Publications by authors named "Tse-Ching Chen"

164 Publications

The optimal timing of interval laparoscopic cholecystectomy following percutaneous cholecystostomy based on pathological findings and the incidence of biliary events.

J Hepatobiliary Pancreat Sci 2021 Jun 15. Epub 2021 Jun 15.

Division of General Surgery, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.

Background: The incidence of biliary events (BE) following percutaneous cholecystostomy (PC) in acute cholecystitis (AC) patients is high. Therefore, definitive laparoscopic cholecystectomy (LC) is recommended. We aimed to investigate the optimal timing of LC following PC with regard to the clinical course and pathological findings.

Methods: All 744 AC patients with PC were included. The incidence and median number of BE were investigated with the concept of competing risks. The 344 patients with interval LC were divided into two groups based on the pathological findings of resected gallbladders: the acute/acute-and-chronic group (AANC group) (n = 221) and the chronic group (n = 123). A comparative analysis of the demographic data and perioperative outcomes was performed.

Results: Among the 744 AC patients with PC, 142 patients experienced recurrent BE. The cumulative incidence of BE was 26.6%, and the median time to recurrence was 67.5 days. The PC-to-LC days of the chronic group were longer than those of the AANC group (73.51 vs 63.00, P < .001). The multivariate analysis indicated that the operation time was longer in the AANC group than in the chronic group (P = .040).

Conclusion: In terms of the clinical course and sequential pathological changes in the gallbladder, a 9- to 10-week interval after PC is the optimal timing for LC.
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http://dx.doi.org/10.1002/jhbp.1012DOI Listing
June 2021

Laryngeal Infection and Laryngeal Cancer-Case Series and a Systematic Review.

Microorganisms 2021 May 23;9(6). Epub 2021 May 23.

Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, Taoyuan City 33305, Taiwan.

() infection involves the development of gastric cancer and may be associated with laryngeal cancer. However, laryngeal infection in Taiwanese patients with newly diagnosed laryngeal cancer has not been reported. This study was aimed to investigate the possible association between laryngeal infection and laryngeal cancer in Taiwan and perform a systematic review of previous reports in other countries. An analysis of 105 patients with laryngeal lesions found the positive rates of DNA (determined by polymerase chain reaction) and antigen (determined by immunohistochemistry) of the laryngeal lesions were relatively low (vocal polyps: 3% and 3%; vocal fold leukoplakia: 0% and 0%; laryngeal cancers: 0% and 2%). Furthermore, -associated laryngopharyngeal reflux and the expression of and (determined by immunohistochemistry) were comparable among the three subgroups. Fifteen studies were involved in the systematic review of the digital literature database, distributed to February 2021. The data of patients with laryngeal cancer and controls showed that the laryngeal infection rates were 29.4% and 16.7%, respectively. Although current evidence supported that laryngeal infection was associated with laryngeal cancer globally, it might not play a role in the development of laryngeal cancer in Taiwan.
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http://dx.doi.org/10.3390/microorganisms9061129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224578PMC
May 2021

Effects of Epstein-Barr Virus Infection on the Risk and Prognosis of Primary Laryngeal Squamous Cell Carcinoma: A Hospital-Based Case-Control Study in Taiwan.

Cancers (Basel) 2021 Apr 6;13(7). Epub 2021 Apr 6.

Faculty of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan.

Mounting molecular evidence supports Epstein-Barr virus (EBV) involvement in the pathogenesis of laryngeal squamous cell carcinoma (LSCC); however, the epidemiological data are inconsistent. In this retrospective case-control study, we aimed to determine whether EBV infection underlies the risk and prognosis of LSCC. The prevalence of EBV infection, as analyzed using an EBV DNA polymerase chain reaction assay, was significantly higher in 42 Taiwanese patients with newly diagnosed primary LSCC, compared to 39 age- and sex-matched control patients without cancer (48% vs. 19%). Furthermore, most of the signals detected using in situ hybridization were localized to the nuclei of tumor-infiltrating lymphocytes. In multivariate analysis, EBV DNA positivity, age ≥ 55 years, cigarette smoking, and high , , and expression (assessed using immunohistochemistry) were identified as independent risk factors for LSCC. Furthermore, five-year local recurrence and disease-free survival rates were 34% and 58%, respectively, with a high signal and low expression independently predicting five-year local recurrence and disease-free survival. Our comprehensive profiling data accurately identified patients at risk for LSCC development, local recurrence, or disease-free survival. The information obtained in this study improves our understanding of EBV infection in LSCC, and may guide precision medicine for patients with LSCC.
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http://dx.doi.org/10.3390/cancers13071741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038767PMC
April 2021

Role of Pneumococcal NanC in the Severe Disease of Superinfection with Influenza.

Immunohorizons 2021 Apr 28;5(4):210-218. Epub 2021 Apr 28.

Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Guishan, Taoyuan City, Taiwan;

Bacterial superinfection aggravates the disease of influenza. is the most common bacterial pathogen. Synergistic virulence has been demonstrated between influenza neuraminidase and pneumococcal NanA and NanB. NanC, the other pneumococcal neuraminidase infrequently present in clinical isolates, is not well characterized. In this study, we report that superinfection with a NanC-negative pneumococcus strain suppresses anti-influenza immunity and impairs viral clearance with higher TGF-β activation in mice. Bacterial load in the lungs also increases as the host immunity is suppressed. -positive isogenic mutant reverses wild type -mediated immune suppression and facilitates virus clearance. However, it causes more severe disease as the augmented inflammation causes collateral damage. Both virus-mediated damage and immune response-mediated inflammation are important for pathogenesis of severe influenza. Inflammation may be more critical than virus-mediated damage in influenza with bacterial superinfection.
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http://dx.doi.org/10.4049/immunohorizons.2100020DOI Listing
April 2021

Impact of Pancreatic Resection on Survival in Locally Advanced Resectable Gastric Cancer.

Cancers (Basel) 2021 Mar 14;13(6). Epub 2021 Mar 14.

Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan.

Whether gastric adenocarcinoma (GC) patients with adjacent organ invasion (T4b) benefit from aggressive surgery involving pancreatic resection (PR) remains unclear. This study aimed to clarify the impact of PR on survival in patients with locally advanced resectable GC. Between 1995 and 2017, patients with locally advanced GC undergoing radical-intent gastrectomy with and without PR were enrolled and stratified into four groups: group 1 (G1), pT4b without pancreatic resection (PR); group 2 (G2), pT4b with PR; group 3 (G3), positive duodenal margins without Whipple's operation; and group 4 (G4), cT4b with Whipple's operation. Demographics, clinicopathological features, and outcomes were compared between G1 and G2 and G3 and G4. G2 patients were more likely to have perineural invasion than G1 patients (80.6% vs. 50%, < 0.001). G4 patients had higher lymph node yield (40.8 vs. 31.3, = 0.002), lower nodal status ( = 0.029), lower lymph node ratios (0.20 vs. 0.48, < 0.0001) and higher complication rates (45.2% vs. 26.3%, = 0.047) than G3 patients. The 5-year disease-free survival (DFS) and overall survival (OS) rates were significantly longer in G1 than in G2 (28.1% vs. 9.3%, = 0.003; 32% vs. 13%, = 0.004, respectively). The 5-year survival rates did not differ between G4 and G3 (DFS: 14% vs. 14.4%, = 0.384; OS: 12.6% vs. 16.4%, = 0.321, respectively). In conclusion, patients with T4b lesion who underwent PR had poorer survival than those who underwent resection of other adjacent organs. Further Whipple's operation did not improve survival in pT3-pT4 GC with positive duodenal margins.
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http://dx.doi.org/10.3390/cancers13061289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001184PMC
March 2021

The clinicopathological significance of SWI/SNF alterations in gastric cancer is associated with the molecular subtypes.

PLoS One 2021 22;16(1):e0245356. Epub 2021 Jan 22.

Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan.

The clinicopathological significance of altered SWI/SNF complex has not been well evaluated in gastric cancer (GC). We examined SMARCA2, SMARCA4, SMARCB1 and ARID1A expression by immunohistochemistry in 1224 surgically resected GCs with subtyping into Epstein-Barr virus (EBV), microsatellite instability (MSI) and non-EBV/MSI Lauren histotypes. SWI/SNF mutations were investigated using the GC dataset of the TCGA Pan-Cancer Atlas. Clinicopathological association was assessed by statistical analysis. There were 427 cases (35%) of SWI/SNF-attenuated GC, including 344 SMARCA2 (28%), 28 SMARCA4 (2%), 11 SMARCB1 (1%) and 197 ARID1A (16%) cases. Simultaneous alterations of multiple subunits were observed. Compared to SWI/SNF-retained cases, SWI/SNF-attenuated GC exhibited a significant predilection to older ages, EBV and MSI genotypes, higher lymphatic invasion and less hematogenous recurrence (P < 0.05). SWI/SNF attenuation was an independent risk factor for short overall survival (P = 0.001, hazard ratio 1.360, 95% confidence interval 1.138-1.625). The survival impact stemmed from SMARCA2-attenuated GCs in stage III and non-EBV/MSI diffuse/mixed subtypes (P = 0.019 and < 0.001, respectively). ARID1A-lost/heterogeneous GCs were more aggressive in the EBV genotype (P = 0.016). SMARCB1 or SMARCA4 loss was not restricted to rhabdoid/undifferentiated carcinoma. In the TCGA dataset, 223 of 434 GCs (52%) harbored deleterious SWI/SNF mutations, including ARID1A (27%), SMARCA2 (9%), ARID2 (9%), ARID1B (8%), PBRM1 (7%), and SMARCA4 (7%). SWI/SNF-mutated GCs displayed a favorable outcome owing to the high percentage with the MSI genotype. In conclusion, SWI/SNF-altered GCs are common and the clinicopathological significance is related to the genotype.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245356PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822341PMC
June 2021

Uterine Malakoplakia Identified by Diagnostic Hysteroscopy.

J Minim Invasive Gynecol 2021 May 22;28(5):924-926. Epub 2020 Nov 22.

Departments of Obstetrics and Gynecology (Drs. Wu, Wang, Weng, and Chao), Chang Gung Memorial Hospital Linkou Medical Center; Gynecologic Cancer Research Center, Chang Gung University College of Medicine (Dr. Chao), Taoyuan, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.jmig.2020.11.009DOI Listing
May 2021

Influence of sodium-modified Ni/SiO catalysts on the tunable selectivity of CO hydrogenation: Effect of the CH selectivity, reaction pathway and mechanism on the catalytic reaction.

J Colloid Interface Sci 2021 Mar 29;586:514-527. Epub 2020 Oct 29.

Center for General Education, Chang Gung University, 259, Wen-Hua 1st Rd., Guishan Dist., Taoyuan City 33302, Taiwan, Republic of China; Department of Pathology, Chang Gung Memorial Hospital Linkou, 5, Fusing St, Guishan Dist, Taoyuan City 33302, Taiwan, Republic of China. Electronic address:

CO hydrogenation over Ni/SiO catalysts with and without Na additives was investigated in terms of the catalytic activity, selectivity of CO methanation and reaction mechanism. Na additives could cause the formation of NaO species that might deposit on the Ni surface of Ni/SiO (NiNa/SiO). When the Ni metal is partially covered with NaO species, a highly positive charge on the Ni metal could occur compared to the original Ni/SiO catalyst. The addition of Na to the Ni/SiO catalyst could influence selectivity toward CO formation. The adsorbed formic acid is the major intermediate on the Ni/SiO catalyst during CO hydrogenation. The formic acid species might decompose into adsorbed CO complexes in the forms of linear CO, bridged CO and multibonded CO. CH formation should be ascribed to the hydrogenation of these adsorbed CO complexes. The Ni/SiO catalyst with the Na additive might have very weak ability for H and CO adsorption, thus making it difficult for CO methanation to occur. The hydrogen carbonate species adsorbed on the NiNa/SiO catalysts were proposed to be the key intermediate, and they might decompose to CO or be hydrogenated to form CH.
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http://dx.doi.org/10.1016/j.jcis.2020.10.117DOI Listing
March 2021

Successful Localization and Resection of Small Pancreatic Cystic Insulinoma Using Intraoperative Near-Infrared Fluorescence Imaging: A Case Report and Literature Review.

Pancreas 2020 Nov/Dec;49(10):1388-1392

From the Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University, Linkou Medical Center, Guishan, Taoyuan.

Pancreatic cystic insulinoma is an uncommon tumor. Perioperative localization remained challenging if the tumor is atypical with cystic feature or in small size. Near-infrared (NIR) imaging is a technique by injecting fluorescent dye intravenously, which accumulates to the target lesion and creating signal by laser sources. The signal helps surgeons to identify the lesion during operation, but little experience has been reported regarding the use of imaging NIR technique for localizing cystic insulinoma. We present a 29-year-old female patient with a symptomatic pancreatic cystic insulinoma (1.2 cm) as assessed by clinical symptom, laboratory evidence, and magnetic resonance cholangiopancreatography. With an aid of NIR imaging technique, this cystic tumor was localized easily at operation. Also, the fluorescence imaging visualized the tumor part, guided us to identify the safe margin, and preserved the normal pancreatic structure. Pathologic report confirmed that the tumor was a well-differentiated cystic insulinoma. This case demonstrates that pancreatic cystic insulinoma in small size can be intraoperatively localized by NIR imaging, a relatively safe and easy technique.
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http://dx.doi.org/10.1097/MPA.0000000000001678DOI Listing
October 2020

Different surgical outcome and follow-up status between dMMR and pMMR colorectal cancer patients who fulfilled with Amsterdam-II criteria.

World J Surg Oncol 2020 Aug 7;18(1):195. Epub 2020 Aug 7.

Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan.

Background: Although hereditary non-polyposis colorectal cancer (HNPCC) could be subtyped into proficient or deficient mismatch repair gene expression (pMMR or dMMR), distinct clinical features between these two subgroups patients were rarely reported.

Methods: We retrospectively analyzed 175 hereditary non-polyposis colorectal cancer (HNPCC) patients between January 1995 and December 2012. Cox proportional hazards model was used to compare the differences between two subgroups.

Results: Significant differences of disease free survival (DFS) and overall survival (OS) exist between dMMR and pMMR. In addition to other factors including younger mean age of diagnosis for dMMR patients (48.6 years vs. 54.3 years), operation type (more extended colectomy for dMMR 35.8% vs. 14.5%), tumor location (right colon predominance for dMMR 61.7% vs. 27.3% and more rectum cases for pMMR 41.8% vs. 11.7%), tumor differentiation (more poor differentiation for dMMR 23.3% vs. 9.0%), N staging (more N0 cases for dMMR 70.8% vs. 50.9%), more frequently presence of extra-colonic tumors for dMMR (16.7% vs.1.8%), and lower recurrence rates (9.1% vs.35.3%). Significantly different cumulative incidences of developing metachronous colorectal cancer were observed with 6.18 for pMMR patients and 20.57 person-years for dMMR patients (p < 0.001).

Conclusions: Distinct clinicopathological features significantly exist between dMMR and pMMR subtypes patient, MMR status should be consider to tailor operation types and follow up surveillance between these two subgroups patients who all fulfilled with Amsterdam-II criteria.
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http://dx.doi.org/10.1186/s12957-020-01976-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414700PMC
August 2020

Cytomegalovirus esophagitis with symptoms of gastroesophageal reflux disease in a kidney transplant recipient.

Kaohsiung J Med Sci 2020 Oct 15;36(10):859-860. Epub 2020 Jul 15.

Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.

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http://dx.doi.org/10.1002/kjm2.12264DOI Listing
October 2020

The clinicopathological and molecular analysis of gastric cancer with altered SMARCA4 expression.

Histopathology 2020 Aug 2;77(2):250-261. Epub 2020 Jul 2.

Department of Anatomic Pathology, College of Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.

Aims: In this study, we examine the clinicopathological and molecular features of gastric cancer (GC) with SMARCA4 alterations.

Methods And Results: We screened SMARCA4 alterations using immunohistochemistry on 1199 surgically resected GCs with information on Epstein-Barr virus (EBV), microsatellite instability (MSI) and other SWI/SNF subunits. SMARCA4, SMARCA2 and ARID1A mutations were investigated by targeted sequencing. The clinicopathological significance was determined by statistical analysis. Twenty-seven cases (2%) with altered SMARCA4 expression were identified, exhibiting completely lost (six), reduced (nine) or heterogeneous (12) patterns. Frequent concomitant alterations of other SWI/SNF subunits were noted with an unusual discordant spatial heterogeneity. In comparison with SMARCA4-retained GCs, SMARCA4-lost GCs were observed more frequently in the non-EBV/MSI subgroup (five of six) and reduced or heterogeneous SMARCA4 expression mainly occurred in EBV- or MSI-associated cases (six of nine and six of 12, respectively; P < 0.001). Histologically, SMARCA4-altered GC, irrespective of expression pattern, demonstrated divergent histomorphology, spanning tubular, poorly cohesive or mixed, neuroendocrine to solid and undifferentiated carcinoma, with a predilection to the latter two (P < 0.001). De-differentiation-like transition and rhabdoid features were noted in a minority of cases. For overall survival, altered SMARCA4 expression was an unfavourable prognostic factor in stage III, EBV-associated GC and non-EBV/MSI intestinal subtype (P ≤ 0.001). SMARCA4 or ARID1A mutations were detected mainly in SMARCA4-lost or reduced GC, respectively.

Conclusions: SMARCA4-altered GCs are rare and have intratumoral heterogeneity, histomorphological diversity, conditional prognostic significance and various genetic drivers. SMARCA4-lost GC may represent a genuine SMARCA4-deficient neoplasm, but most SMARCA4-reduced/heterogeneous cases are secondary to ARID1A collapse or associated with different genotypes.
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http://dx.doi.org/10.1111/his.14117DOI Listing
August 2020

Is Adjuvant Chemotherapy Necessary for Patients with Deficient Mismatch Repair Gastric Cancer?-Autophagy Inhibition Matches the Mismatched.

Oncologist 2020 07 14;25(7):e1021-e1030. Epub 2020 Feb 14.

Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Purpose: The use of microsatellite instability (MSI) and mismatch repair (MMR) as predictive biomarkers for fluorouracil-based adjuvant chemotherapy in colorectal cancer has been a paradigm shift. However, whether this applies to gastric cancer is questionable. Furthermore, we herein investigated whether and how autophagy plays a role in MSI-relevant chemoresistance.

Materials And Methods: A total of 929 patients with deficient MMR (dMMR) and proficient MMR (pMMR) gastric cancers who underwent curative-intent gastrectomy were enrolled. We compared clinicopathological variables and survival among dMMR and pMMR cohorts and tested the responses of MSI-high and microsatellite stable (MSS) gastric cancer cell lines to 5-fluorouracil (5-FU) with or without chloroquine, an autophagy inhibitor.

Results: We identified an 8.9% prevalence of dMMR cases (83 out of 929) in our cohort. This was associated with old age, tumor site at the distal stomach, an intestinal phenotype, fewer nodal metastasis, and early pathological stages. MMR was an independent prognostic factor after multivariate adjustment. Overall survival (OS) of dMMR patients was better than that of the pMMR patients but was only applicable to stage III patients. There was no difference in OS between dMMR patients treated with or without adjuvant chemotherapy, although the latter showed more medical morbidities. The MSI-high gastric cancer cell lines, versus the MSS counterparts, displayed increased resistance to 5-FU and increased autophagy. Interestingly, autophagy inhibition abrogated the chemoresistance.

Conclusion: Our data show that fluorouracil-based adjuvant chemotherapy does not work for dMMR cases, if not worse. Autophagy inhibition and/or immune checkpoint inhibition might be promising alternative strategies for gastric cancer treatment.

Implications For Practice: The use of microsatellite instability (MSI) and mismatch repair (MMR) as predictive biomarkers for adjuvant chemotherapy in colorectal cancer has caused a paradigm shift in cancer therapy, although its implications in gastric cancer are still questionable. The data obtained in the current study indicate that MSI-MMR is an independent prognostic factor for gastric cancer. Standard fluorouracil-based adjuvant chemotherapy did not work for deficient MMR cases, and was likely worse. Instead, strategies like autophagy inhibition and/or immune checkpoint inhibition should be taken into consideration in the future.
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http://dx.doi.org/10.1634/theoncologist.2019-0419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356708PMC
July 2020

Functional Genomics Identifies Hepatitis-Induced STAT3-TYRO3-STAT3 Signaling as a Potential Therapeutic Target of Hepatoma.

Clin Cancer Res 2020 03 12;26(5):1185-1197. Epub 2019 Dec 12.

Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Purpose: Hepatitis promotes the development and recurrence of hepatocellular carcinoma (HCC). Receptor tyrosine kinases (RTK) play critical roles in the development of many cancers. We explored the potential roles of RTKs in hepatitis-related liver cancers.

Experimental Design: We conducted loss-of-function screening to elucidate the roles of RTKs in the development of HCC and .

Results: Many RTKs were coexpressed in HCC and were involved in tumor development and growth. Of these, TYRO3 promoted tumor growth and was clinically associated with hepatitis activity and poor prognosis. In mice, chemical-induced hepatitis transcriptionally activated Tyro3 expression via IL-6/IL6R-STAT3 signaling. Moreover, hepatitis-associated apoptotic cells facilitated the presentation of GAS6, a TYRO3 ligand, to further activate TYRO3-mediated signaling. Furthermore, TYRO3 activation elicited intracellular SRC- and STAT3 signaling. In mice, hepatitis and Tyro3 synergistically promoted HCC development. Silencing TYRO3 expression or inhibiting its kinase activity suppressed xenograft HCC growth in nude mice.

Conclusions: Many RTKs are simultaneously involved in HCC development. Hepatitis exerts dual effects on the activation of TYRO3-mediated signaling in HCC cells, which further elicits the "TYRO3-STAT3-TYRO3" signaling loop to facilitate tumor growth. Our findings unveil a previously unrecognized link between RTKs and hepatitis-associated HCC and suggest TYRO3 as a marker and therapeutic target for the HCCs with higher hepatitis activity.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3531DOI Listing
March 2020

Effect of aloin on viral neuraminidase and hemagglutinin-specific T cell immunity in acute influenza.

Phytomedicine 2019 Nov 4;64:152904. Epub 2019 Apr 4.

Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, Guishan- 33333, Taoyuan City, Taiwan. Electronic address:

Background: Millions of people are infected by the influenza virus worldwide every year. Current selections of anti-influenza agents are limited and their effectiveness and drug resistance are still of concern.

Purpose: Investigation on in vitro and in vivo effect of aloin from Aloe vera leaves against influenza virus infection.

Methods: In vitro antiviral property of aloin was measured by plaque reduction assay in which MDCK cells were infected with oseltamivir-sensitive A(H1N1)pdm09, oseltamivir-resistant A(H1N1)pdm09, H1N1 or H3N2 influenza A or with influenza B viruses in the presence of aloin. In vivo activity was tested in H1N1 influenza virus infected mice. Aloin-mediated inhibition of influenza neuraminidase activity was tested by MUNANA assay. Aloin treatment-mediated modulation of anti-influenza immunity was tested by the study of hemagglutinin-specific T cells in vivo.

Results: Aloin significantly reduced in vitro infection by all the tested strains of influenza viruses, including oseltamivir-resistant A(H1N1)pdm09 influenza viruses, with an average IC value 91.83 ± 18.97 μM. In H1N1 influenza virus infected mice, aloin treatment (intraperitoneal, once daily for 5 days) reduced virus load in the lungs and attenuated body weight loss and mortality. Adjuvant aloin treatment also improved the outcome with delayed oseltamivir treatment. Aloin inhibited viral neuraminidase and impeded neuraminidase-mediated TGF-β activation. Viral neuraminidase mediated immune suppression with TGF-β was constrained and influenza hemagglutinin-specific T cell immunity was increased. There was more infiltration of hemagglutinin-specific CD4+ and CD8+ T cells in the lungs and their production of effector cytokines IFN-γ and TNF-α was boosted.

Conclusion: Aloin from Aloe vera leaves is a potent anti-influenza compound that inhibits viral neuraminidase activity, even of the oseltamivir-resistant influenza virus. With suppression of this virus machinery, aloin boosts host immunity with augmented hemagglutinin-specific T cell response to the infection. In addition, in the context of compromised benefit with delayed oseltamivir treatment, adjuvant aloin treatment ameliorates the disease and improves survival. Taken together, aloin has the potential to be further evaluated for clinical applications in human influenza.
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http://dx.doi.org/10.1016/j.phymed.2019.152904DOI Listing
November 2019

Subtraction of Epstein-Barr virus and microsatellite instability genotypes from the Lauren histotypes: Combined molecular and histologic subtyping with clinicopathological and prognostic significance validated in a cohort of 1,248 cases.

Int J Cancer 2019 12 1;145(12):3218-3230. Epub 2019 Mar 1.

Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan.

Limited studies investigated clinicopathological and prognostic significance of histologic and molecular subgroups of gastric cancer concurrently. We retrospectively enrolled 1,248 patients with gastric cancer who received radical gastrectomy with lymphadenectomy and classified these cases into the Epstein-Barr virus (EBV)-associated and microsatellite instability (MSI)-associated subtypes by EBV-encoded small RNA in situ hybridization and immunohistochemical stains for DNA mismatch repair proteins, respectively. The remaining cases were categorized as the Lauren intestinal and diffuse/mixed subtypes. The clinicopathological and prognostic significance of the subtypes was examined by statistical analysis. In total, 65 (5.2%), 116 (9.3%), 496 (39.7%), 431 (34.5%) and 140 (11.2%) cases were identified as EBV-associated, MSI-associated, intestinal, diffuse and mixed subtypes, respectively. The EBV-associated, MSI-associated, intestinal and diffuse/mixed subtypes exhibited distinctive clinicopathological characteristics, including differences in age, gender, stump cancer, gastric location, tumor size, TNM stage, margin involvement, lymphatic/perineural invasion, HER2 status and recurrence pattern. The log-rank test showed survival discrimination (p < 0.001), and the multivariate analysis identified EBV-associated and MSI-associated cases demonstrated better outcomes than the diffuse/mixed subtype (EBV, HR 0.464, 95% CI 0.296-0.727, p = 0.001; MSI, HR 0.590, 95% CI 0.407-0.856, p = 0.005). EBV-associated lymphoepithelioma-like carcinoma cases had the most favorable outcome (HR 0.138, 95% CI 0.033-0.565, p = 0.006). In different clinical groups, the subtypes exhibited survival discrepancies. The EBV-associated and diffuse/mixed cases exhibited more favorable response to chemotherapy. In conclusion, this combined classification, in parallel with the molecular subtypes specified in the Cancer Genome Atlas study, has implications for the clinical management of gastric cancer.
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http://dx.doi.org/10.1002/ijc.32215DOI Listing
December 2019

Preoperative tyrosine kinase inhibitors risks bowel anastomotic healing in patients with advanced primary and recurrent/metastatic gastrointestinal stromal tumors--- A rose has its thorns.

Eur J Surg Oncol 2019 02 17;45(2):153-159. Epub 2018 Oct 17.

Department of Surgery, Chang Gung Memorial Hospital at LinKou, Chang Gung University Medical College, Taoyuan, Taiwan. Electronic address:

Background: The combination of tyrosine kinase inhibitors (TKIs) and surgery has created a paradigm shift for advanced primary and metastatic gastrointestinal stromal tumors (GISTs). However, the associated surgical morbidity rate is reportedly high, which we hypothesized is attributable to the adverse effects of the previous use of TKIs on bowel anastomosis healing.

Methods: A total of 613 GIST patients with (n = 108) and without (n = 505) preoperative TKI treatment were enrolled. Propensity score matching compared the surgical morbidities and mortalities between the two cohorts. An animal model was used to elucidate the relevant mechanism.

Results: After propensity score matching, the incidence and severity of surgical complications were higher in patients with preoperative TKIs than in those without (34% vs 10%, p < 0.0001; grades 3-5, 16% vs 2%, p < 0.0001). Specifically, the incidence of bowel anastomosis leakage was increased in those with versus those without preoperative TKI (18% vs 6%, p = 0.032). A constellation of mucosal shedding, shortening of villus height and crypt depth, and disarrayed epithelial lining of the bowel was observed with preoperative TKI treatment. The animal model showed that bowel anastomosis healing was weakened by imatinib through the downregulation of Col1A1, Col3A1, and MMPs.

Conclusions: Impaired bowel anastomosis healing was responsible for the extraordinarily high surgical morbidity rate of patients with GIST after TKI treatment. The mechanism involved altered tissue microarchitecture and dysregulated Col1A1, Col3A1, and MMP expressions.
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http://dx.doi.org/10.1016/j.ejso.2018.09.029DOI Listing
February 2019

The Adhesion G Protein-Coupled Receptor GPR97/ Is Expressed in Human Granulocytes and Triggers Antimicrobial Effector Functions.

Front Immunol 2018 3;9:2830. Epub 2018 Dec 3.

Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

The adhesion family of G protein-coupled receptors (aGPCRs) comprises 33 members in human, several of which are distinctly expressed and functionally involved in polymorphonuclear cells (PMNs). As former work indicated the possible presence of the aGPCR GPR97 in granulocytes, we studied its cellular distribution, molecular structure, signal transduction, and biological function in PMNs. RNA sequencing and mass-spectrometry revealed abundant RNA and protein expression of ADGRG3/GPR97 in granulocyte precursors and terminally differentiated neutrophilic, eosinophilic, and basophilic granulocytes. Using a newly generated GPR97-specific monoclonal antibody, we confirmed that endogenous GPR97 is a proteolytically processed, dichotomous, N-glycosylated receptor. GPR97 was detected in tissue-infiltrating PMNs and upregulated during systemic inflammation. Antibody ligation of GPR97 increased neutrophil reactive oxygen species production and proteolytic enzyme activity, which is accompanied by an increase in mitogen-activated protein kinases and IκBα phosphorylation. In-depth analysis of the GPR97 signaling cascade revealed a possible switch from basal Gαs/cAMP-mediated signal transduction to a Gαi-induced reduction in cAMP levels upon mutation-induced activation of the receptor, in combination with an increase in downstream effectors of Gβγ, such as SRE and NF-κB. Finally, ligation of GPR97 increased the bacteria uptake and killing activity of neutrophils. We conclude that the specific presence of GPR97 regulates antimicrobial activity in human granulocytes.
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http://dx.doi.org/10.3389/fimmu.2018.02830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287011PMC
October 2019

Induction of liver-specific intrahepatic myeloid cells aggregation expands CD8 T cell and inhibits growth of murine hepatoma.

Oncoimmunology 2018;7(12):e1502129. Epub 2018 Sep 19.

School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

Toll-Like Receptor 9 (TLR9) stimulation selectively triggers the formation of a cell cluster termed intrahepatic myeloid aggregation for T cell expansion" (iMATE) in a mouse chronic viral hepatitis model. iMATE expands cytotoxic T cells and controls viral hepatitis infection. The liver-specific immune response prompted this investigation of whether the effect could control tumor growth in the murine hepatic tumor model. Murine hepatic BNL cells were used to establish an orthotropic liver tumor model. We found that intravenous infusion of TLR 9 agonist, CpG oligodeoxynucleotide (ODN) induced iMATE formation in non-tumor parts of liver and suppressed the murine BNL tumor growth. The ratio of intra-tumor CD8 T cells have increased after CpG ODN. These cells expressed higher levels of effector and checkpoint molecules, and produce more Th1 cytokine upon ex vivo stimulation. The CD11bLy6CLy6G subset of CD11b myeloid cells in the tumor microenvironment has increased. Both CD11bLy6CLy6G and CD11bLy6CLy6G subsets expressed higher level of interferon-gamma post CpG ODN treatment, although still presented a suppressive phenotype. Their suppressive ability was decreased, instead, the targeted CD8 T cell proliferation was promoted at a higher dose of CD11bLy6CLy6G cells. The phenomenon was further proven in DEN induced liver tumor model. In conclusion, systemic CpG ODN treatment induced iMATE formation that expanded effector CD8 T cells to control tumor growth in the mouse hepatic tumor model. This novel strategy provides a new rationale for liver-specific tumor immunotherapy.
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http://dx.doi.org/10.1080/2162402X.2018.1502129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279338PMC
September 2018

Targeting PKCδ as a Therapeutic Strategy against Heterogeneous Mechanisms of EGFR Inhibitor Resistance in EGFR-Mutant Lung Cancer.

Cancer Cell 2018 12;34(6):954-969.e4

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Multiple mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of nuclear protein kinase Cδ (PKCδ) as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation. Moreover, the level of nuclear PKCδ is associated with TKI response in patients. The combined inhibition of PKCδ and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations.
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http://dx.doi.org/10.1016/j.ccell.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886126PMC
December 2018

Low expression of pRB predicts disease relapse in early glottic cancer treated with transoral laser microsurgery.

Laryngoscope 2019 06 1;129(6):E220-E226. Epub 2018 Nov 1.

Department of Nuclear Medicine and Molecular Imaging Center, Linkou-Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.

Objectives/hypothesis: To elucidate the associations among the immunohistochemical expression of tumor markers, clinicopathological variables, and disease-free survival (DFS) in patients with early-stage glottic squamous cell carcinoma (SCC) who underwent transoral laser microsurgery (TLM) as the primary treatment.

Study Design: Retrospective chart review.

Methods: The records of consecutive patients with Tis-T2N0 glottic SCC who underwent TLM between August 1, 2012 and October 31, 2015 were reviewed. Expression of Bcl-2, pRB, p16 , p53, c-Myc, E-cadherin, and EGFR was examined using tissue microarrays containing tumor specimens through immunohistochemistry. Three-year DFS rates were calculated.

Results: A total of 65 consecutive patients were identified, of which 28 were excluded due to insufficient tissue (n = 22) and low biomarker quality (n = 6). Therefore, 37 patients with complete records were included. The included patients were significantly older and had a more advanced type of cordectomy than did the excluded patients (P = .015 and .009, respectively). According to the findings of univariate analysis, age, betel quid chewing, type of cordectomy, BCL-2 expression, and pRB expression significantly predicted 3-year DFS. According to the findings of multivariate analysis, age (adjusted hazard ratio: 0.94, 95% CI: 0.88-1.00), betel quid chewing (adjusted hazard ratio: 5.07, 95% CI: 1.32-19.44), and pRB expression (adjusted hazard ratio: 0.02, 95% CI: 0.00-0.28) were independent predictors of 3-year DFS.

Conclusions: Low pRB expression is a potential biomarker for predicting disease relapse after primary TLM for early-stage glottic SCC and may help to identify high-risk patients who can subsequently undergo intensive management.

Level Of Evidence: 4 Laryngoscope, 129:E220-E226, 2019.
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http://dx.doi.org/10.1002/lary.27612DOI Listing
June 2019

Au Nanoparticles Deposited on Magnetic Carbon Nanofibers as the Ultrahigh Sensitive Substrate for Surface-Enhanced Raman Scattering: Detections of Rhodamine 6G and Aromatic Amino Acids.

Langmuir 2018 11 13;34(47):14158-14168. Epub 2018 Nov 13.

Center for General Education , Chang Gung University , 259, Wen-Hua 1st Rd. , Guishan Dist., Taoyuan City 33302 , Taiwan , Republic of China.

Surface-enhanced Raman scattering (SERS) is a unique spectroscopy that can offer high-sensitive detection for many molecules. Herein, the Au particles deposited on carbon nanofiber-encapsulated magnetic Ni nanoparticles (NPs) ([email protected]@Au) have been successfully synthesized for SERS measurements. The [email protected]@Au substrates have the advantages of a high SERS sensitivity and good magnetic response. The [email protected] could be directly obtained from CO hydrogenation on a Ni catalyst, which has been characterized as having rich carboxylic acid groups, graphitic structures, and a high surface area. The [email protected] surface could effectively increase the density of hotspots during Au NP aggregation and influence the morphology of the Au nanostructures. The spherical shape, oval shape, and coral-like Au nanostructures were prepared on [email protected] with various Au concentrations. Brunauer-Emmett-Teller, zeta potential, high-resolution transmission electron microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy measurements were used to characterize the [email protected]@Au samples. The Au NPs deposited on the [email protected] presented a suitable oval shape, and an average size of ∼30-40 nm. The size allowed surprisingly ultrasensitive SERS detection of rhodamine 6G (R6G) with a resolution of approximately a single molecule under an excitation wavelength of 532 nm. Using 785 nm excitation, a low R6G concentration of ∼1 × 10 M was detected. Moreover, the [email protected]@Au substrates could be rapidly magnetically separated after adsorption. Phenylalanine and tyrosine amino acids, which are associated with the liver disease, were examined using SERS with the [email protected]@Au substrate. Ultralow concentrations of ∼1 × 10 M for phenylalanine and ∼1 × 10 M for tyrosine were clearly measured. The [email protected]@Au substrates exhibited applicability as excellent SERS detection platforms that combine high-sensitivity and rapid magnetic separation for various adsorption molecules.
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http://dx.doi.org/10.1021/acs.langmuir.8b02488DOI Listing
November 2018

CD44 Predicts Early Recurrence in Pancreatic Cancer Patients Undergoing Radical Surgery.

In Vivo 2018 Nov-Dec;32(6):1533-1540

Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan, R.O.C.

Background/aim: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of digestive cancer. Recurrence within one year after surgery is inevitable in most PDAC patients. Recently, cluster of differentiation 44 (CD44) has been shown to be associated with tumor initiation, metastasis and prognosis. This study aimed to explore the correlation of CD44 expression with clinicopathological factors and the role of CD44 in predicting early recurrence (ER) in PDAC patients after radical surgery.

Materials And Methods: PDAC patients who underwent radical resection between January 1999 and March 2015 were enrolled in this study. Tumor recurrence within 6 months after surgery was defined as ER. Immunohistochemical staining was performed with anti-CD44 antibodies. The association between clinicopathological parameters and CD44 expression was analyzed. Predictors for ER were also assessed with univariate and multivariate analyses.

Results: Overall, 155 patients were included in this study. Univariate analysis revealed CA19-9 levels (p=0.014), CD44 histoscores (H-scores; p=0.002), differentiation (p=0.010), nodal status (p=0.005), stage (p=0.003), vascular invasion (p=0.007), lymphatic invasion (p<0.001) and perineural invasion (p=0.042) as risk factors for ER. In multivariate analysis, high CA19-9 levels and CD44 H-scores and poor differentiation independently predicted ER.

Conclusion: High CA19-9 levels, CD44 H-scores and poor differentiation are independent predictors for ER in PDAC patients undergoing radical resection. Therefore, the determination of CD44 expression might help in identifying patients at a high risk of ER for more aggressive treatment after radical surgery.
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http://dx.doi.org/10.21873/invivo.11411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365743PMC
January 2019

The 8th edition American Joint Committee on gastric cancer pathological staging classification performs well in a population with high proportion of locally advanced disease.

Eur J Surg Oncol 2018 10 11;44(10):1634-1639. Epub 2018 Jun 11.

Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address:

Background: The 8th edition of AJCC gastric cancer pathological staging system (AJCC8) derived from the IGCA database needs an external validated in cohorts with higher proportion of advanced disease.

Patients And Methods: A total of 5386 gastric cancer patients treated at Chang Gung Memorial Hospital (CGMH) and Veteran General Hospital in Taipei (TVGH) were enrolled. Clinicopathological data of the IGCA series and the CGMH/TVGH cohort were compared. Cumulative survival curves of the CGMH/TVGH cohort as stratified by the AJCC7 and the AJCC8 were compared. Lymph node ratio (LNR) was analyzed in patients with N3b disease.

Results: Patients in the CGMH/TVGH cohort were older and had more advanced tumor stage (stage III, 49% versus 26%, p < 0.001) than those in the IGCA cohort. The median survival of stages IIIA, IIIB, and IIIC as defined by the AJCC 8 were 49, 27 and 15 months, respectively, with narrower 95% confidence intervals, in comparison with 62, 30 and 18 months, respectively, as defined by the AJCC7. The AJCC8 exhibited better homogeneity within stages and discriminatory ability between stages, compared to the AJCC7. Six hundred and four patients with N3b disease were stratified by LNR into three subgroups, and their median survival were 31, 17, and 11 months, respectively (p < 0.001). LNR further appeared as a powerful outcome predictor of N3b disease (HR, 3.1).

Conclusion: The AJCC8 performs well in patients with high proportion of advanced gastric cancer. We recommend that LNR is a supplementary prognostic indicator for N3b disease.
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http://dx.doi.org/10.1016/j.ejso.2018.05.036DOI Listing
October 2018

Synergistic antiproliferative effects of an mTOR inhibitor (rad001) plus gemcitabine on cholangiocarcinoma by decreasing choline kinase activity.

Dis Model Mech 2018 05 14;11(8). Epub 2018 May 14.

Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan 333, Taiwan

Although gemcitabine plus cisplatin is the gold standard chemotherapy regimen for advanced cholangiocarcinoma, the response rate has been disappointing. This study aims to investigate a novel therapeutic regimen [gemcitabine plus everolimus (rad001), an mTOR inhibitor] for cholangiocarcinoma. Gemcitabine, oxaliplatin, cetuximab and rad001 in various combinations were first evaluated using six cholangiocarcinoma cell lines. therapeutic efficacies of gemcitabine and rad001 alone and their combination were further evaluated using a xenograft mouse model and a chemically induced orthotopic cholangiocarcinoma rat model. In the study, gemcitabine plus rad001 exerted a synergistic therapeutic effect on the cholangiocarcinoma cells, irrespective of the mutation status. In the xenograft study, gemcitabine plus rad001 showed the best therapeutic effect on tumor volume change, and was associated with increased caspase-3 expression, decreased eIF4E expression, as well as overexpression of both death receptor- and mitochondrial apoptotic pathway-related genes. In a chemically induced cholangiocarcinoma-afflicted rat model, the gemcitabine plus rad001 treatment suppressed tumor glycolysis as measured by F-fludeoxyglucose micro-positron emission tomography. Also, increased intratumoral free choline, decreased glycerophosphocholine and nearly undetectable phosphocholine levels were demonstrated by proton nuclear magnetic resonance, supported by results of decreased choline kinase expression in western blotting. We concluded that gemcitabine plus rad001 has a synergistic antiproliferative effect on cholangiocarcinoma, irrespective of the mutation status. The antitumor effect is associated with activation of both death receptor and mitochondrial pathways, as well as the downregulation of choline kinase activity, resulting in a characteristic change in choline metabolism.
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http://dx.doi.org/10.1242/dmm.033050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124555PMC
May 2018

A pilot study on primary cultures of human respiratory tract epithelial cells to predict patients' responses to H7N9 infection.

Oncotarget 2018 Mar 20;9(18):14492-14508. Epub 2018 Feb 20.

Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan 33302, Taiwan, ROC.

Avian influenza A(H7N9) virus infections frequently lead to acute respiratory distress syndrome and death in humans. We aimed to investigate whether primary cultures of human respiratory tract epithelial cells are helpful to understand H7N9 virus pathogenesis and tissue tropism, and to evaluate how patient-related characteristics can affect the host's response to infection. Normal human bronchial epithelial cells (isolated from two different donors) and primary epithelial cells (harvested from 27 patients undergoing airway surgery) were experimentally infected with H7N9 and/or H1N1pdm for 72 h. After virus infection, the culture media were collected for viral RNA quantitation and cytokine detection. Both H7N9 and H1N1pdm viruses replicated and induced a cytokine response differently for each donor in the normal human bronchial epithelial model. H7N9 replicated equivalently in epithelial cells harvested from the inferior turbinate and paranasal sinus, and those from the larynx and bronchus, at 72 h post-infection. Viral RNA quantity at 72 h was significantly higher in patients aged 21-64 years than in patients aged ≥ 65 years; however, no effects of sex, medical comorbidities, and obesity were noted. H7N9-infected cultured cells released multiple cytokines within 72 h. Levels of interleukin-1β, interleukin-6, interleukin-8, interferon-γ, and tumor necrosis factor-α were associated differently with patient-related characteristics (such as age, sex, obesity, and medical comorbidities). In the era of precision medicine, these findings illustrate the potential utility of this primary culture approach to predict a host's response to H7N9 infection or to future infection by newly emerging viral infections, and to dissect viral pathogenesis.
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http://dx.doi.org/10.18632/oncotarget.24537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865685PMC
March 2018

Circulating microRNA-196a is an early gastric cancer biomarker.

Oncotarget 2018 Feb 7;9(12):10317-10323. Epub 2017 Dec 7.

Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.

MicroRNA-196a (miRNA-196a) is associated with the development of gastric cancer and metastasis. Intestinal metaplasia and low- or high-grade dysplasia are considered to be precursors of intestinal type gastric cancer. Accordingly, we investigated the expression of plasma miRNA-196a as an early detection biomarker in precancerous gastric lesions and early cancer (pT1a/b), which is otherwise treated with endoscopic submucosal dissection. Our data showed that levels of circulating (plasma) miRNA-196a were higher in patients with precancerous lesions/early gastric adenocarcinoma than in healthy controls. The area under the receiver operating characteristic curve (AUC) for healthy controls vs. intestinal metaplasia was 0.9736; healthy controls vs. low-grade/high-grade dysplasia 0.9495; and healthy controls vs. early gastric cancer 0.9318. These results indicate that circulating miRNA-196a is a novel biomarker for detection of early gastric cancer and its precursor.
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http://dx.doi.org/10.18632/oncotarget.23126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828184PMC
February 2018

Human papillomavirus infection is not associated with laryngeal squamous cell carcinoma in Taiwan.

J Microbiol Immunol Infect 2020 Feb 21;53(1):79-86. Epub 2018 Feb 21.

Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan; Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan; Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan. Electronic address:

Background/purpose: To examine whether the prevalence rate of human papillomavirus (HPV) infection in Taiwanese patients with primary laryngeal squamous cell carcinoma (LSCC) is different from that in those with a vocal polyp (VP) or vocal fold leukoplakia (VFL).

Methods: This prospective cohort study recruited 41 consecutive patients with primary LSCC and 27 and 20 patients with VP and VFL, respectively. The HPV L1 gene in surgical specimens was detected using polymerase chain reaction. High-risk HPV DNA in tissue microarray specimens was detected using in situ hybridization. Expression of p16 in tissue microarray specimens was determined through immunohistochemistry.

Results: The prevalence of HPV L1 DNA in the LSCC group was equivalent to that in the VP and VFL groups (7.3% vs. 7.4% vs. 10.0%; P = 0.929; effect size = 0.20). High-risk HPV DNA detected using in situ hybridization was relatively rare in all groups (2.6% vs. 5.3% vs. 0.0%; P = 0.636; effect size = 0.81). The prevalence of p16 positivity was significantly lower in the LSCC group than in the VP and VFL groups (5.1% vs. 58.8% vs. 14.3%; P < 0.001). Multivariate analysis results revealed that age ≥65 years (adjusted odds ratio, 4.09; 95% confidence interval, 1.21-13.91; P = 0.024) and p16 positivity (adjusted odds ratio, 0.10; 95% confidence interval, 0.02-0.53; P = 0.006) were LSCC risk factors.

Conclusion: HPV infection is uncommon in Taiwanese patients with LSCC and seems not to be associated with an increased LSCC risk. Larger sample size is warranted for further study.
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http://dx.doi.org/10.1016/j.jmii.2018.02.002DOI Listing
February 2020

Clinical manifestations and STK11 germline mutations in Taiwanese patients with Peutz-Jeghers syndrome.

Asian J Surg 2018 Sep 30;41(5):480-485. Epub 2017 Aug 30.

Chang Gung University, College of Medicine, Tao-Yuan, Taiwan; Department of Pathology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan. Electronic address:

Backgrounds: Clinical manifestations and molecular basis of Taiwanese patients with Peutz-Jeghers syndrome (PJS) were investigated to add the knowledge of phenotype and genotype of the disease.

Methods: Based on the Pathology Data Bank and the Colorectal Cancer Register, we collected their clinical data. The entire coding sequence of the STK11 gene was amplified and analyzed by sequencing using the genomic DNA.

Results: Fifteen patients diagnosed with PJS from 11 unrelated families were collected until 2015. The median age at the onset of symptoms was 19 years with intussusception as the most frequent presenting symptom. Ten patients developing 11 cancers at various anatomical sites, including two cases of sinonasal cancer, two lung cancers, two breast cancers, two rectal cancers, two gynecological cancers and one small bowel cancer. Five of the deceased patients had died of cancers. The median age of diagnosis of first cancer in the probands was 32 years. Seventy patients (7 of 10) diagnosed before age of 40. Mutations found in eight families included five novel mutations (exon 6, c.843 ins G; exon 8, c.2065 delete A; exon 8, c.G923A, nonsense; exon 6, c.748dupA; and mTOR c.5107dupA) and three previously reported mutations. The other three PJS families without detectable STK11 mutations did not develop malignancies so far.

Conclusion: This is the first comprehensive study of patients with Peutz-Jeghers syndrome in the Taiwanese. We have demonstrated that the phenotype of Peutz-Jeghers syndrome varies greatly among the patients. Patients with detectable STK11 mutations have very high risk of developing cancers.
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http://dx.doi.org/10.1016/j.asjsur.2017.08.002DOI Listing
September 2018

Composite hepatocellular carcinoma and small cell carcinoma with early nodal metastasis: A case report.

Medicine (Baltimore) 2017 Aug;96(34):e7868

Department of Pathology, Chang Gung Memorial Hospital, Guishan Department of Pathology, Chang Gung University School of Medicine, Taoyuan, Taiwan.

Rationale: Hepatocellular carcinoma (HCC) is known to grow in a mosaic pattern, and it can sometimes be combined with non-hepatocellular cells. Despites the variety of combination, HCC with a significant neuroendocrine carcinoma (NEC) component remains very rare. Most of the reported cases were treated as conventional HCC with a relatively poor prognosis. Early diagnosis may lead to a better treatment modality. Here, we report a case of composite HCC and small cell carcinoma (SCC) with nodal metastasis of the SCC component alone.

Patient Concerns: A 65-year-old man with chronic viral hepatitis C presented with abdominal discomfort for 2 months. Computed tomography and angiography of the liver showed a 4.3 cm hypervascular tumor in segment 4 and enlargement of the perihilar and paracaval lymph nodes.

Interventions: Extended left lobectomy and regional lymph node dissection were performed.

Diagnosis: The hepatic tumor was heterogeneous with two distinct gross components. The green part showed a grade III hepatocellular carcinoma with an immunoreaction to Hep Par 1, glypican 3 and α-fetoprotein, whereas the white part exhibited a small cell carcinoma, as evidenced by expressions of chromogranin A and synaptophysin. The lymph node was metastasized by the SCC component. The SCC part was also positive for vimentin with perivascular accentuation. ß-catenin immunostain showed reduced membranous expression in the SCC component, as compared to HCC.

Outcomes: The patient expired 39 days after the surgical intervention.

Lessons: Clinicians should be highly alert to a composite hepatic tumor, especially in dealing with a small heterogeneous tumor (< 5 cm) with early lymph node metastasis.
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http://dx.doi.org/10.1097/MD.0000000000007868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572022PMC
August 2017
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