• Biomolecules & Therapeutics
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• v.25 no.5
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• pp.482-489
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• 2017

Individual differences in drug responses are associated with genetic and epigenetic variability of pharmacogene expression. We aimed to identify the relevant miRNAs which regulate pharmacogenes associated with drug responses. The miRNA and mRNA expression profiles derived from data for normal and solid tumor tissues in The Cancer Genome Atlas (TCGA) Research Network. Predicted miRNAs targeted to pharmacogenes were identified using publicly available databases. A total of 95 pharmacogenes were selected from cholangiocarcinoma and colon adenocarcinoma, as well as kidney renal clear cell, liver hepatocellular, and lung squamous cell carcinomas. Through the integration analyses of miRNA and mRNA, 35 miRNAs were found to negatively correlate with mRNA expression levels of 16 pharmacogenes in normal bile duct, liver, colon, and lung tissues (p<0.05). Additionally, 36 miRNAs were related to differential expression of 32 pharmacogene mRNAs in those normal and tumorigenic tissues (p<0.05). These results indicate that changes in expression levels of miRNAs targeted to pharmacogenes in normal and tumor tissues may play a role in determining individual variations in drug response.

• Radiation Oncology Journal
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• v.10 no.1
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• pp.49-58
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• 1992

From January 1985 to September 1990, 7 patients with carcinoma of the extrahepatic biliary system received external radiaiton therapy combined with hyperthermia. Of the 3 patients with extrahepatic bile duct cancer, two were primary cholangiocarcinoma and one was metastatic peripancreatic carcinoma. Of the 4 patients with carcinoma of the gallbladder, two were locor-egionally advanced and unresectable carcinoma and the remaining two were local-regional recurrence after cholecystectomy. They were all pathologicallly proven adenocarcinoma. The radiation dose received ranged from 3000 cGy/2weeks to 5040 cGy/7 weeks. The hyperthermia was done once or twice a week and 4 to 12 sessions in total. The tumor response was confirmed by T-tube cholangiography, percutaneous transhepatic cholangiography and CT scan. 6 out of 7 ($86\%$) showed partial regression of the tumor. The median survival time was 7 months (range $4\~11$ months).6 out of 7 patients were dead: one died of septicemia, 4 of primary disease, one of distant metastases. Only one out of 7 patients is still alive but new metastatic lesion was found. There was not any treatment related deaths. There was also no evidence of treatment related problems with liver, stomach and duodenum, although the observation period was short.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5381-5384
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• 2012

Background and Aim: Cholangiocarcinoma (CCA) is an uncommon malignancy of the bile duct, occurring in nearly 2 out of 100,000 people. It is a type of adenocarcinoma that originates in the mucous glands of the epithelium, or surface layers of the bile ducts. The aim of this study was to evaluate the clinical features, diagnostic results and factors associated with survival, morbidity and mortalityof cholangiocarcinoma cases in Iranian patients. Method: In this retrospective study the hospital medical records of 283 patients with a primary or final diagnosis of cholangiocarcinoma who had been admitted to gastroenterology ward of our hospital from 2004 to 2011 were retrospectively reviewed. Results: 283 patients (180 male, 63%, and 103 female, 38.6%) with a mean age of $59.7{\pm}14.4$ years were studied. The most frequent symptoms were painless jaundice (190, 66.9%), abdominal pain (77, 27%), pruritus 133 (46.8%) and weight loss (169, 59.5%). The most frequent associated risk factors and diseases were as follows: gallstones (72, 25.4%), diabetes (70, 24.6%), HBV infection (52 (18.3%), HCV infection 43 (15%), primary sclerosing cholangitis (16, 5.6%) and smoking (120, 42.3%). The most frequent type of cholangiocarcinoma in ERCP and MRCP was hilar. The mean survival time was $7.42{\pm}5.76$ months. Conclusion: The mean survival time in our study was lower than one year. Moreover the most frequent risk factors and associated diseases were smoking, gallstones and diabetes. Painless jaundice, abdominal pain and weight loss were the most clinical features related to cholangiocarcinoma. Additionally survival time did not correlate with risk factors, associated diseases and clinical presentations, but was linked to biliary metallic stenting and surgery.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.5
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• pp.1737-1742
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• 2015

Background: Mitochondrial DNA (mtDNA) mutations have been shown to be associated with cancer. This study explored whether mtDNA mutations enhance cholangiocarcinoma (CCA) development in individuals. Materials and Methods: The whole mitochondrial genome sequences of 25 CCA patient tissues were determined and compared to those of white blood cells from the corresponding individuals and 12 healthy controls. The mitochondrial genome was amplified using primers from Mitoseq and compared with the Cambridge Reference Sequence. Results: A total of 161 mutations were identified in CCA tissues and the corresponding white blood cells, indicating germline origins. Sixty-five (40%) were new. Nine mutations, representing those most frequently observed in CCA were tested on the larger cohort of 60 CCA patients and 55 controls. Similar occurrence frequencies were observed in both groups. Conclusions: While the correspondence between the cancer and mitochondrial genome mutation was low, it is of interest to explore the functions of the missense mutations in a larger cohort, given the possibility of targeting mitochondria for cancer markers and therapy in the future.

• 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.

• Journal of Digestive Cancer Research
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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.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.