Rahul Pannala

Differences in Clinical Profile and Relapse Rate of Type 1 Versus Type 2 Autoimmune Pancreatitis

BACKGROUND & AIMS Autoimmune pancreatitis (AIP) has been divided into subtypes 1 (lymphoplasmacytic sclerosing pancreatitis) and 2 (idiopathic duct centric pancreatitis). We compared clinical profiles and long-term outcomes of types 1 and 2 AIP. METHODS We compared clinical presentation, relapse, and vital status of 78 patients with type 1 AIP who met the original HISORt criteria and 19 patients with histologically confirmed type 2 AIP. RESULTS At presentation, patients with type 1 AIP were older than those with type 2 AIP (62 +/- 14 vs 48 +/- 19 years; P < .0001) and had a greater prevalence of increased serum levels of immunoglobulin G4 (47/59 [80%] vs 1/6 [17%]; P = .004). Patients with type 1 were more likely than those with type 2 to have proximal biliary, retroperitoneal, renal, or salivary disease (60% vs 0; P < .0001). Inflammatory bowel disease was associated with types 1 and 2 (6% vs 16%; P = .37). During median clinical follow-up periods of 42 and 29 months, respectively, 47% of patients with type 1 and none of those with type 2 experienced a relapse. In type 1 AIP, proximal biliary involvement (hazard ratio [HR], 2.12; P = .038) and diffuse pancreatic swelling (HR, 2.00; P = .049) were predictive of relapse, whereas pancreaticoduodenectomy reduced the relapse rate (vs the corticosteroid-treated group; HR, 0.15; P = .0001). After median follow-up periods of 58 and 89 months (types 1 and 2, respectively), the 5-year survival rates for both groups were similar to those of the age- and sex-matched US population. CONCLUSIONS Types 1 and 2 AIP have distinct clinical profiles. Patients with type 1 AIP have a high relapse rate, but patients with type 2 AIP do not experience relapse. AIP does not affect long-term survival.

New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer.

Pancreatic cancer has a dismal prognosis because cancer-specific symptoms occur only at an advanced stage. If the cancer is to be discovered early, screening will need to be done in asymptomatic individuals. Because the incidence of pancreatic cancer is low, screening for asymptomatic cancer in the general population is not feasible; therefore, screening will need to be restricted to people at high risk of this disease. The proportion of patients with pancreatic cancer who also have hyperglycaemia or diabetes has previously been under appreciated. New data show that up to 80% of patients are either hyperglycaemic or diabetic, both of which can be detected in the presymptomatic phase. Diabetes has been shown to improve after pancreatic-cancer resection, suggesting that diabetes is caused by the cancer. Conversely, older patients with new-onset diabetes have about an eight-times higher risk of having pancreatic cancer than the general population. Recognition of new-onset diabetes as an early manifestation of pancreatic cancer could lead to the diagnosis of asymptomatic, early-stage pancreatic cancer. However, primary type-2 diabetes is common in the general population and pancreatic cancer is relatively uncommon, and the two forms of diabetes are clinically indistinguishable. The success of a strategy using new-onset hyperglycaemia and diabetes as a screening tool to identify people with a high likelihood of having asymptomatic pancreatic cancer will depend largely on our ability to differentiate pancreatic-cancer-associated diabetes from the more common type-2 diabetes by use of a (serological) biomarker.

Prevalence and Clinical Profile of Pancreatic Cancer–Associated Diabetes Mellitus

BACKGROUND & AIMS Information on the clinical profile of pancreatic cancer (PaC) associated diabetes (DM) is limited. We compared the prevalence and clinical characteristics of DM in subjects with and without PaC. METHODS We prospectively recruited 512 newly diagnosed PaC cases and 933 controls of similar age, who completed demographic and clinical questionnaires and had fasting blood glucose (FBG) levels measured at recruitment and after pancreaticoduodenectomy (n = 105). Subjects with a FBG level >126 mg/dL or who were on antidiabetic treatment were classified as having DM. RESULTS DM was more prevalent (47% vs 7%; P < .001) and predominantly of new onset (<2-year duration) (74% vs 53%; P = .002) among cases compared with controls. Among PaC cases, those with DM (n = 243) were older (68 +/- 10 vs 64 +/- 12 years; P < .001), reported higher usual adult body mass index (30 +/- 6 vs 27 +/- 5 kg/m(2); P < .001), and had a greater frequency of family history of DM (47% vs 31%; P < .001) compared with those without DM (n = 269). After pancreaticoduodenectomy, while DM resolved in 17 of 30 patients (57%) with new-onset DM, its prevalence was unchanged in patients with long-standing DM (n = 11) (P = .009). CONCLUSIONS PaC is a powerful diabetogenic state; DM associated with PaC is often new-onset, resolves following cancer resection, and appears to be associated with conventional risk factors for DM. New-onset DM in patients with PaC is likely induced by the tumor.

Temporal Association of Changes in Fasting Blood Glucose and Body Mass Index With Diagnosis of Pancreatic Cancer

OBJECTIVES:Although the association between diabetes mellitus (DM) and pancreatic cancer is well described, temporal patterns of changes in fasting blood glucose (FBG) and body mass index (BMI) before pancreatic cancer diagnosis are not known.METHODS:We reviewed the medical records of pancreatic cancer cases seen at the Mayo Clinic from 15 January 1981 through to 9 July 2004 and selected those residing within 120 miles of Rochester, MN and who were seen at the Mayo Clinic within 30 days of the date of cancer diagnosis (index date). We identified approximately two matched controls per case residing locally and seen at Mayo in the year of their case index date. For the 736 cases and 1,875 controls with at least one outpatient FBG measurement, we abstracted all FBG values, and corresponding heights and weights up to 60 months before the index date and grouped them into 12-month intervals preceding the index. We compared FBG and BMI in each interval between cases and controls.RESULTS:Mean FBG values were similar between cases, compared with controls, in the intervals from months −60 to −48 (102 mg per 100 ml vs. 100 mg per 100 ml, P=0.34) and from months −48 to −36 (106 mg per 100 ml vs. 102 mg per 100 ml, P=0.09), but progressively increased in the intervals from months −36 to −24 (105 mg per 100 ml vs. 100 mg per 100 ml, P=0.01), from months −24 to −12 (114 mg per 100 ml vs. 102 mg per 100 ml, P=0.001), and from months −12 to +1 (123 mg per 100 ml vs. 102 mg per 100 ml, P<0.0001). Though mean BMI values were generally similar in cases and controls up to 12 months before index, they were significantly lower in cases vs. controls in the interval from months −12 to +1 (P<0.001).CONCLUSIONS:Pancreatic cancer is characterized by progressive hyperglycemia beginning up to 24 months before cancer diagnosis in the setting of decreasing BMI. Pancreatic cancer can potentially be diagnosed early if biomarkers are identified that can distinguish pancreatic cancer–induced DM from type II DM.

Prevalence, diagnosis, and profile of autoimmune pancreatitis presenting with features of acute or chronic pancreatitis.

BACKGROUND & AIMS Little is known about how many patients with features of acute pancreatitis (AP) or chronic pancreatitis (CP) have autoimmune pancreatitis (AIP); most information comes from case reports. We explored the clinical profiles and relationship between these diseases. METHODS We evaluated 178 patients presenting to our Pancreas Clinic between January 2005 and June 2006 for evaluation of the etiology of their suspected pancreatitis; AIP was diagnosed when patients met HISORt (Histology, Imaging features, Serology, Other organ involvement and Response to steroid treatment) criteria. In a separate cohort of patients with AIP from our database, we identified patients who presented with features of AP (>/=2 of abdominal pain, increased pancreatic enzymes, pancreatic inflammation determined by imaging analyses) or CP (>/=1 of pancreatic calcification, irregular main pancreatic duct dilation, or marked atrophy) and determined their clinical profile. RESULTS Only 7/178 (3.9%) patients evaluated for etiology of suspected pancreatitis had AIP. Among 63 AIP patients in our database, 22 (34.9%) had features of AP (n = 15) or CP (n = 7) at presentation (average age 53.4 +/- 19.0 years, all males). Patients with AIP and pancreatitis were characterized by presence of obstructive jaundice (59.1%), increased levels of liver enzymes (81.8%), increased levels of serum immunoglobulin G4 (80.9%), and other organ involvement (69.1%). All 19 patients presenting with pancreatitis who were treated with steroids responded to treatment. CONCLUSIONS While AIP is an uncommon etiology for acute or chronic pancreatitis, >33% of AIP have features of acute or chronic pancreatitis at presentation.

ASGE Technology Committee systematic review and meta-analysis assessing the ASGE Preservation and Incorporation of Valuable Endoscopic Innovations thresholds for adopting real-time imaging–assisted endoscopic targeted biopsy during endoscopic surveillance of Barrett’s esophagus

BACKGROUND AND AIMS Endoscopic real-time imaging of Barretts esophagus (BE) with advanced imaging technologies enables targeted biopsies and may eliminate the need for random biopsies to detect dysplasia during endoscopic surveillance of BE. This systematic review and meta-analysis was performed by the American Society for Gastrointestinal Endoscopy (ASGE) Technology Committee to specifically assess whether acceptable performance thresholds outlined by the ASGE Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) document for clinical adoption of these technologies have been met. METHODS We conducted meta-analyses calculating the pooled sensitivity, negative predictive value (NPV), and specificity for chromoendoscopy by using acetic acid and methylene blue, electronic chromoendoscopy by using narrow-band imaging, and confocal laser endomicroscopy (CLE) for the detection of dysplasia. Random effects meta-analysis models were used. Statistical heterogeneity was evaluated by means of I(2) statistics. RESULTS The pooled sensitivity, NPV, and specificity for acetic acid chromoendoscopy were 96.6% (95% confidence interval [CI], 95-98), 98.3% (95% CI, 94.8-99.4), and 84.6% (95% CI, 68.5-93.2), respectively. The pooled sensitivity, NPV, and specificity for electronic chromoendoscopy by using narrow-band imaging were 94.2% (95% CI, 82.6-98.2), 97.5% (95% CI, 95.1-98.7), and 94.4% (95% CI, 80.5-98.6), respectively. The pooled sensitivity, NPV, and specificity for endoscope-based CLE were 90.4% (95% CI, 71.9-97.2), 98.3% (95% CI, 94.2-99.5), and 92.7% (95% CI, 87-96), respectively. CONCLUSIONS Our meta-analysis indicates that targeted biopsies with acetic acid chromoendoscopy, electronic chromoendoscopy by using narrow-band imaging, and endoscope-based CLE meet the thresholds set by the ASGE PIVI, at least when performed by endoscopists with expertise in advanced imaging techniques. The ASGE Technology Committee therefore endorses using these advanced imaging modalities to guide targeted biopsies for the detection of dysplasia during surveillance of patients with previously nondysplastic BE, thereby replacing the currently used random biopsy protocols.

Corticosteroid treatment for autoimmune pancreatitis

Autoimmune pancreatitis (AIP) is the only pancreatic disorder responsive to steroid treatment. AIP has recently been subclassified into type 1 and type 2 AIP.1 Type 1 AIP is the pancreatic manifestation of immunoglobulin G4 (IgG4)-associated systemic disease (ISD), a fibroinflammatory autoimmune disorder that involves multiple organ systems and is characteristically associated with elevation of serum levels of IgG4.2 Commonly used diagnostic criteria for AIP include the Asian Consensus diagnostic criteria3 and the Mayo Clinic HISORt criteria4 (histology, imaging, serology, other organ involvement and response to corticosteroid treatment). Treatment protocols for AIP are still evolving, but corticosteroids are generally considered to be very effective in the initial inflammatory phase of the disease. Several small case series have reported that corticosteroids are effective in inducing remission in AIP, but larger series and controlled trials are lacking. In this issue of Gut ( see page 1504 ), Kamisawa and colleagues5 report results from a large, multicentre, retrospective survey of 563 patients with AIP treated at 17 referral centres in Japan. Their study highlights the fact that though a substantial proportion of patients with AIP may achieve spontaneous remission (77/104 patients, 74%), corticosteroids are also highly effective in inducing remission (451/459 patients, 98%). This study, despite the limitations of a retrospective and cross-sectional study design, provides the best evidence to date of the efficacy of corticosteroid treatment in the initial presentation of AIP. However, our knowledge of the natural history of AIP, predictors of relapse, need for maintenance treatment and the optimal type of maintenance treatment is still limited. The objective of this commentary is to provide a brief overview of the issues associated with corticosteroid treatment in AIP. The goals of treatment in the initial inflammatory phase of AIP are symptom alleviation (eg, jaundice and abdominal discomfort), …

Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections

Background and aims Peripancreatic fat necrosis occurs frequently in necrotising pancreatitis. Distinguishing markers from mediators of severe acute pancreatitis (SAP) is important since targeting mediators may improve outcomes. We evaluated potential agents in human pancreatic necrotic collections (NCs), pseudocysts (PCs) and pancreatic cystic neoplasms and used pancreatic acini, peripheral blood mononuclear cells (PBMC) and an acute pancreatitis (AP) model to determine SAP mediators. Methods We measured acinar and PBMC injury induced by agents increased in NCs and PCs. Outcomes of caerulein pancreatitis were studied in lean rats coadministered interleukin (IL)-1β and keratinocyte chemoattractant/growth-regulated oncogene, triolein alone or with the lipase inhibitor orlistat. Results NCs had higher fatty acids, IL-8 and IL-1β versus other fluids. Lipolysis of unsaturated triglyceride and resulting unsaturated fatty acids (UFA) oleic and linoleic acids induced necro-apoptosis at less than half the concentration in NCs but other agents did not do so at more than two times these concentrations. Cytokine coadministration resulted in higher pancreatic and lung inflammation than caerulein alone, but only triolein coadministration caused peripancreatic fat stranding, higher cytokines, UFAs, multisystem organ failure (MSOF) and mortality in 97% animals, which were prevented by orlistat. Conclusions UFAs, IL-1β and IL-8 are elevated in NCs. However, UFAs generated via peripancreatic fat lipolysis causes worse inflammation and MSOF, converting mild AP to SAP.

Eosinophilia and Allergic Disorders in Autoimmune Pancreatitis

OBJECTIVES:In autoimmune pancreatitis (AIP), the prevalence, interrelationships, and significance of peripheral eosinophilia, allergic disorders, and eosinophil infiltration in the pancreas remain unclear.METHODS:From medical records, we obtained data on peripheral eosinophil counts at presentation and follow-up, and clinical diagnoses of allergic disorders in 97 AIP patients (78 type 1 and 19 type 2), which were compared with matched healthy controls. Available pancreatic histologic specimens were graded for eosinophils. Peripheral eosinophilia was defined as counts >0.5 × 109 per liter. We examined nature of and association between these parameters in AIP.RESULTS:Among 78 type 1 AIP patients (mean age 62±14 years, 77% men), peripheral eosinophilia at presentation was diagnosed in 12% and allergic disorders in 15% (vs. 0 and 4% in controls, P=0.0004 and 0.006, respectively). Allergic disorders were observed in 27 and 11% of type 1 AIP with and without eosinophilia, respectively (P=0.08). Patients with and without peripheral eosinophilia were similar in clinical profile. Moderate-to-severe eosinophil infiltration was present in 67% of pancreas resection specimens and did not correlate with peripheral eosinophilia. Type 2 AIP did not differ from type 1 AIP in any of these parameters.CONCLUSIONS:Peripheral eosinophilia, allergic disorders, and pancreatic eosinophil infiltration are associated with AIP. Eosinophilia in AIP may not reflect an allergic phenomenon, but appears to be consistent with autoimmune mechanism.

Long-Term Survival and Prognostic Indicators in Small (≤2 cm) Pancreatic Cancer

Objectives: In a matched analysis, we investigated clinical, histopathological, and survival characteristics of small (≤2 cm) pancreatic cancer (PaC) as compared to large PaC. Methods: From the Mayo pathology database, we identified 41 consecutive patients with small PaC and 94 matched controls with margin-negative PaC >2 cm. Two experienced pathologists, who were blinded to survival data, independently reviewed tumor stage and differentiation. Kaplan-Meier survival analysis and Cox proportional hazards models were applied for data analyses. Results: In patients with localized disease (stages I and II), survival was similar in small and large PaC but survival was significantly better in small PaC with regional nodal metastasis (stage III) as compared to similar stage large PaC (5-year survival 44 vs. 7%, median survival 58 vs.18 months, p < 0.001). Well-differentiated small and large PaC had similar median survival (76 vs. 74 months, p = NS). In multivariate analysis, tumor differentiation, not tumor size, was the only independent factor predicting survival in PaC (risk ratio, RR, for moderate vs. well- differentiated: 2.6, 95% confidence interval, CI, 1.5–4.5, and RR for poorly differentiated vs. well-differentiated: 5.0, 95% CI 2.4–10.1). Conclusion: Tumor differentiation may be a better predictor of survival in resectable PaC than tumor stage.