National Cancer Institute®
Last Modified: April 1, 2002
UI - 11891193
AU - Abraham SC; Wu TT; Hruban RH; Lee JH; Yeo CJ; Conlon K; Brennan M;
TI - Cameron JL; Klimstra DS Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway.
SO - Am J Pathol 2002 Mar;160(3):953-62
AD - Department of Pathology, Division of GI/LiverPathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA. email@example.com
Acinar cell carcinomas (ACCs) are rare malignant tumors of the exocrine pancreas. The specific molecular alterations that characterize ACCs have not yet been elucidated. ACCs are morphologically and genetically distinct from the more common pancreatic ductal adenocarcinomas. Instead, the morphological, immunohistochemical, and clinical features of ACCs overlap with those of another rare pancreatic neoplasm, pancreatoblastoma. We have recently demonstrated a high frequency of allelic loss on chromosome arm 11p and mutations in the APC/beta-catenin pathway in pancreatoblastomas, suggesting that similar alterations might also play a role in the pathogenesis of some ACCs. We analyzed a series of 21 ACCs for somatic alterations in the APC/beta-catenin pathway and for allelic loss on chromosome 11p. In addition, we evaluated the ACCs for alterations in p53 and Dpc4 expression using immunohistochemistry, and for microsatellite instability (MSI) using polymerase chain amplification of a panel of microsatellite markers. Allelic loss on chromosome 11p was the most common genetic alteration in ACCs, present in 50% (6 of 12 informative cases). Molecular alterations in the APC/beta-catenin pathway were detected in 23.5% (4 of 17) of the carcinomas, including one ACC with an activating mutation of the beta-catenin oncogene and three ACCs with truncating APC mutations. One ACC (1 of 13, 7.6%) showed allelic shifts in four of the five markers tested (MSI-high), two (15.4%) showed an allelic shift in only one of the five markers tested (MSI-low), and no shifts were detected in the remaining 10 cases. The MSI-high ACC showed medullary histological features. In contrast, no loss of Dpc4 protein expression or p53 accumulation was detected. These results indicate that ACCs are genetically distinct from pancreatic ductal adenocarcinomas, but some cases contain genetic alterations common to histologically similar pancreatoblastomas.
UI - 11753797
AU - Tannapfel A; Witzigmann H; Wittekind C
TI - [Pancreatic intraepithelial neoplasia in chronic pancreatitis]
SO - Zentralbl Chir 2001 Nov;126(11):879-83
AD - Institut fur Pathologie der Universitat Leipzig, Germany. firstname.lastname@example.org
Chronic pancreatitis causes destruction of the pancreatic gland which leads to tissue fibrosis and regenerative hyperplasia of the epithelium of pancreatic ducts and ductules. Morphological studies revealed distinct proliferative lesions in the pancreatic ducts and ductules adjacent to infiltrating adenocarcinomas of the pancreas. A stepwise progression from mild to severe dysplasia in these hyperplastic lesions has been reported. These lesions, called Pancreatic Intraepithelial Neoplasia (PanIN), harbour a number of well-characterised genetic alterations. Therefore, PanINs were defined as true clonal neoplastic lesions with minimal to moderate and severe cytological and architectural atypia. Almost all of the genetic alterations that have been identified in pancreatic adenocarcinomas have also been identified in PanIN lesions. The prevalence of genetic changes increases as the degree of cytological atypia and histological dysplasia in the PanIN lesions increases. However, some genetic abnormalities have also been found in chronic pancreatitis and normal pancreas, e. g. K-ras mutations. However, due to intratumorous heterogeneity of the genetic changes, further studies are necessary to search for more specific and homogeneous expressed molecular markers. A better understanding of the molecular genetic changes occurring during neoplastic progression in the pancreas will form the basis for future strategies of early tumour detection and improved therapy.
UI - 11753800
AU - Bottger T; Kirsch D; Hengstler JG; Bauer A; Wolf HK; Junginger T
TI - [Hereditary pancreatitis - a clinically relevant cause of pancreatic adenocarcinoma?]
SO - Zentralbl Chir 2001 Nov;126(11):897-900
AD - Klinik und Poliklinik fur Allgemein- und Abdominalchirurgie, Johannes Gutenberg Universitat Mainz, Germany.
Hereditary pancreatitis is an autosomal dominant disease. Recently, the genetic defect has been mapped to chromosome 7q35 and consists mainly of a point mutation in exon 3 of the cationic trypsinogen gene which causes an Arg(CGC)-His(CAC) substitution at residue 117. In patients with hereditary pancreatitis the estimated cumulative risk for pancreatic carcinoma to age 70 approaches 40 %. Thus, the role of hereditary pancreatitis in the pathogenesis of pancreatic carcinoma is of interest.PATIENTS AND METHODS: DNA was extracted from peripheral blood (n = 16), fresh tumor tissue (n = 29) and formalin fixed and paraffin embedded tumor tissue (n = 5) of 50 patients with ductal adenocarcinoma of the pancreas. We specifically amplified exon 3 and the intronic flanking sequences of the cationic trypsinogen gene by nested PCR and performed restriction fragment length polymorphism analysis using the restriction enzyme Afl III. In patients with hereditary pancreatitis the G : A point mutation creates a recognition site for Afl III which is not present in unaffected individuals.RESULTS: None of the 50 patients with ductal adenocarcinoma of the pancreas revealed the G : A point mutation in exon 3 of the cationic trypsinogen gene which is characteristic of hereditary pancreatitis. In addition sequencing of exon 3 did not reveal any other mutations in the DNA of patients with pancreatic adenocarcinoma.CONCLUSION: Although hereditary pancreatitis markedly increases the risk for pancreatic cancer, it is rare and probably of little significance with respect to the pathogenesis of the majority of pancreatic adenocarcinomas.
UI - 11753804
AU - Niedergethmann M; Rexin M; Knob S; Hartel M; Sturm JW; Richter A; Post S
TI - [Detection of micrometastases after curative resection for ductal adenocarcinoma of the pancreas]
SO - Zentralbl Chir 2001 Nov;126(11):917-21
AD - Chirurgische Klinik, Universitatsklinikum Mannheim, Fakultat fur klinische Medizin Mannheim der Universitat Heidelberg, Germany.
OBJECTIVES: Despite apparently curative resection adenocarcinomas of the pancreas early recur. Thus, the pathological examination should be enriched by sensitive methods to detect minimal residual disease (MRD). Mutant K-ras is the most promising genetic alteration in ductal adenocarcinoma and may serve to detect malignant cells by polymerase chain reaction (PCR) based techniques. Therefore, we set out to detect K-ras mutations by PCR for evaluation of MRD in patients after curative resection of pancreatic adenocarcinoma. PATIENTS AND METHODS: Tumor tissue and corresponding paraaortic lymph nodes were obtained from 51 patients, who underwent surgery for pancreatic head tumors. The paraaortic lymph nodes were staged as tumor-free by routine histopathology in all cases diagnosed for ductal adenocarcinoma (study group, n = 40) or other tumors (control group, n = 11). Therefore, DNA of both primary tumors and lymph nodes was extracted and analysed by a PCR-based assay with respect to mutated K-ras. As a positive control the human pancreatic cancer cell line PaTu-8902 was used. RESULTS: K-ras mutations were detected in 73 % (29/40) of primary tumors of ductal adenocarcinomas and in 17 % (5/29) in the corresponding paraaortic lymph nodes, which were diagnosed as tumor-free by routine pathology. The identical type of point mutation was found in primary tumors and corresponding lymph nodes by use of sequence specific primers. In the control group no K-ras mutation was detected. CONCLUSION: Tumor cell DNA can be detected sensitively in tumor- and lymph node specimen with the described method. Routinely assessed, this method is able to detect MRD and could enrich the pathological examination, in order to determine prognostic relevant subgroups of patients.
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 - 11920553
AU - Takahashi S; Hasebe T; Oda T; Sasaki S; Kinoshita T; Konishi M; Ochiai
TI - T; Ochiai A Cytoplasmic expression of laminin gamma2 chain correlates with postoperative hepatic metastasis and poor prognosis in patients with pancreatic ductal adenocarcinoma.
SO - Cancer 2002 Mar 15;94(6):1894-901
AD - Pathology Division, National Cancer Center Research Institute East, Chiba, Japan.
BACKGROUND: The laminin gamma2 chain is involved in tumor invasion and metastasis, but the significance of laminin gamma2 chain expression remains unclear in patients with pancreatic carcinoma. METHODS: Laminin gamma2 chain expression was examined immunohistochemically in 48 patients with pancreatic ductal adenocarcinoma who were followed closely to elucidate the correlations between clinicopathologic factors, postoperative recurrence, and overall survival. Prognostic factors for postoperative survival were examined comparing clinicopathologic factors and laminin gamma2 chain expression. RESULTS: Two different staining patterns of laminin gamma2 chain expression, cytoplasmic expression and basement membrane expression, were detected in tumors from all 48 patients. Tumors were then classified into two types according to the dominant pattern of laminin gamma2 chain expression: the cytoplasmic expression dominant type (CYT; n = 26 patients) and the basement membrane expression dominant type (BM; n = 22 patients). Tumor differentiation was associated statistically with the BM type of laminin gamma2 chain expression (P = 0.0002). The CYT type of laminin gamma2 chain expression was associated significantly with the occurrence of postoperative hepatic metastasis (P = 0.0011) and also was the strongest predictive factor for poorer overall survival in patients with pancreatic ductal adenocarcinomas (P = 0.0161). CONCLUSIONS: The cytoplasmic expression of the laminin gamma2 chain represents the high invasive potential of the tumor and is correlated with distant metastasis, especially hepatic metastasis, and with a poorer prognosis in patients with pancreatic ductal adenocarcinoma. Copyright 2002 American Cancer Society.
UI - 11920515
AU - Niijima M; Yamaguchi T; Ishihara T; Hara T; Kato K; Kondo F; Saisho H
TI - Immunohistochemical analysis and in situ hybridization of cyclooxygenase-2 expression in intraductal papillary-mucinous tumors of the pancreas.
SO - Cancer 2002 Mar 1;94(5):1565-73
AD - First Department of Medicine, Chiba University School of Medicine, Chiba, Japan. firstname.lastname@example.org
BACKGROUND: The objective of this study was to investigate COX-2 expression in intraductal papillary-mucinous tumor of the pancreas (IPMT) using immunohistochemical staining (IH) and in situ hybridization (ISH). METHODS: Immunohistochemical staining of COX-2 was performed using samples from 42 patients with IPMT (hyperplasia, 10; adenoma, 13; noninvasive adenocarcinoma, 13; invasive adenocarcinoma, 6) and from 10 patients with ductal pancreatic adenocarcinoma, 10 with chronic pancreatitis, and 6 normal pancreatic tissues as controls. Also, COX-2 was determined in five patients with IPMT noninvasive adenocarcinoma, in whom all histologic types, hyperplasia, adenoma, and adenocarcinoma were observed in the same excised specimens. Furthermore, IH of proliferating cell nuclear antigen (PCNA) was performed, and the labeling index (LI) was calculated to investigate the correlation with COX-2. To confirm COX-2 mRNA, the authors performed ISH in 20 IPMT patients. RESULTS: COX-2 was positive in 0%, 0%, and 10% of pancreatic duct epithelial cells from normal pancreatic tissue, chronic pancreatitis, and IPMT hyperplasia, respectively. Whereas it was positive in 69%, 77%, 67%, and 80% of IPMT adenoma, IPMT noninvasive adenocarcinoma, IPMT invasive adenocarcinoma, and ductal pancreatic adenocarcinoma, respectively, showing significant differences between IPMT hyperplasia and IPMT adenoma or IPMT adenocarcinoma (noninvasive and invasive adenocarcinoma). In the same patient, COX-2 was negative in the hyperplasia region but positive in adenoma and adenocarcinoma regions, showing results reflecting the progression of the disease. In the COX-2 negative group, PCNA-LI was 19.2 +/- 17.9%, and 33.5 +/- 15.7% in the positive group, a significant difference. On ISH, COX-2 mRNA was expressed in three of four and seven of eight COX-2 positive patients with IPMT adenoma and adenocarcinoma, respectively. CONCLUSIONS: COX-2 was highly expressed in adenoma and adenocarcinoma in IPMT, showing a relation to the histologic grade of IPMT. Copyright 2002 American Cancer Society.
UI - 11901838
AU - Rindi G; Villanacci V; Ubiali A; Scarpa A
TI - Endocrine tumors of the digestive tract and pancreas: histogenesis, diagnosis and molecular basis.
SO - Expert Rev Mol Diagn 2001 Sep;1(3):323-33
AD - Department of Pathology, Universita di Brescia-Spedali, Civili, Anatomia Patologica 2, Piazza Spedali Civili 1, I-25124 Brescia, Italy. email@example.com
Although relatively rare, endocrine tumors of the digestive tract and pancreas have been widely investigated and represent a complex tumor entity. The two major categories of well-differentiated and poorly differentiated tumors show important phenotypic and clinical differences. In well-differentiated tumors the multiple endocrine neoplasia syndrome of Type 1 (MEN1) gene is frequently abnormal, though a complex multiple gene involvement is postulated for different tumor types. Poorly differentiated carcinomas show frequent p53 gene hyperexpression/defects, characterizing severe cell abnormality and possibly accounting for the malignancy of such carcinomas.
UI - 11906855
AU - Valls C; Andia E; Sanchez A; Fabregat J; Pozuelo O; Quintero JC; Serrano
TI - T; Garcia-Borobia F; Jorba R Dual-phase helical CT of pancreatic adenocarcinoma: assessment of resectability before surgery.
SO - AJR Am J Roentgenol 2002 Apr;178(4):821-6
AD - Institut de Diagnostic per la Imatge, Hospital Duran i Reynals, Ciutat Sanitaria i Universitaria de Bellvitge, Autovia de Castelldefels km 2, 7, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
OBJECTIVE: The aim of our study was to prospectively evaluate the accuracy of dual-phase helical CT in the preoperative assessment of resectability in patients with suspected pancreatic cancer using surgical and histopathologic correlation. SUBJECTS AND METHODS: Between cancer underwent preoperative evaluation and staging with dual-phase helical CT (3-mm collimation for pancreatic phase, 5-mm collimation for portal phase). Iodinated contrast material was injected IV (170 mL at a rate of 4 mL/sec); acquisition began at 40 sec during the pancreatic phase and at 70 sec during the portal phase. Three radiologists prospectively evaluated the imaging findings to determine the presence of pancreatic tumor and signs of unresectability (liver metastasis, vascular encasement, or regional lymph nodes metastasis). The degree of tumor-vessel contiguity was recorded for each patient (no contiguity with tumor, contiguity of < 50%, or contiguity of > or =50%). RESULTS: Thirty-nine patients with pancreatic adenocarcinoma were surgically explored. Curative resections were attempted in 34 patients and were successful in 25. The positive predictive value for resectability was 73.5%. Nine patients considered resectable on the basis of CT findings were found to be unresectable at surgery because of liver metastasis (n = 5), vascular encasement (n = 2), or lymph node metastasis (n = 2). We found that the overall accuracy of helical CT as a tool for determining whether a pancreatic adenocarcinoma was resectable was 77% (30/39 patients). CONCLUSION: Dual-phase helical CT is a useful technique for preoperative staging of pancreatic cancer. The main limitation of CT is that it may not reveal small hepatic metastases.
UI - 11906856
AU - Horton KM; Fishman EK
TI - Multidetector CT angiography of pancreatic carcinoma: part I, evaluation of arterial involvement.
SO - AJR Am J Roentgenol 2002 Apr;178(4):827-31
AD - Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, 601 N. Caroline St., Rm. 3253, Baltimore, MD 21287, USA.
UI - 11906858
AU - Horton KM; Fishman EK
TI - Multidetector CT angiography of pancreatic carcinoma: part 2, evaluation of venous involvement.
SO - AJR Am J Roentgenol 2002 Apr;178(4):833-6
AD - Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, 601 N. Caroline St., Rm. 3253, Baltimore, MD 21287, USA.
UI - 11862480
AU - Raida M; Kliche KO; Schwabe W; Hausler P; Clement JH; Behnke D; Hoffken
TI - K Circadian variation of dihydropyrimidine dehydrogenase mRNA expression in leukocytes and serum cortisol levels in patients with advanced gastrointestinal carcinomas compared to healthy controls.
SO - J Cancer Res Clin Oncol 2002 Feb;128(2):96-102
AD - Klinik und Poliklinik fur Innere Medizin II, (Onkologie, Hamatologie, Endokrinologie und Stofwechselerkrankungen), Friedrich-Schiller-Universitat Jena, Germany. firstname.lastname@example.org
PURPOSE: The activity of dihydropyrimidine dehydrogenase (DPD) - the rate-limiting enzyme in fluorouracil (5-FU) catabolism - has been reported to vary according to the time of day. On the basis of this data, so-called chronomodulated chemotherapy regimens with variable-rate infusions of 5-FU have been investigated in the treatment of advanced colorectal cancer. Recent results suggest lower toxicity of 5-FU by chronomodulated application. However, the pattern of circadian DPD activity levels have been shown to vary considerably. METHODS: We, therefore, studied the circadian changes in mRNA expression of DPD in leukocytes of ten patients with advanced gastrointestinal carcinomas prior to chronomodulated 5-FU-based salvage therapy and in 5five healthy controls. Simultaneously, we measured serum cortisol levels (SCL) to evaluate the endogenous circadian hormone rhythm. RESULTS: SCL displayed a consistent circadian rhythm with the mean peak value of serum cortisol at 8 a.m. and the mean trough value at 11 p.m. both in patients and in controls. However, mean minimum-maximum serum cortisol differences of SCL were significantly lower in patients compared to controls. In the 5fivehealthy controls, a trend towards a circadian rhythm of DPD mRNA expression was observed with the peak of expression at 5 a.m. which was significantly different from the trough at 2 p.m. ( P<0.005 Mann-Whitney-Wilcoxon test). When each control was studied separately, only two individuals showed circadian variations that could be fitted to a cosine wave ( P=0.001, P=0.014, Cosinor analysis). In contrast, DPD mRNA expression in patients with advanced gastrointestinal carcinomas did not demonstrate any consistent circadian rhythm. Pairwise comparisons of groups of DPD mRNA levels at different times of the day did not show significant differences. CONCLUSIONS: In conclusion, our analysis of DPD mRNA expression in leukocytes from healthy controls demonstrates first evidence for a circadian DPD mRNA expression periodicity. In patients with advanced gastrointestinal carcinomas, however, this rhythm seems to be disturbed although circadian endogenous cortisol secretion pattern is maintained.
UI - 11875594
AU - Hanbidge AE
TI - Cancer of the pancreas: the best image for early detection--CT, MRI, PET or US?
SO - Can J Gastroenterol 2002 Feb;16(2):101-5
AD - Division of Abdominal Imaging, Mount Sinai Hospital, University Health Network, Toronto, Ontario M5G 2C4, Canada. email@example.com
Pancreatic cancer has a poor prognosis, and the best chance for survival is to diagnose the tumour at an early stage. Abdominal ultrasound, computed tomography, magnetic resonance imaging and endoscopic retrograde cholangiopancreatography are the most commonly used radiological techniques for imaging the pancreas. The diagnostic evaluation should be tailored to the individual patient. Dual-phase helical computed tomography and magnetic resonance imaging have similar accuracies for detecting and staging pancreatic adenocarcinoma. Sonography results are highly dependent on the skill and persistence of the operator. No radiological examination is very sensitive at visualizing small metastases in the lymph nodes and peritoneum, or on the surface of the liver. Thus, it is difficult to establish with certainty whether a tumour is resectable. Another major challenge is to differentiate cancer from an inflammatory mass in chronic pancreatitis. Functional imaging (using positron emission tomography with fluorodeoxyglucose) may be helpful, especially if the images are fused with those of computed tomography or magnetic resonance imaging. The diagnostic accuracies, applications and limitations of the various modalities are discussed.
UI - 11875595
AU - Wiersema MJ
TI - Identifying contraindications to resection in patients with pancreatic carcinoma: the role of endoscopic ultrasound.
SO - Can J Gastroenterol 2002 Feb;16(2):109-14
AD - Eisenberg 8A, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. firstname.lastname@example.org
OBJECTIVE: To present recently published material comparing the performance of endosonography relative to other imaging modalities when evaluating the patient with a suspected or known pancreas carcinoma. METHODS: Medline was searched using the terms "endosonography" and "pancreas neoplasms". References from retrieved papers were reviewed to identify other reports. Emphasis was placed on peer-reviewed material published within the past three years that included comparison with other imaging modalities. RESULTS: Despite advances in cross-sectional imaging modalities, endosonography remains the most sensitive and specific method for identifying pancreatic mass lesions. The resectability of pancreatic carcinoma is best determined with dual-phase helical computed tomography, although endosonography may be slightly more accurate for lymph node assessment. Endoscopic ultrasound-guided fine needle aspiration biopsy has a high sensitivity (93%) and specificity (100%) when used in patients with masses in whom pancreatic cancer is suspected but prior biopsies have been negative. CONCLUSIONS: Endosonography helps in the diagnosis of pancreatic neoplasms through definitive inclusion or exclusion of a mass lesion as well as biopsy confirmation of malignancy. The role of endosonography in the determination of resectability has been eclipsed by dual-phase helical computed tomography. However, endoscopic ultrasound with fine needle aspiration of nonperitumoral lymph nodes may identify advanced disease with sufficient frequency to justify its routine use in patients with lesions that are thought to be resectable based on helical computed tomography.
UI - 11920604
AU - Isaksson B; Jonsson F; Pedersen NL; Larsson J; Feychting M; Permert J
TI - Lifestyle factors and pancreatic cancer risk: a cohort study from the Swedish Twin Registry.
SO - Int J Cancer 2002 Mar 20;98(3):480-2
UI - 11868016
AU - Levy MJ; Vazquez-Sequeiros E; Wiersema MJ
TI - Evaluation of the pancreaticobiliary ductal systems by intraductal US.
SO - Gastrointest Endosc 2002 Mar;55(3):397-408
AD - Mayo Clinic Foundation, Division of Gastroenterology and Hepatology, 200 First Street SW, Rochester, MN 55905, USA.
UI - 11870593
AU - Eberle MA; Pfutzer R; Pogue-Geile KL; Bronner MP; Crispin D; Kimmey MB;
TI - Duerr RH; Kruglyak L; Whitcomb DC; Brentnall TA A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromosome 4q32-34.
SO - Am J Hum Genet 2002 Apr;70(4):1044-8
AD - Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Pancreatic cancer is the fifth leading cause of cancer death in the United States. Nearly every person diagnosed with pancreatic cancer will die from it, usually in <6 mo. Familial clustering of pancreatic cancers is commonly recognized, with an autosomal dominant inheritance pattern in approximately 10% of all cases. However, the late age at disease onset and rapid demise of affected individuals markedly hamper collection of biological samples. We report a genetic linkage scan of family X with an autosomal dominant pancreatic cancer with early onset and high penetrance. For the study of this family, we have developed an endoscopic surveillance program that allows the early detection of cancer and its precursor, before family members have died of the disease. In a genomewide screening of 373 microsatellite markers, we found significant linkage (maximum LOD score 4.56 in two-point analysis and 5.36 in three-point analysis) on chromosome 4q32-34, providing evidence for a major locus for pancreatic cancer.
UI - 11884763
AU - Saddig C; Bender R; Starke AA
TI - A new classification plot for the C-peptide suppression test.
SO - JOP 2002 Jan;3(1):16-25
AD - Department of Metabolic Diseases and Nutrition, Heinrich-Heine-University of Duesseldorf, Duesseldorf, Germany.
CONTEXT AND OBJECTIVE: To evaluate the C-peptide suppression test as a screening test in patients with symptoms of hypoglycemia as compared to the standard fasting test. DESIGN: Retrospective discriminant analysis of data from C-peptide suppression tests. SETTING: Clinical study. PATIENTS: Patients with insulinomas and patients without insulinomas but having symptoms compatible with hypoglycemia. INTERVENTIONS: The results from C-peptide suppression tests of 26 patients with insulinomas and 100 patients without insulinomas were compared. MAIN OUTCOME MEASURES: A classification plot which introduces two discriminant parameters for the C-peptide suppression test: the ratio of [blood glucose]/[C-peptide] at the lowest C-peptide concentration and mean glycemia during insulin infusion. RESULTS: In patients with insulinomas, minimal serum C-peptide levels were higher (1.81+/- 0.87 ng/mL; median 1.83 ng/mL; maximal suppression 37 +/- 24% of basal C-peptide levels) as compared to patients without insulinoma (0.40 +/- 0.15 ng/mL; median 0.30 ng/mL; maximal suppression of 75 +/- 9%; P<0.001). Mean glycemia during the test was lower in patients with insulinomas (30.8 +/- 3.3 vs. 47.5 +/- 8.3 mg/dL; P<0.001) as was the [blood glucose]/[C-peptide] ratio (21.9 +/- 14.6 vs. 139.2 +/- 43.8; P<0.001). Discriminant analysis revealed a specificity of 96% to rule out the diagnosis of 'insulinoma' at a 1% probability threshold with a sensitivity of 100%. CONCLUSIONS: We developed a new classification plot for the C-peptide suppression test in order to accurately identify those patients whose symptoms of hypoglycemia are not due to endogenous hyperinsulinemia/insulinomas. Thus, the need for fasting tests and hospitalization costs can be reduced.
UI - 11885004
AU - Lange S; Alzen G; Leder H; Reither M; Weiss-Perrakis M; Kellner MW
TI - [Solid-pseudopapillary tumors in childhood]
SO - Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 2002 Mar;174(3):286-90
AD - Rontgenabteilung, Kinderkrankenhaus der Stadt Koln, Germany.
We report on fife female patients with solid pseudopapillary tumors of the pancreas. The tumors are extremely rare in children. They occur mainly in adolescent and young adult females. The tumors are neoplasms of low malignancy with infrequent metastases, for instance, in the liver or the peritoneum. Although the tumors had reached a large diameter, all of them underwent complete tumor resection. After that the patients have a very good prognosis. Thus, so it is important to distinguish solid-pseudopapillary tumors from other tumors of the pancreas.
UI - 11925786
AU - Brizi MG; Natale L; Manfredi R; Barbaro B; Vecchioli A; Marano P
TI - Staging of pancreatic ductal adenocarcinoma with spiral CT and MRI.
SO - Rays 2001 Apr-Jun;26(2):151-9
AD - Istituto di Radiologia, Universita Cattolica del S. Cuore, Policlinico A. Gemelli, Largo A. Gemelli 8, 00168 Rome, Italy. email@example.com
Detection of pancreatic adenocarcinoma is crucial for accurate staging both with spiral CT and dynamic MRI; consequently an accurate technique is required and so-called pancreatic phase is recognized as the best one for tumor conspicuity. For vascular involvement optimal results have been achieved in assessing unresectability; vein involvement seems more difficult to be defined as it is sustained by a different spread compared to arterial involvement. Grading of vessel circumference contact represents the best tool in "venous" staging, but shape deformation and collateral veins dilation are also important signs. Lymph node staging is less accurate, lacking in specificity, but spiral CT demonstrated better results if compared with dynamic MRI. Assessment of liver metastases has been improved by the advent of spiral CT and dynamic contrast enhanced MRI, while peritoneal staging seems to be unaffected. In conclusion, both spiral CT and dynamic contrast enhanced MRI are accurate in pancreatic adenocarcinoma staging, mainly for vessels and liver involvement; no definite differences have been established, because only a few studies have compared them both with state-of-art techniques. Therefore standardized multicentric trials are desirable. Up to now, the choice of which technique to employ should be based on local expertise; moreover, the aggressive approach of surgical equipes should be kept in mind.
UI - 8694562
AU - Tumminello FM; Leto G; Pizzolanti G; Candiloro V; Crescimanno M; Crosta
TI - L; Flandina C; Montalto G; Soresi M; Carroccio A; Bascone F; Ruggeri I; Ippolito S; Gebbia N Cathepsin D, B and L circulating levels as prognostic markers of malignant progression.
SO - Anticancer Res 1996 Jul-Aug;16(4B):2315-9
AD - Section of Chemotherapy, School of Medicine, University of Palermo, Policlinico P. Giaccone, Italy.
Growing evidence indicates that lysosomal Cathepsins D (CD), B (CB) and L (CL) may promote carcinogenesis and tumor progression. Therefore, we evaluated their potential value as biochemical parameters of malignant progression in patients with benign diseases which may undergo malignant transformation, such as liver cirrhosis (LC) and chronic pancreatitis (CHP) as well as in hepatocellular carcinoma (HCC) and pancreatic cancer (DPC). CD, CB and CL serum levels were determined by immunoenzymatic assays in LC, CHP, HCC or DPC patients and correlated with a number of biochemical and clinical parameters of these diseases. CD serum levels were increased in LC, CHP and HCC, but not in the DPC group as compared to normal subjects (NS) (P < 0.01). Interestingly, higher levels of this enzyme were observed in LC patients compared to HCC patients ( P < 0.01). CB serum concentrations were increased in all patient groups (P < 0.01). However no difference was evidenced between benign and malignant diseases. CL serum levels were significantly increased only in DPC as compared to NS (P < 0.01) or CHP patients (P < 0.02) and in HCC as compared to NS (P < 0.01). The evaluation of CD, CB and CL serum pattern in LC, CHP, HCC and DPC patients may be useful as additional biochemical parameters in the differential diagnosis and therapeutic monitoring of these diseases. Prospective clinical investigations to assess the potential value of these enzymes as biochemical markers of malignant progression of LC or CHP are warranted by the present data.
UI - 9218518
AU - Chung DC; Smith AP; Louis DN; Graeme-Cook F; Warshaw AL; Arnold A
TI - A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications.
SO - J Clin Invest 1997 Jul 15;100(2):404-10
AD - Laboratory of Endocrine Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. firstname.lastname@example.org
The molecular pathogenesis of pancreatic endocrine tumors is largely unknown. Such tumors are more likely to develop in individuals with the von Hippel-Lindau (VHL) syndrome. We sought to determine whether allelic loss of the recently identified VHL tumor suppressor gene on chromosome 3p25-26 occurs in the more common sporadic forms of these tumors. Allelic loss on chromosome 3p was identified in 33% of 43 patients with endocrine tumors of the pancreas. The smallest common region of allelic loss, however, centered not at the VHL locus, but rather at 3p25, centromeric to VHL. Furthermore, no mutations of the VHL gene were identified in these tumors. Loss of alleles on chromosome 3p was associated with clinically malignant disease, whereas tumors with retained 3p alleles were more likely to be benign. Thus, the VHL gene does not appear to play a pathogenic role in the development of sporadic pancreatic endocrine tumors. Instead, a locus at chromosome 3p25 may harbor a novel pancreatic endocrine tumor suppressor gene, and allelic loss of this chromosomal region may serve as a molecular marker that helps distinguish benign from clinically malignant disease.
UI - 10354869
AU - Hes FJ; Feldberg MA
TI - Von Hippel-Lindau disease: strategies in early detection (renal-, adrenal-, pancreatic masses).
SO - Eur Radiol 1999;9(4):598-610
AD - Department of Internal Medicine, University Hospital Utrecht, The Netherlands.
Von Hippel-Lindau disease (VHL) is a hereditary syndrome characterized by a predisposition for bilateral and multicentric retinal angiomas, hemangioblastomas in the central nervous system (CNS), renal cell carcinomas, pheochromocytomas, islet cell tumors of the pancreas, and endolymphatic sac tumors, as well as cysts in the kidney, pancreas, and epididymis. This review focuses on developments in imaging of renal, adrenal, and pancreatic masses in VHL. Radiology still has a central place in managing of VHL. Radiologists should therefore be aware of the importances of MRI, CT, and US compared with other radiodiagnostic tools for these three organs. Since a conservative approach to the treatment of VHL lesions is now becoming more widely accepted, ongoing follow-up by careful radiological screening with US, and especially with MRI, will play a central role in managing the disease. We also give an overview of recent advances in the molecular biology of VHL, because the combination of imaging with (presymptomatic) DNA analysis has made early detection and screening of lesions possible and led to a reduction in morbidity and mortality.
UI - 10362809
AU - Su GH; Hruban RH; Bansal RK; Bova GS; Tang DJ; Shekher MC; Westerman AM;
TI - Entius MM; Goggins M; Yeo CJ; Kern SE Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers.
SO - Am J Pathol 1999 Jun;154(6):1835-40
AD - Departments of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder characterized by hamartomatous polyps in the gastrointestinal tract and by pigmented macules of the lips, buccal mucosa, and digits. Less appreciated is the fact that PJS also predisposes patients to an increased risk of gastrointestinal cancer, and pancreatic cancer has been reported in many PJS patients. It was recently shown that germline mutations of the STK11/LKB1 gene are responsible for PJS. We investigated the role of STK11/LKB1 in the development of pancreatic and biliary cancer in patients with and without the PJS. In a PJS patient having a germline splice site mutation in the STK11/LKB1 gene, sequencing analysis of an intestinal polyp and pancreatic cancer from this patient revealed loss of the wild-type allele of the STK11/LKB1 gene in the cancer. Inactivation of STK11/LKB1, by homozygous deletions or somatic sequence mutations coupled with loss of heterozygosity, was also demonstrated in 4-6% of 127 sporadic pancreatic and biliary adenocarcinomas. Our results demonstrate that germline and somatic genetic alterations of the STK11/LKB1 gene may play a causal role in carcinogenesis and that the same gene contributes to the development of both sporadic and familial forms of cancer.
UI - 10342012
AU - DeLellis RA
TI - The hereditary forms of pancreatic neuroendocrine tumors.
SO - Adv Anat Pathol 1999 May;6(3):149-53
AD - Department of Pathology, New York Presbyterian Hospital, NY, USA.
Pancreatic endocrine tumors occur sporadically or in the setting of multiple endocrine neoplasia type I (MEN-1) or von-Hippel-Lindau disease. In the latter circumstances, the tumors are often multiple. This commentary addresses the differences in clinical, pathologic, and molecular features of MEN-1 and von Hippel-Lindau disease associated pancreatic endocrine tumors.
UI - 10942118
AU - Bradley JF; Lin EC; Rothberg PG
TI - Gene symbol: VHL. Disease: pancreatic cancer.
SO - Hum Genet 2000 Jun;106(6):671
AD - Children's Mercy Hospital, Clinical Molecular Genetics, Kansas City, MO 64108, USA.
UI - 11085546
AU - Izuishi K; Kato K; Ogura T; Kinoshita T; Esumi H
TI - Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy.
SO - Cancer Res 2000 Nov 1;60(21):6201-7
AD - Investigative Treatment Division, National Cancer Center Research Institute East, Kashiwa, Chiba, Japan.
We hypothesized that the tolerance for nutrient deprivation as well as angiogenesis might be an important factor for tumor progression under hypovascular conditions. When normal human fibroblasts were subjected to extreme nutrient starvation by culturing in a medium without serum, glucose, and amino acids, cells died within 24 h. When substituted with liver cancer cell lines HepG2, Hep3B, HLE, and HuH-7, cell death occurred within 36 h. In contrast, four of six pancreas cancer cell lines, PANC-1, AsPC-1, BxPC-1, and KP-3, survived for remarkably longer periods; >50% of the cells survived, even after starvation for 48 h. Among three gastric cancer cell lines, MKN28, MKN45, and MKN74, only the most poorly differentiated MKN45 cells survived >36 h. More than 50% of the cells in colon cancer cell lines SW480, WiDr, and DLD-1 survived after 36 h, and the most undifferentiated SW480 cell line survived longest. We examined the possible involvement of PKB/Akt expression in the survival of various cell lines under nutrient starvation conditions. High expression of PKB/Akt was found to be associated with tolerance for nutrient starvation. When Akt antisense RNA expression vectors were introduced into PANC-1 cells, the tolerance was partially but significantly diminished by vectors for Akt1 and Akt2 but not Akt3. Because elimination of the tolerance might serve as a new strategy for cancer therapy, several compounds were tested for this purpose, and troglitazone, an insulin sensitizer, as well as LY294002, a phosphatidylinositol 3-kinase inhibitor, were found to kill PANC-1 cells only under nutrient starvation conditions.
UI - 11156232
AU - Tezel E; Hibi K; Nagasaka T; Nakao A
TI - PGP9.5 as a prognostic factor in pancreatic cancer.
SO - Clin Cancer Res 2000 Dec;6(12):4764-7
AD - Department of Surgery II, Nagoya University School of Medicine, Japan.
The expression of PGP9.5 was evaluated using immunohistochemistry in 69 resected ductal carcinomas of the pancreas and in normal pancreatic tissue. Overexpression did not seem to differ with histological type or pathological stage. A significant negative correlation was found between overexpression of PGP9.5 and postoperative survival. Multivariate analysis also suggested PGP9.5 along with tumor stage and extrapancreatic plexus invasion as strong predictors of the outcome. This study suggests that PGP9.5 expression may be used as a marker for predicting the outcome of resection-treated pancreatic cancer patients.
UI - 11141506
AU - Moore PS; Zamboni G; Brighenti A; Lissandrini D; Antonello D; Capelli P;
TI - Rigaud G; Falconi M; Scarpa A Molecular characterization of pancreatic serous microcystic adenomas: evidence for a tumor suppressor gene on chromosome 10q.
SO - Am J Pathol 2001 Jan;158(1):317-21
AD - Departments of Pathology and Surgery, Universita di Verona, Verona, Italy.
Pancreatic serous microcystic adenomas (SCAs) are rare, benign tumors with a striking female preference. Virtually no information is available about chromosomal or genetic anomalies in this disease. We performed extensive molecular characterization of 21 cases of formalin-fixed, paraffin-embedded sporadic SCAs consisting in genome-wide allelic loss analysis with 79 microsatellite markers covering all 22 autosomes, assessment of microsatellite instability, and mutational analysis of the VHL, K-ras, and p53 genes in nine cases for which frozen tissue was available. Although no case showed microsatellite instability of the type seen in mismatch repair-deficient tumors, a relatively low fractional allelic loss of 0.08 was found. Losses on chromosome 10q were the most frequent event in SCAs (50% of cases), followed by allelic losses on chromosome 3p (40% of cases). Moderately frequent losses (>25% of cases) were found on chromosomes 1q, 2q, and 7q. The VHL gene, located on chromosome 3p, had somatic inactivating mutations in two of nine cases (22%), whereas no mutations were found in either K-ras or p53, in agreement with the finding that all 21 cases stained negative for p53 by immunohistochemistry. Our study indicates that the involvement of chromosomal arms 10q and 3p is characteristic of SCAs and that the VHL gene is involved in a subset of sporadic cases.
UI - 10972974
AU - Boucher MJ; Morisset J; Vachon PH; Reed JC; Laine J; Rivard N
TI - MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells.
SO - J Cell Biochem 2000 Sep 7;79(3):355-69
AD - Groupe du Conseil de Recherches Medicales sur le Developpement Fonctionnel et la Physiopathologie du Tube Digestif, Departement d'Anatomie et Biologie Cellulaire, Universite de Sherbrooke, Sherbrooke, Quebec, J1H 5N4, Canada.
BACKGROUND AND AIMS: Growth factors are well known for their participation in the regulation of cell proliferation and survival. However, the intracellular signaling pathways by which growth factors promote survival are still poorly understood. In the present study, using the MIA PaCa-2 cell line, a well-established model of pancreatic cancer cells, we analyzed the roles of ERK1/2 activities in the regulation of cell survival and investigated some of the mechanisms involved. METHODS: The ability of the MEK inhibitor PD98059 to modulate survival of the MIA PaCa-2 cells was evaluated, and the responses were correlated with expression of Bcl-2 homologs and caspases 1, 3, 6, 8, and 9 activities. RESULTS: Herein, we showed that inhibition of ERK1/2 activities caused (1) a G1 arrest; (2) a down-regulation of the expression levels of the anti-apoptotic homologs Bcl-2, Mcl-1, and Bcl-X(L) without affecting the pro-apoptotic levels of Bax and Ba