Solid waste and pancreatic cancer: an ecologic study in Florida, USA

BACKGROUND: Other than cigarette smoking, modifiable risk factors for pancreatic cancer have not been consistently identified. This study explored the ecologic relationship between pancreatic cancer incidence and measures of cigarette smoking, income, and solid waste collection for Florida's 67 counties. METHODS: We used Florida's population-based cancer registry to compare county-specific incidence rates of pancreatic cancer among Whites to median household income, the per county prevalence of cigarette smoking, and to measures of per capita municipal solid waste collected. RESULTS: County-specific incidence rates for pancreatic cancer ranged from 0 to 8.1 per 100,000 per year and were significantly correlated with income (r = 0.35), cigarette smoking (r = 0.39), and solid waste (r = 0.47). The correlation between pancreatic cancer and solid waste was largely attributable to one sub-component of solid waste, yard trash (grass clippings, and tree and shrub trimmings) (r = 0.42). Using a stepwise regression procedure, only cigarette smoking and yard trash remained significant in the model. CONCLUSIONS: These data suggest that some factor associated with grass and tree trimmings, e.g. insecticides and herbicides, may increase the risk for pancreatic cancer. This hypothesis is consistent with several reports of pancreatic cancer and insecticide exposure in individuals and may suggest new avenues for research in pancreatic cancer.     

The HER2/neu-derived peptide p654-662 is a tumor-associated antigen in human pancreatic cancer recognized by cytotoxic T lymphocytes

The protooncogene HER2/neu encodes a 185-kDa transmembrane protein with extensive homology to the epidermal growth factor receptor. It is overexpressed in several human cancers of epithelial origin, such as pancreatic cancer. Previously, we demonstrated that cytotoxic T lymphocytes (CTL) derived from breast, ovarian, and non-small cell lung cancer recognized a peptide derived from HER2/neu. To evaluate whether this HLA-A2-binding peptide is a tumor-associated antigen (TAA) in pancreatic cancer, the ability of HER2/neu-reactive CTL to lyse human pancreatic carcinoma cells was tested. CTL were generated from tumor-associated T lymphocytes from HLA-A2+ HER2/neu+ breast and ovarian cancer patients. All CTL recognized autologous and allogeneic HER2/ neu+ tumor cells in an HLA-A2-restricted fashion. Furthermore, all CTL recognized p654-662 (GP2) derived from HER2/neu. These CTL also recognized HER2/neu+ pancreatic cancer cells in an HLA-A2-restricted fashion. HER2/neu+ HLA-A2- pancreatic cancer were not or only poorly lysed. Repeated stimulation of HLA-A2+ PBL from pancreatic cancer patients using the HER2/neu-derived peptide resulted in specific recognition of this peptide and, more importantly, HER2/neu+ pancreatic tumors in an HLA-A2-restricted fashion. Autologous HLA-A2+ fibroblasts or HLA-A2+ malignant melanoma cells were not recognized. HLA-A2- peptide-stimulated T lymphocytes showed no significant cytotoxicity. These results demonstrate that this HER2/neu-derived peptide is a shared TAA among several adenocarcinomas including pancreatic carcinoma, suggesting a common mechanism of recognition of these human tumors by T lymphocytes. The identification of the HER2/neu-derived peptide GP2 as a TAA in pancreatic cancer provides an opportunity for the design of novel immunotherapy and vaccine strategies.     

Annular dilatation increases stress in the mitral valve and delays coaptation: a finite element computer model

This report summarizes results from an initial clinical evaluation of radioimmunodetection (RAID) in patients with pancreatic cancer using murine monoclonal antibody Nd2, directed against mucins from pancreatic cancer. Nd2 (2 mg) was labeled with 111In (2 mCi) and injected into 19 patients suspected of having pancreatic cancer. Planar scintigrams were taken 3 days post-infusion. As for final diagnoses after surgery, 14 cases were pancreatic cancer, and one case each was chronic pancreatitis, neurilemmoma, islet cell carcinoma, cholangioma, and apparent absence of suspected recurrent lesion of pancreatic cancer. Of 14 patients with pancreatic cancer, RAID was positive in 10 cases (71.4%). Cases other than pancreatic cancer were all negative, so the specificity was 100%. These results demonstrate that RAID using 111In-Nd2 can be useful in differentiating exocrine pancreatic cancer from benign conditions and other types of carcinomas in the pancreatoduodenal regions.     

Review article: current treatment and optimal patient management in pancreatic cancer

Pancreatic cancer is the tenth most prevalent malignancy and the fifth most common cause of cancer death in the developed world. Less than 10% of patients survive for more than 1 year following diagnosis and the 5-year survival rate (0.4%) is the lowest of any cancer. The poor prognosis associated with this diagnosis led in the past to therapeutic nihilism on the part of clinicians who were all too aware of the limitations of their available therapeutic strategies. Breaking this therapeutic impasse requires a significant expansion in the knowledge of clinicians concerning the pathogenesis and behaviour of pancreatic cancer. Recent advances in the scientific understanding of the aetiology of pancreatic cancer has facilitated progress towards the development of promising and innovative approaches to the early detection and diagnosis of pancreatic cancer. While acknowledging that pancreatic cancer will continue to present significant challenges to both scientists and clinicians in the foreseeable future, it is becoming increasingly clear that recent advances in our scientific knowledge base holds the potential to significantly improve prognosis for patients. The challenge facing both scientists and clinicians is how best to translate such promising scientific advances into survival and quality of life benefits to patients.     

Telomerase activity detected in pancreatic juice 19 months before a tumor is detected in a patient with pancreatic cancer

We report a patient with pancreatic cancer in whom telomerase activity had been detected in the pancreatic juice 19 months before he was diagnosed as having pancreatic cancer. A 61-yr-old alcoholic man complaining of epigastric and back pain was diagnosed as having groove pancreatitis based on the presence of inflammation in the pancreatic head and its extension to the duodenal mucosa with an associated elevated serum amylase level. All imaging modalities showed no sign of a tumor. However, high telomerase activity was detected in the pancreatic juice collected during endoscopic retrograde pancreatography. His symptoms subsided due to abstinence from alcohol. A tumor, however, was recognized on computed tomography 19 months later, at which time the patient immediately underwent a pylorus-preserving pancreaticoduodenectomy. The carcinoma was located mainly in the Santorini duct region. High telomerase activity in the pancreatic juice may precede clinical detection of pancreatic cancer and thus could be a useful early diagnostic marker for pancreatic cancer.     

Ultrastructural study of anionic sites in glomerular basement membranes at different perfusion pressures by quick-freezing and deep-etching method

In a previous large scale screen for differentially expressed genes in pancreatic cancer, we identified a gene highly overexpressed in cancer encoding a novel putative transmembrane protein with two Kunitz-type serine protease inhibitor domains. The identified gene named kop (Kunitz domain containing protein overexpressed in pancreatic cancer) was assigned to chromosome 19 in the region 19q13.1. Kop was detected at high levels in pancreatic cancer cell lines and was overexpressed in pancreatic cancer tissues as compared to both, normal pancreas and chronic pancreatitis tissues. Being a member of the Kunitz-type serine protease inhibitor family, this new gene may participate in tumour cell invasion and metastasis and in the development of the marked desmoplastic reaction typical for human pancreatic cancer tissues. In this context, the fact that kop has a putative transmembrane domain may have functional implications of particular interest.     

Experimental milk formulae with reduced protein content and desialylated milk proteins: influence on the faecal flora and the growth of term newborn infants

Diagnosing and monitoring pancreatic cancer is an ongoing challenge. Conventional markers such as tumor-associated antigens might be supplemented by molecular markers such as gene mutations and growth factor/growth factor receptor alterations in the future. Tumor-associated antigens can easily be measured by different EIA/ELISA systems, but the analysis of gene mutations, growth factors and their receptors requires advanced molecular techniques. CA 19-9 is the most widely used conventional marker for pancreatic cancer and is a useful tool in the diagnosis and follow-up of patients after tumor resection. Nonetheless, its role in detecting early pancreatic cancer is limited. The detection of K-ras and p53 mutations, which occur in about 90 and 50% of pancreatic cancers, respectively, in blood, stool, or bile samples, seems to be a promising approach in the diagnosis. Growth factor and growth factor receptor alterations are often associated with increased tumor aggressiveness and shorter survival following tumor resection. To date the analysis of growth factors/growth factor receptors in pancreatic cancer has not entered clinical use, but further molecular characterization of pancreatic cancer is necessary for earlier and more accurate diagnosis and it may result in new treatment options.     

Referral of patients with pain from pancreatic cancer for neurolytic celiac plexus block

OBJECTIVE: To assess whether patients with pancreatic cancer-associated pain living near a pain control center were more likely to undergo neurolytic celiac plexus block (NCPB) than those living at a distance and to determine the rationale of physicians at our institution for referring patients for NCPB. DESIGN: We retrospectively reviewed the frequency of use of NCPB in patients with pancreatic cancer and conducted an anonymous physician survey of referral patterns for NCPB for such patients. MATERIAL AND METHODS: A prospective database of medical diagnoses and a clinical database at our institution were used to identify patients with pancreatic cancer within three geographic regions who were assessed during the inclusive years 1980 through 1989: group I ("local") = all patient with pancreatic cancer in Olmsted County, Minnesota; group II ("surrounding") and group III ("distant") = patients referred for pancreatic cancer evaluation who lived within 100 miles of our institution (excluding Olmsted County) or more than 100 miles from our institution, respectively. Medical records were retrospectively reviewed to assess the use of NCPB at any time during the course of pancreatic cancer. For the physician survey component, all medical oncologists, gastroenterologists, and general surgeons at our institution who might be responsible for the care of patients with pancreatic cancer were sent a questionnaire about their referral patterns for NCPB among patients with pancreatic cancer. RESULTS: Overall, approximately 15% of the 292 patients with pancreatic cancer studied underwent NCPB. Distance from our pain control center was not found to be associated with frequency of use of NCPB. Of the 78 physicians surveyed, 59 (76%) responded, and 35 of the responders (59%) had encountered at least 1 patient with pancreatic cancer during the preceding 12 months. In that subset of physicians, perceived barriers for referral for NCPB were limited appointment availability and need for repeating the procedure. CONCLUSION: On the basis of this study, referral patterns for NCPB in patients with pancreatic cancer do not seem to be associated with the geographic distance of a patient's residence from a pain control center. Improving appointment availability for NCPB might increase the number of patients offered this technique for control of pain.     

Pancreatic cancer screening. Analysis of the problem and the role of radionuclide imaging

The clinical, surgical, and pathologic findings in a five year prospective study of 192 patients referred with a high probability of pancreatic cancer are reported. We have defined the requirements of any pancreatic imaging procedure as its ability to distinguish a normal pancreas from pancreatic cancer or chronic pancreatitis and the capability of detecting tumors less than 5 cm in diameter. There was a 47 percent incidence of pancreatic disease (27 percent pancreatic cancer and 20 percent chronic pancreatitis). Prospective radionuclide imaging as routinely performed was found to be of little clinical value in this patient population; it was neither specific nor sensitive to pancreatic cancer or chronic pancreatitis. Preliminary data with longitudinal multiplane emission tomography show an improved diagnostic accuracy and the ability to detect resectable tumors, but its efficacy needs to be prospectively compared with other screening tests on a carefully defined patient population.     

The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer

Heparan sulfate proteoglycans (HSPGs) play diverse roles in cell recognition, growth, and adhesion. In vitro studies suggest that cell-surface HSPGs act as coreceptors for heparin-binding mitogenic growth factors. Here we show that the glycosylphosphatidylinositol- (GPI-) anchored HSPG glypican-1 is strongly expressed in human pancreatic cancer, both by the cancer cells and the adjacent fibroblasts, whereas expression of glypican-1 is low in the normal pancreas and in chronic pancreatitis. Treatment of two pancreatic cancer cell lines, which express glypican-1, with the enzyme phosphoinositide-specific phospholipase-C (PI-PLC) abrogated their mitogenic responses to two heparin-binding growth factors that are commonly overexpressed in pancreatic cancer: fibroblast growth factor 2 (FGF2) and heparin-binding EGF-like growth factor (HB-EGF). PI-PLC did not alter the response to the non-heparin-binding growth factors EGF and IGF-1. Stable expression of a form of glypican-1 engineered to possess a transmembrane domain instead of a GPI anchor conferred resistance to the inhibitory effects of PI-PLC on growth factor responsiveness. Furthermore, transfection of a glypican-1 antisense construct attenuated glypican-1 protein levels and the mitogenic response to FGF2 and HB-EGF. We propose that glypican-1 plays an essential role in the responses of pancreatic cancer cells to certain mitogenic stimuli, that it is relatively unique in relation to other HSPGs, and that its expression by pancreatic cancer cells may be of importance in the pathobiology of this disorder.     

Aberrant expression of type I fibroblast growth factor receptor in human pancreatic adenocarcinomas

Acidic and basic fibroblast growth factors are mitogenic polypeptides that are overexpressed in pancreatic cancer. To determine whether fibroblast growth factors may exert direct effects on pancreatic cancer cells in vivo, we compared the expression of the high-affinity type I fibroblast growth factor receptor (FGFR-1) in human pancreatic tissues. In the normal pancreas, FGFR-1 immunostaining was seen mainly in acinar cells. In pancreatic cancers, FGFR-1 was abundant in ductal-like cancer cells which also exhibited many FGFR-1 mRNA in situ hybridization grains. Analysis by the polymerase chain reaction and RNase protection revealed that the 2-immunoglobulin-like and the 3-immunoglobulin-like forms of FGFR-1 were expressed in all tissue samples, and that the 2-immunoglobulin-like form was overexpressed in the cancer tissues by comparison with the normal tissues. These findings suggest that the 2-immunoglobulin-like form of FGFR-1 may contribute to aberrant autocrine and paracrine pathways in pancreatic cancer.     

Unresectable pancreatic cancer: is a multi-modality approach a promising therapeutical alternative?

BACKGROUND/AIMS: The aim of this study was to evaluate the combination of immunochemotherapy and stop-flow upper abdominal chemotherapy in the prolongation of survival in patients with unresectable pancreatic cancer. METHODOLOGY: Thirty unresectable pancreatic cancer patients were treated with immuno-chemotherapy in combination with stop-flow upper abdominal chemotherapy, in an attempt to improve survival time. RESULTS: The results obtained in this study indicate that this kind of treatment is feasible, safe and effective for patients suffering from Stage III and IV pancreatic duct carcinoma. Twenty per cent of the patients within this group were able to undergo radical resection and remain alive and free of disease, with a mean survival rate of 16 months. CONCLUSION: The multi-modality approach used in this study achieved promising results for pancreatic cancer patients and is recommended as a promising therapeutic alternative.     

Genetic basis of cancer of the pancreas: diagnostic and therapeutic applications

Relatively little is known about the molecular basis of pancreatic cancer despite it being one of the most common cancers in the developed world. Recent studies have shown that in human pancreatic cancer there are abnormalities in the structure or function, or both, of several oncogenes, notably the c-erb B-2 proto-oncogene and the Ki-ras oncogene. These genetic alterations will have both diagnostic and therapeutic implications. The Ki-ras gene is mutated at codon 12 in about 90% of pancreatic cancers and there is abnormal expression of the c-erb B-2 oncogene in nearly 20%, although mutational activation of the latter is not seen in human pancreatic adenocarcinoma. There is considerable evidence to support the hypothesis that neoplastic transformation requires many genetic events, and it is likely therefore that there are other molecular abnormalities in pancreatic cancer. The sequence of their activation and the agents responsible for that activation have not yet been elucidated, and both laboratory and animal experiments are needed to define which molecular events activate the neoplastic genotype and phenotype and how.     

Growth and development of twins compared with singletons at ages one and four years

To assess the relationship of smoking and coffee, tea, and alcohol intake to the risk of cancer of the exocrine pancreas, analyses were performed using data from a prospective cohort study of 33,976 postmenopausal Iowa women who responded to a mailed questionnaire in 1986 and were followed through 1994 for cancer incidence and total mortality. At baseline, information on cigarette smoking, consumption of tea, coffee, and alcoholic beverages, and other dietary and lifestyle factors was obtained. Age-adjusted relative risks of pancreatic cancer (n = 66 cases) showed a dose-response association with smoking. Those with fewer than 20 pack-years and those with 20 or more pack-years of smoking exposure were 1.14 (95% confidence interval, 0.53-2.45) and 1.92 (95% confidence interval, 1.12-2.30) times more likely, respectively, to develop pancreatic cancer than were nonsmokers. Current smokers were twice as likely as were nonsmokers to develop pancreatic cancer. Relative risks of pancreatic cancer increased with the amount of alcohol consumed (Ptrend = 0.11) after adjustment for age, smoking status, and pack-years of smoking. Relative risks of pancreatic cancer according to alcoholic beverage intake were as strong among never-smokers as they were in the total cohort. After the data were adjusted for age, smoking status, and pack-years of smoking, there was a statistically significant 2-fold (95% confidence interval, 1.08-4.30) elevated risk of pancreatic cancer for those who drank > 17.5 cups of coffee per week, compared to those who consumed < 7 cups/week; among never-smokers, the relative risks across coffee intake categories were still positive but were attenuated somewhat (P trend = 0.17). Tea intake was not related to cancer incidence. In summary, these findings provide evidence of an association of both alcoholic beverage and coffee consumption with pancreatic cancer incidence that is independent of age and cigarette smoking.     

Ovarian function in ewes made hypogonadal with GnRH antagonist and stimulated with FSH in the presence or absence of low amplitude LH pulses

Keratinocyte growth factor (KGF) is an angiogenic and mitogenic polypeptide that has been implicated in cancer growth and tissue development and repair. Its actions are dependent on its binding to a specific cell-surface KGF receptor (KGFR), which is encoded by the fibroblast growth factor (FGF) receptor type II (FGFR-2) gene. In the present study, we compared the immunohistochemical localization of KGF and KGFR/FGFR-2 in the normal and cancerous pancreas using specific antibodies that recognize KGF and KGFR/FGFR-2 and examined the expression of KGF, KGFR, and FGFR-2 in human pancreatic cancer by in situ hybridization with the corresponding riboprobes. In the normal pancreas, KGF immunoreactivity was present principally in the islet cells, whereas KGFR/FGFR-2 immunoreactivity was present both in the islet and ductal cells. In the pancreatic cancers, moderate KGF and moderate to strong KGFR/FGFR-2 immunoreactivity was present in many of the cancer cells. Furthermore, the ductal and acinar cells adjacent to the cancer cells exhibited moderate to strong KGF and KGFR/FGFR-2 immunoreactivity. By in situ hybridization, KGF, KGFR, and FGFR-2 were overexpressed and co-localized in the cancer cells within the pancreatic tumor mass but were even more abundant in the acinar and ductal cells adjacent to the cancer cells. These findings indicate that KGF, KGFR, and FGFR-2 are overexpressed in both the cancer cells and the adjacent pancreatic parenchyma and raise the possibility that KGF may act in an autocrine and paracrine manner to enhance pancreatic cancer cell growth in vivo.     

The splice-pattern of CD44 is altered in chronic pancreatitis exhibiting dysplastic changes

Recent studies have shown that several splice variants of CD44, might be involved in tumor progression. Since chronic pancreatitis is suggested to be a risk factor for pancreatic cancer we investigated the splice pattern of CD44 in chronic pancreatitis to elucidate the role of CD44 in pancreas tumorigenesis. The expression of CD44-isoforms was examined in 40 specimens of chronic pancreatitis and 12 specimens of normal pancreas by immunohistochemistry, Westernblotting and exon specific RT-PCR. Pancreatic cancer tissue from two patients who developed pancreatic cancer 2 and 3 years following surgery for chronic pancreatitis were analyzed. Strong expression of CD44s was found in all cells, whereas the expression of CD44v6 was restricted to ductal cells. Westernblotting revealed an overexpression of CD44v6 in chronic pancreatitis as compared to normal pancreas. Exon specific analysis revealed an altered splice pattern of CD44, similar to that in pancreatic cancer, in 12.5% of the chronic pancreatitis specimens. Both patients who developed pancreatic cancer after chronic pancreatitis exhibited this altered splice pattern in both, chronic pancreatitis and pancreatic cancer. These results suggest that variant forms of CD44-mRNA might be expressed in early dysplastic alterations in chronic pancreatitis.     

Indirect antiproliferative effect of the somatostatin analog octreotide on MIA PaCa-2 human pancreatic carcinoma in nude mice

Analogs of somatostatin (SRIF) such as octreotide exert antiproliferative effects that are mediated directly by tumoral SRIF receptors or indirectly by down-modulation of factors that stimulate tumor growth. Direct and indirect antiproliferative effects have been demonstrated in certain SRIF receptor-positive and -negative human breast cancer models in nude mice, respectively. These antiproliferative mechanisms are also being explored in other cancer types including pancreatic cancer. While clinical pilot studies have indicated that a fraction of pancreatic adenocarcinomas respond to high-dose octreotide treatment, it is known from receptor autoradiographic and scintigraphic studies that human pancreatic carcinomas fail to express SRIF receptors, in contrast to rat pancreatic carcinomas or human endocrine pancreatic cancer. Studies on the potential anticancer effect of octreotide on the growth of experimental human pancreatic cancer and its SRIF receptor status have been controversial. Therefore, we investigated in vivo the effects of octreotide on the growth of MIA PaCa-2 human pancreatic carcinomas raised from cultured cells with a low passage number after receipt from the American Type Culture Collection. Nude mice bearing MIA PaCa-2 tumors were treated with a single injection of the recently developed octreotide long-acting release formulation, "SMS pa LAR." This treatment was well tolerated and resulted in a highly significant inhibition of tumor growth during weeks three and eight after administration. MIA PaCa-2 tumors were removed after eight weeks and processed for RT-PCR analysis using probes specific for each of the five somatostatin receptor subtypes sst1-sst5. This analysis revealed that MIA PaCa-2 tumors, like human pancreatic adenocarcinomas, do not express any of the five SRIF receptor subtypes, suggesting an indirect mode of tumor growth inhibition. In summary, the depot formulation SMS pa LAR exerted long-lasting antiproliferative effects in SRIF receptor-negative human pancreatic carcinomas in nude mice.     

Altropane, a SPECT or PET imaging probe for dopamine neurons: II. Distribution to dopamine-rich regions of primate brain

Our understanding of the molecular pathology underlying the development and progression of ductal pancreatic cancer has been revolutionised during the last 5 years due to the spectacular development of novel molecular biological techniques. In the present article, we describe key molecular alterations of sporadic and inherited ductal pancreatic cancer. Overexpression of growth factors and growth factor receptors are present in a significant proportion of this tumour type. Mutation of the K-ras oncogene, and disruption of p53 or p16 tumour suppressor gene abrogates the control of the cyclin-dependent kinases (cdk) and retinoblastoma (Rb) gene pathway, causing continuous growth of the pancreatic tumour. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor beta signalling pathway. Lost or decreased expression of retinoid receptors and failure of telomerase activity may play a role in pancreatic carcinogenesis. Tumour-associated proteinases, matrix metalloproteinases and plasminogen activators are reported to be involved in pancreatic cancer invasion and metastasis. Furthermore, the cytogenetic changes in this cancer are summarised. This molecular pattern distinguishes pancreatic cancer from other epithelial tumours and represents a promising basis for the development of diagnostic and other clinical applications.