated immediately but the patient deteriorated and died three weeks later. In conclusion, patients presenting with rapidly growing lung mass and massive splenomegaly raise the possibility of aggressive pulmonary lymphoma. Extranodal NK/T-cell lymphoma with high baseline plasma EBV DNA levels signifies poor prognosis. Identifying young high-risk patients may have benefits for early aggressive and successful treatment.© 2012 Tianjin Lung Cancer Institute and Wiley Publishing Asia Pty Ltd.


PubMed | Graduate Institute of Pathology
Type: Journal Article | Journal: The Kaohsiung journal of medical sciences | Year: 2012

Overexpression of hypoxia-inducible factor-1 alpha is noted during the invasive and metastatic process of transitional cell carcinoma. It will upregulate vascular endothelial growth factor (VEGF) and drive proliferation, invasiveness, metastasis, and antiapoptotic ability of cancer cells. We proposed that tyrosine kinase receptor inhibitor, sunitinib malate-(Sutent; Pfizer Inc., Taiwan), combined with chemotherapeutic drug may present synergistic cytotoxic enhancement to transitional cell carcinoma cells with subsequent inhibition of their cellular behaviors, including proliferation, invasiveness, and metastatic activity. The contents of VEGF-A in mouse bladder tumor cells (MBT-2) and culture medium were detected by quantification-polymerase chain reaction and Western blot individually. The inhibitory concentrations of various chemotherapeutic drugs, sunitinib, and their combination treatment in MBT-2 were determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Microchamber transmembrane migration assay was applied in evaluation of the inhibitory effects of different dosages of sunitinib and combination treatment on tumor cells. The cell cycle and apoptosis were analyzed after combination therapy by flow cytometry. Variation in apoptotic pathway was elucidated by Western blot using specific antibodies with cleaved PARP and caspase-3. Metastatic animal model mimicked by tail vein injection of MBT-2 cells was used to evaluate the treatment efficiency in tumor weight and survival rate. The mRNA and protein level of VEGF-A in MBT-2 cells increased by 70% at 48 hours interval under hypoxia stress condition. In MTT assay, MBT-2 cells had shown the highest sensitivity to epirubicin. Sunitinib combined with epirubicin had shown a synergistic cytotoxic effect to MBT-2 cells. Sunitinib and its combination with epirubicin showed significant inhibition on MBT-2 cells migration in microchambers. G2/M phase arrest and increased subG1 in cell cycle was seen in the epirubicin and sunitinib combination treatment group. The activation of apoptosis pathway was confirmed by increased cleaved caspase-3 and cleaved PARP in MBT-2 cells. In tail vein tumor inoculation C3H mice model, epirubicin alone and sunitinib combination therapy decreased tumor growth in lungs with marginal effect. Sunitinib and epirubicin combination had shown a synergistic cytotoxic effect and inhibited cell migration ability in MBT-2 cells. The combination can induce cell cycle arrest at G2/M phase and increase subG1 cells. Metastatic animal study also showed that sunitinib combined with epirubicin has a marginal effect on inhibition of tumor growth of lungs. The tyrosine kinase receptor inhibitor-targeted combined chemotherapy regimen may provide as a new treatment modality for advanced bladder cancer in the future.

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