Olivia Hentic

The natural history of hereditary pancreatitis: a national series.

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.

Neuroendocrine tumors of midgut and hindgut origin: Tumor‐node‐metastasis classification determines clinical outcome

Prognostic classification of neuroendocrine tumor (NET) patients is difficult due to the complexity of current classification systems. A recent proposal for a tumor‐node‐metastasis (TNM) classification and a grading system based on the proliferative fraction proved valid in NETs of foregut origin. The purpose of this study was to test the efficacy of a proposal for TNM staging and grading for midgut and hindgut NETs.

Pancreatic endocrine tumors: tumor blood flow assessed with perfusion CT reflects angiogenesis and correlates with prognostic factors.

PURPOSE To prospectively correlate multidetector computed tomographic (CT) perfusion measurement of pancreatic endocrine tumors with tumor microvascular density (MVD) assessed by using histologic techniques and to determine whether perfusion CT parameters differ between tumor grades. MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. Thirty-six patients (15 men, 21 women; mean age, 53 years; range, 18-78 years) with resectable pancreatic endocrine tumors underwent presurgical dynamic perfusion CT. Twenty-eight (78%) of 36 patients were included in the study group; eight were excluded because of artifacts that were not compatible with perfusion postprocessing. Multidetector CT perfusion data were analyzed to calculate tumor and normal pancreatic blood flow, blood volume, mean transit time, and permeability-surface area product. Multidetector CT perfusion parameters were compared with intratumoral MVD by using the Spearman correlation coefficient and with World Health Organization (WHO) classification, tumor size, tumor proliferation index, hormonal profile, and presence of metastases by using Mann-Whitney tests. RESULTS High correlation (r = 0.620, P < .001) was observed between tumor blood flow and intratumoral MVD. Blood flow was significantly higher (P = .02) in the group of benign tumors (WHO 1) than in the groups of tumors of indeterminate prognosis (WHO 2) or well-differentiated carcinomas (WHO 3). Blood flow was significantly higher in tumors with a proliferation index of 2% or less (P = .005) and in those without histologic signs of microscopic vascular involvement (P = .008). Mean transit time was longer in tumors with lymph node (P = .02) or liver (P = .05) metastasis. CONCLUSION Perfusion CT is feasible in patients with pancreatic endocrine tumors and reflects MVD. Perfusion CT measurements are correlated with histoprognostic factors, such as proliferation index and WHO classification.

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.

Outcome of Patients With Type 1 or 2 Autoimmune Pancreatitis

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.

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

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.

Two-step surgery for synchronous bilobar liver metastases from digestive endocrine tumors: a safe approach for radical resection.

Objective:We describe the early and distant results of a 2-step surgical strategy that enables complete resection in selected patients with primary digestive endocrine tumors (DET) and synchronous bilobar liver metastases (LM). Background:Frequent synchronous and bilobar liver involvement limits indications of surgery in LM from DET. Study Design:From 1996 to 2004, of 41 patients with synchronous bilobar LM from DET, 23 (56%) were selected for 2-step surgery. The first step included resection of the primary tumor and limited (nonanatomic) resection of left LM (segments 1–4) associated with a right portal vein ligation. After 8 weeks, following hypertrophy of the cleared left liver, a right or extended right hepatectomy was planned. Results:At the first step, all primary tumors (bowel = 12, distal pancreas = 10, rectal = 1) were resected and LM were resected in 20 patients (87%). One patient did not have second-step due to tumor progression. The second step (n = 19; 83%) was performed after a median interval of 8 weeks (range, 6–13) and a 54 ± 21% mean left liver hypertrophy rate. Postoperatively, 4 (17%) and 4 (21%) patients developed nonlethal complications and the median hospital stay was 11 (range, 7–26) and 13 (range, 9–17) days after the first and the second step, respectively. The median number of resected LM was 4 (range, 1–9) and 7 (range, 4–17), respectively. With a median follow-up of 64 months (range, 6–122), of the 19 patients who had complete 2-step surgery, all except one are alive. The 2-, 5-, and 8-year Kaplan-Meier overall and disease-free survival rates were 94%, 94%, 79% and 85%, and 50% and 26%, respectively. Conclusions:This 2-step surgery approach enables complete resection with no mortality, acceptable morbidity, and good long-term survival in selected patients with synchronous bilobar LM from DET.

Chemotherapy for Gastro-Enteropancreatic Endocrine Tumours

Despite similar histological and morphological aspects, gastro-enteropancreatic (GEP) endocrine tumours represent a heterogeneous group of tumours with varying clinical expression depending on tumour type (functional or not), origin and extension, but also on histological differentiation and proliferative capacity. The natural history of well-differentiated tumours is often favourable without treatment and GEP endocrine tumours may remain indolent for many years. Chemotherapy may however be indicated in the presence of symptomatic non-progressive disease (progression evaluated over 3–6 months). In contrast, poorly differentiated GEP endocrine tumours are frequently aggressive and early treatment is required. Accurate staging is mandatory and where surgery is possible (even in the event of limited metastatic disease), this option should be re-evaluated in a multidisciplinary approach. Approximately 2/3 of malignant GEP tumours are metastatic at discovery and surgery is possible in a minority of patients; therefore, chemotherapy, with/without other strategies (e.g. local ablation), is frequently indicated in patients with symptomatic, bulky or progressive disease. For well-differentiated pancreatic tumours, the reference association is Adriamycin with streptozotocin yielding objective responses (OR) in 40–60% of patients. Prolonged treatment is limited due to potential cardiotoxicity of Adriamycin and standard 2nd-line regimens are not of proven efficacy; thus, other treatment modalities are usually additionally required (e.g. chemo-embolisation). A significant OR may render a small number of patients secondarily amenable to surgery. Published series evaluating chemotherapy for midgut endocrine tumours are outdated and disappointing. Objective response rates with combined associations (including either 5-fluorouracil and/or streptozotocin) rarely exceed 20% and where possible, chemo-embolisation for hepatic metastases combined with somatostatin analogues (± interferon) should be preferred. Poorly differentiated GEP tumours are generally aggressive tumours with metastases at diagnosis and tend to progress rapidly. Surgery is rarely possible and ineffective even in locally advanced disease due to a high risk of recurrence. Chemotherapy, using cisplatin and etoposide, is the reference treatment and frequently yields OR rates >50%. However, despite being chemosensitive, disease control is limited (8–10 months). Overall, advances in therapeutic chemotherapeutic options are required in the management of all types of advanced GEP endocrine tumours and evaluation of new drugs (e.g. irinotecan) and combination strategies (chemotherapy with local ablative therapies) are required in the future.

Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors

Liver biopsy of metastatic pancreatic endocrine tumors allows confirmation of the diagnosis and assessment of prognosis. However, sampling variability is a potential limitation. Our aim was to use the tissue microarray technique to assess the heterogeneity of three prognostic markers, ie, MIB-1 proliferation index, microvascular density and somatostatin receptor type 2, inside single or between synchronous or metachronous liver metastases of pancreatic endocrine tumors. Tissue microarrays were constructed, which included core biopsies taken from surgically resected liver metastases in 29 patients. MIB-1, microvascular density and somatostatin receptor type 2 were evaluated after immunostaining. The heterogeneity was highlighted by the calculation of the reproducibility of the values of two cores randomly selected among all the cores studied. For quantitative variables, it was assessed by the intraclass correlation coefficient and by a Bland–Altman approach. For qualitative variables, observed agreement and weighted κ were given. A total of 184 liver metastases were analyzed. For MIB-1, the intraclass correlation coefficients were 0.63, 0.69 and 0.67 and for microvascular density, the intraclass correlation coefficients were 0.48, 0.60 and 0.00, respectively, in single, synchronous and metachronous liver metastases. The variability increased for higher mean values of microvascular density. For somatostatin receptor type 2, the observed agreements were 91% (κ=0.81), 69% (κ=0.49) and 79% (κ=0.68) in single, synchronous and metachronous liver metastases, respectively. In conclusion, tissue microarray analysis identifies heterogeneity of protein expression in pancreatic endocrine metastases, which depends on the marker tested. The reproducibility is better for MIB-1 and somatostatin receptor type 2 than for microvascular density. Sampling variability should be taken into consideration as a potential limitation to the assessment of prognostic and therapeutic markers in biopsy samples from metastatic pancreatic endocrine tumors.

Ki-67 index, tumor differentiation, and extent of liver involvement are independent prognostic factors in patients with liver metastases of digestive endocrine carcinomas

The prognosis remains ill-defined in patients with liver metastases of well-differentiated (WD) digestive endocrine carcinomas (DEC) with high Ki-67 index. The objectives of this study were to determine whether Ki-67 index, tumor differentiation, and extent of liver involvement are independent prognostic factors in patients with DEC, and whether chemotherapy commonly used in patients with poorly differentiated (PD) carcinomas might be applied to those with high Ki-67 index but well-differentiated DEC. Sixty-three patients with DEC metastatic to the liver were retrospectively studied and divided into three prognostic groups. Group 1 comprised patients with well-differentiated carcinomas and Ki-67 index<15% (n=28), group 2 comprised those with well-differentiated carcinomas and Ki-67 index≥15% (n=17), and group 3 comprised those with poorly differentiated carcinomas (n=18). Therapeutic strategy was decided in accordance to guidelines, and tumoral response rate was assessed by computed tomography scan (RECIST). Prognostic factors were determined by uni/multivariate analysis. The 5-year survival rates were 89, 36, and 6% in groups 1, 2, and 3 respectively (P<0.001). Multivariate analysis showed that Ki-67 index≥15%, poor tumor differentiation, and large liver tumor burden were independent predictors of poorer survival. Disease control rates after etoposide-cisplatin were 50 and 53% in groups 2 and 3 respectively (NS). In conclusion, Ki-67 index, tumor differentiation, and extent of liver involvement are independent prognostic factors in patients with liver metastases of DEC. Patients with well-differentiated carcinomas with high Ki-67 index (≥15%) have intermediate prognosis and a similar response rate to the etoposide-cisplatin combination as those with poorly differentiated carcinomas.