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Biomedical subjects

Philippe Ruszniewski

Publications and source records attributed to Philippe Ruszniewski.

At least 19 recordsLinked to original sources
PubMed2006

Hereditary pancreatitis caused by triplication of the trypsinogen locus.

Hereditary pancreatitis has been reported to be caused by 'gain-of-function' missense mutations in the cationic trypsinogen gene (PRSS1). Here we report the triplication of a approximately 605-kb segment containing the PRSS1 gene on chromosome 7 in five families with hereditary pancreatitis. This triplication, which seems to result in a gain of trypsin through a gene dosage effect, represents a previously unknown molecular mechanism causing hereditary pancreatitis.

Adolescent↗
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

Pancreaticoduodenectomy with mesentericoportal vein resection for adenocarcinoma of the pancreatic head.

BACKGROUND: The value of mesentericoportal vein resection (VR) associated with pancreaticoduodenectomy (PD) for pancreatic-head adenocarcinoma still remains controversial. METHODS: From 1989 to 2003, 45 consecutive patients with pancreatic-head adenocarcinoma underwent PD with mesentericoportal VR due to intraoperative macroscopic involvement of the superior mesenteric or portal vein (VR+ group). They were compared with 88 patients who underwent PD for adenocarcinoma without VR over the same time period (VR- group) and matched for age, American Society of Anesthesiologists (ASA) score, pathological diagnosis, and nodal involvement. Preoperative features, intraoperative parameters, postoperative course, and survival were compared between the VR+ group and VR- group. Factors that may influence survival were determined by univariate and multivariate analyses. RESULTS: Mortality, morbidity, and mean hospital stay did not differ between the two groups (VR+ 4.4%, 56%, and 22.6 days, respectively; VR- 5.7%, 64%, 24.6 days, respectively). In the group VR+, vein invasion was histologically proven in 29 (64%) patients. Three-year global survival and 3-year disease-free survival did not differ between the two groups: VR+ 22% and 14%, respectively; VR- 25% and 21%, respectively (log-rank: P=0.69 and P=0.39, respectively). Neither VR nor histologically proven vein involvement significantly impacted survival duration. On multivariate analysis, tumor-free margin was the most important prognostic factor. CONCLUSIONS: Vein resection during PD can be performed safely. Patients with adenocarcinoma who require VR during PD have a survival not different from that of patients who undergo standard PD. Macroscopic isolated mesentericoportal vein involvement is not a contraindication for PD in patients with adenocarcinoma provided disease-free margins can be obtained.

Adenocarcinoma↗
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

Dorsal pancreatectomy: an embryology-based resection.

In a 45-year-old man with acute pancreatitis and recent onset of diabetes mellitus, intraductal papillary mucinous neoplasm (IPMN) associated with pancreas divisum was found. There were no arguments for an invasive component in the IPMN lesions, which seemed to involve nearly all the dorsal pancreas. Resection of only the dorsal pancreas was performed with division of the pancreas at the internal side of the duodenum and at the anterior edge of the common bile duct. The gastroduodenal artery was preserved resulting in good vascularization of both common bile duct and proximal duodenum. Postoperative course was marked by a transient pancreatic fistula. Definitive pathological examination revealed noninvasive IPMN involving several branch ducts and partially the cephalic dorsal duct, with an 8 mm tumor-free segment from the transection level. Twelve months after resection, the patient had normal gastrointestinal function with neither clinical exocrine insufficiency nor uncontrolled diabetes. Postoperative magnetic resonance imaging revealed no signs of recurrence in the ventral pancreas. In patients with pancreas divisum, dorsal pancreatectomy can be proposed for noninvasive IPMN involving only the dorsal pancreas to avoid drawbacks of total duodenopancreatic resection.

Acute Disease↗
PubMed2006

Impact of irritable bowel syndrome (IBS) on health-related quality of life (HRQOL).

AIMS: To assess the impact of irritable bowel syndrome (IBS) on patient-reported health-related quality of life (HRQOL). METHODS: Two HRQOL instruments were administered by telephone interviews to a sample of 253 IBS French patients recruited from the general population. IBS was diagnosed according to the Manning, Rome I and Rome II criteria. Patients with organic diseases were excluded from the study. A generic instrument, the Short Form 36 (SF-36), and an IBS disease-specific instrument, the IBSQOL, were used. RESULTS: Patients with IBS had statistically significant (P<0.05) lower scores for all SF-36 QOL domains compared with the general French population. Women (N=192) reported significantly (P<0.05) poorer HRQOL on both the SF-36 and the IBSQOL scores than men (N=61) for all domains except energy on the SF36 and the sleep on the IBSQOL. HRQOL deteriorated with time since onset of IBS symptoms for some domains such as diet. For both instruments, a positive correlation was observed between low scores and intensity of pain and discomfort. IBS patients with a predominance of diarrhea (N=72) exhibited significantly greater impairment of HRQOL in the emotional domain than IBS persons with constipation predominance (N=65) (P<or=0.05). CONCLUSION: IBS has a significant impact on HRQOL of patients. In addition, specific characteristics such as gender, symptom severity and time since onset of symptoms are predictive of more impaired health-related quality of life.

Adolescent↗
PubMed2006

Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome.

It has been suggested that microadenomatosis of the endocrine pancreas is a hallmark of the multiple endocrine neoplasia type 1 syndrome (MEN1). This study attempts to elucidate the relationship between pancreatic microadenomatosis and the MEN1 and von Hippel-Lindau (VHL) syndromes. Pancreatic tissue specimens from 37 patients (with either microadenomatosis or the MEN1 syndrome) were analyzed using immunohistochemistry, confocal laser scanning microscopy, and morphometric methods. The MEN1 and the VHL status were assessed on the basis of clinical criteria (all patients) and PCR-based mutational analysis (15 and 5 patients, respectively). Pancreatic microadenomatosis was found in 35 of 37 patients, 28 of whom fulfilled the clinicopathologic criteria and 13 the genetic criteria for MEN1, whereas none of the patients had evidence of a VHL syndrome. Microadenomas were present in 26 of the 28 MEN1 patients, and all these tumors were consistently multihormonal. Five of the 9 patients with microadenomatosis and no clinical evidence for MEN1 or VHL also lacked mutations for the respective genes. Five of these 9 patients suffered from hyperinsulinism and revealed multiple insulin-positive tumors. The other patients were nonsymptomatic and showed multiple glucagon-expressing neoplasms. In microadenomatosis patients with and without the MEN1 syndrome, a subset of morphologically normal-appearing islets showed increased endocrine cell proliferation. In conclusion, endocrine multihormonal microadenomatosis of the pancreas is a feature of MEN1. In addition, a monohormonal type of pancreatic microadenomatosis was identified that consisted of either insulinomas or glucagon-producing tumors and was not associated with MEN1 or VHL.

Adenoma, Islet Cell↗
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↗
PubMed2006

Can fluorodihydroxyphenylalanine PET replace somatostatin receptor scintigraphy in patients with digestive endocrine tumors?

UNLABELLED: The aim of this study was to evaluate whether (18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA) PET is accurate for the diagnosis and follow-up of any type of well-differentiated digestive endocrine tumor and to assess its performance compared with standard somatostatin receptor scintigraphy (SRS) using (111)In-pentetreotide. METHODS: We reviewed the results of 33 evaluable (18)F-FDOPA PET and (111)In-pentetreotide SRS examinations performed between March 2002 and September 2005 in 30 patients referred for documented well-differentiated digestive endocrine tumor. RESULTS: The sensitivity and accuracy of (18)F-FDOPA PET were significantly better for carcinoid tumors (defined according to the World Health Organization 2000 classification) (n = 19) than for noncarcinoid tumors (n = 14)-that is, 93% versus 25% for sensitivity (P < 0.01) and 89% versus 36% for accuracy (P < 0.01), respectively. In contrast, the performances of (111)In-pentetreotide SRS did not differ according to the carcinoid or noncarcinoid type of the primary endocrine tumor-that is, 81% versus 75% for sensitivity and 79% versus 71% for accuracy, respectively. In carcinoid tumors, comparison between (18)F-FDOPA PET and (111)In-pentetreotide SRS showed that (18)F-FDOPA PET more accurately evaluated the extent of disease than (111)In-pentetreotide SRS. (111)In-Pentetreotide SRS did not reveal any additional lesions in any case. Conversely, in noncarcinoid tumors, the extent of the disease was more accurately evaluated in all cases by (111)In-pentetreotide SRS than by (18)F-FDOPA PET. CONCLUSION: This preliminary study emphasizes the importance of a precise histologic characterization of well-differentiated digestive endocrine tumor to select the best radiopharmaceutical. (18)F-FDOPA PET appears to be useful in carcinoid tumors and could become the first-line scintigraphic imaging modality for these tumors, but (111)In-pentetreotide SRS appeared to be a better first-line scintigraphic imaging modality for noncarcinoid digestive tumors.

Adult↗
PubMed2005

Effect of bile contamination on immediate outcomes after pancreaticoduodenectomy for tumor.

BACKGROUND: The influence of preoperative biliary drainage on the postoperative course of patients undergoing pancreaticoduodenectomy (PD) remains controversial. Among drawbacks of biliary drainage, bile contamination and its consequences are incompletely evaluated. This study aimed to compare outcomes after PD in patients with sterile and those with infected bile. STUDY DESIGN: Seventy-nine consecutive patients underwent PD for periampullary tumor with routine bile culture and antibiotic prophylaxis with cefazolin. The postoperative course of 35 patients with infected bile (group B+) was compared with that of 44 patients with sterile bile (group B-). RESULTS: The distribution of tumors was comparable except for ampullary carcinoma, which was more frequent in group B+ patients (p = 0.001). Interventional biliary endoscopy was performed preoperatively in 80% of patients in group B+ versus 14% in group B- (p < 0.001), including 9 isolated sphincterotomies (20% versus 5%, p < 0.03) and 20 endoprosthesis insertions (57% versus 0%, p < 0.0001). More patients in group B+ were classified as American Society of Anesthesiologists (ASA) 2 (p = 0.04). Operative time and blood loss were similar in both groups. One patient died postoperatively (group B+). Overall morbidity was increased in group B+ (77% versus 59%, p = 0.05). Postoperative infectious complications, all demonstrated bacteriologically, were more frequent in group B+: (65% versus 37%, p = 0.003). In group B+, bile was polybacterial in 54% of patients and isolated microorganisms were resistant to cefazolin in 97%. In patients with infectious complications, the same germ was isolated in bile and another sample in 49%. CONCLUSIONS: In patients undergoing PD, bile infection is related to previous interventional biliary endoscopy in 80% of patients and is associated with an increased rate of postoperative infections. During PD for ampullary carcinoma or after interventional biliary endoscopy, a specific antibioprophylaxis should be evaluated.

Adolescent↗
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

Right intrahepatic pseudocyst following acute pancreatitis: an unusual location after acute pancreatitis.

The location of a pseudocyst (PC) in the liver is an exceptional event, and intrahepatic PCs are mainly located in the left lobe. We report here a case of right intrahepatic PC following acute pancreatitis associated with cystic (aberrant pancreatic) dystrophy of the duodenal wall (CDDW) and chronic pancreatitis. Morphological assessment (ultrasound, computed tomography [CT] scan, and cholangio-magnetic resonance imaging [MRI]) revealed a 10-cm right intrahepatic collection and rupture of the main pancreatic duct. Percutaneous puncture permitted us to detect a high level of amylase in the collection, confirming the diagnosis of intrahepatic PC. Surgical drainage concomitant with pancreatico-duodenectomy for the treatment of CDDW resulted in disappearance of the collection. The mechanism involved in this patient was rupture of the pancreatic duct in the retroperitoneal cavity and erosion reaching the right hepatic parenchyma. Although intrahepatic PCs are rare, the diagnosis of intrahepatic PC complicating acute pancreatitis can be confirmed by a high level of amylase in the collection. Asymptomatic intrahepatic PCs can be treated conservatively, and symptomatic intrahepatic PCs can be managed either transcutaneously or surgically.

Acute Disease↗