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Background: The timeline of progression of pancreatic cancer from resectable to unresectable disease is unknown. New-onset diabetes often occurs in pancreatic cancer. It is unclear if the cancer is resectable at the onset of diabetes. We (a) determined the resectability of pancreatic cancer on abdominal CT scans done prior to clinical diagnosis and (b) correlated resectability with onset of diabetes., Methods: All CT scans done at diagnosis or before pancreatic cancer diagnosis were reviewed and pancreatic changes classified as normal, potentially resectable, or unresectable pancreatic cancer. Fasting blood glucose values obtained at and prior to diagnosis were available in 18 patients. The date of onset of diabetes and the interval between onset of diabetes and diagnosis of cancer were noted., Results: Thirty patients fulfilled inclusion criteria. Prior to diagnosis, 28 patients had 38 CT scans done at a median of 18 months (range 1-41) before cancer diagnosis. At cancer diagnosis, only 7/30 patients could undergo margin-negative surgical resection. CT scans done >/=6 months prior to diagnosis showed either a normal pancreas (N = 20) or a resectable mass (N = 6); none had unresectable cancer. The mean interval between onset of diabetes and diagnosis of pancreatic cancer was 10 months (range 5-29 months). At the onset of diabetes, 3 patients had normal pancreas, 6 had resectable, and 4 had unresectable pancreatic cancer., Conclusions: Pancreatic cancer is frequently undetectable or resectable on CT scans done >/=6 months prior to clinical diagnosis. At onset of diabetes, pancreatic cancers are generally resectable.

Pancreatic cancer has a poor prognosis. Improving survival will require diagnosis of early pancreatic cancer, which can be defined based on resectability, size, or curability. Pancreatic cancer progresses from noninvasive precursor lesions to invasive cancer over a variable time period. Retrospective review of computed tomography (CT) scans performed prior to diagnosis suggests that pancreatic cancer resectability may be significantly improved if detected as few as 6 months before clinical diagnosis. Since pancreatic cancer is relatively uncommon, to allow cost-effective screening the populations will have to be enriched for the disease using two "sieves." The first sieve would identify a population of subjects at higher than average risk of pancreatic cancer and the second sieve could be a characteristic phenotype among the members of the high-risk group, an abnormality seen on noninvasive imaging or a serologic marker of early pancreatic cancer. So far two high-risk groups have been targets of screening for pancreatic cancer: hereditary pancreatic cancer kindreds and new-onset diabetes. There is no serologic marker of early pancreatic cancer. Confirmation of diagnosis usually requires invasive procedures such as endoscopic ultrasonography (EUS). Although much work still needs to be done, the developments in the field provide us with hope that screening for early pancreatic cancer could become a reality in the not-so-distant future.

Objectives: To determine the sensitivity and specificity of elevated serum IgG4 level for the diagnosis of autoimmune pancreatitis (AIP) and its ability to distinguish AIP from pancreatic cancer, its main differential diagnosis., Methods: We measured serum IgG4 levels (normal 8-140 mg/dL) in 510 patients including 45 with AIP, 135 with pancreatic cancer, 62 with no pancreatic disease, and 268 with other pancreatic diseases., Results: Sensitivity, specificity, and positive predictive values for elevated serum IgG4 (>140 mg/dL) for diagnosis of AIP were 76%, 93%, and 36%, respectively, and 53%, 99%, and 75%, respectively, for IgG4 of >280 mg/dL. Among subjects with elevated IgG4, non-AIP subjects (N = 32) differed from AIP subjects (N = 34) in that they were more likely to be female (45%vs 9%, P < 0.001), less likely to have serum IgG4 >280 mg/dL (13%vs 71%, P < 0.001), or elevation of total IgG (16%vs 56%, P < 0.001). Serum IgG4 levels were elevated in 13/135 (10%) pancreatic cancer patients; however, only 1% had IgG4 levels >280 mg/dL compared with 53% of AIP. Compared with AIP, pancreatic cancer patients were more likely to have CA19-9 levels of >100 U/mL (71%vs 9%, P < 0.001)., Conclusion: Elevated serum IgG4 levels are characteristic of AIP. However, mild (<2-fold) elevations in serum IgG4 are seen in up to 10% of subjects without AIP including pancreatic cancer and cannot be used alone to distinguish AIP from pancreatic cancer. Because AIP is uncommon, IgG4 elevations in patients with low pretest probability of having AIP are likely to represent false positives.

Background and Aims: Recent consensus guidelines suggest that presence of > or =1 of the following is an indication for resection (IR) of branch duct intraductal papillary mucinous neoplasm (IPMN-Br): cyst-related symptoms, main pancreatic duct diameter > or =10 mm, cyst size > or =30 mm, intramural nodules, or cyst fluid cytology suspicious/positive for malignancy. Among a cohort of patients with IPMN-Br we determined if the consensus IR (CIR), presence of multifocal IPMN-Br, or growth of cyst size on follow-up predict malignancy., Methods: We identified 147 patients with IPMN-Br of whom 66 underwent surgical resection at diagnosis and 81 were followed conservatively, of whom 11 were resected during follow-up. Clinical, imaging, histological, and cyst fluid characteristics from all 147 patients with IPMN-Br were obtained from clinical records and/or by contacting the patients. In all cases, presence of CIR at baseline and during follow-up (N = 66), presence of multifocal cysts (N = 57), and increase in cyst size (N = 38) were noted., Results: Among the 77 resected IPMN-Brs, at initial evaluation 61 had at least one CIR and 16 had none. Malignancy was present in 9/61 (15%) with CIR and 0/16 without IR (P= 0.1). When presence of any one of the CIR was taken as an indicator of malignancy, the CIR had a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 23%, 14%, and 100%, respectively. Prevalence of malignancy in those with single versus multifocal IPMN-Br was similar (13%vs 11%). No patient has developed malignancy after a median follow-up of 15 months. So far, none of the 38 patients with increase in cyst size on follow-up has developed malignancy related symptoms., Conclusions: Suggested consensus indications for resection identify all patients with malignancy; however, their specificity is low. In the short term it would be safe to follow patients without these features.

Autoimmune pancreatitis (AIP) is a recently defined form of chronic pancreatitis. While numerous case reports and small case series of AIP have been reported from Japan, there have been relatively few from the West. Based on a retrospective review of our experience with resected AIP and a review of the literature, we have identified five cardinal features of AIP in histology, imaging, serology, other organ involvement, and response to steroid therapy, which are summarized in the mnemonic HISORt. A combination of the HISORt criteria can be used to definitively diagnose a wide spectrum of manifestations of AIP.

Purpose: To retrospectively evaluate computed tomographic (CT) and magnetic resonance (MR) imaging renal findings at clinical presentation, during treatment, and at follow-up in patients with autoimmune pancreatitis (AIP)., Materials and Methods: This HIPAA-compliant study received institutional review board approval. All patients included had previously consented to the use of their medical records for the purpose of research. Forty-five patients (38 male and seven female patients; mean age, 64 years) with diagnosis of AIP were included. Forty patients underwent CT or MR imaging at clinical presentation; 33 patients (including five without imaging at presentation) underwent follow-up. CT and MR images were reviewed in consensus by two radiologists for the presence of renal involvement. Various features were evaluated. Clinical characteristics at presentation were compared between patients with and patients without renal involvement., Results: Of the 40 patients who underwent imaging at presentation, 14 (35%) had renal involvement (12 with parenchymal involvement and five with extraparenchymal involvement). Renal parenchymal lesions showed decreased enhancement and appeared as small peripheral cortical nodules, round or wedge-shaped lesions, or diffuse patchy involvement. Thirteen patients with renal involvement at presentation underwent a follow-up study. Renal lesions in 10 patients regressed (in nine, after steroid treatment) but progressed in three patients without steroid treatment. Renal lesions were found in two other patients during follow-up. No significant difference in the clinical characteristics was found between patients with and patients without renal involvement., Conclusion: Renal involvement in patients with AIP is relatively common and predominantly involves the cortex of the kidney. The lesions improve after steroid treatment but can progress without steroid treatment., ((c) RSNA, 2007.)

Autoimmune pancreatitis typically produces an enlarged pancreas with narrowing of the pancreatic duct, and can mimic carcinoma. Autoimmune pancreatitis usually responds to corticosteroid treatment, making it important to differentiate from pancreatic ductal adenocarcinoma. Affected patients often have an elevated serum IgG4. It has been proposed that increased numbers of IgG4-positive plasma cells in tissue might be a marker for the condition. We investigated the role of IgG4 staining in the diagnosis of autoimmune pancreatitis, first in resected pancreas specimens (29 autoimmune pancreatitis, nine chronic alcoholic pancreatitis and 25 pancreatic cancer), then in pancreatic needle biopsies. Immunohistochemical stains for IgG4 were scored as none, mild, moderate or marked, according to published criteria. Moderate to marked numbers of IgG4-positive plasma cells were seen in 21/29 autoimmune pancreatitis patients, and were distributed in and around ducts, in interlobular fibrous tissue and in peripancreatic fat. In contrast, eight of nine examples of chronic alcoholic pancreatitis and 22/25 ductal adenocarcinomas had scores of none or mild. When we subdivided autoimmune pancreatitis into the histologic subtypes lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-destructive pancreatitis, 16/17 lymphoplasmacytic sclerosing pancreatitis had moderate to marked staining, compared to five to 12 idiopathic duct-destructive pancreatitis. Needle biopsies from nine patients suspected of having autoimmune pancreatitis had increased numbers of IgG4 cells. We conclude that pancreatic tissue from patients with autoimmune pancreatitis often shows moderate or marked infiltration by IgG4-positive plasma cells (>10/HPF). This is particularly so in the subtype we have designated lymphoplasmacytic sclerosing pancreatitis. We rarely see IgG4 staining in patients with chronic alcoholic pancreatitis and pancreatic ductal adenocarcinoma. IgG4-positive plasma cells are a useful marker for the tissue diagnosis of autoimmune pancreatitis.

Regulator of G-protein signaling-GAIP-interacting protein COOH terminus (GIPC) is involved in protein trafficking, endocytosis, and receptor clustering and is associated with insulin-like growth factor I receptor (IGF-IR), a receptor important for proliferation and anchorage-independent growth. Here, we described GIPC expression in different human pancreatic adenocarcinoma (PCA) cell lines and we examined the role of GIPC in the regulation of IGF-IR protein levels in PCA. Interestingly, inhibition of GIPC expression by RNA interference led to reduced IGF-IR protein levels and a subsequent decrease in proliferation of PCA cells. We also determined that the PDZ domain of GIPC is essential for the post-translational regulation and the binding of IGF-IR. The importance of GIPC in pancreatic cancer development and progression is supported by tissue microarray data of 300 pancreatic cancer specimens where GIPC is highly expressed in PCA. Taken together, our data suggest that GIPC is a central molecule for the stability of IGF-IR and could be a target for future therapy.

Purpose: We have shown recently that glycogen synthase kinase-3 (GSK-3) beta regulates nuclear factor-kappaB (NF-kappaB)-mediated pancreatic cancer cell survival and proliferation in vitro. Our objective was to determine the localization of GSK-3beta in pancreatic cancer cells and assess the antitumor effect of GSK-3 inhibition in vivo to improve our understanding of the mechanism by which GSK-3beta affects NF-kappaB activity in pancreatic cancer., Experimental Design: Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the localization of GSK-3beta in human pancreatic tumors. We studied the effect of GSK-3 inhibition on tumor growth, cancer cell proliferation, and survival in established CAPAN2 tumor xenografts using a tumor regrowth delay assay, Western blotting, bromodeoxyuridine incorporation, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling., Results: We found nuclear accumulation of GSK-3beta in pancreatic cancer cell lines and in 62 of 122 (51%) human pancreatic adenocarcinomas. GSK-3beta nuclear accumulation is significantly correlated with human pancreatic cancer dedifferentiation. We have found that active GSK-3beta can accumulate in the nucleus of pancreatic cancer cells and that inhibition of GSK-3 kinase activity represses its nuclear accumulation via proteasomal degradation within the nucleus. Lastly, we have found that inhibition of GSK-3 arrests pancreatic tumor growth in vivo and decreases NF-kappaB-mediated pancreatic cancer cell survival and proliferation in established tumor xenografts., Conclusions: Our results show the antitumor effect of GSK-3 inhibition in vivo, identify GSK-3beta nuclear accumulation as a hallmark of poorly differentiated pancreatic adenocarcinoma, and provide new insight into the mechanism by which GSK-3beta regulates NF-kappaB activity in pancreatic cancer.

Background & Aims: The Japan Pancreas Society criteria for diagnosis of autoimmune pancreatitis (AIP) mandate presence of characteristic imaging (diffuse pancreatic enlargement with diffusely irregular, narrow pancreatic duct). AIP has unique histologic features associated with infiltration of tissues of affected organs with abundant IgG4-positive cells. We propose expanded diagnostic criteria for AIP with a cohort of histologically confirmed AIP., Methods: We reviewed the pancreatic imaging findings on computed tomography scans, serum IgG4 levels, other organ involvement, and response to steroids in 29 consecutive patients who met histologic criteria for AIP., Results: Computed tomography scans (n = 22) showed diffuse pancreatic enlargement in 6 (27%) patients; the rest had focal enlargement, distinct mass, normal pancreas, or focal acute pancreatitis. Serum IgG4 level was elevated in 15 of 21 (71%) patients, and other organ involvement (eg, intrahepatic biliary strictures) was noted in 11 of 29 (38%) patients. All 17 patients treated with steroids exhibited resolution/marked improvement of pancreatic/extrapancreatic manifestation. On the basis of this experience we propose that diagnosis of AIP can be made in patients with > or =1 of these criteria: (1) diagnostic histology, (2) characteristic imaging on computed tomography and pancreatography with elevated serum IgG4 level, or (3) response to steroid therapy of pancreatic/extrapancreatic manifestations of AIP. Twenty additional patients met expanded diagnostic criteria for AIP, and their demographic and clinical profile was similar to that of the 29 patients meeting histologic criteria., Conclusions: AIP defined by histological criteria shows a wide spectrum of radiologic features, with characteristic imaging seen only in a minority. Incorporation of additional features into current diagnostic criteria can identify the full spectrum of clinical presentations of AIP.

Background/aims: There is scant information in the literature about the outcomes of endoscopic retrograde cholangiopancreatography (ERCP)-induced severe acute pancreatitis (ESAP). Compared to other causes, higher morbidity and mortality have been reported in ERCP-induced acute pancreatitis. We undertook this study to determine the differences between ESAP and SAP due to other causes (OSAP)., Methods: We retrospectively identified all cases of SAP admitted to our institution during the years 1992-2001. We reviewed the medical records of all SAP patients to obtain information on demographics, interventions, local and systemic complications and outcomes., Results: We identified 207 patients with SAP, of whom 16 (7.7%) had ESAP and 191 OSAP. There was no difference between ESAP and OSAP with regard to demographics, clinical interventions, local and systemic complications and outcomes. Both groups had a similar mortality (25 vs. 18%)., Conclusion: ESAP has a similar morbidity and mortality compared to OSAP., (Copyright 2006 S. Karger AG, Basel and IAP.)

Background and Aims: Diabetes in tropical chronic pancreatitis (TCP), also known as fibrocalculous pancreatic diabetes (FCPD), is frequently seen at diagnosis. The aim of the present study was to determine the natural history of endocrine failure in TCP subjects without diabetes at baseline., Methods: Of 73 TCP subjects without diabetes according to World Health Organization (WHO) criteria at baseline who were seen at an out-patient center, 54 (74.0%) underwent periodic oral glucose tolerance tests on follow up. Another 54 sex-matched, non-diabetic subjects without chronic pancreatitis served as controls. Baseline demographic and clinical characteristics were noted., Results: After a median follow up of 5.0 years in TCP subjects and 7.0 years in controls, 27 of 54 TCP subjects (50%) developed diabetes compared with 14 of 54 controls (25.9%). Of the TCP subjects, those who developed diabetes on follow up were older (31 +/- 12 vs 23 +/- 11 years; P = 0.013), had a higher body mass index (21.7 +/- 4.4 vs 18.2 +/- 3.5 kg/m2; P = 0.004), higher 2 h post-load plasma glucose (8.8 +/- 1.9 vs 6.7 +/- 1.4 mmol/L; P < 0.001) and lower fecal chymotrypsin (2.1 +/- 1.2 vs 4.3 +/- 2.5 U/g; P < 0.001) at baseline compared with those who did not develop diabetes. The median time for the development of diabetes after diagnosis of TCP was 9.6 years (compared with 14.4 years among controls). Only 2 of 13 TCP subjects (15.4%) who had undergone surgical interventions during the normal glucose tolerance phase developed diabetes during follow up., Conclusions: In TCP, there is progressive deterioration of endocrine pancreatic function, with development of diabetes in 50% of patients upon follow up, suggesting that FCPD is merely a later stage in the course of TCP. Early surgery may prevent the development of diabetes in TCP subjects.

Background: Acute pancreatitis has occasionally been associated with Crohn's disease (CD), but whether a causal association exists remains unclear. We sought to determine the frequency of etiologies in a consecutive series of patients with CD with acute pancreatitis., Methods: A centralized diagnostic index was used to identify all patients with CD with acute pancreatitis that were evaluated at Mayo Clinic Rochester between 1976 and 2001. Both diagnoses were made or confirmed at our institution. Records were abstracted for demographics, presenting symptoms, diagnostic tests, risk factors of pancreatitis, treatment, and follow-up., Results: Forty-eight patients with CD with pancreatitis were identified. The median age at diagnosis of acute pancreatitis was 47 years (range, 31-91 yr). Forty-six (96%) met biochemical criteria for acute pancreatitis. The most sensitive radiographic tests were abdominal computed tomography (70%) and abdominal ultrasound (46%). The etiology of pancreatitis was considered to be gallstones (21%), significant alcohol intake (15%), use of purine analogs (13%), duodenal Crohn's involvement (12%), postendoscopic retrograde cholangiopancreatography complications (10%), postoperative complications (12%), use of other medications (4%) and idiopathic (8%). The median length of hospitalization was 7 days (range, 0-40 d). Ten patients (21%) had recurrence of acute pancreatitis. Three patients (6%) were subsequently diagnosed with pancreatic cancer., Conclusions: A definite etiology could be identified in most patients with CD with acute pancreatitis. Gallstones and alcohol accounted for more than one third of cases, whereas CD, either because of duodenal involvement or medications used for its treatment, accounted for more than one quarter of the cases. A small proportion of patients remained idiopathic.

While selected pancreatic diseases may be best treated by total pancreatectomy (TP), the anticipated sequelae of pancreatic insufficiency make TP an undesirable alternative. Our aim was to determine if patients undergoing TP have a worse quality of life (QoL) than age- and gender-matched controls and poor long-term glycemic control. Ninety-nine patients undergoing TP from 1985 through 2002 were identified. The 34 survivors with no recurrent malignancy were surveyed with the Short Form-36 (SF-36), the Audit of Diabetes Dependent QoL (ADD QoL), the European Organization for Research and Treatment in Cancer Pancreas 26 (EORTC PAN 26), and our institutional questionnaire. Operative morbidity and mortality were 32% and 5%, respectively. Three late postoperative deaths (3%) were attributed to hypoglycemia. Of the 34 surviving patients, 27 (79%) agreed to participate at a mean of 7.5 years postoperatively. Seven patients had required 12 hospitalizations for poor glycemic control. Per the SF-36, two domains (role physical and general health) were decreased compared with an age- and gender-matched national population (P < .05). The ADD QoL demonstrated an overall decrease in QoL related specifically to the diabetes mellitus (P < .01), but comparison with insulin-dependent diabetics from other causes showed no significant difference in QoL. The EORTC PAN 26 instrument also showed measurable effects on QoL. Total pancreatectomy can be performed safely. QoL after TP is decreased compared with age- and gender-matched controls but not with diabetes from other causes; however, the changes are not overwhelming. TP should remain a viable option but in selected patients.

Background & Aims: Nonoperative methods for diagnosis of pancreas cysts often lack sufficient accuracy. Accurate diagnosis is needed to determine prognosis and guide clinical management. The aim of this study was to determine whether the tissue obtained by endoscopic ultrasound-guided trucut biopsy (EUS TCB) is sufficient for histologic diagnosis of cystic pancreatic tumors (CPTs)., Methods: EUS TCB was performed in patients with a suspected CPT. A dedicated gastrointestinal pathologist reviewed the core biopsies. The final diagnosis was based on clinical, laboratory, imaging, and biopsy findings, and resected specimens when available., Results: EUS TCB was performed in 10 patients with a suspected CPT. Final diagnoses included serous cystadenoma (SCA, n=5), islet cell tumor (n=2), mixed seromucinous lesion (n=1), polycystic disease of the pancreas (n=1), and pseudocyst (n=1). EUS TCB was nondiagnostic in 3 of 10 patients. Among the other 7 patients, TCB diagnosed 4 SCAs, obviating the need for planned surgery in 3 patients. In the fourth patient with an SCA, the TCB result ruled out metastatic disease from locally recurrent lung cancer, allowing a narrowed radiation field. EUS TCB confirmed the need for surgery in 2 patients with an islet cell tumor. In 1 patient, EUS TCB findings were "partially" diagnostic, leading to previously unplanned surgery., Conclusions: This report establishes the capability and safety of EUS TCB to collect sufficient tissue for diagnosing CPTs. The results might help guide clinical management.

Background & Aims: Although diabetes occurs frequently in pancreatic cancer, the value of new-onset diabetes as a marker of underlying pancreatic cancer is unknown., Methods: We assembled a population-based cohort of 2122 Rochester, Minnesota, residents age > or =50 years who first met standardized criteria for diabetes between January 1, 1950, and December 31, 1994, and identified those who developed pancreatic cancer within 3 years of meeting criteria for diabetes. We compared observed rates of pancreatic cancer with expected rates based on the Iowa Surveillance Epidemiology and End Results registry. In a nested case control study, we compared body mass index (BMI) and smoking status in diabetes subjects with and without pancreatic cancer., Results: Of 2122 diabetic subjects, 18 (0.85%) were diagnosed with pancreatic cancer within 3 years of meeting criteria for diabetes; 10 of 18 (56%) were diagnosed <6 months after first meeting criteria for diabetes, and 3 were resected. The observed-to-expected ratio of pancreatic cancer in the cohort was 7.94 (95% CI, 4.70-12.55). Compared with subjects without pancreatic cancer, diabetic subjects with pancreatic cancer were more likely to have met diabetes criteria after age 69 (OR = 4.52, 95% CI, 1.61-12.74) years but did not differ significantly with respect to BMI values (29.2 +/- 6.8 vs 26.5 +/- 5.0, respectively). A larger proportion of those who developed pancreatic cancer were ever smokers (92% vs 69%, respectively), but this did not reach statistical significance., Conclusions: Approximately 1% of diabetes subjects aged > or =50 years will be diagnosed with pancreatic cancer within 3 years of first meeting criteria for diabetes. The usefulness of new-onset diabetes as marker of early pancreatic cancer needs further evaluation.

The list of diseases associated with autoantibodies against tissues, cells, or specific autoantigens is growing, and many organs in the body are known to be affected by autoimmune injury. Until recently, the most well-known pancreatic autoimmune disorder was type 1 diabetes mellitus, where there is selective destruction of beta cells in the islets of Langerhans. Although an autoimmune process affecting the exocrine pancreas was suspected over four decades ago, it is only in the past 10 years or so that autoimmune chronic pancreatitis has been recognized as a distinct entity. Here we review the clinical, serologic, radiologic, and histologic features of autoimmune pancreatitis.

Background: The diagnosis of autoimmune pancreatitis can be difficult and often requires a larger specimen than can be provided by FNA alone to determine if the tissue sample obtained with EUS trucut biopsy (TCB) is sufficient to allow adequate histologic review to establish the diagnosis of autoimmune pancreatitis., Methods: EUS TCB was performed in patients presenting with obstructive jaundice who were suspected of having autoimmune pancreatitis based on their clinical, laboratory and imaging studies. The charts were retrospectively reviewed to determine the feasibility of TCB., Results: Between August 2002 and June 2004, 3 patients with obstructive jaundice and suspected autoimmune pancreatitis (AIP) underwent EUS TCB. In each case, a diagnosis of pancreatic cancer also was considered, and surgical resection was the planned therapy before the patient underwent EUS TCB. Histologic review of the TCB specimens established the diagnosis of AIP in two patients and identified nonspecific changes of chronic pancreatitis in the third patient. EUS-guided FNA was performed in two of the 3 patients and failed to establish the diagnosis in either patient. Other than mild transient abdominal pain (n = 1), no complications were identified., Conclusions: This preliminary study suggests that EUS TCB can safely establish the diagnosis of AIP. Doing so helps guide management and may help to avoid unnecessary surgery. Prospective studies are needed to verify these findings and to more clearly define the role of EUS TCB in these patients.

Background/aims: Defective DNA mismatch repair (MMR) in pancreatic cancer, reported in up to 13% of sporadic pancreatic cancers, may predict a good prognosis. To determine if long-term survival in pancreatic cancer could be attributed to defective DNA MMR, we ascertained its prevalence in 35 pancreatic cancer patients who survived > or =3 years after surgery., Methods: We performed immunohistochemistry (IHC) for MMR proteins hMLH1, hMSH2, and hMSH6 in all 35 tumors and microsatellite instability (MSI) studies in 34/35 tumors using 10 microsatellite markers in paired normal and tumor DNA. Defective DNA MMR was defined as absence of protein expression on IHC and/or MSI in > or =30% of markers studied., Results: On IHC, 3/35 (8.6%) tumors had defective DNA MMR. All 3 had absent expression of a DNA MMR protein (hMLH1 in 2 and hMSH2) and 2/3 also had MSI; the third could not be tested. Definitely 2, and probably all 3 patients had hereditary nonpolyposis colon cancer as determined by clinical and genetic profiles., Conclusion: Defective DNA MMR is uncommon in long-term survivors of pancreatic cancer and does not account for the survival benefit in those with sporadic pancreatic cancer.

Herein, we show that the hematopoietic-specific GEF VAV1 is ectopically expressed in primary pancreatic adenocarcinomas due to demethylation of the gene promoter. Interestingly, VAV1-positive tumors had a worse survival rate compared to VAV1-negative tumors. Surprisingly, even in the presence of oncogenic KRAS, VAV1 RNAi abrogates neoplastic cellular proliferation in vitro and in vivo, thus identifying Vav1 as a growth-stimulatory protein in this disease. Vav1 acts synergistically with the EGF receptor to stimulate pancreatic tumor cell proliferation. Mechanistically, the effects of Vav1 require its GEF activity and the activation of Rac1, PAK1, and NF-kappaB and involve cyclin D1 upregulation. Thus, the discovery of prooncogenic pathways regulated by Vav1 makes it an attractive target for therapeutic intervention.

Background/aims: To gain insights into pathogenesis of pancreatic cancer-associated diabetes., Methods: Using homeostasis model assessment (HOMA), we estimated beta-cell function (BCF) and insulin resistance (IR) from fasting plasma glucose (FPG) and insulin in 67 normoglycemic controls and 62 age- and BMI-matched normoglycemic pancreatic cancer patients. In addition, we studied 73 pancreatic cancer subjects with glucose intolerance; 21 had impaired FPG and 51 had diabetes., Results: BCF was similar in controls and normoglycemic pancreatic cancer subjects (64 +/- 5 vs. 78 +/- 9, p = ns), while IR was higher in pancreatic cancer subjects with normal FPG (1.6 +/- 0.6 vs. 1.1 +/- 0.1, p = 0.002). Among pancreatic cancer subjects, those with impaired FPG had markedly decreased BCF compared to those with normal FPG (44 +/- 5 vs. 78 +/- 9, p < 0.02) without significant difference in IR (1.9 +/- 0.2 vs. 1.6 +/- 0.6, p = ns). In cancer subjects, those with diabetes had markedly increased IR compared to those with impaired FPG (3.2 +/- 0.3 vs. 1.9 +/- 0.2, p < 0.0001), while the BCF was similar (37 +/- 4 vs. 44 +/- 5)., Conclusion: Diabetes associated with pancreatic cancer is likely due to a combination of marked decline in BCF and increased insulin resistance.

Background & Aims: Pancreatic mucin-producing cystic neoplasms are classified into 2 distinct entities: mucinous cystic neoplasm (MCN) and intraductal papillary mucinous neoplasm (IPMN). In previous studies, MCN often has been defined loosely and has not always been distinguished clearly from IPMN. Our aims were to determine the demographics, clinical features, and prevalence of invasive cancer in MCN defined by the presence of characteristic ovarian stroma., Methods: By using the presence of ovarian stroma as a requisite criterion for diagnosis of MCN, a single pathologist, unaware of clinical information, identified 56 MCNs from 243 mucin-producing neoplasms resected at Mayo Clinic between 1986 and 2003. Medical records of the MCN patients were reviewed to obtain clinical and demographic data., Results: Patients with MCN were almost exclusively (98%) women; we identified 1 man with a neoplasm containing ovarian stroma. The mean (+/-SD) age at resection was 48 +/- 15 years (84% < 60 y). Abdominal pain was the most common presenting symptom; 16% were asymptomatic. Most MCN (93%) were in the pancreatic body/tail region. Their median size was 5 cm (61% > or =5 cm). Histologically, 50 (89%) were adenomas, 2 (4%) had carcinoma-in-situ, and 4 (7%) had invasive cancer. None of the 22 MCNs <5 cm in size had invasive cancer. No patient with noninvasive disease had a recurrence after resection., Conclusions: MCN defined by ovarian stroma has a distinct demographic and clinical profile and a low prevalence of invasive cancer. These observations suggest that ovarian stroma should be used as the defining criterion for diagnosing MCN.

In the United States, mortality rates from pancreatic cancer (PCa) have not changed significantly over the past 50 years. This is due, in part, to the lack of early detection methods for this particularly aggressive form of cancer. The objective of this study was to use high-throughput protein profiling technology to identify biomarkers in the serum proteome for the early detection of resectable PCa. Using surface-enhanced laser desorption/ionization mass spectrometry, protein profiles were generated from sera of 49 PCa patients and 54 unaffected individuals after fractionation on an anion exchange resin. The samples were randomly divided into a training set (69 samples) and test set (34 samples), and two multivariate analysis procedures, classification and regression tree and logistic regression, were used to develop classification models from these spectral data that could distinguish PCa from control serum samples. In the test set, both models correctly classified all of the PCa patient serum samples (100% sensitivity). Using the decision tree algorithm, a specificity of 93.5% was obtained, whereas the logistic regression model produced a specificity of 100%. These results suggest that high-throughput proteomics profiling has the capacity to provide new biomarkers for the early detection and diagnosis of PCa.

Objective: Our purpose was to determine whether abdominal CT can detect pancreatic cancer before its clinical diagnosis., Subjects and Methods: Two radiologists interpreted in a blinded manner 62 CT scans in 28 pancreatic cancer patients that were obtained before histologic diagnosis and 89 CT scans in 89 control subjects and noted specific CT findings. The presence of pancreatic cancer was characterized as definite, suspicious, low probability, or normal. The scans of the pancreatic cancer patients were divided into four groups on the basis of the time interval preceding cancer diagnosis (0-2, 2-6, 6-18, or > 18 months), and one scan (closest to 18 months) was selected per patient per time interval. Sensitivity and specificity for pancreatic cancer and interobserver agreement for CT findings were calculated., Results: Radiologists agreed that CT findings definite or suspicious for pancreatic cancer were present in 50% of the scans obtained 2-6 and 6-18 months before the diagnosis of pancreatic cancer (3/6 and 4/8 scans, respectively), but they noted such CT findings in only 7% (1/15) of the scans obtained more than 18 months before diagnosis. Pancreatic duct dilatation and cutoff were early CT findings identified by both radiologists and were associated with near-perfect and substantial interobserver agreement (kappa = 0.84 and 0.76, respectively). Ninety-five percent confidence intervals of specificity for tumor absence ranged from 92% to 100%., Conclusion: CT can detect a significant proportion of asymptomatic incident pancreatic cancers before the clinical diagnosis of pancreatic cancer. CT should be considered in screening at-risk patient populations. Pancreatic duct dilatation and cutoff are early findings associated with the development of pancreatic cancer and can be detected on CT with a high degree of reproducibility.

Background and Aims: We have observed intraductal papillary mucinous neoplasm (IPMN) associated with pancreatic calcification. The aim of this study is to describe the profile of IPMN associated with calcification and gain insights into the pathogenesis of calcification in IPMN., Methods: We identified 10 patients with IPMN with pancreatic calcification, of whom 7 underwent pancreatic resection. We reviewed demographic data, history of previous pancreatitis, and radiological and histological features of these patients., Results: In patients with IPMN with calcification (mean age, 65 +/- 12 yr; 50% men), a diagnosis of chronic calcifying pancreatitis was entertained in 5 of 10 patients; 2 patients had undergone previous endoscopic therapy for stone removal. There was no previous history of pancreatitis in 9 of 10 patients. Radiologically, calcifications were seen diffusely throughout the gland in 8 of 10 patients and interpreted as chronic calcific pancreatitis. Although 1 of the 7 patients who underwent resection had diffuse IPMN throughout the gland, 6 patients had IPMN confined to the head or uncinate process (mean size, 2.75 cm; range, 1.1-5 cm). Histologically, 6 of 7 IPMNs were adenomas, and 1 patient had invasive cancer. No patient had intratumoral calcification. All 7 patients had calcification within the main pancreatic duct and/or side branches, often within inspissated mucus., Conclusions: IPMN associated with pancreatic calcification can lead to misdiagnosis and inappropriate treatment for chronic calcifying pancreatitis. In the absence of intratumoral calcification or a previous history of long-standing chronic pancreatitis, calcification in IPMN likely represents a unique and hitherto unrecognized form of calcifying obstructive pancreatitis caused by prolonged partial obstruction of the pancreatic duct.

Because pancreatic cancer patients seldom exhibit disease-specific symptoms until the cancer is at an advanced stage, its diagnosis is a virtual death sentence. Therefore, to make a significant impact on long-term survival for subjects with pancreatic cancer, asymptomatic individuals would have to be screened for premalignant precursors of pancreatic cancer or for asymptomatic pancreatic cancer. A number of formidable obstacles limit the ability of healthcare providers to screen for early neoplastic changes and to make a very early and specific diagnosis of pancreatic cancer. These include lack of a high-risk population for sporadic pancreatic cancer and lack of a simple, noninvasive test sensitive enough to detect small cancers. However, progress is being made in defining various high-risk groups for pancreatic cancer, and improvements in imaging modalities make detection of premalignant lesions and small cancers possible in such individuals. The protocols currently being studied, including use of endoscopic ultrasound and endoscopic retrograde cholangiopancreatography to detect precancerous lesions and small pancreatic cancer in high-risk patients, are still in the research arena and not yet ready for clinical practice.

Introduction: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas was first reported in 1982. It is not clear whether the appearance of this neoplasm is a new epidemic or an old disease previously overlooked., Aim: To determine whether IPMN existed as a separate entity before 1982., Methodology: We reviewed our pathology reports from all cases of pancreatic cancer diagnosed between 1960 and 1980. Pathologic specimens with descriptors--"mucinous," "cystic," or "papillary"--underwent histologic reexamination. Medical records for patients given a new diagnosis of IPMN from this pathologic review were assessed., Results: Eighty-four of more than 4,000 pathology reports reviewed contained a key word triggering histologic review. IPMN was identified in 21 patients. Patients had a mean age of 63 years (range, 44-77 years) with symptoms present for a mean of 76 months (median, 15 months; range, 1-516 months). Reported symptoms were abdominal pain in 17, jaundice in 13, weight loss in 12, and pancreatic insufficiency in 7 patients. On pathologic review, the in situ component was graded as adenoma in 4, borderline in 4, and carcinoma in 13. Parenchymal invasion was present in 11/21 (52%). Excluding four postoperative mortalities, mean time to death was 58 months (median, 15 months; range, 2-264 months). Seven patients died of IPMN, 4 of other causes without evidence of recurrence, and 6 of unknown causes., Conclusions: IPMN existed in its current known form prior to 1982. Our study cannot determine whether the prevalence or incidence has changed since that time.

Background & Aims: Little is known about subjects with idiopathic tumefactive chronic pancreatitis (TCP), that is, chronic pancreatitis whose clinical presentation, usually with a mass or obstructive jaundice, suggests cancer., Methods: We independently reviewed clinical data and histology of 45 TCP (27 idiopathic, 18 alcohol induced) resected at Mayo Clinic (January 1985-March 2001). Follow-up data were obtained from medical records and mailed questionnaires., Results: Compared with alcoholic subjects, idiopathic TCP patients were older (58 +/- 2 vs. 48 +/- 3 yr, P < 0.001), had shorter symptom duration (median 3 vs. 24 wk, P < 0.001), were more likely to have no or mild abdominal pain (70% vs. 17%, P = 0.001), and were more often jaundiced (67% vs. 33%, P = 0.02). Three distinct histologic patterns were identified in TCP. Typical CP (n = 19) showed lobular atrophy, fat necrosis, and ductal changes (dilatation, protein plugs, and stones). Lymphoplasmacytic sclerosing pancreatitis (LPSP) (n = 14) was characterized by periductal lymphoplasmacytic infiltration, obliterative phlebitis, and cholangitis with edema. Idiopathic duct-centric CP (IDCP) (n = 12) had neutrophil-predominant lobular inflammation, without phlebitis. On correlation of clinical and histologic diagnosis, 17 of 18 (94%) patients with alcohol-induced TCP had typical CP, and 25 of 27 (93%) with idiopathic TCP had LPSP or IDCP. LPSP and IDCP were indistinguishable clinically except for higher incidence of jaundice in LPSP (93% vs. 42%, P = 0.005). In idiopathic TCP no recurrence of symptoms was observed after resection (median follow-up 49 mo)., Conclusions: Idiopathic TCP is clinically and histologically distinct from alcohol-induced TCP. It is unclear whether LPSP and IDCP, 2 unique patterns of histologic injury observed in idiopathic TCP, are part of the spectrum of the same disease or represent 2 or more different entities. Resection of mass prevents recurrence of symptoms in idiopathic TCP.

Objectives: Patients with severe necrotizing pancreatitis are at risk for infection, a major cause of morbidity and mortality. Most patients with infected pancreatic tissue require surgical intervention (necrosectomy), which is associated with high morbidity and mortality. A subset of these patients can be managed successfully with conservative management combined with prolonged courses of antibiotics., Methods: Three cases of severe acute pancreatitis seen at our institution are described, in which the patients developed aspirate-proven pancreatic infections. The patients were nonetheless stable from a clinical standpoint and were treated with long courses of antibiotics known to penetrate the pancreas; emergent surgery was deferred., Results: In two patients, surgery was completely avoided, with good clinical outcome. In the third patient, elective surgery was undertaken 12 wk after the episode of acute pancreatitis, to perform necrosectomy on organized pancreatic necrosis and to evaluate the patient's biliary tree. There were no postoperative complications., Conclusions: A subset of patients with severe acute pancreatitis complicated by infection can be successfully managed with long term antibiotics and other supportive measures. High risk necrosectomy can, in some instances, be delayed or avoided entirely.

Background & Aims: The aim of this study was to determine recurrence and long-term survival after resection of pancreatic intraductal papillary mucinous neoplasm and to correlate recurrence and survival with histology, extent of resection, and duration of follow-up., Methods: A single pathologist, without knowledge of previous interpretations of histology or clinical data, retrospectively reviewed and classified 113 resected intraductal papillary mucinous neoplasms as invasive carcinoma (n = 40) or as noninvasive neoplasms (adenoma, borderline, or carcinoma in situ; n = 73). Data on recurrence (locoregional or metastatic), follow-up, and cause of death were obtained from patient records and/or by contacting patients and their physicians., Results: In invasive intraductal papillary mucinous neoplasm, recurrence was similar after partial pancreatectomy (18/27; 67%) and total pancreatectomy (8/13; 62%) and occurred within 3 years of resection in 91%. Among noninvasive neoplasms, 5 of 60 (8%) recurred after partial pancreatectomy (median follow-up, 37 months); none recurred after total pancreatectomy (n = 13; median follow-up, 32 months). Recurrence after resection in noninvasive neoplasms was diagnosed after a median of 40 months (range, 23-75 months); recurrence was noninvasive in 3 and invasive cancer in 2. Five-year survival was better for noninvasive compared with invasive intraductal papillary mucinous neoplasm (84.5% vs. 36%; P < 0.001)., Conclusions: Invasive intraductal papillary mucinous neoplasm recurs frequently even after a complete "curative" resection and portends poor survival. In contrast, noninvasive intraductal papillary mucinous neoplasm recurs infrequently after resection, and survival is excellent regardless of the degree of epithelial dysplasia in the tumor.

Surgical resection is the treatment of choice for intraductal papillary mucinous tumor. In intraductal papillary mucinous neoplasm, the extent of resection is determined by the extent of the disease. If, by pre- and intraoperative assessment, the disease appears localized, limited resection (pancreaticoduodenectomy or distal pancreatectomy) should be performed, ensuring that frozen sections show negative margins. Total pancreatectomy should be considered for extensive disease.

An increasing number of novel mutations are associated with chronic pancreatitis. Some cause a high-penetrance, autosomal dominant type of clinical picture (eg, mutations at codons 29 and 122 of the cationic trypsinogen gene), whereas others have a low penetrance or are frequent in the general population (eg, mutations in Kazal type 1 [SPINK1] and in codons 16, 22, and 23 of the cationic trypsinogen gene) and act as disease modifiers. The results of recent studies indicate that smoking adversely affects the course and complications of chronic pancreatitis (more frequent and faster rate of calcification and higher risk of development of pancreatic cancer). Thus, regardless of the cause of chronic pancreatis, patients with this condition should not smoke. Using current diagnostic criteria, the accuracy of endoscopic ultrasound for the diagnosis of chronic pancreatitis is not good. For example, 39% of dyspeptic persons without any other evidence of chronic pancreatitis fulfilled the endoscopic ultrasound criteria for chronic pancreatitis. Diabetes frequently occurs in chronic pancreatitis, but it is not prevented or increased by pancreatic surgery. Islet cell autotransplantation holds promise for the prevention of diabetes in patients requiring total pancreatectomy if the pancreas is not extensively fibrotic. Splenic vein occlusion is present in 7% of patients undergoing surgery for chronic pancreatitis, but fewer than one fifth of these patients have variceal bleeding before or after surgery.