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Abramson Cancer Center
NCI CANCERLIT® Search: Diagnosis-Histopathology-Pathogenesis of Pancreatic Cancer - February 2002
National Cancer Institute®
Last Modified: February 1, 2002
Table of Contents
1
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. koichikoyama@mac.com
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.
2
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.
3
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. trlynch@creighton.edu
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.
4
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.
5
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. dli@mdanderson.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.
6
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.
7
UI - 11808968
AU - Tendler DA
TI -
Malignant gastric outlet obstruction: bridging another divide.
SO - Am J Gastroenterol 2002 Jan;97(1):4-6
8
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.
9
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. thara@chiba-cc.pref.chiba.jp
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.
10
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. escourrou.j@chu-toulouse.fr
11
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
12
UI - 11740691
AU - Seitz K
TI -
[Update on pancreas sonography]
SO - Ultraschall Med 2001 Dec;22(6):245
13
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.
14
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.
15
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.
16
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. wangchunwei@btamail.net.cn
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.
17
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. skawapc@hsp.md.shinshu-u.ac.jp
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.
18
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. i-hirai@yf6.so-net.ne.jp
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.
19
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.
boros@gcrc.rei.edu
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.
20
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.
kkaneko@int3.tohoku.ac.jp
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.
21
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.
k1@bekkoame.ne.jp
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.
22
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.
23
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.
24
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.
25
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.
26
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.
27
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%.
28
UI - 9424865
AU - Knast W; Wierzbicki J; Markocka-Maczka K; Lewandowski A; Wozniak S;
TI -
Geneja M
[Intraoperative portography in operations for resection of pancreas
neoplasms]
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