National Cancer Institute®
Last Modified: February 1, 2002
UI - 11545191
AU - Koyama K; Okamura T; Kawabe J; Nakata B; Chung KH; Ochi H; Yamada R
TI - Diagnostic usefulness of FDG PET for pancreatic mass lesions.
SO - Ann Nucl Med 2001 Jun;15(3):217-24
AD - Department of Radiology, Osaka City University School of Medicine, Osaka, Japan. firstname.lastname@example.org
The purpose of this study was to investigate the feasibility of [18F]2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) in patients with a pancreatic mass by comparing the results with those of X-ray computed tomography (CT) and magnetic resonance (MR) imaging. METHODS: Eighty-six patients with pancreatic lesions, included 65 malignant tumors and 21 benign masses (55 masses were proven histologically and the others were diagnosed clinically), were studied. The diagnostic factors of CT and MR imaging were evaluated, and those of FDG PET were also evaluated for malignant and benign masses by visual interpretation and quantitative interpretation with the standardized uptake value (SUV) and SUVgluc which was designed to reduce the effects of a high blood sugar level. Visual interpretations were evaluated only in FDG PET images, and quantitative interpretations were evaluated by referring to CT and/or MR imaging. The correlation between SUV and the degree of histological differentiation in pancreatic ductal adenocarcinoma was investigated. RESULTS: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for CT imaging were 91, 62, 88, 68 and 84%, and for MR imaging 78, 70, 88, 54 and 76%, respectively. In visual interpretation of FDG PET images, the sensitivity, specificity, PPV, NPV and accuracy were 82, 81, 93, 59 and 81%, respectively. Significant differences between malignant and benign lesions existed in SUV and SUVgluc (p < 0.0001, each). With the cutoff value of SUV as 2.1 and SUVgluc as 2.2, the accuracy of diagnosis was maximal. With that cutoff value, the sensitivity, specificity, PPV, NPV and accuracy for SUV were 89, 76, 92, 70 and 86%, and for SUVgluc 91, 76, 92, 73 and 87%, respectively. The sensitivity and NPV of SUVgluc were higher than those of SUV, which suggests that SUVgluc may be more useful in reducing the number of overlooked malignant tumors. The specificity and PPV of FDG PET were superior to those of CT and MR imaging. There were no significant differences between the SUVs of moderately differentiated adenocarcinomas and those of well differentiated adenocarcinomas. CONCLUSION: To improve the diagnostic procedure for classifying masses, FDG PET with not only SUV but also SUV corrected by the blood sugar level is required in addition to morphological diagnosis by CT and/or MR imaging.
UI - 11815961
AU - Adsay NV; Conlon KC; Zee SY; Brennan MF; Klimstra DS
TI - Intraductal papillary-mucinous neoplasms of the pancreas: an analysis of in situ and invasive carcinomas in 28 patients.
SO - Cancer 2002 Jan 1;94(1):62-77
AD - Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 1002, USA.
BACKGROUND: Intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas are intraductal tumors with variable amounts of papilla formation, mucin production, and cytoarchitectural atypia. Associated invasive carcinomas, reported to occur in up to 30% of patients, often are mucinous and clinically indolent. METHODS: The clinical and pathologic features of 28 IPMNs resected at Memorial Sloan-Kettering Cancer Center between 1983 and 1997 were reviewed. RESULTS: There were 16 females and 12 males with a mean age of 68 years (range, 44-79 years) and a mean tumor size of 4.5 cm (range, 1.5-11.0 cm). The head of the gland was the predominant tumor site (89%). Abdominal pain, weight loss, and acholic stool were the most common symptoms at presentation. According to histology, two types of papillae were identified: intestinal (22 patients) and pancreatobiliary (6 patients). In the intraductal component, cytologic atypia was minimal (i.e., intraductal papillary-mucinous [IPM] adenoma) in 2 patients and moderate (IPM borderline tumor) in 5 patients, and severe atypia (IPM carcinoma in situ) was seen at least focally in 21 patients. In addition, invasive carcinoma was identified in 15 patients (53%), 4 of whom had only microscopic foci. Invasive carcinoma was of the mucinous type (colloid) in six patients and of the tubular type (conventional ductal adenocarcinoma) in nine patients. At a median follow-up of 35 months, four patients died of disease; two of these patients had only borderline atypia with no identified in situ or invasive carcinoma in the sections submitted. Eighteen patients had no evidence of disease, 1 patient was alive with recurrent disease, and 5 patients died of other causes. The actuarial 5-year disease free survival rate was 78%. Of the 14 patients with invasive carcinoma, 5 of 6 patients with colloid type tumors were free of tumor at a mean of 55 months. Of the patients with tubular type invasive carcinoma, two patients died of their disease (at 4 years and 7 years), three patients died of other causes, and four patients were alive (three were free of disease, and one experienced disease recurrence) at an average follow-up of 7.5 years. CONCLUSIONS: Two distinct patterns of intraductal papillae are seen in patients with IPMNs: intestinal and pancreatobiliary. Both in situ and invasive carcinoma may be encountered more commonly than previously recognized. Tubular type invasive carcinomas occur as well as mucinous type (colloid) carcinomas. Although the neoplasms are less aggressive as a group than conventional pancreatic ductal adenocarcinoma, patients with IPMNs may pursue a deadly course, even in the absence of identifiable invasive carcinoma. Conversely, patients with tubular type invasive carcinoma arising in the background of IPMN may follow a more favorable course than patients with conventional ductal adenocarcinoma without IPMN, emphasizing the importance of recognizing the IPMN component in patients with pancreatic adenocarcinoma. Copyright 2002 American Cancer Society.
UI - 11815963
AU - Lynch HT; Brand RE; Hogg D; Deters CA; Fusaro RM; Lynch JF; Liu L;
TI - Knezetic J; Lassam NJ; Goggins M; Kern S Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome.
SO - Cancer 2002 Jan 1;94(1):84-96
AD - Department of Preventive Medicine, Creighton University School of Medicine, Omaha, Nebraska 68178, USA. email@example.com
BACKGROUND: Hereditary pancreatic carcinoma shows extant phenotypic and genotypic heterogeneity as evidenced by its integral association with a variety of hereditary cancer syndromes inclusive of the familial atypical multiple mole melanoma (FAMMM) syndrome in concert with CDKN2A (p16) germline mutations. METHODS: Creighton University's familial pancreatic carcinoma resource comprises 159 families of which 19 (12%) show the FAMMM cutaneous phenotypes. The authors describe eight families with the FAMMM-pancreatic carcinoma (FAMMM-PC) association in concert with a CDKN2A germline mutation. Each family was thoroughly educated about all facets of the study, including the molecular genetics, reduced penetrance of CDKN2A mutations, and their variable expressivity. Genetic counseling was provided to each patient. RESULTS: Diversity in cancer presentation within and among the families was noteworthy, wherein melanoma predominated in certain of the families whereas pancreatic carcinoma predominated in others. Early-onset pancreatic carcinoma (at ages 35, 45, 46, and 49 years) appeared in some of the families whereas markedly later-onset pancreatic carcinoma occurred in others. There were four incidences of melanoma and pancreatic carcinoma as double primaries in the same individuals. One patient with melanoma and pancreatic carcinoma had a third primary of breast carcinoma. Another patient had sarcoma, esophageal carcinoma, and two melanoma primaries, whereas his daughter had sarcoma and was a carrier of a CDKN2A mutation. CONCLUSIONS: The authors suggest that these tumors may collectively, in concert with CDKN2A mutations, constitute a "new" putative hereditary carcinoma syndrome referred to as FAMMM-PC. More clinical and molecular genetic research on additional families with pancreatic carcinoma in concert with the FAMMM will be required. Copyright 2002 American Cancer Society.
UI - 11807625
AU - Perez SA; Sotiropoulou PA; Sotiriadou NN; Mamalaki A; Gritzapis AD;
TI - Echner H; Voelter W; Pawelec G; Papamichail M; Baxevanis CN HER-2/neu-derived peptide 884-899 is expressed by human breast, colorectal and pancreatic adenocarcinomas and is recognized by in-vitro-induced specific CD4(+) T cell clones.
SO - Cancer Immunol Immunother 2002 Jan;50(11):615-24
AD - Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 115 22 Athens, Greece.
HER-2/neu peptides recognized in the context of HLA-DR molecules by CD4(+) Th lymphocytes on antigen-presenting cells have been identified. In this report, we demonstrate for the first time that HER-2/neu helper epitopes are also expressed on the surface of metastatic breast, colorectal and pancreatic carcinomas. Peripheral blood mononuclear cells from an HLA-DR4 healthy donor were used to induce HER-2/neu peptide-specific CD4(+) T cell clones by in vitro immunization with HER-2/neu peptide (884-899)-pulsed autologous dendritic cells (DCs). Strong proliferation and significant levels of IFN-gamma were induced by the CD4(+) T cell clones in response to specific stimulation with autologous DCs loaded with HER-2(884-899). Furthermore, these clones also recognized HER-2/neu(+) tumor cell lines, and tumor cells from breast, colorectal and pancreatic adenocarcinomas induced to express HLA-DR4, but also the HLA-DR4(+) melanoma cell line FM3 transfected to express HER-2/neu. The recognition of tumor cells was strongly inhibited by an anti-HLA-DR mAb. Taken altogether, we provide novel information for the role of HER-2(884-899) as a naturally processed epitope expressed by breast, colorectal and pancreatic carcinomas and the capacity of HER-2/neu protein to follow the endogenous class II processing pathway. Our results suggest that HER-2(884-899) might be attractive for broadly applicable vaccines and may prove useful for adoptive immunotherapy designed for breast, colorectal and pancreatic carcinomas.
UI - 11719088
AU - Li D; Firozi PF; Zhang W; Shen J; DiGiovanni J; Lau S; Evans D; Friess
TI - H; Hassan M; Abbruzzese JL DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer.
SO - Mutat Res 2002 Jan 15;513(1-2):37-48
AD - Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, The University of Texas, 1400 Holcombe Blvd., Box 426, Houston, TX 77030, USA. firstname.lastname@example.org
To test the hypothesis that carcinogen exposure and oxidative stress are involved in pancreatic carcinogenesis in susceptible individuals, aromatic DNA adducts and 8-hydroxyguanosine (8-OH-dG) were measured by (32)P-postlabeling and HPLC-EC, respectively, in 31 pancreatic tumors and 13 normal tissues adjacent to the tumor from patients with pancreatic cancer. Normal pancreatic tissues from 24 organ donors, from six patients with non-pancreatic cancers, and from five patients with chronic pancreatitis served as controls. It was found that tissue samples from patients with pancreatic cancer had significantly higher levels of both aromatic DNA adducts and 8-OH-dG compared with control samples. The mean (+/-S.D.) levels of aromatic DNA adducts were 101.8+/-74.6, 26.9+/-26.6, and 11.2+/-6.6 per 10(9) nucleotides in adjacent tissues, tumors, and controls, respectively. The mean (+/-S.D.) levels of 8-OH-dG were 11.9+/-9.6, 10.8+/-10.6, and 6.7+/-4.6 per 10(5) nucleotides in adjacent tissues, tumors, and controls, respectively. Polymorphisms of the CYP1A1, CYP2E1, NAT1, NAT2, GSTM1, MnSOD, and hOGG1 genes were determined in these patients. The level of aromatic DNA adducts was significantly associated with polymorphism of the CYP1A1 gene. No significant correlation was found between the level of 8-OH-dG and the MnSOD, GSTM1, and hOGG1 polymorphisms. However, one novel polymorphism/mutation of the hOGG1 gene was found in a pancreatic tumor. Mutation at codon 12 of the K-ras gene was found in 25 (81%) of 31 pancreatic tumors, including three G-to-A transitions and 22 G-to-T transversions. Patients with the G-to-T mutation had a significantly higher level of aromatic DNA adducts than those with G-to-A or wild-type codon (P=0.02). On the other hand, the K-ras mutation profile was not related to the level of 8-OH-dG. Given the limitation of sample size, these preliminary data lend further support the hypothesis that carcinogen exposure and oxidative stress are involved in pancreatic carcinogenesis.
UI - 10535205
AU - Clave P; Boadas J; Gonzalez-Carro P; Mora J; Perez C; Martinez A; Roca
TI - M; Lluis F; Farre A [Accuracy of imaging techniques and tumor markers in the diagnosis of pancreatic cancer]
SO - Gastroenterol Hepatol 1999 Aug-Sep;22(7):335-41
AD - Laboratori d'Investigacio Gastrointestinal, Hospital de la Santa Creu i Sant Pau, Barcelona.
OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of: a) three imaging techniques: ultrasonography (US), computed tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP), and b) the serum tumor markers CEA, CA 19-9 and CA 125, in the diagnosis of pancreatic cancer. PATIENTS AND METHODS: A total of 137 patients were prospectively evaluated. Pancreatic cancer was diagnosed in 25 patients; chronic pancreatitis in 24; acute pancreatitis in 22; extrapancreatic malignancies in 24, and benign digestive disease in 42. The reference interval for each marker was determined in 36 healthy volunteers. Diagnostic accuracy was determined using receiver operating characteristic (ROC) curves. Each diagnostic test was used in order: a) to diagnose pancreatic cancer when the disease was clinically suspected, and b) to differentiate between pancreatic cancer and chronic pancreatitis. RESULTS: CT (0.976-0.888) and US (0.857) diagnostic accuracy resulted greater than the best serum tumor marker CA 19-9 (0.755-0.786) (p = NS), in both diagnostic conditions. To obtain a diagnostic specificity of 90% in pancreatic cancer, the CA 19-9 cutoff level should increase up to 3 and 7.5 folds being in this case better than CEA and CA 125 (p < 0.05). CONCLUSIONS: CT scan offers the greatest accuracy in the diagnosis of PC. Among the tumor markers, CA 19-9 offers the best accuracy in the diagnosis of pancreatic cancer.
UI - 11677955
AU - Linder S; Castanos-Velez E; von Rosen A; Biberfeld P
TI - Immunohistochemical expression of extracellular matrix proteins and adhesion molecules in pancreatic carcinoma.
SO - Hepatogastroenterology 2001 Sep-Oct;48(41):1321-7
AD - Department of Surgery, Stockholm Soder Hospital, Stockholm, Sweden.
BACKGROUND/AIMS: Carcinoma invasion and metastasis in general involve multiple steps including dynamic changes in the composition and structure of extracellular matrix proteins and cell surface receptors. In the present study, the usually highly invasive carcinoma of the pancreas was investigated regarding the expression of various extracellular matrix proteins and their corresponding integrin receptors, as well as E-cadherin. METHODOLOGY: Phenotypic expression of various markers was investigated immunohistochemically in frozen sections of 16 pancreatic carcinomas and normal pancreatic tissue. RESULTS: An irregular and discontinuous deposition of type IV collagen and laminin in the basement membrane was found in cancer tissue and a pronounced desmoplastic reaction with deposition of type I, type III, and type IV collagen in the tumor stroma. In contrast, the noninvolved pancreas showed an intact basement membrane and a sparse stroma. The collagen type IV and laminin receptors alpha 2, alpha 3, and beta 1 integrin subunits were expressed on pancreatic cancer cells but not the alpha 6 integrin subunit normally present on epithelial cells, suggesting anchorage independence of the carcinoma cells. An increased capacity for cancer cell motility was suggested by the abundant expression of the "antiadhesive" extracellular matrix proteins, tenascin and vitronectin close to the cancer cells, and the expression of cell surface receptors such as alpha v (vitronectin-binding). Expression of the alpha 4 integrin subunit was also increased on cancer cells. CONCLUSIONS: The distribution of extracellular matrix proteins and the cell surface immune phenotype differed in pancreatic carcinoma as compared to normal pancreatic tissue. The present findings substantiate the notion that disseminated growth of highly malignant carcinomas of the pancreas reflects an invasive interaction of the tumor cells with extracellular matrix proteins of a well-established stroma. Similar findings were observed regardless of tumor histology and patient survival time.
UI - 11781278
AU - Hara T; Yamaguchi T; Ishihara T; Tsuyuguchi T; Kondo F; Kato K; Asano T;
TI - Saisho H Diagnosis and patient management of intraductal papillary-mucinous tumor of the pancreas by using peroral pancreatoscopy and intraductal ultrasonography.
SO - Gastroenterology 2002 Jan;122(1):34-43
AD - First Department of Medicine, Chiba University School of Medicine, Chiba, Japan. email@example.com
BACKGROUND & AIMS: Intraductal papillary-mucinous tumor (IPMT) of the pancreas has attracted increasing interest because of its unique presentation. The differential diagnosis between malignant and benign tumors is extremely important in the determination of the therapy for IPMT. The aims of this study are to determine the usefulness of peroral pancreatoscopy (POPS) and intraductal ultrasonography (IDUS) in IPMT for the differentiation of malignant from benign disease, and to evaluate the significance of these techniques as new preoperative examinations. METHODS: Sixty histopathologically confirmed patients with IPMT underwent POPS and/or IDUS preoperatively. POPS was perfomed in all patients, and IDUS in 40. Findings of POPS and IDUS were compared with histopathology of resected specimens. The postoperative follow-up data were analyzed. RESULTS: Protruding lesions were detected by POPS in 40 patients. They were classified into 5 groups. Fish-egg-like type with vascular images, villous type, and vegetative type were considered to be malignant. By IDUS, lesions protruding 1 mm or more were observed in 36 patients. Of the lesions protruding 4 mm or more, 88% were malignant. Combination of POPS and IDUS improved the differential diagnosis between benign and malignant IPMT. The 3-year cumulative survival rate and disease-free survival rate were extremely high at 95% and 93%, respectively. CONCLUSIONS: The combination of POPS and IDUS results in a considerably improved differential diagnosis between malignant and benign IPMT and is useful for determining an effective therapeutic approach. These new techniques can contribute to improvements in postoperative results.
UI - 11787377
AU - Escourrou J; Buscail L; Pages P; Moreau J; Faure P
TI - [Prognosis of pancreatic adenocarcinoma]
SO - Gastroenterol Clin Biol 2001 Sep;25 Spec No 2():C30-3
AD - Service de Gastroenterologie, Hopital de Rangueil, 1 Avenue Jean Poulhes, 31403 Toulouse. firstname.lastname@example.org
UI - 11529235
AU - Schulz MR; Hertz-Picciotto I; van Wijngaarden E; Hernandez JC; Ball LM
TI - Dose-response relation between acrylamide and pancreatic cancer.
SO - Occup Environ Med 2001 Sep;58(9):609
UI - 11740694
AU - Bunk A; Pistorius S; Konopke R; Ockert D; Kuhlisch E; Saeger HD
TI - [The value of colour duplex sonography in the assessment of surgical resectability of pancreatic tumors]
SO - Ultraschall Med 2001 Dec;22(6):265-73
AD - Klinik und Poliklinik fur Viszeral-, Thorax- und Gefasschirurgie, Universitatsklinikum Carl Gustav Carus an der TU Dresden, Germany.
The Value of Colour Duplex Sonography in the Assessment of Surgical Resectability of Pancreatic Tumors. AIM: The aim of this study was to evaluate the assessment by modern colour duplex imaging (CDI) concerning the relation between tumour and vessels including haemodynamic parameters in the main abdominal arteries and the portal system, and to evaluate the influence of these results on surgical decision making. the pancreas were included in a prospective study. Tumour contact to vessels and to the retroperitoneum, data on the flow in the main abdominal arteries and the portal circulation (regional topography) as well as the detection of liver metastases, enlarged lymph nodes and peritoneal carcinomatosis were defined as representing criteria of resectability. The results were compared with the intraoperative situation and with the definite histological findings. RESULTS: In 57 resectable tumours, the portal system was found to be infiltrated by the tumour up to a length of 1.5 cm. The flow velocity reached between 4 and 53 cm/s (mean flow) and 9 to 105 cm/s (maximum flow). Out of 146 pancreatic tumours, 89 were found as being non-resectable. In these cases, the measured parameters differed depending on the degree of tumour infiltration in to the portal circulation. We measured values from 0 to 96 cm/s (mean flow) and from 0 to 201 cm/s (maximum flow) with loss of breath-dependent modulation. The contact area between tumor and portal vessel was longer than 2 cm. Pathological flow in the main abdominal arteries was only found in 2 of 13 cases. The local situation was assessed correctly in 140 out of 146 cases by CDI (sensitivity of 93.0 %, specificity of 97.8 %, positive predictive value of 96.4 %, negative predictive value of 95.6 %). Regarding the complete oncological status (local situation, metastases, lymph node involvement and peritoneal carcinomatosis), a sensitivity of 82.5 % and a specificity of 92.1 % (positive predictive value of 87.0 %, negative predictive value of 89.1 %) was found. CONCLUSION: Modern CDI can reliably assess the resectability of pancreatic tumours by the evaluation of morphological and haemodynamic parameters. There are still difficulties in the assessment of lymph node involvement as well as in the detection of small liver metastases and of peritoneal carcinomatosis without ascites.
UI - 11743665
AU - Glazyrin AL; Chinni S; Alhasan S; Adsay VN; Vaitkevicius VK; Sarkar FH
TI - Molecular mechanism(s) of actinomycin-D induced sensitization of pancreatic cancer cells to CD95 mediated apoptosis.
SO - Int J Oncol 2002 Jan;20(1):201-5
AD - Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
The death receptor CD95 transduces apoptotic death signaling in many cell types. However, in pancreatic tumor cells CD95 mediated apoptotic machinery is blocked by unknown protein(s). We and others have recently demonstrated that actinomycin-D (ActD) treatment induces sensitization of pancreatic cancer cells as well as other cell types to CD95 mediated apoptosis. In addition, NF-kappaB/Akt system has been implicated in the processes of CD95 mediated apoptosis, however the precise mechanism by which ActD sensitizes pancreatic tumor cells to CD95 mediated apoptosis is still unknown. In the present study, we demonstrated that HPAC and PANC1 pancreatic cancer cells constitutively express high levels of NF-kappaB and phosphorylated form of Akt. ActD at a dose that is known to sensitize pancreatic cancer cells to CD95 mediated apoptosis abrogated the DNA binding activity of NF-kappaB but did not affect expression of phosphorylated Akt. Co-treatment of pancreatic cancer cells with ActD and agonist anti-CD95 antibodies showed no effect on the abrogation on the DNA binding activity of NF-kappaB, but decreased the expression of phosphorylated Akt. Moreover, treatment with PI3-kinase inhibitor LY294002 did not show any sensitization of pancreatic cancer cells to CD95 mediated apoptosis. Our data suggest that ActD sensitizes pancreatic cancer cells to CD95 mediated apoptosis through the abrogation of DNA binding activity of NF-kappaB, rather than PI3-kinase/Akt system. Over-expression of phosphorylated Akt in pancreatic cancer cells is controlled by effective apoptotic signaling from CD95 receptors, but do not protect tumor cells from CD95 induced apoptosis. Thus, our results indicate that modulation of NF-kappaB activity rather then Akt may provide a useful tool to sensitize pancreatic cancer cells to CD95 mediated apoptosis.
UI - 11781662
AU - Wesseling JG; Yamamoto M; Adachi Y; Bosma PJ; van Wijland M; Blackwell
TI - JL; Li H; Reynolds PN; Dmitriev I; Vickers SM; Huibregtse K; Curiel DT Midkine and cyclooxygenase-2 promoters are promising for adenoviral vector gene delivery of pancreatic carcinoma.
SO - Cancer Gene Ther 2001 Dec;8(12):990-6
AD - Department of Experimental Hepatology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Midkine (MK), a heparin binding growth factor, and cyclooxygenase-2 (COX-2), a key enzyme in the conversion of arachidonic acid to prostaglandin, are both up-regulated at the mRNA or protein level in many human malignant tumors. Here, we investigated the tumor specificity of both MK and COX-2 promoters in human pancreatic cancer, with the aim to improve the selectivity of therapeutic gene expression. We constructed recombinant adenoviral (Ad) vectors containing either the luciferase (Luc) reporter gene under the control of the COX-2 or MK promoter or the herpes simplex virus thymidine kinase (HSV Tk) gene under the control of the COX-2 promoter and compared the expression with the cytomegalovirus (CMV) promoter. AdMKLuc achieved moderate to relatively high activity upon infection to both primary and established pancreatic carcinoma cells. Of the two COX-2 promoter regions (COX-2M and COX-2L), both revealed a high activity in primary pancreatic carcinoma cells, whereas in the established pancreatic carcinoma cell lines, COX-2L has an approximately equal high activity compared to CMV. In addition, both AdCOX-2M Tk and AdCOX-2L Tk induced marked cell death in response to ganciclovir (GCV) in three of four established pancreatic carcinoma cell lines. From these results, and because it has been reported that AdMKTk and AdCOX-2L Tk in combination with GCV did not reveal significant liver toxicity, we conclude that the MK as well as the COX-2 promoters are promising tumor-specific promoters for Ad vector-based gene therapy of pancreatic cancer.
UI - 11780432
AU - Wang C; Lu X; Liu G; Dai L; Xu T; Chen Y; Gao C; Wen X; Qian J
TI - Detailed deletion mapping on chromosome region 9p21 in human periampullary neoplasms.
SO - Chin Med J (Engl) 2001 Jun;114(6):588-91
AD - Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China. email@example.com
OBJECTIVE: To further define the extent of chromosome 9p21 deletion in periampullary neoplasms. METHODS: The loss of heterozygosity at 5 microsatellite polymorphic markers on chromosome 9p21 was detected by polymerase chain reaction (PCR), polyacrylamide gel electrophoresis (PAGE) and silver staining in 35 specimens of periampullary neoplasms and their matching blood samples. RESULTS: Fifty percent (4/8) of pancreatic cancer cases showed the loss of heterozygosity at one or more microsatellite loci, with the more frequent sites of D9S974 (37.5%) and D9S942 (28.6%), and some showing consecutive allelic loss. Sixty-two point five percent (5/8) of ampullary carcinoma cases showed loss of heterozygosity at one or more of the loci, frequent site of loss being D9S942 (42.9%) and the next most frequent being IFNA (37.5%) and D9S171 (37.5%). Loss of one locus was observed in 14.2% (1/7) of insulinoma. CONCLUSION: The minimal common region of chromosome deletion in periampullary neoplasms is defined between the D9S974 and D9S942 loci within a 15 kb interval in 9p21, suggesting the involvement of a novel tumor suppressor gene in their carcinogenesis.
UI - 11741176
AU - Kawa S; Nikaido T; Unno H; Usuda N; Nakayama K; Kiyosawa K
TI - Growth inhibition and differentiation of pancreatic cancer cell lines by PPAR gamma ligand troglitazone.
SO - Pancreas 2002 Jan;24(1):1-7
AD - The Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan. firstname.lastname@example.org
INTRODUCTION: Ligand activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) results in growth inhibition and differentiation of various cancer cells. AIMS: We determined whether the PPAR gamma ligand, troglitazone, inhibits the growth of pancreatic cancer cells and clarified the underlying mechanisms with a special focus on restriction point control of the late G1 phase of the cell cycle. METHODOLOGY: Nine pancreatic cancer cell lines were used to study a variety of troglitazone effects on cell growth by MTT assay, on cell cycle by flow cytometry, on cell cycle regulating factors of late G1 phase by Western and Northern blotting and CDK2 kinase assay, and on morphology by collagen gel culture and electron-microscopy. RESULTS: Troglitazone showed a potent dose-response effect on the growth inhibition of six pancreatic cancer cell lines, which were suppressed to less than 50% of control at the concentration of 10 microM. The growth inhibition was linked to the G1 phase cell cycle arrest through the upregulation of p21 mRNA and protein expression simultaneously with the inhibition of CDK2 kinase activity and the hypophosphorylation of Rb protein. The upregulation of expression of p21 mRNA was mainly due to stabilization of mRNA. Troglitazone induced significant morphologic changes of duct structure with apoptotic cells in the lumen. CONCLUSION: Troglitazone had growth inhibitory and differentiation induction effects on the pancreatic cancer cell lines through the upregulation of p21 expression, suggesting that ligand activation of PPAR gamma is a new molecular target for effective therapy against pancreatic cancer.
UI - 11741178
AU - Hirai I; Kimura W; Ozawa K; Kudo S; Suto K; Kuzu H; Fuse A
TI - Perineural invasion in pancreatic cancer.
SO - Pancreas 2002 Jan;24(1):15-25
AD - First Department of Surgery, Yamagata University School of Medicine, Yamagata, Japan. email@example.com
INTRODUCTION: Perineural invasion is regarded as a factor associated with local recurrence of pancreatic cancer. AIM: To examine perineural invasion of pancreatic cancer pathologically and clinically. METHODOLOGY: In 24 cases of surgically resected pancreatic cancer, correlations among the degree of perineural invasion, differentiation, interstitial connective tissue, lymph node metastasis, and survival rate were examined. Consecutive 5-microm serial sections (n = 1072) were made in six cases that showed characteristic mode of perineural invasion. RESULTS: Perineural invasion was observed in 17 cases (70.8%; ne0-7; ne1-6; ne2-9; and ne3-2 cases). Perineural invasion was absent in three of five cases of papillary carcinoma, but was observed in 12 of 14 cases of moderately differentiated carcinoma. The survival rate for ne0 was better than that of the other groups, with the 3-year survival rate being 57.1%. Perineural cancer glands had developed discontinuously in two cases. CONCLUSIONS: Perineural invasion is an important prognostic factor in pancreatic cancer, increasing as the cancer becomes undifferentiated. Even if there are no cancer cells at the margin of the pancreas at the time of surgery, the cancer cells may spread further to the noncancerous pancreas or retroperitoneum. Sufficient dissection of the neural plexus or intraoperative radiation may be required.
UI - 11741179
AU - Boros LG; Lee WN; Go VL
TI - A metabolic hypothesis of cell growth and death in pancreatic cancer.
SO - Pancreas 2002 Jan;24(1):26-33
AD - Harbor-University of California Los Angeles Research and Education Institute, UCLA School of Medicine, Torrance, California 90502, USA. firstname.lastname@example.org
INTRODUCTION: Tumor cells, just as other living cells, possess the potential for proliferation, differentiation, cell cycle arrest, and apoptosis. There is a specific metabolic phenotype associated with each of these conditions, characterized by the production of both energy and special substrates necessary for the cells to function in that particular state. Unlike that of normal living cells, the metabolic phenotype of tumor cells supports the proliferative state. AIM: To present the metabolic hypothesis that (1) cell transformation and tumor growth are associated with the activation of metabolic enzymes that increase glucose carbon utilization for nucleic acid synthesis, while enzymes of the lipid and amino acid synthesis pathways are activated in tumor growth inhibition, and (2) phosphorylation and allosteric and transcriptional regulation of intermediary metabolic enzymes and their substrate availability together mediate and sustain cell transformation from one condition to another. CONCLUSION: Evidence is presented that demonstrates opposite changes in metabolic phenotypes induced by TGF-beta, a cell-transforming agent, and tumor growth-inhibiting phytochemicals such as genistein and Avemar, or novel synthetic anti-leukemic drugs such as STI571 (Gleevec). Intermediary metabolic enzymes that mediate the growth signaling pathways and promote malignant cell transformation may serve as high-efficacy nongenetic novel targets for cancer therapies.
UI - 11741180
AU - Kaneko K; Satoh K; Masamune A; Satoh A; Shimosegawa T
TI - Myosin light chain kinase inhibitors can block invasion and adhesion of human pancreatic cancer cell lines.
SO - Pancreas 2002 Jan;24(1):34-41
AD - Department of Gastroenterology, Division of Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyaga, Japan. email@example.com
INTRODUCTION: Invasion and metastasis of pancreatic cancer (PC) require cell motility and adhesion, which depend on the activity of cytoskeleton. A cytoskeletal component indispensable for these processes is myosin II, the cytoplasmic analogue of smooth and skeletal muscle myosin. AIMS AND METHODOLOGY: Because the activity of myosin II is accelerated by phosphorylation of myosin II on its regulatory light chain (RLC) by myosin light chain kinase (MLCK), we used two specific MLCK inhibitors, ML-7 and ML-9, for suppression of motility and adhesion of PC cell lines. RESULTS: Both drugs were potent inhibitors, as measured by in vitro motility assay and adhesion assay. When treated with the same concentration of ML-7, the PC cells were rounded up, and the number of stress fibers was reduced markedly. The in vitro migration and adhesion of PC cells were inhibited by ML-7 and ML-9 in a dose-dependent manner, supporting a specific and competitive inhibition of MLCK by these drugs. The inhibition occurred at nontoxic concentrations. CONCLUSIONS: These results highlight the importance of myosin II in the invasion and metastasis of PC cells and suggest the possibility that blocking of myosin II activity by a specific MLCK inhibitor may be a therapeutic strategy for preventing the invasion and metastasis of PC.
UI - 11741188
AU - Suzuki K; Takahashi S; Aiura K; Hayatsu S; Kitago M; Hoshimoto S;
TI - Kitajima M Evaluation of the usefulness of percutaneous transhepatic portal catheterization for preoperatively diagnosing the localization of insulinomas.
SO - Pancreas 2002 Jan;24(1):96-102
AD - Department of Surgery, Keio University School of Medicine, Tokyo, Japan. firstname.lastname@example.org
INTRODUCTION: The precise intraoperative localization of insulinoma is essential for successful surgical management. AIMS: To assess the usefulness of measuring insulin levels by preoperative percutaneous transhepatic portal catheterization (PTPC) and intraoperative ultrasonography (US). METHODOLOGY: PTPC and other preoperative procedures (enhanced computed tomography [CT], arteriography, and US) were performed in eight patients with insulinoma based on our experience during the past 18 years. Intraoperative US was performed in six of the eight patients. RESULTS: PTPC was undertaken in all eight patients, and increased levels of insulin at the sites corresponding to tumors were observed in all patients. Intraoperative US was performed in six patients, which made it possible to detect insulinomas as hypoechoic masses in all of these patients. All tumors were found to exist as single entities. CONCLUSION: PTPC showed the highest diagnostic accuracy in detecting the number of and accurately localizing the tumors before surgery. Meanwhile, all findings from intraoperative US were identical to those of the resection samples, suggesting that this method is a highly reliable examination technique. We conclude that a combination of PTPC and intraoperative US may be essential for the successful surgical management of insulinomas.
UI - 11770320
AU - Bednarz W
TI - [Chronic pancreatitis as a risk of pancreatic cancer]
SO - Pol Merkuriusz Lek 2001 Oct;11(64):360-1
AD - Katedra i Klinika Chirurgii Ogolnej i Endokrynologicznej Akademii Medycznej im. Piastow Slaskich we Wroclawiu.
The epidemiologic and clinical studies and the results of investigations on molecular level in aspect of the risk of pancreatic cancer in patients suffering from chronic pancreatitis are presented. The risk of pancreatic cancer is significantly elevated in subjects with chronic fibrous pancreatitis.
UI - 11756230
AU - Alguacil J; Porta M; Malats N; Kauppinen T; Kogevinas M; Benavides FG;
TI - Partanen T; Carrato A; PANKRAS II Study Group Occupational exposure to organic solvents and K-ras mutations in exocrine pancreatic cancer.
SO - Carcinogenesis 2002 Jan;23(1):101-6
AD - Institut Municipal d'Investigacio Medica, Universitat Autonoma de Barcelona, Carrer del Doctor Aiguader 80, E-08003 Barcelona, Catalonia, Spain.
Occupational exposure to hydrocarbon solvents has been found to be associated with an increased risk of exocrine pancreatic cancer (EPC), the human tumor with the highest prevalence of K-ras mutations. Ras genes are critical DNA targets for chemical carcinogens. We analysed the relationship between past occupational exposure to hydrocarbon solvents and mutations in codon 12 of the K-ras gene in 107 incident cases of EPC. Information on occupational factors and life-style was obtained from personal interviews conducted during hospital stay. Occupational exposure to hydrocarbon solvents (aliphatic, aromatic, chlorinated, benzene, other organic solvents) was examined using two methods: expert assessment and the Finnish job-exposure matrix (Finjem). Exposure among K-ras mutated EPC cases (n = 83) was compared with that of K-ras wild-type EPC cases (n = 24). An association between K-ras mutations and solvent exposure was observed with Finjem but barely so with the expert assessment. Over 7-fold increased odds ratios (OR) were found for every group of solvents evaluated with Finjem (all P < 0.05). On the basis of the expert assessment, K-ras mutations were significantly associated only with exposure to benzene in men (OR = 7.07, P < 0.05). When requiring exposure to have occurred according to both the experts and Finjem, over 4-fold risks were obtained for aromatic, aliphatic, and for "any hydrocarbon solvent". A significantly higher proportion of cases with a mutation from glycine to valine (GGT-->GTT) or to aspartic acid (GGT-->GAT) were exposed to a hydrocarbon solvent. The results raise the possibility that hydrocarbon solvents might be involved in the pathogenesis of EPC, possibly through indirect modulation of K-ras activation. Since this is only the first study on occupational exposures and K-ras mutations in EPC, studies able to refute or to confirm the findings are required before public health implications, if any, are assessed.
UI - 11590318
AU - Stagge V; Seufferlein T; Durschmied D; Menke A; Adler G; Beil M
TI - Integrin-mediated differentiation of a pancreatic carcinoma cell line is independent of FAK or MAPK activation levels.
SO - Pancreas 2001 Oct;23(3):236-45
AD - Department of Internal Medicine I, University of Ulm, Germany.
INTRODUCTION: The extracellular matrix (ECM) plays a salient role for proliferation and differentiation of epithelial cells. It was demonstrated that cell-ECM interactions mediated through integrins control gene expression and the tissue phenotype even in malignant tumors. Alterations of the ECM are a key feature of ductal adenocarcinoma of the pancreas. AIMS: To examine the role of integrins and related signaling events for differentiation. METHODOLOGY AND RESULTS: We established an in vitro model for ECM-induced differentiation of poorly differentiated pancreatic carcinoma cells and found that a specific pattern of ECM proteins resembling basal laminas (matrigel) induces differentiation of the PaTu-II pancreatic carcinoma cell line to a ductal phenotype. Both beta1- and beta4-integrins are required for cellular differentiation. Integrin-associated signaling events include activation of pp125 focal adhesion kinase (FAK) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs). However, beta1- and beta4-integrin-mediated differentiation of PaTu-II cells was independent from FAK, ERK, and JNK activation levels. Inhibition of MAPK kinases by PD98059 led to a reduction of proliferation but did not interfere with cellular differentiation of PaTu-II cells on matrigel. CONCLUSION: The integrin-mediated differentiation of PaTu-II cells is regulated and maintained through FAK- and MAPK-independent signal transduction pathways.
UI - 11590320
AU - Satoh K; Kaneko K; Hirota M; Masamune A; Satoh A; Shimosegawa T
TI - Tumor necrosis factor-related apoptosis-inducing ligand and its receptor expression and the pathway of apoptosis in human pancreatic cancer.
SO - Pancreas 2001 Oct;23(3):251-8
AD - Department of Gastroenterology, Tohoku University Graduate School of Medicine, Aobaku, Sendai, Japan. email@example.com
METHODOLOGY: The authors performed the reverse transcription-polymerase chain reaction (RT-PCR) in 17 cases of pancreatic ductal cell carcinoma (PDC) and five cases of normal pancreatic tissues to determine the expression of tumor necrosis factor -related apoptosis-inducing factor (TRAIL) and its five receptors in PDC. RESULTS: The expression of TRAIL and its receptors other than osteoprotegerin was found frequently in both PDC and normal tissues. whereas the expression of osteoprotegerin was detected only in PDC. The authors detected cancer cell death by TRAIL, ranging from 37% to 77% in all the PDC cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Hochest staining revealed that cell death was caused by apoptosis. Caspase-8 and caspase-3 and poly (ADP-ribose) polymerase cleavage was activated within 2 hours after stimulation with 200 ng/mL TRAIL. CONCLUSION: These findings suggest a relation between osteoprotegerin expression and the biologic aggressiveness of PDC and the involvement of caspase-8 and caspase-3 activation in the TRAIL-mediated apoptosis pathway in PDC.
UI - 11590324
AU - Poch B; Gansauge F; Schwarz A; Seufferlein T; Schnelldorfer T; Ramadani
TI - M; Beger HG; Gansauge S Epidermal growth factor induces cyclin D1 in human pancreatic carcinoma: evidence for a cyclin D1-dependent cell cycle progression.
SO - Pancreas 2001 Oct;23(3):280-7
AD - Department of General Surgery, University of Ulm, Germany.
INTRODUCTION: We recently showed that cyclin D1 is overexpressed in human pancreatic carcinoma cells, and that this overexpression correlates significantly with a poor prognosis. AIMS: To assess the interrelations of epidermal growth factor (EGF), EGF receptor (EGFR), and cyclin D1 in human pancreatic carcinoma. METHODOLOGY AND RESULTS: In pancreatic carcinoma cell lines (BxPC-3, AsPC-1), cell cycle analysis revealed an increase in cells in the S/G1 phase between 18 and 30 hours after stimulation with 50 ng/mL EGF. Cyclin D1 mRNA increased after 2 hours, corresponding to an increase in cyclin D1 protein, with the maximum level between 7.5 and 10 hours after stimulation, as demonstrated by Western blot analysis. We performed immunohistochemical analysis on 61 adenocarcinoma tissues for the expression of EGF, EGFR, and cyclin D1 and demonstrated an overexpression in the tumor cells in 51%, 54%, and 62.3%, respectively, whereas normal human pancreas stained negative for all of the three factors. Interestingly, EGF and EGFR expression correlated significantly with the cyclin D1 expression in human pancreatic tumor cells (p < 0.001 and p < 0.01, respectively). CONCLUSION: These results demonstrate that cyclin D1 overexpression in the tumor cells of pancreatic carcinoma tissue is at least partly dependent on the mitogenic effects of EGF signaling through the EGFR.
UI - 9424861
AU - Pirski MI; Gacyk W; Kostro J; Witkowski P; Draczkowski T
TI - [Diagnosis of pancreatic neoplasm--possibilities and limitations]
SO - Wiad Lek 1997;50 Suppl 1 Pt 2():135-9
AD - I Katedry i Kliniki Chirurgii Akademii Medycznej w Gdansku.
75 consecutive patients treated for pancreatic cancer were submitted to prospective trial. 1 to 12 weeks passed from the onset of symptoms before diagnosis was established. 61 (81%) patients were admitted due to symptoms and 14 (19%)--due to USG findings. Sensitivity and selectivity of imaging techniques was as follows: USG-87% and 73%, ERCP-72% and 72%, CT-100% and 82% respectively. Staging of the lesions estimated by CT (AJCC/TNM scale) 34 patients qualified as stage I, 15 as stage II, 14 as III and 12 as stage IV. Surgery was undertaken in 71 patients and resective procedures in 32 of them (43%). The final diagnosis was established by one biopsy in 21 patients, and in the further 8 cases 2-3 biopsies were necessary. In 3 cases cancer cells were found only during histological examination of the whole resected specimen. The follow up in resected group was 1-30 months. One year survival was 72%, actuarial survival is 38%.