Expression of collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of the metalloproteinases (TIMP1) in pancreatic and ampullary disease.

It is now recognised that epithelial-stromal interactions are important in a wide range of disease processes including neoplasia and inflammation. Metalloproteinases are central to matrix degradation and remodelling, which are key events in tumour invasion and metastasis and may also be involved in tissue changes occurring in chronic inflammation. Immunohistochemistry was performed on sections from 50 patients with pancreatic cancer (n = 27), ampullary cancer (n = 12), low bile duct cancer (n = 3), neuroendocrine tumours (n = 3) and chronic pancreatitis (n = 5), using antibodies raised against collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of metalloproteinase (TIMP1) and developed using the avidin-biotin complex method. Abundance of MMP2, MMP3 and TIMP1 was greater in pancreatic and ampullary cancer than any other pathology and immunoreactivity in the malignant epithelial cells in pancreatic and ampullary cancer was greater than in the stromal tissues (in pancreatic cancer: MMP2 100% vs 37%, MMP3 93% vs 15%, TIMP1 93% vs 4%, P < 0.0001). There were strong correlations between the immunoreactivity of the two antibodies for MMP2 (P < 0.0001), between MMP2 and TIMP1 (P < 0.0001) and between MMP3 and TIMP1 (P < 0.0001). The immunoreactivity for TIMP1 in pancreatic and ampullary cancers with lymph node metastases was significantly less compared with those cases without lymph node metastases (P < 0.02) and there was an association between increased immunoreactivity for MMP2 and the degree of tumour differentiation (P < 0.01). The results implicate MMP2, MMP3 and TIMP1 in the invasive phenotype of pancreatic and ampullary cancer

Acute liver failure due to primary angiosarcoma: A case report and review of literature

<p>Abstract</p> <p>Background</p> <p>Hepatic angiosarcoma is a primary sarcoma of the liver, accounting for only 2% of all primary hepatic malignancies. Acute liver failure is an extremely rare presentation of a primary liver tumour.</p> <p>Case presentation</p> <p>We report a case of a seventy year-old man who presented with a very short period of jaundice leading to fulminant hepatic failure (FHF). On further investigation he was found to have primary angiosarcoma of liver.</p> <p>Conclusion</p> <p>The treatment outcomes for hepatic angiosarcoma are poor, we discuss the options available and the need for prompt investigation and establishment of a diagnosis</p

A preoperative predictive score of pancreatic fistula following pancreatoduodenectomy

AbstractBackgroundVarious factors are related to the occurrence of postoperative pancreatic fistula (POPF) following pancreatoduodenectomy (PD). Some of the strongest are identified intra- or postoperatively, which limits their utility in predicting this complication. The preoperative prediction of POPF permits an individualized approach to patient consent and selection, and may influence postoperative management. This study sought to develop and test a score to predict POPF.MethodsA post hoc analysis of a prospectively maintained database was conducted. Consecutive patients were randomly selected to modelling and validation sets at a ratio of 2:1, respectively. Patient data, preoperative blood tests and physical characteristics of the gland (assessed from preoperative computed tomography images) were subjected to univariate and multivariate analysis in the modelling set of patients. A score predictive of POPF was designed and tested in the validation set.ResultsPostoperative pancreatic fistula occurred in 77 of 325 (23.7%) patients. The occurrence of POPF was associated with 12 factors. On multivariate analysis, body mass index and pancreatic duct width were independently associated with POPF. A risk score to predict POPF was designed (area under the receiver operating characteristic curve: 0.832, 95% confidence interval 0.768–0.897; P < 0.001) and successfully tested upon the validation set.ConclusionsPreoperative assessment of a patient's risk for POPF is possible using simple measurements. The present risk score is a valid tool with which to predict POPF in patients undergoing PD

A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer

Pancreatic cancer is the fifth most common cause of cancer death in the western world and the prognosis for unresectable disease remains poor. Recent advances in conventional chemotherapy and the development of novel ‘molecular’ treatment strategies with different toxicity profiles warrant investigation as combination treatment strategies. This randomised study in pancreatic cancer compares marimastat (orally administered matrix metalloproteinase inhibitor) in combination with gemcitabine to gemcitabine alone. Two hundred and thirty-nine patients with unresectable pancreatic cancer were randomised to receive gemcitabine (1000 mg m−2) in combination with either marimastat or placebo. The primary end-point was survival. Objective tumour response and duration of response, time to treatment failure and disease progression, quality of life and safety were also assessed. There was no significant difference in survival between gemcitabine and marimastat and gemcitabine and placebo (P=0.95 log-rank test). Median survival times were 165.5 and 164 days and 1-year survival was 18% and 17% respectively. There were no significant differences in overall response rates (11 and 16% respectively), progression-free survival (P=0.68 log-rank test) or time to treatment failure (P=0.70 log-rank test) between the treatment arms. The gemcitabine and marimastat combination was well tolerated with only 2.5% of patients withdrawn due to presumed marimastat toxicity. Grade 3 or 4 musculoskeletal toxicities were reported in only 4% of the marimastat treated patients, although 59% of marimastat treated patients reported some musculoskeletal events. The results of this study provide no evidence to support a combination of marimastat with gemcitabine in patients with advanced pancreatic cancer. The combination of marimastat with gemcitabine was well tolerated. Further studies of marimastat as a maintenance treatment following a response or stable disease on gemcitabine may be justified

Application of Portsmouth modification of physiological and operative severity scoring system for enumeration of morbidity and mortality (P-POSSUM) in pancreatic surgery

<p>Abstract</p> <p>Background</p> <p>Pancreatoduodenectomy (PD) is associated with high incidence of morbidity and mortality. We have applied P-POSSUM in predicting the incidence of outcome after PD to identify those who are at the highest risk of developing complications.</p> <p>Method</p> <p>A prospective database of 241 consecutive patients who had PD from January 2002 to September 2005 was retrospectively updated and analysed. P-POSSUM score was calculated for each patient and correlated with observed morbidity and mortality.</p> <p>Results</p> <p>30 days mortality was 7.8% and morbidity was 44.8%. Mean physiological score was 16.07 ± 3.30. Mean operative score was 13.67 ± 3.42. Mean operative score rose to 20.28 ± 2.52 for the complex major operation (p < 0.001) with 2 fold increase in morbidity and 3.5 fold increase in mortality. For groups of patients with a physiological score of (less than or equal to) 18, the O:P (observed to Predicted) morbidity ratio was 1.3–1.4 and, with a physiological score of >18, the O:P ratio was nearer to 1. Physiological score and white cell count were significant in a multivariate model.</p> <p>Conclusion</p> <p>P-POSSUM underestimated the mortality rate. While P-POSSUM analysis gave a truer prediction of morbidity, underestimation of morbidity and potential for systematic inaccuracy in prediction of complications at lower risk levels is a significant issue for pancreatic surgery</p

Analytic results for Gaussian wave packets in four model systems: I. Visualization of the kinetic energy

Using Gaussian wave packet solutions, we examine how the kinetic energy is distributed in time-dependent solutions of the Schrodinger equation corresponding to the cases of a free particle, a particle undergoing uniform acceleration, a particle in a harmonic oscillator potential, and a system corresponding to an unstable equilibrium. We find, for specific choices of initial parameters, that as much as 90% of the kinetic energy can be localized (at least conceptually) in the `front half' of such Gaussian wave packets, and we visualize these effects.Comment: 22 pages, RevTeX, four .eps figures, to appear in Found. Phys. Lett. Vol. 17, Dec. 200

Explicit solution for a Gaussian wave packet impinging on a square barrier

The collision of a quantum Gaussian wave packet with a square barrier is solved explicitly in terms of known functions. The obtained formula is suitable for performing fast calculations or asymptotic analysis. It also provides physical insight since the description of different regimes and collision phenomena typically requires only some of the terms.Comment: To be published in J. Phys.

Small Corrections to the Tunneling Phase Time Formulation

After reexamining the above barrier diffusion problem where we notice that the wave packet collision implies the existence of {\em multiple} reflected and transmitted wave packets, we analyze the way of obtaining phase times for tunneling/reflecting particles in a particular colliding configuration where the idea of multiple peak decomposition is recovered. To partially overcome the analytical incongruities which frequently rise up when the stationary phase method is adopted for computing the (tunneling) phase time expressions, we present a theoretical exercise involving a symmetrical collision between two identical wave packets and a unidimensional squared potential barrier where the scattered wave packets can be recomposed by summing the amplitudes of simultaneously reflected and transmitted wave components so that the conditions for applying the stationary phase principle are totally recovered. Lessons concerning the use of the stationary phase method are drawn.Comment: 14 pages, 3 figure

Endostatin expression in pancreatic tissue is modulated by elastase

Pancreatic tumours are scirrhous, avascular tumours, suggesting that they may produce angiogenesis inhibitors that suppress the growth of the vasculature to the tumour and metastases. We have sought evidence for the angiogenesis inhibitor, endostatin, in normal and cancerous pancreatic tissue. Using Western blotting, we found mature 20 kDa endostatin in cancer tissue but not in normal tissue. Several endostatin-related peptides of higher mol wt were present in both tissues. Extracts from normal tissue were able to degrade exogenous endostatin, whereas extracts from cancer were without effect. Although the exocrine pancreas secretes inactive proenzymes of trypsin, chymotrypsin and elastase, their possible role in this degradation was examined. The trypsin/chymotrypsin inhibitor, Glycine max, did not prevent the degradation of endostatin by normal pancreatic extracts but elastatinal, a specific inhibitor of elastase, reduced the rate of degradation. Extracts of pancreatic tumours did not express any detectable elastase activity, but an elastase (Km 1.1 mM) was expressed by extracts of normal pancreas. We conclude that endostatin is present and stable in pancreatic cancer tissues, which may explain their avascular nature, but that normal pancreatic tissue expresses enzymes, including elastase, which rapidly degrade endostatin. The stability of endostatin may have implications for its therapeutic use

Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial

This randomised, double-blind, placebo-controlled study was designed to evaluate the ability of the orally administered matrix metalloproteinase inhibitor, marimastat, to prolong survival in patients with non-resectable gastric and gastro-oesophageal adenocarcinoma. Three hundred and sixty-nine patients with histological proof of adenocarcinoma, who had received no more than a single regimen of 5-fluorouracil-based chemotherapy, were randomised to receive either marimastat (10 mg b.d.) or placebo. Patients were treated for as long as was tolerable. The primary endpoint was overall survival with secondary endpoints of time to disease progression and quality of life. At the point of protocol-defined study completion (85% mortality in the placebo arm) there was a modest difference in survival in the intention-to-treat population in favour of marimastat (P=0.07 log-rank test, hazard ratio=1.23 (95% confidence interval 0.98–1.55)). This survival benefit was maintained over a further 2 years of follow-up (P=0.024, hazard ratio=1.27 (1.03–1.57)). The median survival was 138 days for placebo and 160 days for marimastat, with 2-year survival of 3% and 9% respectively. A significant survival benefit was identified at study completion in the pre-defined sub-group of 123 patients who had received prior chemotherapy (P=0.045, hazard ratio=1.53 (1.00–2.34)). This benefit increased with 2 years additional follow-up (P=0.006, hazard ratio=1.68 (1.16–2.44)), with 2-year survival of 5% and 18% respectively. Progression-free survival was also significantly longer for patients receiving marimastat compared to placebo (P=0.009, hazard ratio=1.32 (1.07–1.63)). Marimastat treatment was associated with the development of musculoskeletal pain and inflammation. Events of anaemia, abdominal pain, jaundice and weight loss were more common in the placebo arm. This is one of the first demonstrations of a therapeutic benefit for a matrix metalloproteinase inhibitor in cancer patients. The greatest benefit was observed in patients who had previously received chemotherapy. A further randomised study of marimastat in these patients is warranted