Publications by authors named "Yan-Shen Shan"

151 Publications

Synchronization of Nanoparticle Sensitization and Radiosensitizing Chemotherapy through Cell Cycle Arrest Achieving Ultralow X-ray Dose Delivery to Pancreatic Tumors.

ACS Nano 2021 May 11. Epub 2021 May 11.

Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan.

Pancreatic cancer is among the leading causes of cancer-related death and remains a formidable therapeutic challenge. To date, surgical resection and chemotherapy have been the standards of care. Methotrexate (MTX), which is recognized as a refractory drug for pancreatic cells, was conjugated to the surface of LiYF:Ce nanoparticles (NP-MTX) through a photocleavable linker molecule. When LiYF:Ce NPs are stimulated by X-rays, they emit light, which induces the photocleavage of the photolabile linker molecule to release MTX. MTX can target pancreatic tumors, which overexpress folic acid (FA) receptors and are internalized into the cell through receptor-mediated endocytosis. The synergistic effect of the NP-MTX treatment initiated by X-ray irradiation occurs due to the combination of nanoparticle sensitization and the radiosensitizing chemotherapy of the photocleaved MTX molecule. This dual sensitization effect mediated by NP-MTX enabled 40% dose enhancement, which corresponded with an increase in the generation of cytotoxic cellular reactive oxygen species (ROS) and enhanced S phase arrest within the cell cycle. The delivery of an ultralow radiation dose of 0.1 Gy resulted in the photocleavage of MTX from NP-MTX, and this strategy demonstrated efficacy against AsPC-1 and PANC-1 xenografted pancreatic tumors.
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http://dx.doi.org/10.1021/acsnano.1c02283DOI Listing
May 2021

The Fibronectin Expression Determines the Distinct Progressions of Malignant Gliomas via Transforming Growth Factor-Beta Pathway.

Int J Mol Sci 2021 Apr 6;22(7). Epub 2021 Apr 6.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Due to the increasing incidence of malignant gliomas, particularly glioblastoma multiforme (GBM), a simple and reliable GBM diagnosis is needed to screen early the death-threaten patients. This study aimed to identify a protein that can be used to discriminate GBM from low-grade astrocytoma and elucidate further that it has a functional role during malignant glioma progressions. To identify proteins that display low or no expression in low-grade astrocytoma but elevated levels in GBM, glycoprotein fibronectin (FN) was particularly examined according to the mining of the Human Protein Atlas. Web-based open megadata minings revealed that FN was mainly mutated in the cBio Cancer Genomic Portal but dominantly overexpressed in the ONCOMINE (a cancer microarray database and integrated data-mining platform) in distinct tumor types. Furthermore, numerous different cancer patients with high FN indeed exhibited a poor prognosis in the PrognoScan mining, indicating that FN involves in tumor malignancy. To investigate further the significance of FN expression in glioma progression, tumor specimens from five malignant gliomas with recurrences that received at least two surgeries were enrolled and examined. The immunohistochemical staining showed that FN expression indeed determined the distinct progressions of malignant gliomas. Furthermore, the expression of vimentin (VIM), a mesenchymal protein that is strongly expressed in malignant cancers, was similar to the FN pattern. Moreover, the level of epithelial-mesenchymal transition (EMT) inducer transforming growth factor-beta (TGF-β) was almost recapitulated with the FN expression. Together, this study identifies a protein FN that can be used to diagnose GBM from low-grade astrocytoma; moreover, its expression functionally determines the malignant glioma progressions via TGF-β-induced EMT pathway.
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http://dx.doi.org/10.3390/ijms22073782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038731PMC
April 2021

An updated analysis of the epidemiologic trends of neuroendocrine tumors in Taiwan.

Sci Rep 2021 Apr 12;11(1):7881. Epub 2021 Apr 12.

National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.

The incidence of neuroendocrine tumors (NETs) has been increasing in recent decades. Previously, we reported the incidence and survival of NETs in Taiwan by analyzing the 1996-2008 data from the Taiwan Cancer Registry. Here we performed an updated analysis on the incidence and survival of NETs in Taiwan from 1996 to 2015. The incidence of NETs was 0.244 per 100,000 in 1996 and increased to 3.162 per 100,000 in 2015. The most common site of NETs was rectum (29.65%), followed by lung/bronchus (17.22%), and pancreas (10.71%). The 5- and 10-year overall survival rates of all NETs were 54.6% and 45.3%, respectively. Female and younger NETs patients had a better survival. The survival of all NETs diagnosed between 2010 and 2015 was better than those diagnosed between 2004 and 2009. Among the common sites of NETs, an improved survival of pancreatic NETs diagnosed between 2010 and 2015 compared to those diagnosed between 2004 and 2009 was observed. Overall, the incidence of NETs in Taiwan has continued to increase. The survival of pancreatic NET has shown a recent improvement. The development of novel therapeutic agents has the potential to improve the prognosis of NETs of other sites in the near future.
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http://dx.doi.org/10.1038/s41598-021-86839-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041887PMC
April 2021

Comparing the Clinicopathological Characteristics of Combined Hepatocellular-Cholangiocarcinoma with Other Primary Liver Cancers Using the Updated WHO Classification.

Histopathology 2021 Apr 10. Epub 2021 Apr 10.

Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an uncommon hepatic malignancy with a poor outcome. The 2019 WHO classification modified the definition and discarded the subtypes harboring stem cell features. However, the differences among cHCC-CCA, hepatocellular carcinoma (HCC), HCC with stem cell features (HCCscf) and intrahepatic cholangiocarcinoma (iCCA) remain undetermined. The aim of the study is to investigate the characteristics of cHCC-CCA in comparisons with other primary liver cancers utilizing the updated WHO classification.

Methods And Results: We retrospectively analyzed 64 cHCC-CCA and 55 HCCscf patients from Dec2007 to May2018. A propensity score matching was conducted to compare with HCC and iCCA patients. Clinicopathological characteristics, event-free (EFS) and overall survival (OS) were evaluated with multivariate Cox proportional hazard regression. In a median follow-up of 55.9 months, patients with cHCC-CCA had a significantly poor survival as compared with HCCscf and an intermediate survival outcome between HCC and iCCA. HBV infection and high tumor infiltrating lymphocytes (TILs) were associated with a favorable survival in cHCC-CCA. In the multivariate analysis, poor hepatic reserve, absence of HBV infection, stage IV disease and low TILs were significant negative prognostic factors in cHCC-CCA. After pooling with other primary liver cancers, tumor type of cHCC-CCA and iCCA predicted the worse survival results.

Conclusion: cHCC-CCA have an intermediate survival between HCC and iCCA and HBV infection and high TILs predict the favorable survival. Our study provides clinical correlations for the new 2019 WHO classification.
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http://dx.doi.org/10.1111/his.14384DOI Listing
April 2021

Correction to: A multi-mode Wnt- and stemness-regulatory module dictated by FOXM1 and ASPM isoform I in gastric cancer.

Gastric Cancer 2021 May;24(3):640-641

Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wuxing St., Xinyi Dist., Taipei City, 110301, Taiwan.

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http://dx.doi.org/10.1007/s10120-021-01185-6DOI Listing
May 2021

High expression of krüppel-like factor 10 or Smad4 predicts clinical benefit of adjuvant chemoradiotherapy in curatively resected pancreatic adenocarcinoma: From a randomized phase III trial.

Radiother Oncol 2021 May 3;158:146-154. Epub 2021 Mar 3.

Department of Radiation Oncology, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan; Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, and Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan. Electronic address:

Purpose: Our previous studies have demonstrated that Krüppel-like factor 10 (Klf10) modulated tumor radiation resistance and helps to predict clinical outcomes of pancreatic adenocarcinoma (PDAC). This study aimed to evaluate whether the expression levels of Klf10, Smad4 and Runx3 can help predict the benefits of adjuvant chemoradiotherapy (CRT) in resected PDAC.

Methods And Materials: Tissue specimens were collected from 111 patients with curatively resected PDAC who were enrolled into a randomized trial comparing adjuvant gemcitabine with or without CRT. Immunohistochemical expression of biomarkers was quantified by pathologists blinded to patient outcomes through a grading system based on the extent and intensity of staining. The predictive value of biomarkers was analyzed using SAS statistical software.

Results: In total, 56 and 55 patients received adjuvant gemcitabine alone and additional CRT, respectively. The expression levels of Klf10, Smad4 and postoperative CA19-9 were significantly correlated with overall survival (OS) (p = 0.013, 0.045, and 0.047, respectively). Multivariable analysis showed that the expression level of postoperative serum CA19-9 and tumor tissue Klf10 expression level were significant predictors for OS (p = 0.038, and 0.028, respectively). Patients with high Klf10 or Smad4 (n = 55), had a significantly better local recurrence-free survival (∞ vs 19.8 months; p = 0.026) and a longer OS (33.0 vs 23.0 months; p = 0.12) if they received additional adjuvant CRT than gemcitabine only. The results were similar after adjusted by postoperative level of CA19-9.

Conclusion: Patients with curatively resected PDAC and a high expression of either Klf10 or Smad4 have high chances of benefiting from adjuvant CRT. Combining Klf10 and Smad4 to predict the benefits of adjuvant CRT in resected PDAC deserves further validation.
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http://dx.doi.org/10.1016/j.radonc.2021.02.037DOI Listing
May 2021

A multi-mode Wnt- and stemness-regulatory module dictated by FOXM1 and ASPM isoform I in gastric cancer.

Gastric Cancer 2021 May 29;24(3):624-639. Epub 2021 Jan 29.

Laboratory of Advanced Molecular Therapeutics, Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wuxing St., Xinyi Dist., Taipei City, 110301, Taiwan.

Background: Gastric cancer (GC) is the third leading cause of cancer mortality globally and a molecularly heterogeneous disease. Identifying the driver pathways in GC progression is crucial to improving the clinical outcome. Recent studies identified ASPM (abnormal spindle-like microcephaly-associated) and FOXM1 (Forkhead box protein M1) as novel Wnt and cancer stem cell (CSC) regulators; their pathogenetic roles and potential crosstalks in GC remain unclarified.

Methods: The expression patterns of ASPM isoforms and FOXM1 were profiled in normal gastric epithelial and GC tissues. The functional roles of ASPM and FOXM1 in Wnt activity, cancer stemness and GC progression, and the underlying signaling processes were investigated.

Results: Approximately one third of GC cells upregulate the expression of ASPM isoform I (ASPMiI) in their cytoplasm; the tumors with a high ASPMiI positive score (≥ 10%) are associated with a poor prognosis of the patients. Mechanistically, the molecular interplay among FOXM1, ASPMiI and DVL3 was found to converge on β-catenin to control the Wnt activity and the stemness property of GC cells. This multi-mode Wnt-regulatory module serves to reinforce Wnt signals in CSCs by transcriptional regulation (FOXM1-ASPM), protein-protein interactions (ASPMiI-DVL3-β-catenin), and nuclear translocation (FOXM1-β-catenin).

Conclusions: This study illuminates a novel Wnt- and stemness-regulatory mechanism in GC cells and identifies a novel subset of FOXM1ASPMiI GC with potential to guide Wnt- and stemness-related diagnostics and therapies.
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http://dx.doi.org/10.1007/s10120-020-01154-5DOI Listing
May 2021

Development of Possible Next Line of Systemic Therapies for Gemcitabine-Resistant Biliary Tract Cancers: A Perspective from Clinical Trials.

Biomolecules 2021 01 13;11(1). Epub 2021 Jan 13.

Center for Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan.

Biliary tract cancer (BTC) compromises a heterogenous group of tumors with poor prognoses. Curative surgery remains the first choice for localized disease; however, most BTC patients have had unresectable or metastatic disease. The gold standard therapy for these patients is chemotherapy with gemcitabine and cisplatin. There are no consensus guidelines for standard treatment in a second-line setting, although the data of the ABC-06 trial showed a slight survival benefit from oxaliplatin and 5-fluorouracil combination chemotherapy. Recent progress in comprehensive genomic profiling for advanced BTC (ABTC) has helped to clarify tumorigenesis and facilitate the coming era of precision medicine. Generally, targeted agents fail to show significant clinical benefits in unselected populations. Only fibroblast growth factor receptor 2 () fusion and isocitrate dehydrogenase ()- and mutation-enriched populations have survival benefits from the corresponding inhibitors. Several interesting targeted agents for monotherapies or combination therapies with other compounds are currently ongoing or recruiting. Here, we review the published data from clinical trials of second-line therapies after the failure of gemcitabine-based chemotherapy in ABTC. The results were stratified by different genetic alternations, as well as by chemotherapy, targeted therapy and immunotherapy.
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http://dx.doi.org/10.3390/biom11010097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828560PMC
January 2021

Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer.

Int J Med Sci 2021 1;18(1):256-269. Epub 2021 Jan 1.

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.

Ampullary cancer is a rare periampullary cancer currently with no targeted therapeutic agent. It is important to develop a deeper understanding of the carcinogenesis of ampullary cancer. We attempted to explore the characteristics of ampullary cancer in our dataset and a public database, followed by a search for potential drugs. We used a bioinformatics pipeline to analyze complementary (c)DNA microarray data of ampullary cancer and surrounding normal duodenal tissues from five patients. A public database from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) was applied for external validation. Bioinformatics tools used included the Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID), MetaCore, Kyoto Encyclopedia of Genes and Genomes (KEGG), Hallmark, BioCarta, Reactome, and Connectivity Map (CMap). In total, 9097 genes were upregulated in the five ampullary cancer samples compared to normal duodenal tissues. From the MetaCore analysis, genes of peroxisome proliferator-activated receptor alpha () and retinoid X receptor ()-regulated lipid metabolism were overexpressed in ampullary cancer tissues. Further a GSEA of the KEGG, Hallmark, Reactome, and Gene Ontology databases revealed that and lipid metabolism-related genes were enriched in our specimens of ampullary cancer and in the NCBI GSE39409 database. Expressions of messenger (m)RNA and the PPAR-α protein were higher in clinical samples and cell lines of ampullary cancer. US Food and Drug Administration (FDA)-approved drugs, including alvespimycin, trichostatin A (a histone deacetylase inhibitor), and cytochalasin B, may have novel therapeutic effects in ampullary cancer patients as predicted by the CMap analysis. Trichostatin A was the most potent agent for ampullary cancer with a half maximal inhibitory concentration of < 0.3 μM. According to our results, upregulation of and lipid metabolism-related genes are potential pathways in the carcinogenesis and development of ampullary cancer. Results from the CMap analysis suggested potential drugs for patients with ampullary cancer.
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http://dx.doi.org/10.7150/ijms.48123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738964PMC
January 2021

Author Correction: The Impact of Liposomal Irinotecan on the Treatment of Advanced Pancreatic Adenocarcinoma: Real-World Experience in a Taiwanese Cohort.

Sci Rep 2020 Nov 13;10(1):20199. Epub 2020 Nov 13.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-77250-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666201PMC
November 2020

c-Myc promotes lymphatic metastasis of pancreatic neuroendocrine tumor through VEGFC upregulation.

Cancer Sci 2021 Jan 24;112(1):243-253. Epub 2020 Nov 24.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

Pancreatic neuroendocrine tumor (pNET) is a pancreatic neoplasm with neuroendocrine differentiation. pNET in early stage can be treated with surgical resection with long-term survival, whereas the prognosis of pNET with locoregional or distant metastasis is relatively poor. Lymphangiogenesis is essential for tumor metastasis via the lymphatic system and may overhead distant metastasis. c-Myc overexpression is involved in tumorigenesis. The role of c-Myc in lymphangiogenesis is unclear. In this study, we evaluated the mechanism and effect of c-Myc on lymphangiogenesis of pNET via interaction of lymphatic endothelial cells (LECs) and pNET cells. Lymph node metastasis was evaluated in pNET xenograft mice. Potential target agents to inhibit lymph node metastasis were evaluated in an animal model. We found that vascular endothelial growth factor C (VEGFC) expression and secretion was increased in pNET cell lines with c-Myc overexpression. c-Myc transcriptionally upregulates VEGFC expression and the secretion of pNET cells by directly binding to the E-box of the VEGFC promoter and enhances VEGF receptor 3 phosphorylation and the tube formation of LECs. c-Myc overexpression is associated with lymph node metastasis in pNET xenograft mice. Combinational treatment with an mTOR inhibitor and c-Myc inhibitor or VEGFC-neutralizing chimera protein reduced lymph node metastasis in the mice with c-Myc overexpression. The mTOR inhibitor acts on lymphangiogenesis by reducing VEGFC expression in pNET cells and inhibiting the tube formation of LECs. In conclusion, mTOR and c-Myc are important for lymphangiogenesis of pNET and are potential therapeutic targets for prevention and treatment of lymph node metastasis in pNET.
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http://dx.doi.org/10.1111/cas.14717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780026PMC
January 2021

Combination Delivery of Alpha-Tocopheryl Succinate and Curcumin Using a GSH-Sensitive Micelle (PAH-SS-PLGA) to Treat Pancreatic Cancer.

Pharmaceutics 2020 Aug 16;12(8). Epub 2020 Aug 16.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No.138, Sheng Li Road, Tainan 704, Taiwan.

Pancreatic cancer is one of the highest causes of mortality throughout the world; thus, it requires an effective treatment strategy. Some chemotherapeutic agents used in the clinics or under clinical trials are hydrophobic and have poor aqueous solubility; consequently, they also have minimal systemic bioavailability. Nanoparticle-based drug delivery tactics have the potential for overcoming these limitations and enhancing their therapeutic efficacy. Herein, a glutathione (GSH)-sensitive micelle (PAH-SS-PLGA) was synthesized for the combined delivery of alpha-tocopheryl succinate (TOS) and curcumin to improve its therapeutic efficacy. The chemical structures of PAH-SS-PLGA were analyzed using Proton Nuclear Magnetic Resonance (H-NMR) and Fourier Transform Infrared (FTIR) spectroscopy, whereas the particle size, zeta potential, and surface morphology were observed using dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release results revealed that more TOS and curcumin were released in the presence of GSH (5 mM) than the physiological pH value. Fluorescence microscopy images revealed that nanoformulated curcumin/rhodamine was uptaken by PAN02 pancreatic cancer cells. In vitro cytotoxicity assays showed higher cytotoxicity for nanoformulated TOS and/or curcumin than free TOS and/or curcumin. In addition, higher cytotoxicity was observed for combination drugs than free drugs alone. Most interestingly, at all tested concentrations of nanoformulated drugs (PAH-SS-PLGA, TOS, and curcumin), the calculated combination index (CI) value was less than one, which shows that TOS and curcumin have a synergistic effect on cellular proliferation inhibition. Overall, synthesized co-polymers are the best carriers for combination drugs, TOS, and curcumin, because they enhance the therapeutic efficacy and improve pancreatic cancer treatments.
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http://dx.doi.org/10.3390/pharmaceutics12080778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464675PMC
August 2020

Cancer-Derived Transforming Growth Factor-β Modulates Tumor-Associated Macrophages in Ampullary Cancer.

Onco Targets Ther 2020 3;13:7503-7516. Epub 2020 Aug 3.

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.

Purpose: Tumor-associated macrophages (TAMs) originate from monocytes and differentiate into mature macrophages. The interaction between cancer cells and TAMs promotes tumor growth and suppresses immunosurveillance. However, this phenomenon has seldom been observed in ampullary cancer.

Patients And Methods: TAMs in ampullary cancer were investigated using immunohistochemical (IHC) staining of cancer tissues. Bioinformatic analysis of data from the Gene Expression Omnibus (GEO) database revealed transforming growth factor-beta (TGF-β) signaling in ampullary cancer. The complementary DNA microarray of cancer was compared with adjacent normal duodenum and enzyme-linked immunosorbent assay of serum was used to verify TGF-β signaling in patients. The THP-1 cell line was activated to imitate M2 TAMs. ClueGo and CluePedia software were operated to simulate TGF-β-related networks in ampullary cancer.

Results: The IHC study revealed that the majority of TAMs inside ampullary cancer were cluster of differentiation (CD)163 cells and that the expression of mature CD68 macrophages was correlated with advanced cancer stage. Bioinformatics analysis revealed that TGF-β and its downstream signaling were significantly upregulated. To verify our bioinformatics-derived predictions, we performed several experiments and demonstrated that increased TGF-β expression was detected in the cDNA microarray. Higher serum levels of TGF-β were correlated with fewer CD68 and more inducible nitric oxide synthase macrophages in ampullary cancer. Treatment with TGF-β induced modulation of THP-1-derived macrophages.

Conclusion: The present study demonstrates that TGF-β modulates macrophage activity in ampullary cancer. Targeting TGF-β could be an approach to activating immunosurveillance.
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http://dx.doi.org/10.2147/OTT.S246714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423398PMC
August 2020

Increased expression of secreted frizzled related protein 1 (SFRP1) predicts ampullary adenocarcinoma recurrence.

Sci Rep 2020 08 6;10(1):13255. Epub 2020 Aug 6.

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Ampullary adenocarcinoma is a rare gastrointestinal cancer in which WNT signalling dysregulation has been previously reported. Secreted frizzled related protein 1 (SFRP1) is one of the extracellular ligands of WNT signalling. We performed bioinformatics analyses of SFRP1 expression in human cancer. Microarray analysis of SFRP1 in periampullary adenocarcinoma was obtained from the Gene Expression Omnibus GSE39409 dataset. SFRP1 expression in ampullary adenocarcinoma was detected by immunohistochemistry staining and correlated with patients' clinical outcomes. Our results showed that SFRP1 expression had different clinical applications in all types of human cancer. No detected alteration of SFPR1 gene and SFRP1 expression in ampullary adenocarcinoma was lower than that in other periampullary adenocarcinomas. However, high expression levels of SFRP1 protein were correlated with cancer recurrence, peritoneal carcinomatosis and poor patient prognosis. Gene set enrichment analysis showed downregulation of multiple WNT-related genes in primary culture cells from ampullary adenocarcinoma, but SFRP1 expression was increased. We found an interaction between WNT, bone morphogenetic protein and hedgehog signalling with SFRP1. Furthermore, a high expression of SFRP1 predicted poor prognosis for ampullary adenocarcinoma patients. Because it is a multifunctional protein, SFRP1 targeting serves as a potential therapy for ampullary adenocarcinoma patients.
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http://dx.doi.org/10.1038/s41598-020-69899-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413269PMC
August 2020

Risk factors for pancreatic fistula grade C after pancreatoduodenectomy: A large prospective, multicenter Japan-Taiwan collaboration study.

J Hepatobiliary Pancreat Sci 2020 Sep 6;27(9):622-631. Epub 2020 Aug 6.

Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan.

Background/purpose: Grade C postoperative pancreatic fistula (POPF), as defined by International Study Group of Pancreatic Fistula (ISGPF), is the most life-threatening complication after pancreatoduodenectomy (PD). This study aims to evaluate risk factors for Grade C POPF after PD.

Methods: This is a prospective, multicenter study based in Japan and Taiwan. Between December 2014 and May 2017, 3022 patients were enrolled in this study and 2762 patients were analyzed. We analyzed risk factors of Grade C POPF based on the updated 2016 ISGPF scheme (organ failure, reoperation, and/or death).

Results: Among 2762 patients, 46 patients (1.7%) developed Grade C POPF after PD. The mortality rate of the 46 patients with Grade C POPF was 37.0%. On the multivariate analysis, six independent risk factors for Grade C POPF were found; BMI ≥ 25.0 kg/m , chronic steroid use, preoperative serum albumin <3.0 mg/dL, soft pancreas, operative time ≥480 minutes, and intraoperative transfusion. The c-statistic of our risk scoring model for Grade C POPF using these risk factors was 0.77. The score was significantly higher in Grade C POPF than in Grade B POPF (P < .001) or none/biochemical leak (P < .001).

Conclusions: This prospective study showed risk factors for Grade C POPF after PD.
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http://dx.doi.org/10.1002/jhbp.799DOI Listing
September 2020

Epigenetic silencing of AATK in acinar to ductal metaplasia in murine model of pancreatic cancer.

Clin Epigenetics 2020 06 17;12(1):87. Epub 2020 Jun 17.

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA).

Results: By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice.

Conclusion: Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.
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http://dx.doi.org/10.1186/s13148-020-00878-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301993PMC
June 2020

Multicentre, phase II study of gemcitabine and S-1 in patients with advanced biliary tract cancer: TG1308 study.

Liver Int 2020 10 9;40(10):2535-2543. Epub 2020 Jun 9.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

Background & Aims: Gemcitabine plus cisplatin (GC) remains the standard, frontline therapy for advanced biliary tract cancer (ABTC). The JCOG1113 study suggested that gemcitabine plus S-1 (GS) had noninferior median overall survival and comparable incidence of significant neutropenia as compared to GC treatments. This study evaluates the efficacy and safety of a modified GS regimen.

Methods: The eligible patients with chemonaive, measurable ABTC received 800 mg/m of gemcitabine on day 1 and 80 mg/m /day of S-1 (80/100/120 mg for patients with body surface <1.25/ ≥1.25 and <1.5/ ≥1.5 m respectively). The primary endpoint was the 12-week disease control rate (12-week DCR: objective response and stable disease ≥ 12 weeks). Per the p0 = 40% and p1 = 60% (α/β = 0.05/0.2) assumption, Simon's optimal two-stage design indicated 12-week DCR in ≥ 24 of 46 evaluable patients for significant activity. Tumour responses were assessed every 6 weeks.

Results: Fifty-one patients were enrolled and most of them had intrahepatic cholangiocarcinoma (64.7%), metastatic disease (84.3%) and disease-related symptoms (82.4%). On intention-to-treat analysis, 11 (21.6%) patients showed partial response, whereas 21 (41.2%) showed stable disease ≥ 12 weeks. The progression-free and overall survival were 5.4 months (95% confidence interval [CI]: 3.5-7.0), and 12.7 months (95% CI: 6.1-15.6) respectively. The study met its primary endpoint with a 12-week DCR of 69.6% in 46 evaluable patients. Grade 3/4 treatment-related adverse eventsoccurred in < 6% of patients of all individual items. The mean dose intensities of S-1 and gemcitabine were 87.1% and 92.5% respectively.

Conclusions: Modified GS showed moderate efficacy with a favourable safety profile in ABTC patients, thus mandating further assessment. ClinicalTrials.gov number: NCT02425137.
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http://dx.doi.org/10.1111/liv.14538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540301PMC
October 2020

Validation of genome-wide association study-identified single nucleotide polymorphisms in a case-control study of pancreatic cancer from Taiwan.

J Biomed Sci 2020 May 26;27(1):69. Epub 2020 May 26.

National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.

Background: Due to differences in genetic background, it is unclear whether the genetic loci identified by the previous genome-wide association studies (GWAS) of pancreatic cancer also play significant roles in the development of pancreatic cancer among the Taiwanese population.

Methods: This study aimed to validate the 25 pancreatic cancer GWAS-identified single nucleotide polymorphisms (SNPs) in a case-control study (278 cases and 658 controls) of pancreatic cancer conducted in Taiwan. Statistical analyses were conducted to determine the associations between the GWAS-identified SNPs and pancreatic cancer risk. Gene-environment interaction analysis was conducted to evaluate the interactions between SNPs and environmental factors on pancreatic cancer risk.

Results: Among the 25 GWAS-identified SNPs, 7 (rs2816938 (~ 11 kb upstream of NR5A2), rs10094872 (~ 28 kb upstream of MYC), rs9581943 (200 bp upstream of PDX1) and 4 chromosome 13q22.1 SNPs: rs4885093, rs9573163, rs9543325, rs9573166) showed a statistically significant association with pancreatic cancer risk in the current study. Additional analyses showed two significant gene-environment interactions (between poor oral hygiene and NR5A2 rs2816938 and between obesity and PDX1 rs9581943) on the risk of pancreatic cancer.

Conclusions: The current study confirmed the associations between 7 of the 25 GWAS-identified SNPs and pancreatic risk among the Taiwanese population. Furthermore, pancreatic cancer was jointly influenced by lifestyle and medical factors, genetic polymorphisms, and gene-environment interaction. Additional GWAS is needed to determine the genetic polymorphisms that are more relevant to the pancreatic cancer cases occurring in Taiwan.
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http://dx.doi.org/10.1186/s12929-020-00664-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251895PMC
May 2020

Laparoscopic Splenic Vessels and Spleen Preservation Distal Pancreatectomy Via Inferior-Posterior Splenic Vein Approach.

Surg Laparosc Endosc Percutan Tech 2020 Oct;30(5):424-429

Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University.

Background: Preservation of splenic vessels can minimize the risks of splenic infarction and gastric varices in laparoscopic spleen preserving distal pancreatectomy. A well-established procedure would provide high splenic vessels and spleen preservation rate. This study evaluated the outcomes and depending factors of laparoscopic splenic vessels and spleen preservation distal pancreatectomy (LsvspDP) via inferior-posterior splenic vein approach.

Materials And Methods: This retrospective study enrolled patients who underwent LsvspDP via inferior-posterior splenic vein approach in National Cheng-Kung University Hospital from February 2009 to June 2019. The clinic-pathologic data were collected and analyzed. The primary outcome of this study was the learning curve based on the cumulative sum analysis. The secondary outcomes were to evaluate the critical factors for the failure of splenic vessels and spleen preservation.

Results: During the study period, a total of 64 patients received LsvspDP attempt. Splenic vessels were successfully preserved in 49 patients and the overall spleen preservation rate was 76.6%. According to cumulative sum analysis, the learning curve of LsvspDP was the 33rd case and several plateaus were observed during the learning curve phase. Old age (P=0.001), tail location (P=0.038), and large tumor (P=0.01) were independent risk factors of failed splenic vessels preservation, whereas the cut-off point of tumor size for prediction of spleen preservation was 5.4 cm. The complication rates were 7.8%, 7.8%, and 12.5% for Clavien grade I, II, and III, respectively, and 0% for Clavien grade IV or V. The rate of postoperative pancreatic fistula-grade B was 14.8%, among which the tail location was lower than the nontail location (0% vs. 24.3%; P=0.008). The mean value of operative time, blood loss, and hospital stay were 198±67 minutes, 139±242 mL, and 8.5±5.6 days, respectively.

Conclusions: In LsvspDP, the inferior-posterior splenic vein approach resulted in high splenic vessels and spleen preservation rate. Thirty-three patients were required to overcome the learning curve. Old age, tail location, and large tumor size were independent factors for the failure of splenic vessels preservation, whereas the cut-off value for tumor size was 5.4 cm to predict splenic vessels preservation.
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http://dx.doi.org/10.1097/SLE.0000000000000804DOI Listing
October 2020

The Impact of Liposomal Irinotecan on the Treatment of Advanced Pancreatic Adenocarcinoma: Real-World Experience in a Taiwanese Cohort.

Sci Rep 2020 05 4;10(1):7420. Epub 2020 May 4.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

Liposomal irinotecan plus 5-fluorouracil/leucovorin (nal-IRI + 5-FU/LV) has shown to provide survival benefits for patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) in NAPOLI-1 trial, in which Asian patients experienced more hematological toxicity and subsequent dose modification. A retrospective chart review to investigate the administration pattern, therapeutic efficacy and safety profile of nal-IRI + 5-FU/LV in 44 consecutive patients with gemcitabine-refractory advanced PDAC treated between December 2016 and December 2018 in National Cheng Kung University Hospital, Taiwan. Most of them had metastatic diseases (88.6%), one-line of prior treatment (72.7%), ECOG PS 0-1 (72.7%) and starting dose of nal-IRI at 60 mg/m (≈52 mg/m irinotecan free-base) in 65.9%. The overall response rate was 9.1%. The median OS was 6.6 months for the entire cohort, and 7.8 and 2.7 months for patients of ECOG PS 0-1 and>2, respectively. The median OS of ECOG PS 0-1 patients with nal-IRI starting doses at 80 mg/m (≈70 mg/m irinotecan free-base, n = 13) and 60 mg/m (n = 19) were 7.5 and 8.4 months, respectively. Thirty-four percent of patients experienced manageable grade 3-4 hematological toxicity. Our results confirm the clinical benefit of nal-IRI + 5-FU/LV for patients of gemcitabine-refractory advanced PDAC with good performance status in a real-world setting.
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http://dx.doi.org/10.1038/s41598-020-64421-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198559PMC
May 2020

DUSP2 regulates extracellular vesicle-VEGF-C secretion and pancreatic cancer early dissemination.

J Extracell Vesicles 2020 4;9(1):1746529. Epub 2020 Apr 4.

Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Early dissemination is a unique characteristic and a detrimental process of pancreatic ductal adenocarcinoma (PDAC); however, the underlying mechanism remains largely unknown. Here, we investigate the role of dual-specificity phosphatase-2 (DUSP2)-vascular endothelial growth factor-C (VEGF-C) axis in mediating PDAC lymphangiogenesis and lymphovascular invasion. Expression of DUSP2 is greatly suppressed in PDAC, which results in increased aberrant expression of extracellular vesicle (EV)-associated VEGF-C secretion. EV-VEGF-C exerts paracrine effects on lymphatic endothelial cells and autocrine effects on cancer cells, resulting in the lymphovascular invasion of cancer cells. Tissue-specific knockout of in mouse pancreas recapitulates PDAC phenotype and lymphovascular invasion. Mechanistically, loss-of-DUSP2 enhances proprotein convertase activity and vesicle trafficking to promote the release of the mature form of EV-VEGF-C. Collectively, these findings represent a conceptual advance in understanding pancreatic cancer lymphovascular invasion and suggest that loss-of-DUSP2-mediated VEGF-C processing may play important roles in early dissemination of pancreatic cancer. DUSP2: dual-specificity phosphatase-2; VEGF-C: vascular endothelial growth factor-C; EV: extracellular vesicles; PDAC: pancreatic ductal adenocarcinoma; KD: knockdown.
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http://dx.doi.org/10.1080/20013078.2020.1746529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170376PMC
April 2020

Exploring Circulating Tumor Cells in Cholangiocarcinoma Using a Novel Glycosaminoglycan Probe on a Microfluidic Platform.

Adv Healthc Mater 2020 05 24;9(10):e1901875. Epub 2020 Apr 24.

Institute of Nanoengineering and Microsystems, National Tsing Hua University, Hsinchu, 30013, Taiwan.

The search of alternative approaches to epithelial cell adhesion molecule (EpCAM), for the isolation of circulating tumor cells (CTC), is on the rise. This work attempts at evaluating the feasibility of using a new glycosaminoglycan, SCH45, as a probe to isolate CTCs from the peripheral blood of 65 advanced/metastatic cholangiocarcinoma (CCA) patients. The positive enrichment of CTCs from 1 mL of blood using SCH45-bound magnetic beads and subsequent staining on an integrated microfluidic platform is demonstrated. Results detailing CTC concentrations averaging ≥1 CTCs mL of blood are shown, and a conventional protein biomarker, EpCAM, has been used to corroborate the finding that 100% of the patients possess CTCs in their blood. Studies detailing the use of CTCs in the prognostic monitoring and treatment effectiveness of advanced/metastatic CCA are scarce, and the isolation of CTCs from all CCA patients tested has not been reported yet. A strong correlation between CTC counts and disease progression at the time of and/or in advance of radiographic imaging in patients receiving chemotherapy is also reported. This study is one of its kind with the new probe and reduced sample volume and has potential for use in CCA diagnosis and prognosis in the near future.
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http://dx.doi.org/10.1002/adhm.201901875DOI Listing
May 2020

Loss of EGR-1 uncouples compensatory responses of pancreatic β cells.

Theranostics 2020 4;10(9):4233-4249. Epub 2020 Mar 4.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Taiwan, ROC.

: Subjects unable to sustain β-cell compensation develop type 2 diabetes. Early growth response-1 protein (EGR-1), implicated in the regulation of cell differentiation, proliferation, and apoptosis, is induced by diverse metabolic challenges, such as glucose or other nutrients. Therefore, we hypothesized that deficiency of EGR-1 might influence β-cell compensation in response to metabolic overload. : Mice deficient in EGR-1 () were used to investigate the roles of EGR-1 in regulation of glucose homeostasis and beta-cell compensatory responses. : In response to a high-fat diet, mice failed to secrete sufficient insulin to clear glucose, which was associated with lower insulin content and attenuated hypertrophic response of islets. High-fat feeding caused a dramatic impairment in glucose-stimulated insulin secretion and downregulated the expression of genes encoding glucose sensing proteins. The cells co-expressing both insulin and glucagon were dramatically upregulated in islets of high-fat-fed mice. EGR-1-deficient islets failed to maintain the transcriptional network for β-cell compensatory response. In human pancreatic tissues, expression correlated with the expression of β-cell compensatory genes in the non-diabetic group, but not in the diabetic group. : These results suggest that EGR-1 couples the transcriptional network to compensation for the loss of β-cell function and identity. Thus, our study highlights the early stress coupler EGR-1 as a critical factor in the development of pancreatic islet failure.
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http://dx.doi.org/10.7150/thno.40664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086362PMC
March 2020

OSU-A9 induced-reactive oxygen species cause cytotoxicity in duodenal and gastric cancer cells by decreasing phosphorylated nuclear pyruvate kinase M2 protein levels.

Biochem Pharmacol 2020 04 16;174:113811. Epub 2020 Jan 16.

Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; College of Medicine, School of Medicine, China Medical University, Taichung, Taiwan. Electronic address:

Pyruvate kinase M2 (PKM2) is a key enzyme responsible for the final step of glycolysis. It is still unclear whether PKM2 is involved in reactive oxygen species (ROS)-mediated cytotoxicity in gastrointestinal cancer, and what mechanisms are involved. One duodenal (AZ521) and two gastric (NUGC and SCM-1) cancer cell lines were treated with an indole-3-carbinol derivative OSU-A9, which caused cytotoxicity in acute myeloid leukemia through ROS generation. OSU-A9 caused a dose- and time-dependent cytotoxicity and induced apoptosis in duodenal and gastric cancer cells through ROS generation. Pretreatment with ROS scavengers rescued cancer cells from apoptosis and concomitant poly (ADP-ribose) polymerase cleavage, implying a key role of ROS in OSU-A9-induced cell death. Moreover, OSU-A9-induced ROS generation decreased protein levels of p-PKM2, and this effect was rescued by pretreatment with ROS scavengers. Interestingly, p-PKM2 protein levels decreased in the cell nucleus rather than in the cytoplasm. PKM2 overexpression partially rescued the survival of duodenal and gastric cancer cells treated with OSU-A9. Furthermore, the anticancer activity of OSU-A9 extended in vivo, as OSU-A9 administered by oral gavage suppressed the growth of AZ521 xenograft tumors in nude mice without obvious toxicity. In conclusion, OSU-A9 inhibited duodenal and gastric cancer cell proliferation through ROS generation and caused a subsequent decrease in nuclear p-PKM2 protein. These findings provide evidence for the non-canonical activity of PKM2 in cancer cell survival. Furthermore, they highlight the potential role of PKM2 as a future therapeutic target for duodenal and gastric cancer.
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http://dx.doi.org/10.1016/j.bcp.2020.113811DOI Listing
April 2020

An Open-Label, Single-Arm, Two-Stage, Multicenter, Phase II Study to Evaluate the Efficacy of TLC388 and Genomic Analysis for Poorly Differentiated Neuroendocrine Carcinomas.

Oncologist 2020 05 18;25(5):e782-e788. Epub 2019 Dec 18.

Taipei Veterans General Hospital, Taipei, Taiwan.

Background: The discovery of effective therapeutic options for treating metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum-based chemotherapy remains elusive. This study analyzed the efficacy of TLC388 (Lipotecan) Hydrochloride, a novel camptothecin analog, for pretreated patients with metastatic NEC.

Methods: This single-arm, two-stage, phase II clinical trial was conducted at four community and academic centers in Taiwan. Patients aged 20 years or older with confirmed metastatic NEC and who had received prior systemic therapy with etoposide plus cisplatin were enrolled between July 2015 and May 2018. Patients received 40 mg/m of TLC388 intravenously on days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxic effects. Gene mutations were analyzed by next-generation sequencing.

Results: Twenty-three patients with a median age of 61 (range, 44-73) years, 18 of whom were men (78%), were enrolled. Patients received a median of 2 (range, 0-6) treatment cycles. Among 20 evaluable patients, 3 patients exhibited stable disease and no patient experienced a complete or partial remission, resulting in a disease control rate of 15%. Median progression-free survival was 1.8 (95% confidence interval [CI], 0.4-15) months, and the median overall survival was 4.3 (95% CI, 1.7-15) months. The most common treatment-related hematologic adverse events at grade 3 or higher were leukopenia (22.7%), anemia (31.8%), and thrombocytopenia (18.2%). The most frequent mutated genes in 35 patients with NEC were ARSA, DPYD, HEXB, BRCA1, HPD, MYBPC3, BBS2, IL7R, HSD17B4, and PRODH.

Conclusion: TLC388 demonstrates limited antitumor activity in metastatic NEC. ClinicalTrials.gov identifier: NCT02457273.

Implications For Practice: Poorly differentiated neuroendocrine carcinomas (NECs) are rare and aggressive. Currently, effective therapeutic options for treating metastatic poorly differentiated NECs beyond platinum-based chemotherapy remain elusive. In this single-arm, multicenter, phase II study, 23 patients with NEC were enrolled and received TLC388 (Lipotecan) Hydrochloride, which is a novel camptothecin analog. The results demonstrated the disease control rate of 15%, the median progression-free survival of 1.8 (95% confidence interval [CI], 0.4-15) months, and the median overall survival of 4.3 (95% CI, 1.7-15) months. Most importantly, several novel genetic mutations and pathways were identified. These results offer the opportunity to develop future treatment strategies in this rare cancer.
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http://dx.doi.org/10.1634/theoncologist.2019-0490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216444PMC
May 2020

Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI-1 study.

Cancer Sci 2020 Feb 20;111(2):513-527. Epub 2019 Dec 20.

National Institute of Cancer Research, National Health Research Institutes (NHRI), Tainan, Taiwan.

The global, randomized NAPOLI-1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine-based therapy. Median overall survival (OS) with nal-IRI+5-FU/LV was 6.1 vs 4.2 months with 5-FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post-hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal-IRI+5-FU/LV (n = 34) had significantly longer median OS versus 5-FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal-IRI+5-FU/LV versus 5-FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal-IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5-FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal-IRI+5-FU/LV versus 5-FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal-IRI+5-FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine-based therapy, with a safety profile agreeing with previous findings. The nal-IRI+5-FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506).
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http://dx.doi.org/10.1111/cas.14264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004519PMC
February 2020

A multicenter, phase I/II trial of biweekly S-1, leucovorin, oxaliplatin and gemcitabine in metastatic pancreatic adenocarcinoma-TCOG T1211 study.

Eur J Cancer 2020 01 22;124:123-130. Epub 2019 Nov 22.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Background: This phase I/II study evaluated the feasibility and efficacy of S-1, leucovorin, oxaliplatin and gemcitabine (SLOG), a triplet regimen, for treating patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

Methods: Patients with chemo-naive, metastatic PDAC were eligible to receive fixed-rate infusion (10 mg/m/min) of gemcitabine of 800 mg/m followed by oxaliplatin of 85 mg/m on day 1 plus oral S-1 and leucovorin (20 mg/m) twice daily from days 1 to 7 in a 2-week cycle. The dose of S-1 would be escalated from 20, 30, 35 to 40 mg/m2 in a 3 + 3 designed phase I part to determine the maximum tolerated dose (MTD) for phase II study, in which the primary end-point was objective response rate (ORR). The recommended dose of S-1 was from phase I. This trial is registered at ClinicalTrials.gov: NCT01415713.

Results: Seventy-three patients were enrolled. In the phase I study (n = 19), the MTD of S-1 was 35 mg/m twice daily. Of 54 patients in phase II, the ORR was 40.7% (95% confidence interval [CI], 28%-55%). The median progression-free survival and overall survival were 7.6 (95% CI, 5.6-11.0) and 11.4 (95% CI, 8.1-16.3) months, respectively. The most common grade III/IV adverse event was neutropenia (40.7%). Twenty-four percent of patients had SLOG treatment for more than 1 year. The mean relative dose intensities of gemcitabine, oxaliplatin, and S-1 were 92%, 92% and 89%, respectively.

Conclusion: Biweekly SLOG is a feasible regimen with promising activity and safety profiles. A randomised study comparing SLOG versus modified folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) in advanced PDAC is ongoing (ClinicalTrials.gov: NCT03443492).
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http://dx.doi.org/10.1016/j.ejca.2019.10.023DOI Listing
January 2020

Pancreatic stellate cells activated by mutant KRAS-mediated PAI-1 upregulation foster pancreatic cancer progression via IL-8.

Theranostics 2019 23;9(24):7168-7183. Epub 2019 Sep 23.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

The dense fibrotic stroma enveloping pancreatic tumors is a major cause of drug resistance. Pancreatic stellate cells (PSCs) in the stroma can be activated to induce intra-tumor fibrosis and worsen patient survival; however, the molecular basics for the regulation of PSC activation remains unclear. The coculture system was used to study cancer cell-PSC interactions. Atomic force microscopy was used to measure the stiffness of tumor tissues and coculture gels. Cytokine arrays, qPCR, and Western blotting were performed to identify the potential factors involved in PSC activation and to elucidate underlying pathways. PSC activation characterized by α-SMA expression was associated with increased pancreatic tumor stiffness and poor prognosis. Coculture with cancer cells induced PSC activation, which increased organotypic coculture gel stiffness and cancer cell invasion. Cancer cells-derived PAI-1 identified from coculture medium could activate PSCs, consistent with pancreatic cancer tissue microarray analysis showing a strong positive correlation between PAI-1 and α-SMA expression. Suppression by knocking down PAI-1 in cancer cells demonstrated the requirement of PAI-1 for coculture-induced PSC activation and gel stiffness. PAI-1 could be upregulated by KRAS in pancreatic cancer cells through ERK. In PSCs, inhibition of LRP-1, ERK, and c-JUN neutralized the effect of PAI-1, suggesting the contribution of LRP-1/ERK/c-JUN signaling. Furthermore, activated PSCs might exacerbate malignant behavior of cancer cells via IL-8 because suppression of IL-8 signaling reduced pancreatic tumor growth and fibrosis . KRAS-mutant pancreatic cancer cells can activate PSCs through PAI-1/LRP-1 signaling to promote fibrosis and cancer progression.
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http://dx.doi.org/10.7150/thno.36830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831292PMC
September 2020

The differential distributions of ASPM isoforms and their roles in Wnt signaling, cell cycle progression, and pancreatic cancer prognosis.

J Pathol 2019 12 23;249(4):498-508. Epub 2019 Oct 23.

Laboratory of Advanced Molecular Therapeutics, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and treatment-resistant malignancy. The lack of pathway-informed biomarkers hampers the development of rational diagnostics or therapies. Recently, the protein abnormal spindle-like microcephaly-associated (ASPM) was identified as a novel Wnt and stemness regulator in PDAC, while the pathogenic roles of its protein isoforms remain unclarified. We developed novel isoform-specific antibodies and genetic knockdown (KD) of putative ASPM isoforms, whereby we uncovered that the levels of ASPM isoform 1 (iI) and ASPM-iII are variably upregulated in PDAC cells. ASPM isoforms show remarkably different subcellular locations; specifically, ASPM-iI is exclusively localized to the cortical cytoplasm of PDAC cells, while ASPM-iII is predominantly expressed in cell nuclei. Mechanistically, ASPM-iI co-localizes with disheveled-2 and active β-catenin as well as the stemness marker aldehyde dehydrogenase-1 (ALDH-1), and its expression is indispensable for the Wnt activity, stemness, and the tumorigenicity of PDAC cells. By contrast, ASPM-iII selectively regulates the expression level of cyclin E and cell cycle progression in PDAC cells. The expression of ASPM-iI and ASPM-iII displays considerable intratumoral heterogeneity in PDAC tissues and only that of ASPM-iI was prognostically significant; it outperformed ALDH-1 staining and clinico-pathological variables in a multivariant analysis. Collectively, the distinct expression patterns and biological functions of ASPM isoforms may illuminate novel molecular mechanisms and prognosticators in PDAC and may pave the way for the development of therapies targeting this novel oncoprotein. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899738PMC
December 2019

Nuclear KIT induces a NFKBIB-RELA-KIT autoregulatory loop in imatinib-resistant gastrointestinal stromal tumors.

Oncogene 2019 09 30;38(38):6550-6565. Epub 2019 Jul 30.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.

Gastrointestinal stromal tumors (GISTs) are frequently driven by auto-activated, mutant KIT and have durable response to KIT tyrosine kinase inhibitor. However, acquired resistance is an increasing clinical issue in GIST patients receiving front-line imatinib therapy. Our previous studies showed the colocalization of KIT with DAPI-stained nuclei in GIST cells without knowing the role of nuclear KIT in GIST tumorigenesis. In this article, we first identified the binding of nuclear KIT to the promoter of NFKB inhibitor beta (NFKBIB) by chromatin immunoprecipitation (ChIP) sequencing and ChIP assays, which was accompanied with enhanced NFKBIB protein expression in GIST cells. Clinically, high NCCN risk GISTs had significantly higher mean expression levels of nuclear phospho-KIT and NFKBIB as compared with those of intermediate or low/very low-risk GISTs. Conversely, downregulation of NFKBIB by siRNA led to RELA nuclear translocation that could bind to the KIT promoter region and subsequently reduced KIT transcription/expression and the viability of GIST cells. These findings were further confirmed by either RELA overexpression or NFKB/RELA inducer, valproic acid, treatment to result in reduced KIT expression and relative cell viability of imatinib-resistant GIST cells. Combining valproic acid with imatinib showed significantly better growth inhibitory effects on imatinib-resistant GIST48 and GIST430 cells in vitro, and in the GIST430 animal xenograft model. Taken together, these results demonstrate the existence of a nuclear KIT-driven NFKBIB-RELA-KIT autoregulatory loop in GIST tumorigenesis, which are potential targets for developing combination therapy to overcome imatinib-resistant of KIT-expressing GISTs.
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http://dx.doi.org/10.1038/s41388-019-0900-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756115PMC
September 2019