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Dermot O'Toole

Publications and source records attributed to Dermot O'Toole.

At least 19 recordsLinked to original sources
PubMed2006

Identification of potential therapeutic targets by gene-expression profiling in pancreatic endocrine tumors.

BACKGROUND & AIMS: Prediction of biological behavior in pancreatic endocrine tumors (PET) is difficult on histologic criteria alone. The aim of this study was to characterize PET gene expression by complementary DNA (cDNA) microarray and identify specific differences in gene-expression profiles between nonmetastatic and metastatic tumors. METHODS: We studied 24 well-differentiated PETs corresponding to 12 benign tumors and to 12 carcinomas with metastasis. Total RNAs were extracted followed by microarray hybridization, imaging scan procedure, and statistical anaylsis. PET tissue arrays were constructed from 129 archival tumors for immunohistochemical validation of microarray data. RESULTS: A total of 123 transcripts were found to separate nonmetastatic from metastatic PETs (ie, 72 up-regulated and 51 down-regulated genes in malignant tumors). Some of these genes were involved in pathways related to (1) angiogenesis and remodeling (CD34, cadherin-5, E-selectin, semaphorin E, and fibrillin), (2) signal transduction through tyrosine kinases (tyrosine kinase-2, platelet-derived growth factor-Rbeta, MKK4, and discoidin domain receptor-1), (3) calcium-dependent cell signaling (transient receptor potential cation channel-1, calcium channel voltage-dependent beta2, neurocalcin delta, and GABA-A receptor gamma2), and (4) response to drug (MDR1 and carcinoembryonic antigen-related cell adhesion molecule 6). By using tissue arrays, we confirmed the differential expression of CD34 (P = .0008), E-selectin (P = .003), MKK4 (P = .0001), and MDR1 (P = .0003) in metastatic vs nonmetastatic PETs. CONCLUSIONS: This study provides insight into tumorigenic pathways in PET. Some of the genes identified are potentially new molecular markers for the detection and treatment of these tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

CD10 expression in pancreatic endocrine tumors: correlation with prognostic factors and survival.

CD10 is a cell surface metalloprotease expressed by a variety of hematopoietic and solid tumors. Immunohistochemical expression of CD10 was examined in 91 pancreatic endocrine tumors (PETs) included in tissue microarrays and representing various stages of tumorigenesis as well as in 10 normal pancreas tissues. The results were correlated with histoprognostic factors, namely, Ki-67 index and microvascular density. Thirty PETs (33%) presented positive cytoplasmic staining, and in 7 cases (8%), membranous staining also was observed. Stromal CD10 positivity was observed in 29 PETs (32%). In nontumoral pancreatic tissue, the islets were consistently negative. Epithelial cytoplasmic expression of CD10 increased with World Health Organization classification: CD10 was detected in 12% of benign tumors, 29% of tumors of uncertain prognosis, 38% of well-differentiated carcinomas, and 86% of poorly differentiated carcinomas. Membranous expression of CD10 correlated with poor differentiation (P = .0004). Expression of CD10 also correlated significantly with a high proliferative index (P = .020), low microvascular density (P = .043), large tumor size (P = .023), and presence of metastasis (P = .013). Expression was associated with poorer survival (P = .017). No statistical relation was observed between stromal CD10 expression and any of the histopathologic criteria examined. In conclusion, CD10 is expressed in a subset of PETs and correlates with histopathologic indicators of poor outcome, suggesting a role for this molecule in tumorigenesis and prognostic analysis.

Adult↗
PubMed2006

Natural history of intraductal papillary mucinous tumors of the pancreas: actuarial risk of malignancy.

BACKGROUND & AIMS: Natural history of intraductal papillary mucinous tumors of the pancreas (IPMTs) is unknown. Cross-sectional studies suggest that exclusive branch duct (BD) involvement is associated with a lower risk of carcinoma than main pancreatic duct (MPD) involvement. The aim of our study was to calculate longitudinal risk of malignant transformation of IPMT since the first sign. METHODS: All the patients with a diagnosis of highly probable or histologically proven IPMT were included. Actuarial risks of occurrence of at least low-grade dysplasia (>or=LGD), high-grade dysplasia (>or=HGD), or invasive carcinoma (IC) were calculated by Kaplan-Meier method from the first sign attributable to IPMT. The risks according to sex, acute pancreatitis, tumor size, and involvement of MPD were compared by log-rank test. RESULTS: One hundred six patients were included with a proven (n = 76) or probable (n = 30) IPMT. The tumor was confined to BD in 53 cases. Median duration since the onset of the first sign to the end of follow-up was 21 months (range, 0-241). Ten-year actuarial risk that IPMT grade was >or=LGD, >or=HGD, or IC was 67%, 49%, and 29%, respectively. The only morphologic risk factor of malignant transformation was involvement of MPD, with a 5-year actuarial risk of >or=HGD of 63% in the MPD group compared with 15% in the BD group (P < .001). CONCLUSIONS: Longitudinal risk of at least HGD or IC is time-dependent. Patients with BD IPMT present a much lower risk, justifying a nonoperative surveillance.

Actuarial Analysis↗
PubMed2006

Fatal cardiomyopathy associated with pegylated interferon/ribavirin in a patient with chronic hepatitis C.

We report the case of a 45-year-old man with HCV treated with pegylated interferon-alpha/ribavirin, in whom fatal cardiomyopathy occurred. Cardiomyopathy is a rare complication of high dose of standard interferon but has never been reported with pegylated interferon. The relationship between pegylated interferon-alpha/ribavirin and the development of cardiomyopathy is highly probable for the following reasons: (1) a cardiologist consultation with specific investigations had been performed before treatment excluding a pre-existing cardiomyopathy; (2) symptoms of advanced dilated cardiomyopathy appeared immediately after the end of treatment; (3) other causes of cardiomyopathy have been ruled out. In all except one of the 21 reported cases with standard interferon, cardiomyopathy was reversible. In our patient, fatal cardiomyopathy occurred with a usual dose of pegylated interferon-alpha. Clinicians should be aware of this potential complication when evaluating the ratio benefit/risk of treatment in patients with chronic hepatitis C infection.

Antiviral Agents↗
PubMed2006

Long-term outcome of biliary and duodenal stents in palliative treatment of patients with unresectable adenocarcinoma of the head of pancreas.

BACKGROUND: Life expectancy in patients with unresectable pancreatic cancer has improved by using new chemotherapeutic regimens. Biliary and digestive stenoses can be endoscopically treated in most cases. However, long-term efficacy of these stenting procedures remains unknown. AIM: To evaluate the incidence of biliary and duodenal stenoses as well as technical success and short- and long-term patency of endoscopically deployed stents in patients with unresectable pancreatic cancer. PATIENTS AND METHODS: All consecutive patients with unresectable cancer of the pancreatic head seen between January 1999 and September 2003 in our center were retrospectively studied. Patients with biliary and/or duodenal stenoses underwent endoscopic stent insertion as first intention therapy. Outcomes included technical and clinical success, stent patency, and survival. RESULTS: One hundred patients, median age 65 yr (32-85), with locally advanced (62%) or metastatic (38%) pancreatic cancer were studied. Eighty-three percent received at least one line of chemotherapy. The actuarial median survival was 11 months (0.7-29.3). Biliary and duodenal stenoses occurred in 81 and 25 patients, respectively. A biliary stent was successfully placed in 74 patients (91%). When a self-expandable metallic stent was first introduced (N = 59), a single stent was sufficient in 41 patients (69%) (median duration of stent patency 7 months (0.4-21.1)). Duodenal stenting was successful in 24 patients (96%); among them, 96% required a single stent (median duration of stent patency 6 months [0.5-15.7]). In the 23 patients who developed both biliary and duodenal stenoses, combined stenting was successful in 91% of cases. No major complication or death occurred related to endoscopic treatment. CONCLUSION: Endoscopic palliative treatment of both biliary and duodenal stenoses is safe and effective in the long term, including in patients with combined obstructions. Use of such palliative management is justified as repeat procedures are rarely required even in patients who have a long survival.

Adenocarcinoma↗
PubMed2006

The analysis of quantitative expression of somatostatin and dopamine receptors in gastro-entero-pancreatic tumours opens new therapeutic strategies.

OBJECTIVE: Somatostatin (sst) are present in the majority of gastro-entero-pancreatic (GEP) tumours. Effects of somatostatin receptor (sst) analogues are partial and of limited duration. Cell lines derived from GEP express dopaminergic receptors D(2). New chimeric analogues simultaneously recognising sst(2) and sst(5) or sst(2) and D(2) have additive effects in inhibition of GH and prolactin secretion in pituitary adenomas. Our aim was to quantify the expression of sst and D(2) mRNA in human GEP tumours. DESIGN AND METHODS: mRNA expression of sst(1), sst(2), sst(3) and sst(5) as well as D(2), was analysed using real-time PCR (TaqMan probe) in a series of 35 patients with GEP tumours (pancreas (n = 19) and intestinal (n = 16)). Levels of expression were compared with a group of 13 somatotroph adenomas. RESULTS: All GEP tumours express sst(1), sst(2) and D(2). Expression of sst(3) and sst(5) was observed in 89 and 76% of tumours respectively with highly variable levels. sst(2) mRNA expression was higher in nonfunctional tumours (P < 0.009) and sst5 was higher in pancreatic than in intestinal tumours (P < 0.02). Whereas sst(2) levels were similar between GEP and somatotroph tumours, levels of sst(5) and D(2) were higher in the former (394.9 +/- 156.1 x 10(-2) vs 69.7 +/- 19.5 x 10(-2) copy/copy beta-Gus (P < 0.0036) and 519.6 +/- 121.2 x 10(-2) vs 50.0 +/- 21.6 x 10(-2) copy/copy beta-Gus (P < 0.0001) respectively). In small tumours ( < 30 mm), sst(2) density appeared as a crucial parameter in somatostatin receptor scintigraphy results, whereas in big tumours, a consistent bias in SRS results was introduced by the size. In pancreatic GEP, high-level sst(3) expression was found in tumours with more active angiogenesis (higher microvessel density and vascular endothelial growth factor expression (P < 0.03)). CONCLUSIONS: GEP tumours co-express sst(2) and D(2) in 100% of cases and sst(5) in 89% thus supporting the testing of bi-specific agonists (sst(2)/sst(5) or sst(2)/D(2)) in these tumours.

Adult↗
PubMed2005

Low pH and Helicobacter pylori increase nuclear factor kappa B binding in gastric epithelial cells: a common pathway for epithelial cell injury?

Helicobacter pylori infection results in peptic ulceration and chronic gastritis through mechanisms which are not fully elucidated. Live H. pylori activate the pro-inflammatory transcription factor NF-kappaB in gastric epithelial cells. Patients may have peptic ulcer disease in the absence of H. pylori infection; therefore other factors contribute to the inflammatory process. Maximal acid output in patients with H. pylori infection and duodenal ulceration is significantly increased indicating a role for acid in the pathogenesis of mucosal ulceration. The effect of low pH on NF-kappaB activation in gastric epithelial cells has not been studied. Human gastric epithelial cells (AGS) were exposed to a range of pH changes in the presence or absence of H. pylori. NF-kappaB DNA-binding and cytosolic IkappaB-alpha were measured using electrophoretic mobility shift assay and Western blotting. NF-kappaB DNA-binding in gastric epithelial cells dramatically increased when the pH of the culture medium decreased. Increases in NF-kappaB nuclear binding were paralleled by decreasing amounts of cytosolic IkappaB-alpha. These findings were similar but less potent than those observed when cells were exposed to H. pylori. Low pH resulted in enhancement of H. pylori-induced NF-kappaB nuclear binding. DNA binding of NF-kappaB activation secondary to low pH was attenuated by PD98059 but not by SB203580. Similar to H. pylori, low pH potently and independently augments NF-kappaB nuclear binding in AGS cells and such activation appears to be mediated through MEK1-dependant signaling pathways.

Cell Survival↗
PubMed2005

Diagnostic criteria in predicting a biliary origin of acute pancreatitis in the era of endoscopic ultrasound: multicentre prospective evaluation of 213 patients.

BACKGROUND: No study on bioclinical criteria predicting a biliary origin for acute pancreatitis has included endosonography as a reference examination. Re-examination of bioclinical parameters deserves consideration in the era where other causes are known (e.g. hereditary, autoimmune). AIM AND METHODS: To determine the performance of bioclinical markers in predicting a biliary origin of acute pancreatitis where the diagnosis of biliary lithiasis was established or ruled out using endosonography. Only patients with a first acute episode of pancreatitis were included. RESULTS: 213 patients (male: 55%; median age: 56 years) were prospectively included in 14 centres. Causes of acute pancreatitis were: biliary (62%), alcoholic (25%), other (13%). Delay between symptom-onset and admission was <48 h in 80%. Endosonography was the sole method establishing the diagnosis of biliary pancreatitis in 15% of patients. At univariate analysis, age, female sex, declared alcohol consumption, elevated aspartate and alanine transaminases on admission, gammaglutamyl transferase, alkaline phosphatase, total bilirubin, lipase, mean corpuscular volume were predictive of a biliary origin. Only age (p < 0.0001), sex (p < 0.0008) and alanine transaminase (p < 0.0004) remained significant at multivariate analysis. At age 50, the respective sensitivity and specificity were 73 and 65%. With an elevated alanine transaminase at 2 times the upper limit of normal range, the respective sensitivity and specificity were 74 and 84%. The probability of a biliary origin of acute pancreatitis could be estimated by the following formula: = 1/1 + exp(4.6967 - 0.0656 x age + 1.1208 x sex - 0.6909 x alanine transaminase). CONCLUSION: When endosonography is performed to confirm or exclude a biliary origin of acute pancreatitis, age, sex and alanine transaminase at admission are the only factors predictive of a biliary cause.

Acute Disease↗
PubMed2005

Chemoembolization and other ablative therapies for liver metastases of gastrointestinal endocrine tumours.

Hepatic metastases are frequent in patients with gastroentero-pancreatic (GEP) endocrine tumours; their presence significantly influences overall prognosis. Surgery, although the treatment of choice for hepatic metastases, is frequently impossible due to disease extent. Systemic chemotherapy in patients with diffuse and/or progressive liver metastases yields disappointing results especially in patients with metastases from midgut origin. In addition, in patients with carcinoid syndrome, the efficacy of somatostatin analogues wanes due to disease progression and development of tachyphylaxis. Locoregional strategies with vascular occlusion inducing ischemia in these highly vascular GEP tumours are indeed other options and may be performed using either surgical or radiological techniques (e.g. surgical ligation of the hepatic artery, transient hepatic ischemia, or sequential hepatic arterialization). Trans-catheter arterial chemoembolization is efficacious in both the control of hormonal symptoms and yields reliable objective tumour responses. Treatments aimed at regional destruction either alone or in combination with surgery include radiofrequency ablation and cryotherapy and may also be considered in certain circumstances.

Acrylic Resins↗
PubMed2005

Biliary stones: including acute biliary pancreatitis.

The widespread availability of endoscopic ultrasound has facilitated the evaluation of the pancreas and extrahepatic biliary system. Endosonography has been shown to be highly sensitive in the detection of choledocholithiasis (especially in patients with small stones and nondilated bile ducts) and gallbladder microlithiasis; however, the use of this technique in relation to endoscopic retrograde cholangiography and laparoscopic surgery in gallstone disease remains confusing. This article highlights the clinical performance and results of endoscopic ultrasound in this context and proposes strategies in relation to its use in association with endoscopic retrograde cholangiopancreatography and surgery in common clinical practice. Endosonography allows the correct identification of patients with acute biliary pancreatitis and proves an important adjunct in eliminating other causes of undetermined pancreatitis.

Acute Disease↗
PubMed2005

[Acute pancreatitis revealing Behçet disease].

We report here a case of acute pancreatitis revealing Behcet's disease in an 18-year-old woman. Pancreatitis was due to ischemia secondary to severe abnormalities of the celiac trunk arteries with pseudo-aneurysms. The outcome was favourable after the administration of corticosteroids and cyclophosphamide. The patient did not experience relapse of pancreatitis 2 years after diagnosis.

Acute Disease↗
PubMed2005

Is idiopathic chronic pancreatitis an autoimmune disease?

BACKGROUND & AIMS: The proportion of patients with idiopathic chronic pancreatitis (ICP) that have an autoimmune origin is unknown. Three forms of ICP have been described: pseudotumoral, duct-destructive, and usual chronic pancreatitis. The aim of this study was to identify autoimmune stigmata in the 3 forms. METHODS: All patients who underwent exploration for ICP were included. The following data were recorded: examination by an internal medicine specialist, autoantibodies and immunoglobulin screening, and pancreatic duct imaging. RESULTS: Sixty patients were included (pseudotumoral, n = 11; duct-destructive, n = 27; usual, n = 22). There were no significant differences among the 3 types with regard to sex ratio, age, frequency of acute pancreatitis, or obstructive jaundice. Pancreatic calcifications were seen only in the usual form (81%; P = .0001). Autoimmune disease was present in 10 patients: ulcerative colitis in 5 patients, primary sclerosing cholangitis in 2 patients, and Sjögren's syndrome, Hashimoto's thyroiditis, and Graves' disease in 1 patient each. Autoimmune diseases were not more frequent in patients with pseudotumoral (36%) or duct-destructive (19%) forms than in those with the usual form (5%, P = .06). Immunoglobulin G4 levels were increased in 2 of 6 in the pseudotumoral, 1 of 9 in the duct-destructive, and 0 of 12 patients in the usual group. Combining clinical and biochemical autoimmune parameters, 24 patients (40%) had at least 1 autoimmune marker or disease. CONCLUSIONS: Clinical or biochemical autoimmune stigmata are present in 40% of patients with ICP. Autoimmune mechanisms may be frequent in idiopathic pancreatitis.

Adolescent↗
PubMed2005

Endocrine tumor and intraductal papillary mucinous neoplasm of the pancreas: a fortuitous association?

OBJECTIVES: Pancreatic endocrine tumors (PETs) and intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are rare diseases of the pancreas. Cases of association of endocrine and exocrine neoplasms of the pancreas have been reported, corresponding to mixed or amphicrine tumors. The aim of this report is to describe a series of 6 patients with an original association of IPMN and PET of the pancreas. METHODS: Among 108 and 103 patients operated on in our center between January 1997 and December 2003 for PETs and IPMNs, respectively, we identified 6 patients with both PET and IPMN, diagnosed on pathologic examination with an immunohistochemical study. RESULTS: Preoperative diagnosis was unspecified pancreatic tumor (n = 1), IPMN (n = 2), and association of PET and IPMN (n = 3). IPMN involved the main pancreatic duct in 4 patients and was classified as benign (n = 4), borderline (n = 1), or malignant noninvasive (n = 1). PETs measured 1.1 to 3 cm and were malignant in 1 patient (lymph node invasion). When analyzed by immunohistochemistry, 2 cases expressed glucagon, 1 expressed somatostatin, and 1 expressed insulin. CONCLUSION: This study describes a new aspect of endocrine-exocrine pancreatic neoplasm association. The frequency of the association of PET and IPMN is too large to be fortuitous. Further studies are needed to understand its mechanism.

Adenocarcinoma, Mucinous↗
PubMed2005

Severe cholangitis following pancreaticoduodenectomy for pseudotumoral form of lymphoplasmacytic sclerosing pancreatitis.

Cholangitis associated with lymphoplasmacytic sclerosing pancreatitis may occur simultaneously or following diagnosis of pancreatitis. The natural history following inappropriate pancreatic surgery and treatment of cholangitis in this setting are ill-defined. Three patients underwent pancreaticoduodenectomy for pseudotumoral lymphoplasmacytic sclerosing pancreatitis. Jaundice or ascending cholangitis revealed severe biliary strictures at 1, 6, and 11 months, respectively, following surgery. Treatment combining corticosteroids with or without biliary stenting was efficacious in all patients. One patient with subsequent clinical and morphological relapse responded well to reintroduction of steroids. Biliary changes appeared to be immune-related based on pathological examination and response to corticosteroids.

Adrenal Cortex Hormones↗
PubMed2004

Rapid and sustained relief from the symptoms of carcinoid syndrome: results from an open 6-month study of the 28-day prolonged-release formulation of lanreotide.

This 6-month, open, non-controlled, multicenter, dose-titration study evaluated the efficacy and safety of 28-day prolonged-release (PR) lanreotide in the treatment of carcinoid syndrome. Eligible patients had a carcinoid tumor with > or =3 stools/day and/or > or =1 moderate/severe flushing episodes/day. Six treatments of 28-day PR lanreotide were administered by deep subcutaneous injection. The dose for the first two injections was 90 mg. Subsequent doses could be titrated (60, 90, 120 mg) according to symptom response. Seventy-one patients were treated. Flushing decreased from a mean of 3.0 at baseline to 2.3 on day 1, and 2.0 on day 2, with a daily mean of 2.1 for the first week post-treatment (p < 0.05). Diarrhea decreased from a mean of 5.0 at baseline to 4.3 on day 1 (p < 0.05), and 4.5 on day 2, with a daily mean of 4.4 for the first week post-treatment (p < 0.001). Symptom frequency decreased further after the second and third injections, and reached a plateau after the fourth injection. By month 6, flushing and diarrhea had significantly decreased from baseline by a mean of 1.3 and 1.1 episodes/day, respectively (both p < or = 0.001); 65% of patients with flushing as the target symptom and 18% of diarrhea-target patients achieved > or =50% reduction from baseline. Median urinary 5-hydroxyindoleacetic acid and chromogranin A levels decreased by 24 and 38%, respectively. Treatment was well tolerated. 28-day PR lanreotide was effective in reducing the symptoms and biochemical markers associated with carcinoid syndrome.

Adult↗
PubMed2004

Staging of pancreatic head adenocarcinoma with spiral CT and endoscopic ultrasonography: an indirect evaluation of the usefulness of laparoscopy.

BACKGROUND: The interest of laparoscopy in the preoperative staging of pancreatic head adenocarcinoma before curative pancreaticoduodenectomy is a matter of controversy and depends on the accuracy of preoperative imaging techniques. AIM: To assess the potential value of laparoscopy when a standardised and optimal preoperative staging is performed, including spiral computed tomography (CT) and endoscopic ultrasonography (EUS). METHODS: All consecutive patients operated on with a view to curative pancreaticoduodenectomy for pancreatic head or ampullary adenocarcinoma in our centre from January 1998 to August 2000 were retrospectively studied. All of them had preoperative spiral CT and EUS. Tumour resectability was considered as highly probable (HP) or uncertain (U) according to well-defined criteria. Operative records of patients were reviewed to indirectly assess the effective resectability rate and the criteria responsible for unresectability and which of them would have been identified by laparoscopy if initially performed. RESULTS: 69 consecutive patients were studied. Resectability was HP (n = 56) or U (n = 13) after preoperative staging. Curative pancreatoduodenectomy was performed in 53 patients (77%) (48 HP, 5 U). Positive predictive value of preoperative imaging for highly probable resectability was 86% (48/56). Among the 16 unresectable tumours (8 HP, 8 U), the cause of non-resection would have been found at laparoscopy in 9 patients (56%) (6 HP, 3 U). Finally, if initially performed, laparoscopy would have avoided laparotomy in 9/69 patients (13%) (6/56 HP (11%); 3/13 U (23%)). CONCLUSIONS: With accurate preoperative staging using spiral CT and EUS, laparoscopy would detect tumours which were unresectable in 13% of patients with pancreatic head cancer. Laparoscopy remains useful in selected patients, such as those with preoperative uncertain resectability, in whom it can prevent unnecessary laparotomy in one fourth of patients.

Adenocarcinoma↗