Diagnosis of Pancreatic Cancer by Detecting Telomerase Activity in Pancreatic Juice: Comparison With K- Ras Mutations

Uehara, Hiroyuki; Nakaizumi, Akihiko; Tatsuta, Masaharu; Baba, Miyako; Takenaka, Akemi; Uedo, Noriya; Sakai, Noriko; Yano, Hiroyuki; Ohigashi, Hajime; Ishikawa, Osamu; Okada, Shuichi; Kakizoe, Tadao

doi:10.1111/j.1572-0241.1999.01386.x

Cited by 81 publications

(28 citation statements)

References 42 publications

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“…However, none of these tests demonstrated the requisite sensitivity and specificity to be useful as a general screening tool. The same is unfortunately true of a number of other potential targets, including hTert (telomerase catalytic subunit) (Uehara et al 1999), matrix metalloproteinase-2 (MMP-2) (Yokoyama et al 2002), and, more recently, aberrantly methylated promoter CpG islands of key genes (see, e.g., Fukushima et al 2002). Novel labeling and fractionation methods for pancreatic tissue (Chen et al 2005), serum proteins (Yu et al 2005), and secreted proteins (Gronborg et al 2006) coupled with tandem mass spectrometry have suggested additional candidate markers which await validation.…”

Section: Clinical Considerations In Pancreatic Cancermentioning

confidence: 99%

Ductal Pancreatic Cancer in Humans and Mice

Tuveson¹,

Hingorani²

2005

Cold Spring Harbor Symposia on Quantitative Biology

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Animal models of cognate human conditions permit the rigorous exploration of mechanisms of disease pathogenesis and provide systems to devise and test therapeutic and detection strategies. Although inbred mouse strains offer many advantages over other animals for investigations of malignant disease, mice unfortunately do not develop PDA spontaneously or even following carcinogen treatment. Recent technological developments in conditional gene targeting have enabled the generation of mutant mouse cancer models of PanIN and PDA that closely mimic human pancreatic cancer and are thus suitable for investigations of the human disease process. In this paper, we summarize the knowledge of the human disease that has informed the ability to generate accurate mouse models of pancreatic cancer and describe potential biological and clinical applications. EPIDEMIOLOGY OF PANCREATIC CANCEREpithelial carcinomas account for the majority of cancer deaths in the United States, and among them, pancreatic cancer is the fourth most common with the highest case-fatality ratio. Pancreatic ductal adenocarcinomas (PDA) comprise more than 90% of pancreatic cancer cases and are its most lethal form among an assortment of additional histological subtypes including cystic neoplasms, acinar carcinomas, and islet cell endocrine tumors. Risk factors associated with the development of PDA include increased age, tobacco usage (Silverman et al. 1994), African heritage (Ahlgren 1996), and a family history of pancreatic cancer . Despite the relatively large numbers of patients stricken with PDA, estimated at 32,180 for 2005, our expanding knowledge of critical aspects of this disease remains terribly inadequate and undoubtedly contributes to our inability to intervene meaningfully. The impetus to investigate the biological underpinnings of PDA is further motivated by the predicted doubling in PDA incidence over the next two decades as the population ages (Hruban et al. 2006a). Nonetheless, the public investment in pancreatic cancer research is woefully inadequate relative to other malignancies, and consequently, the number of investigators pursuing PDA is unfortunately restricted. GENETICS OF PDA AND PanINPDA is thought to evolve from a preinvasive precursor state termed pancreatic intraepithelial neoplasms (PanINs) because PanINs demonstrate cytological and genetic changes that reflect those evident in invasive PDA. PanINs are divided into three stages characterized by increasing degrees of cellular and architectural atypia. PanIN-1A lesions are flat and contain tall columnar ductal cells in distinction to the short cuboidal cells that line normal pancreatic ducts; PanIN-1B lesions additionally demonstrate mild papillary architecture in the ducts but no nuclear atypia; the PanIN-2 stage signifies cells with moderate nuclear atypia and loss of cellular polarity; PanIN-3s represent the carcinoma-in-situ stage of pancreatic cancer, characterized by marked atypia, dysregulated growth, cribriform structures, and pinched-off clusters of epithelial cells...

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Section: Clinical Considerations In Pancreatic Cancermentioning

confidence: 99%

Ductal Pancreatic Cancer in Humans and Mice

Tuveson¹,

Hingorani²

2005

Cold Spring Harbor Symposia on Quantitative Biology

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“…In pancreatic cancer, few molecularly characterised antigens have so far been available for use in vaccines. However, the catalytic subunit of telomerase, hTERT, expressed in 85 -90% of human cancer tissues (Vasef et al, 1999) and an attractive 'universal' tumour antigen (Autexier, 1999), is also expressed in pancreatic cancer where it has been used diagnostically (Suehara et al, 1998;Uehara et al, 1999). By turning on hTERT and telomerase activity, cancer cells are enabled to maintain functional telomeres at the end of chromosomes, and are prevented from going into senescence.…”

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confidence: 99%

Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study

et al. 2006

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Patients with inoperable pancreatic cancer have a dismal prognosis with a mean life expectancy of 3 -6 months. New treatment modalities are thus urgently needed. Telomerase is expressed in 85 -90% of pancreas cancer, and immunogenic telomerase peptides have been characterised. A phase I/II study was conducted to investigate the safety, tolerability, and immunogenecity of telomerase peptide vaccination. Survival of the patients was also recorded. Forty-eight patients with non-resectable pancreatic cancer received intradermal injections of the telomerase peptide GV1001 at three dose levels, in combination with granulocyte -macrophage colonystimulating factor. The treatment period was 10 weeks. Monthly booster vaccinations were offered as follow-up treatment. Immune responses were measured as delayed-type hypersensitivity skin reaction and in vitro T-cell proliferation. GV1001 was well tolerated. Immune responses were observed in 24 of 38 evaluable patients, with the highest ratio (75%) in the intermediate dose group. Twenty-seven evaluable patients completed the study. Median survival for the intermediate dose-group was 8.6 months, significantly longer for the low-(P ¼ 0.006) and high-dose groups (P ¼ 0.05). One-year survival for the evaluable patients in the intermediate dose group was 25%. The results demonstrate that GV1001 is immunogenic and safe to use. The survival data indicate that induction of an immune response is correlated with prolonged survival, and the vaccine may offer a new treatment option for pancreatic cancer patients, encouraging further clinical studies.

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“…Screening tests for the general population have to be accurate, safe, and convenient, as well as capable of high throughput. Many researchers have devoted considerable effort to discovering biomarkers of pancreatic cancer (8)(9)(10), and CA242 (11), M2-pyruvate kinase (12), PBF-4 (13), MIC-1 (14), PNA-binding glycoprotein (15), hTert (16), MMP-2 (17), and synuclein-g (18) have been reported as candidate biomarkers, but they were not clinically superior to CA19-9 or other clinical examinations.…”

Section: Introductionmentioning

confidence: 99%

A Novel Serum Metabolomics-Based Diagnostic Approach to Pancreatic Cancer

Kobayashi

Nishiumi

Ikeda

et al. 2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

157

144

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Background: To improve the prognosis of patients with pancreatic cancer, more accurate serum diagnostic methods are required. We used serum metabolomics as a diagnostic method for pancreatic cancer.Methods: Sera from patients with pancreatic cancer, healthy volunteers, and chronic pancreatitis were collected at multiple institutions. The pancreatic cancer and healthy volunteers were randomly allocated to the training or the validation set. All of the chronic pancreatitis cases were included in the validation set. In each study, the subjects' serum metabolites were analyzed by gas chromatography mass spectrometry (GC/MS) and a data processing system using an in-house library. The diagnostic model constructed via multiple logistic regression analysis in the training set study was evaluated on the basis of its sensitivity and specificity, and the results were confirmed by the validation set study.Results: In the training set study, which included 43 patients with pancreatic cancer and 42 healthy volunteers, the model possessed high sensitivity (86.0%) and specificity (88.1%) for pancreatic cancer. The use of the model was confirmed in the validation set study, which included 42 pancreatic cancer, 41 healthy volunteers, and 23 chronic pancreatitis; that is, it displayed high sensitivity (71.4%) and specificity (78.1%); and furthermore, it displayed higher sensitivity (77.8%) in resectable pancreatic cancer and lower false-positive rate (17.4%) in chronic pancreatitis than conventional markers.Conclusions: Our model possessed higher accuracy than conventional tumor markers at detecting the resectable patients with pancreatic cancer in cohort including patients with chronic pancreatitis.Impact: It is a promising method for improving the prognosis of pancreatic cancer via its early detection and accurate discrimination from chronic pancreatitis. Cancer Epidemiol Biomarkers Prev; 22(4); 571-9. Ó2013 AACR.

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Diagnosis of Pancreatic Cancer by Detecting Telomerase Activity in Pancreatic Juice: Comparison With K- Ras Mutations

Abstract: It was shown that the detection of telomerase activity in pancreatic juice is a more useful diagnostic tool for pancreatic cancer than that of K-ras mutations.

Cited by 81 publications

References 42 publications

Ductal Pancreatic Cancer in Humans and Mice

Ductal Pancreatic Cancer in Humans and Mice

Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study

A Novel Serum Metabolomics-Based Diagnostic Approach to Pancreatic Cancer

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