• Journal of Digestive Cancer Reports
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• v.7 no.1
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• pp.18-21
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• 2019

Serine protease inhibitor Kazal-type 1 (SPINK1) is a gene expressed from pancreatic acinar cell which its mutation is known to be associated with chronic pancreatitis (CP) and pancreatic cancer. We report a case of a 47-years-old female with nausea and weight loss with yellow discoloration of skin. Initial imaging and endoscopic study led us to an impression of chronic pancreatitis with pancreatic cancer with common bile-duct dilation. Biopsy result was confirmed with pancreatic adenocarcinoma and additional imaging revealed lymph node and bone metastasis. Our genetic analysis revealed 194+2T>C mutation of SPINK1. Biliary obstruction was successfully decompressed by stent insertion and underwent chemotherapy and radiotherapy. Although there is accumulating evidence of association between SPINK1 mutation and CP, the relationship between SPINK1 mutation and pancreatic cancer in CP patient is an emerging concept. Genetic analysis should be considered in patients with young age especially when diagnosed with both CP and pancreatic cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.1995-1997
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• 2012

Background: Brain metastasis from cholangiocarcinoma (CCA) is a rare but fatal event. To the best of our knowledge, only few cases have been reported. Herein, we report the incident rate and a first case series of brain metastases from CCA. Methods: Between January 2006 and December 2010 5,164 patients were treated at Srinagarind hospital, Khon Kaen University; of those, 8 patients developed brain metastasis. Here we reviewed clinical data and survival times. Results: The incident rate of brain metastases from CCA was 0.15%. The median age of the patients was 60 years. Tumor subtypes were intrahepatic in 6 and hilar in 2 patients. All suffered from symptoms related to brain metastasis. Three patients were treated with whole-brain radiation therapy (WBRT), one of whom also underwent surgery. The median survival after the diagnosis of brain metastasis was 9.5 weeks (1-28 weeks). The longest survival observed in a patient in RPA class I with two brain lesions and received WBRT. Conclusion: This is a first case series of brain metastases from CCA with the incident rate of 0.15%. It is rare and associated with short survival time.

• Journal of Digestive Cancer Research
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• v.5 no.1
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• pp.50-54
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• 2017

Pancreatic neuroendocrine tumors are rare pancreatic neoplasms comprising 1-2% of all pancreatic tumors and typically present high attenuating mass on arterial and venous phase images, due to their rich capillary network. A 70-year-old South Korean female visited our hospital presenting with jaundice and dark urine color. She had received an operation for treatment of small bowel perforation seven years ago. On physical examination, icteric sclera was observed but otherwise unremarkable. Laboratory tests were abnormal liver function test and suspected obstructive jaundice. Computed tomography revealed 4 cm sized cystic mass lesion with homogeneous low attenuation in the head of pancreas and distal common bile duct was compressed by the mass. During review of past medical records, we found that the mass was observed and measured about 1.7 cm seven years ago. To resolve obstructive jaundice, pylorus preserving pancreaticoduodenectomy was performed and diagnosed with well differentiated pancreatic neuroendocrine carcinoma with intermediate grade.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.1
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• pp.201-205
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• 2016

Cholangiocarcinoma (CCA) is generally a rare primary liver tumor of the bile duct with extremely poor clinical outcomes due to late diagnosis. Osteopontin (OPN) is the most abundant expressed gene in intrahepatic CCA and its involvement in tumor aggressiveness suggests it could be a useful prognostic biomarker. However, the prognostic significance of OPN expression in CCA is still controversial. We therefore immunohistochemically studied OPN expression in 354 resected CCAs and correlated the results with patient clinicopathological parameters. OPN expression was separately scored according to the percentage of cancer cells or degree of stromal tissue staining and classified as low (score 0-1) and high (score 2-3). OPN expression in CCA cells was found in 177 out of 354 patients (56.5%), whereas stroma was positive in 185 out of 354 patients (52.3%). Univariate analysis with several of the aforementioned parameters revealed that stromal but not cancer cell OPN expression was significantly associated with tumor size, tumor direct invasion into normal liver parenchyma, regional lymph node metastasis and higher staging. The combination of cancer cell and stromal OPN expression demonstrated a positive trend for linkage with lymph node metastasis. Multivariate analysis identified gender, the presence of lymphatic permeation and lymph node metastasis, but not OPN expression, as independent prognostic factors. This study confirms the presence of stromal OPN expression in tumor aggressiveness but not survival in CCA patients.

• BMB Reports
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• v.56 no.11
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• pp.600-605
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• 2023

Intrahepatic cholangiocarcinoma (ICC) is a bile duct cancer and a rare malignant tumor with a poor prognosis owing to the lack of an early diagnosis and resistance to conventional chemotherapy. A combination of gemcitabine and cisplatin is the typically attempted first-line treatment approach. However, the underlying mechanism of resistance to chemotherapy is poorly understood. We addressed this by studying dynamics in the human ICC SCK cell line. Here, we report that the regulation of glucose and glutamine metabolism was a key factor in overcoming cisplatin resistance in SCK cells. RNA sequencing analysis revealed a high enrichment cell cycle-related gene set score in cisplatin-resistant SCK (SCK-R) cells compared to parental SCK (SCK WT) cells. Cell cycle progression correlates with increased nutrient requirement and cancer proliferation or metastasis. Commonly, cancer cells are dependent upon glucose and glutamine availability for survival and proliferation. Indeed, we observed the increased expression of GLUT (glucose transporter), ASCT2 (glutamine transporter), and cancer progression markers in SCK-R cells. Thus, we inhibited enhanced metabolic reprogramming in SCK-R cells through nutrient starvation. SCK-R cells were sensitized to cisplatin, especially under glucose starvation. Glutaminase-1 (GLS1), which is a mitochondrial enzyme involved in tumorigenesis and progression in cancer cells, was upregulated in SCK-R cells. Targeting GLS1 with the GLS1 inhibitor CB-839 (telaglenastat) effectively reduced the expression of cancer progression markers. Taken together, our study results suggest that a combination of GLUT inhibition, which mimics glucose starvation, and GLS1 inhibition could be a therapeutic strategy to increase the chemosensitivity of ICC.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8079-8083
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• 2016

Metformin is an oral anti-hyperglycemic agent, which is the most commonly prescribed medication in the treatment of type-2 diabetes mellitus. It is purportedly associated with a reduced risk for various cancers, mainly exerting anti-proliferation effects on various human cancer cell types, such as pancreas, prostate, breast, stomach and liver. This mini-review highlights the risk and benefit of metformin used for cholangiocarcinoma (CCA) prevention and therapy. The results indicated metformin might be a quite promising strategy CCA prevention and treatment, one mechanism being inhibition of CCA tumor growth by cell cycle arrest in both in vitro and in vivo. The AMPK/mTORC1 pathway in intrahepatic CCA cells is targeted by metformin. Furthermore, metformin inhibited CCA tumor growth via the regulation of Drosha-mediated expression of multiple carcinogenic miRNAs. The use of metformin seems to be safe in patients with cirrhosis, and provides a survival benefit. Once hepatic malignancies are already established, metformin does not offer any therapeutic potential. Clinical trials and epidemiological studies of the benefit of metformin use for CCA should be conducted. To date, whether metformin as a prospective chemotherapeutic for CCA is still questionable and waits further atttention.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.9
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• pp.3849-3856
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• 2015

Background: Cholangiocarcinoma (CCA), or bile duct cancer, is incurable with a high mortality rate due to a lack of effective early diagnosis and treatment. Identifying cytoplasmic membrane proteins of invasive CCA that facilitate cancer progression would contribute toward the development of novel tumor markers and effective chemotherapy. Materials and Methods: An invasive CCA cell line (KKU-100) was stimulated using TNF-${\alpha}$ and then biotinylated and purified for mass spectrometry analysis. Novel proteins expressed were selected and their mRNAs expression levels were determined by real-time RT-PCR. In addition, the expression of ALCAM was selected for further observation by Western blot analysis, immunofluorescent imaging, and antibody neutralization assay. Results: After comparing the proteomics profile of TNF-${\alpha}$ induced invasive with non-treated control cells, over-expression of seven novel proteins was observed in the cytoplasmic membrane of TNF-${\alpha}$ stimulated CCA cells. Among these, ALCAM is a novel candidate which showed significant higher mRNA- and protein levels. Immunofluorescent assay also supported that ALCAM was expressed on the cell membrane of the cancer, with increasing intensity associated with TNF-${\alpha}$. Conclusions: This study indicated that ALCAM may be a novel protein candidate expressed on cytoplasmic membranes of invasive CCA cells that could be used as a biomarker for development of diagnosis, prognosis, and drug or antibody-based targeted therapies in the future.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.17
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• pp.7473-7478
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• 2014

Cholangiocarcinoma (CCA) is a fatal cancer with poor prognosis and less than 10% of CCA patients can be offered surgical cure. Conventional chemotherapy results in unfavorable outcomes. At present, plant-derived compounds are gaining interest as potential cancer therapeutics, particularly for treatment-refractory cancers. In this study, antitumor activity of tiliacorinine, the major alkaloid isolated from a tropical plant, on CCA was first demonstrated. Antiproliferative effects of tiliacorinine on human CCA cell lines were investigated using SRB assays. Acridine orange/ethidium bromide staining, flow cytometric analysis and DNA laddering assays were used for apoptotic determination. Apoptosis-related proteins were verified by Western blotting and antitumor activity of tiliacorinine in vivo was demonstrated in CCA xenografted mice. Tiliacorinine significantly inhibited proliferation of human CCA cell lines with $IC_{50}$ $4.5-7{\mu}M$ by inducing apoptosis through caspase activation, upregulation of BAX, and downregulation of $Bcl_{xL}$ and XIAP. Tiliacorinine considerably reduced tumor growth in CCA xenografted mice. These results demonstrated antitumor effects of tiliacorinine on human CCA in vitro and in vivo. Tiliacorinine may be an effective agent for CCA treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.11
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• pp.4593-4596
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• 2015

Background: Opisthorchis viverrini (OV) infection is the main risk factor for cholangiocarcinoma and is often found in Northeastern Thailand. The prevalence of OV infection and the incidence of cholangiocarcinoma are major public health problems in this region. Objectives: The objectives of this study were to identify factors associated with OV infection among people in Nong Khai Province in order to develop a prevention programme in the community. Materials and Methods: The data were collected in July 2013. Stool specimens were examined for intestinal parasites within hours after collection using a normal saline wet preparation and the modified Kato-Katz technique. A case-control study was conducted to collect information about demographic data, the habit of eating unsafely prepared fish, the safe disposal of waste food, and the practice of defaecating in fields. Structured questionnaires were used to interview 351 participants (117 cases and 234 controls) in a random selection of 30 villages across Nong Khai Province. Multiple logistic regression was used to identify risk factors for OV infection. Results: In the multivariate analysis, the results showed that the factors which had a statistically significant association with OV infection were the habit of consuming unsafely prepared fish ($OR_{adj}=5.17$, 95%CI=2.49-10.74), the similar habit of family members ($OR_{adj}=3.25$, 95%CI=1.63-6.49), a history of O. viverrini infection ($OR_{adj}=5.64$, 95%CI=2.10-15.18), a history of taking praziquantel ($OR_{adj}=5.66$, 95%CI=3.11-10.29), and the unsafe disposal of waste food ($OR_{adj}=2.1$, 95%CI=1.10-3.80). Conclusions: The findings of this study highlight the features on which a community programme should focus in order to reduce the prevalence of opisthorchiasis and incidence of bile duct cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1163-1168
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• 2016

Cholangiocarcinoma (CCA) is the bile duct cancer which constitutes one of the important public health problems in Thailand with high mortality rate, especially in the Opisthorchis viverrini (a parasite risk factor for CCA) endemic area of the northeastern region of the country. This study aimed to identify potential biomarkers from the plasma peptidome by CCA patients. Peptides were isolated using 10 kDa cut-off filter column and the flow-through was then used as a peptidome for LC-MS/MS analysis. A total of 209 peptides were obtained. Among these, 15 peptides were concerned with signaling pathways and 12 related to metabolic, regulatory, and biosynthesis of secondary metabolite pathways. Five exclusive peptides were identified as potential biomarkers, i.e. ETS domain-containing transcription factor ERF (P50548), KIAA0220 (Q92617), phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform 1 (P42338), LP2209 (Q6XYC0), and casein kinase II subunit alpha (P19784). Three of these biomarkers are signaling related molecules. A combination of these biomarkers for CCA diagnosis is proposed.