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Featured researches published by Frédérique Maire.


Gut | 2009

The natural history of hereditary pancreatitis: a national series.

Vinciane Rebours; M. C. Boutron-Ruault; M. Schnee; Claude Férec; C. Le Marechal; Olivia Hentic; Frédérique Maire; Pascal Hammel; Philippe Ruszniewski; Philippe Lévy

Background and aims: The prevalence and natural history of hereditary pancreatitis (HP) remain poorly documented. The aims of this study were to assess genetic, epidemiological, clinical and morphological characteristics of HP in an extensive national survey. Methods: A cohort comprising all HP patients was constituted by contacting all gastroenterologists and paediatricians (response rate 84%) and genetics laboratories (response rate 100%) in France (60 200 000 inhabitants). Inclusion criteria were the presence of mutation in the cationic trypsingen gene (PRSS1 gene), or chronic pancreatitis in at least two first-degree relatives, or three second-degree relatives, in the absence of precipitating factors for pancreatitis. Results: 78 families and 200 patients were included (181 alive, 6673 person-years, males 53%, alcoholism 5%, smoking 34%). The prevalence was 0.3/100 000 inhabitants. PRSS1 mutations were detected in 68% (R122H 78%, N29I 12%, others 10%). Penetrance was 93%. Median age at first symptom, diagnosis and date of last news, were 10 (range 1–73), 19 (1–80) and 30 (1–84) years, respectively. HP was responsible for pancreatic pain (83%), acute pancreatitis (69%), pseudocysts (23%), cholestasis (3%), pancreatic calcifications (61%), exocrine pancreatic insufficiency (34%, median age of occurrence 29 years), diabetes mellitus (26%, median age of occurrence 38 years) and pancreatic adenocarcinoma (5%, median age 55 years). No differences in clinical and morphological data according to genetic status were observed. 19 patients died, including 10 directly from HP (8 from pancreatic adenocarcinoma). Conclusion: The prevalence of HP in France is at least 0.3/100 000. PRSS1 gene mutations are found in 2/3 with a 93% penetrance. Mutation type is not correlated with clinical/morphological expression. Pancreatic adenocarcinoma is the cause of nearly half the deaths.


The American Journal of Gastroenterology | 2008

Risk of Pancreatic Adenocarcinoma in Patients With Hereditary Pancreatitis: A National Exhaustive Series

Vinciane Rebours; Marie-Christine Boutron-Ruault; Matthieu Schnee; Claude Férec; Frédérique Maire; Pascal Hammel; Philippe Ruszniewski; Philippe Lévy

BACKGROUND AND AIMS:An increased risk of pancreatic adenocarcinoma (PA) in patients with hereditary pancreatitis (HP) was previously demonstrated in two multinational studies. The PA frequency in this setting is however unknown due to lack of exhaustive case collection. The aims of this study were to evaluate the standardized incidence ratio (SIR) of PA in an exhaustive national series of patients with HP and to search for risk factors.METHODS:All French genetic laboratories (response rate 100%), pediatricians, and gastroenterologists (response rate 84%) were contacted. Inclusion criteria: mutation in the PRSS1 gene or recurrent, acute, or chronic pancreatitis, with no precipitating factors in two first-degree relatives or ≥3 second-degree relatives in ≥2 generations. Diagnosis of PA was based on histological records.RESULTS:Seventy-eight families and 200 patients were included (181 alive, 6,673 person-years, median number of generations 3, men 53%, alcoholism 5%, and smoking 34%). PRSS1 mutations were searched for in 96% of the patients and were detected in 68% (maternal inheritance 54%, R122H 78%, N29I 12%, and others 10%). Ten PA were diagnosed (median age 55 yr). SIR of PA for the whole population, men, and women were 87 (95% CI 42–113), 69 (25–150), and 142 (38–225), respectively, with no influence of genetic mutation. At ages 50 and 75 yr, the cumulated risk of PA was 11% and 49% for men and 8% and 55% for women, respectively. Smoking and diabetes mellitus were the main associated risk factors.CONCLUSION:Patients with HP have a marked relative and absolute increased risk of PA as compared to the general population, especially in smokers. There is no correlation with the type of PRSS1 mutation.


Gastrointestinal Endoscopy | 2003

Intraductal papillary mucinous tumors of the pancreas: the preoperative value of cytologic and histopathologic diagnosis

Frédérique Maire; Anne Couvelard; Pascal Hammel; Philippe Ponsot; Laurent Palazzo; Alain Aubert; Claude Degott; Alain Dancour; Michèle Felce-Dachez; Dermot O'Toole; Philippe Lévy; Philippe Ruszniewski

BACKGROUND The preoperative diagnosis of intraductal papillary mucinous tumors of the pancreas must be as certain as possible because removal of a large portion of the pancreas or even total pancreatectomy may be necessary. The value of cytologic and histopathologic analysis of specimens obtained by preoperative endoscopic investigations is unknown. The aim of this study was to assess the value of such analyses of specimens obtained by EUS-guided FNA and/or biopsy, or transpapillary biopsy specimens obtained during endoscopic retrograde pancreatography for the diagnosis of intraductal papillary mucinous tumors of the pancreas and for the detection of malignancy. METHODS Between 1992 and 2001, 42 patients (22 men, 20 women; median age 64 years) underwent surgical resection for intraductal papillary mucinous tumors of the pancreas and had preoperative pancreatic tissue sampling. In the case of isolated dilatation of pancreatic ducts, pancreatic juice was obtained by EUS-guided FNA for cytologic analysis. In the presence of a solid lesion or main pancreatic duct stenosis, biopsy specimens were obtained by EUS-guided FNA biopsy or endoscopic retrograde pancreatography, which permitted histopathologic assessment. The accuracy of cytology and histopathology was evaluated for the following: (1) positive diagnosis of intraductal papillary mucinous tumors of the pancreas and (2) assessment of malignancy, by comparison with histopathologic examination of surgical resection specimens. RESULTS Cytologic analysis was performed in 19 patients; it was positive in 4 (21%) and noninformative in 15 (79%). Histopathologic analysis was performed in 23 patients; it was positive in 21 (91%) and negative in 2 (9%). Histopathologic analysis yielded a positive result in 83% of patients who did not have extrusion of mucus from a patulous papilla. The sensitivity, specificity, and positive and negative predictive values of histopathologic analysis for the diagnosis of malignancy were, respectively, 44%, 100%, 100%, and 33%. When histopathologic analysis was positive, the tumor grade was similar to that determined by final histopathologic examination in 38% of patients, whereas the grade was underestimated in 62%. No complication occurred as a result of tissue sampling. CONCLUSIONS The sensitivity of histopathologic analysis of EUS-guided FNA biopsy specimens or transpapillary biopsy specimens is 91% for the positive diagnosis of intraductal papillary mucinous tumors of the pancreas with a solid component, which is of particular interest as extrusion mucus from the papilla was absent in most patients. Histopathologic analysis of biopsy specimens of malignant intraductal papillary mucinous tumors of the pancreas often underestimates tumor grade. The result for cytologic analysis of juice obtained from dilated pancreatic ducts is disappointing.


Gastrointestinal Endoscopy | 2004

Macrocystic pancreatic cystadenoma: the role of EUS and cyst fluid analysis in distinguishing mucinous and serous lesions

Dermot O'Toole; Laurent Palazzo; Pascal Hammel; Lamia Ben YaghlÈne; Anne Couvelard; Michèle Felce-Dachez; Monique Fabre; Alain Dancour; Alain Aubert; Alain Sauvanet; Frédérique Maire; Philippe Lévy; Philippe Ruszniewski

BACKGROUND Benign pancreatic serous cystadenoma usually is morphologically distinguishable from mucinous cystadenomas, which require resection because of their malignant potential. A macrocystic variant of serous cystadenoma recently has been described, rendering this important distinction more difficult. The aim of this study was to determine the EUS and tumor marker characteristics of mucinous cystadenoma compared with macrocystic serous cystadenomas. METHODS Medical records for consecutive patients seen between 1995 and 2002, with a histopathologic diagnosis of mucinous cystadenoma or macrocystic serous cystadenoma after surgery, who had undergone a detailed EUS examination, including EUS-guided FNA, were retrospectively reviewed. RESULTS A resection specimen was available for 32 mucinous cystadenomas and 9 macrocystic serous cystadenomas. No significant differences were observed with regard to clinical data (age, gender, presence of symptoms), lesion size, and location within the pancreas. All mucinous cystadenomas had a discernible cyst wall (thickened, 66%; focal parietal nodules, 25%) compared with 56% of macrocystic serous cystadenomas (p<0.0001). A thick echo content also was more frequent in mucinous cystadenoma (56% vs. 11%; p=0.04; statistical significance removed by the Bonferroni correction). Microcysts were only observed in macrocystic serous cystadenomas (44%; p=0.0008). The combination of a cyst wall that is thickened and the absence of microcysts had a sensitivity of 100% and specificity of 78% for the diagnosis of mucinous cystadenoma compared with macrocystic serous cystadenoma. Although intracystic carbohydrate-associated antigen 72-4 and mucins M1 were non-discriminatory, low carcinoembryonic antigen (<5 ng/mL) and carbohydrate-associated antigen 19-9 (<50,000 U/mL) values were found in macrocystic serous lesions (respectively, 100% and 100%; p=0.0002 and p=0.0002). CONCLUSIONS Although there is considerable overlap, helpful EUS characteristics that differentiate mucinous cystadenoma from macrocystic serous cystadenoma include a thick cyst wall and microcysts. These features, coupled with analysis of aspirated fluid for tumor markers (especially carcinoembryonic antigen), should help to confirm the diagnosis.


The American Journal of Gastroenterology | 2006

Long-term Outcome of Biliary and Duodenal Stents in Palliative Treatment of Patients with Unresectable Adenocarcinoma of the Head of Pancreas

Frédérique Maire; Pascal Hammel; Philippe Ponsot; Alain Aubert; Dermot O'Toole; Olivia Hentic; Philippe Lévy; Philippe Ruszniewski

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.


The American Journal of Gastroenterology | 2011

Outcome of Patients With Type 1 or 2 Autoimmune Pancreatitis

Frédérique Maire; Yann Le Baleur; Vinciane Rebours; Marie Pierre Vullierme; Anne Couvelard; Hélène Voitot; Alain Sauvanet; Olivia Hentic; Philippe Lévy; Philippe Ruszniewski; Pascal Hammel

OBJECTIVES:Autoimmune pancreatitis (AIP) is better described than before, but there is still no international consensus for definition, diagnosis, and treatment. Our aims were to analyze the short- and long-term outcome of patients with focus on pancreatic endocrine and exocrine functions, to search for predictive factors of relapse and pancreatic insufficiency, and to compare patients with type 1 and type 2 AIP.METHODS:All consecutive patients followed up for AIP in our center between 1999 and 2008 were included. Two groups were defined: (a) patients with type 1 AIP meeting HISORt (Histology, Imaging, Serology, Other organ involvement, and Response to steroids) criteria; (b) patients with definitive/probable type 2 AIP including those with histologically confirmed idiopathic duct-centric pancreatitis (“definitive”) or suggestive imaging, normal serum IgG4, and response to steroids (“probable”). AIP-related events and pancreatic exocrine/endocrine insufficiency were looked for during follow-up. Predictive factors of relapse and pancreatic insufficiency were analyzed.RESULTS:A total of 44 patients (22 males), median age 37.5 (19–73) years, were included: 28 patients (64%) with type 1 AIP and 16 patients (36%) with type 2 AIP. First-line treatment consisted of steroids or pancreatic resection in 59 and 27% of the patients, respectively. Median follow-up was 41 (5–130) months. Steroids were effective in all treated patients. Relapse was observed in 12 patients (27%), after a median delay of 6 months (1–70). Four patients received azathioprine because of steroid resistance/dependence. High serum IgG4 level, pain at time of diagnosis, and other organ involvement were associated with relapse (P<0.05). At the end point, pancreatic atrophy was observed in 35% of patients. Exocrine and endocrine insufficiencies were present in 34 and 39% of the patients, respectively. At univariate analysis, no factor was associated with exocrine insufficiency, although female gender (P=0.04), increasing age (P=0.006), and type 1 AIP (P=0.001) were associated with the occurrence of diabetes. Steroid/azathioprine treatment did not prevent pancreatic insufficiency. Type 2 AIP was more frequently associated with inflammatory bowel disease than type 1 AIP (31 and 3%, respectively), but relapse rates were similar in both groups.CONCLUSIONS:Relapse occurs in 27% of AIP patients and is more frequent in patients with high serum IgG4 levels at the time of diagnosis. Pancreatic atrophy and functional insufficiency occur in more than one-third of the patients within 3 years of diagnosis. The outcome of patients with type 2 AIP, a condition often associated with inflammatory bowel disease, is not different from that of patients with type 1 AIP, except for diabetes.


The American Journal of Gastroenterology | 2008

Intraductal Papillary Mucinous Neoplasms of the Pancreas: Performance of Pancreatic Fluid Analysis for Positive Diagnosis and the Prediction of Malignancy

Frédérique Maire; Hélène Voitot; Alain Aubert; Laurent Palazzo; Dermot O'Toole; Anne Couvelard; Philippe Lévy; Michel Vidaud; Alain Sauvanet; Philippe Ruszniewski; Pascal Hammel

INTRODUCTION:The preoperative diagnosis of intraductal papillary mucinous neoplasms (IPMN) of the pancreas must be as reliable as possible because large or even total pancreatectomy may be necessary. Early diagnosis of malignant forms is important to improve prognosis. The diagnostic accuracy of fluid analysis using endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has been confirmed in cystic lesions of the pancreas. It is not known if these results can be applied to IPMN.AIMS: To determine the levels of biochemical and tumor markers in fluid from EUS-FNA in patients with IPMN and to assess the impact on the diagnosis of IPMN.PATIENTS AND METHODS:In total, 41 patients (14 men, median age 64 yr) underwent EUS-FNA before surgical resection of IPMN in our center. Levels of amylase, lipase, carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19.9, and CA 72.4 were measured in the cyst fluid. The performance of the markers was retrospectively evaluated for: (a) a positive diagnosis of IPMN, using cutoffs validated in the literature for mucinous pancreatic lesions and (b) an assessment of malignancy (i.e., high-grade dysplasia or invasive carcinoma) compared with the final pathological examination of the surgical specimen.RESULTS: EUS-FNA was performed in dilated branch ducts (BD) in 39 cases and in the main pancreatic duct in 2 cases. No serious complications occurred. The median fluid levels of amylase, lipase, CEA, CA 19.9, and CA 72.4 were 20,155 U/mL, 59,500 U/mL, 173 ng/mL, 6,400 U/mL, and 11.5 U/mL, respectively. A CEA level >200 ng/mL and a CA 72.4 >40 U/mL had a 44% and a 39% sensitivity, respectively, for the diagnosis of IPMN. The levels of CEA, CA 19.9, and CA 72.4 were significantly different between benign and malignant IPMN. The sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) of a CEA level >200 ng/mL for the diagnosis of malignant IPMN were 90%, 71%, 50%, and 96%, respectively. The sensitivity, specificity, PPV, and NPV of a CA 72.4 level >40 U/mL for this purpose were 87.5%, 73%, 47%, and 96%, respectively.CONCLUSION: CEA and CA 72.4 in pancreatic cyst fluid have excellent NPVs in the preoperative differential diagnosis of benign versus malignant IPMN, and might reinforce the decision of not to operate on patients with BD-type without predictive factors of malignancy.


Clinical Gastroenterology and Hepatology | 2008

Morphologic Changes in Branch Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Midterm Follow-Up Study

Pierre-Emmanuel Rautou; Phillippe Lévy; Marie Pierre Vullierme; Dermot O'Toole; Anne Couvelard; Dominique Cazals–Hatem; Laurent Palazzo; Alain Aubert; Alain Sauvanet; Pascal Hammel; Olivia Hentic; Vinciane Rebours; Anne Laure Pelletier; Frédérique Maire; P. Ruszniewski

BACKGROUND & AIMS Because there is a low risk of malignancy for intraductal papillary and mucinous neoplasms of the pancreas (IPMNs) confined to branch ducts (BD), patient follow-up evaluation without surgery is possible. The aim of this study was to assess time-related morphologic changes and risk of progress to malignancy in patients with BD IPMN. A prospective design was used in an academic tertiary referral center. METHODS All consecutive patients seen from 1999 to 2005 with highly suspected IPMNs confined to BD without criteria suggesting a malignant development (mural nodule, cyst wall thickness >2 mm, BD diameter >30 mm, or main pancreatic duct involvement) were followed up prospectively using computerized tomography, magnetic resonance cholangiopancreatography, and endoscopic ultrasonography. RESULTS A total of 121 patients (median age, 63 y) were included. After a median follow-up period of 33 months, no morphologic changes had occurred in 88 patients. The size of the cyst increased in 30 of the 33 remaining patients, and 12 developed criteria suggesting a malignant development. Surgery, performed in 8 of 12 patients, found 4 IPMN-adenomas, 1 borderline-IPMN, and 4 IPMN carcinoma in situ. The 4 remaining patients did not undergo surgery because of severe comorbid conditions in 2, change in reference hospital in 1, and a mural nodule considered being sequelae of previous fine-needle aspiration in 1 patient. The only factor associated with signs suggesting malignant development was an increase in cyst size to more than 5 mm during the follow-up evaluation. CONCLUSIONS In patients with IPMNs confined to BD, morphologic changes are rare events, justifying a nonsurgical approach. Careful follow-up evaluation remains necessary, particularly in patients with an increase in BD size.


The Journal of Clinical Endocrinology and Metabolism | 2013

Observational Study of Natural History of Small Sporadic Nonfunctioning Pancreatic Neuroendocrine Tumors

Sébastien Gaujoux; Stefano Partelli; Frédérique Maire; Mirko D'Onofrio; Béatrice Larroque; Domenico Tamburrino; Alain Sauvanet; M. Falconi; Philippe Ruszniewski

CONTEXT Asymptomatic sporadic nonfunctioning, well-differentiated pancreatic neuroendocrine tumors (NF-PNETs) are increasingly diagnosed, and their management is controversial because of their overall good but heterogeneous prognosis. OBJECTIVE The objective of the study was to assess the natural history of asymptomatic sporadic NF-PNETs smaller than 2 cm in size and the risk-benefit balance of nonoperative management. EXPERIMENTAL DESIGN From January 2000 to June 2011, 46 patients with proven asymptomatic sporadic NF-PNETs smaller than 2 cm in size were followed up for at least 18 months with serial imaging in tertiary referral centers. RESULTS Patients were mainly female (65%), with a median age of 60 years. Tumors were mainly located in the pancreatic head (52%), with a median lesion size of 13 mm (range 9-15). After a median follow-up of 34 months (range 24-52) and an average of four (range 3-6) serial imaging sessions, distant or nodal metastases appeared on the imaging in none of the patients. In six patients (13%), a 20% or greater increase in size was observed. Overall median tumor growth was 0.12 mm per year, and neither patients nor tumor characteristics were found to be significant predictors of tumor growth. Overall, eight patients (17%) underwent surgery after a median time from initial evaluation of 41 months (range 27-58); all resected lesions were European Neuroendocrine Tumor Society T stage 1 (n = 7) or 2 (n = 1), grade 1, node negative, with neither vascular nor peripancreatic fat invasion. CONCLUSIONS In selected patients, nonoperative management of asymptomatic sporadic NF-PNETs smaller than 2 cm in size is safe. Larger and prospective multicentric studies with long-term follow-up are now needed to validate this wait-and-see policy.


British Journal of Cancer | 2002

Differential diagnosis between chronic pancreatitis and pancreatic cancer: value of the detection of KRAS2 mutations in circulating DNA

Frédérique Maire; S Micard; Pascal Hammel; Hélène Voitot; Philippe Lévy; P-H Cugnenc; P Ruszniewski; P Laurent Puig

KRAS2 mutations in codon 12 have been detected in about 80% of pancreatic cancers. The aim of this study was to evaluate the value of KRAS2 mutations detection in circulating deoxyribo nucleic acid to differentiate pancreatic cancer from chronic pancreatitis. Circulating deoxyribo nucleic acid was isolated from serum in 47 patients with histologically proven pancreatic adenocarcinomas (26 males, median age 65 years) and 31 controls with chronic pancreatitis (26 males, median age 48 years). Mutations at codon 12 of KRAS2 gene were searched for using polymerase chain reaction and allele specific amplification. Serum carbohydrate antigen 19.9 levels were also determined. KRAS2 mutations were found in 22 patients (47%) with pancreatic cancer and in four controls with chronic pancreatitis (13%) (P<0.002). None of the latter developed a pancreatic cancer within the 36 months of median follow-up. The sensitivity, specificity, positive and negative predictive values of serum serum KRAS2 mutations for the diagnosis of pancreatic cancer were 47, 87, 85 and 52%, respectively. KRAS2 mutations were not related to age, gender, smoking habit, tumour stage, or survival. Among the 26 patients with normal or non-contributive (due to cholestasis) serum carbohydrate antigen 19.9 levels, 14 (54%) had KRAS2 mutations. The combination of KRAS2 and carbohydrate antigen 19.9 gave a sensitivity, specificity, positive and negative predictive values for the diagnosis of pancreatic cancer of 98, 77, 87 and 96%, respectively. Detection of KRAS2 mutations in circulating deoxyribo nucleic acid has a low sensitivity but a specificity about 90% for the diagnosis of pancreatic cancer. It seems particularly useful when serum carbohydrate antigen 19.9 levels are normal or inconclusive. A combined normal serum carbohydrate antigen 19.9 and absence of circulating KRAS2 mutations makes the diagnosis of pancreatic cancer extremely unlikely.

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Alain Aubert

University of Paris-Sud

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