Table of Contents
1
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. sabraham@jhmi.edu
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.
2
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.
tana@medizin.uni-leipzig.de
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.
3
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.
4
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.
5
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. ksatoh@int3.med.tohoku.ac.jp
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.
6
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.
7
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. niichan@silk.plada.or.jp
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.
8
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.
rindi@master.cci.unibs.it
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.
9
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.
10
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.
11
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.
12
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. m.raida@icrf.icnet.uk
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.
13
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. anthony.hanbidge@uhn.on.ca
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.
14
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. wiersema.maurits@mayo.edu
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.
15
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
16
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.
17
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.
18
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.
19
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.
20
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. mgbrizi@rm.unicatt.it
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.
21
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.
22
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.
d_chung@helix.mgh.harvard.edu
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.
23
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.
24
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.
25
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.
26
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.
27
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.
28
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.
29
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.
30
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
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