David A. Klibansky

The Clinical Relevance of the Increasing Incidence of Intraductal Papillary Mucinous Neoplasm

BACKGROUND & AIMS The incidence of intraductal papillary mucinous neoplasm (IPMN) is believed to be increasing; we investigated whether this is the result of increasing burden of disease or more diagnostic scrutiny. METHODS In a retrospective cohort study, we calculated a trend in reported incidence of IPMN using data collected from Olmsted County, Minnesota, from 1985 to 2005. Total IPMN cases from the Olmsted database were identified through a keyword and International Classification of Diseases, 9th revision, search using a database from the Rochester Epidemiology Project, with all cases verified by subsequent chart review. The subsequent rate of IPMN-related carcinoma was calculated using data from the national Surveillance Epidemiology and End Results-9 database, reflecting trends from 1982 to 2007. Cases of IPMN-related carcinoma were identified in the Surveillance Epidemiology and End Results-9 database by limiting the search to histology codes for noninvasive and invasive IPMN. RESULTS Between 1985 and 2005, there was a 14-fold increase in the age- and sex-adjusted incidence of IPMN, from 0.31 to 4.35 per 100,000 persons. From 2000 to 2001, the rate of reported carcinoma increased from 0.008 to 0.032 per 100,000 persons, but stabilized afterward, with a rate of 0.06 per 100,000 persons in 2007. Mortality from all causes of pancreatic cancer was stable between 1975 and 2007 (approximately 11 deaths per 100,000 individuals). CONCLUSIONS The incidence of IPMN has increased in the absence of an increase in IPMN-related or overall pancreatic cancer-related mortality, so it likely results from an increase in diagnostic scrutiny, rather than greater numbers of patients with clinically relevant disease.

Pancreatic Cyst Prevalence and the Risk of Mucin-Producing Adenocarcinoma in US Adults

OBJECTIVES:The presence of a pancreatic cyst often prompts concern, although the rate of malignant transformation to mucin-producing adenocarcinoma is not known. We aimed to determine the prevalence rate of mucin-producing adenocarcinoma in US adults with pancreatic cysts.METHODS:This retrospective, population-based cross-sectional study calculated the annual number of mucin-producing adenocarcinomas using the Surveillance Epidemiology and End Results (SEER 18) database and the 2010 US census. The overall prevalence rate of cysts in the population was found using data from large cross-sectional imaging studies of incidental cyst prevalence. Prevalence rates were then calculated by dividing the annual number of mucin-producing adenocarcinomas by the cyst prevalence rate.RESULTS:Between 2005 and 2009, 1,137 mucin-producing adenocarcinomas were estimated to be found annually in a US adult population of 137,154,960. The total number of pancreas cysts, given a cyst prevalence rate of 2.5%, was 3,428,874. Therefore, the prevalence rate of mucin-producing adenocarcinoma arising in patients with pancreatic cysts was 33.2 per 100,000 (95% confidence interval (CI): 21.9–44.5). The prevalence rate was 32.8 per 100,000 (95% CI: 21.6–44.0) in women and 33.5 per 100,000 (95% CI: 22.2–44.8) in men. As expected, the rate of malignant transformation increased linearly with advancing age (highest 38.6 per 100,000 in 80- to 84-year-old men).CONCLUSIONS:Malignant transformation of pancreatic cysts into mucin-producing adenocarcinoma in US adults is a very rare event. Current clinical guidelines and resource allocation for pancreatic cyst disease should be reconsidered given these findings.

Transient elastography for predicting clinical outcomes in patients with chronic liver disease.

Summary.  There is increasing interest in developing noninvasive means to evaluate liver fibrosis in patients with chronic liver disease to determine disease severity, prognosis and optimal treatment. Transient elastography (TE) has previously been demonstrated to predict the presence or absence of advanced fibrosis. The current study was conducted to determine whether TE can identify patients with chronic liver disease at risk of clinical decompensation. A total of 667 patients underwent TE and were followed for a median of 861 days and 57 patients achieved the primary outcome, a composite of clinical endpoints including death, ascites, encephalopathy, increased Child Score ≥2, variceal bleed, hepatocellular carcinoma or listing for transplant. Overall, TE had an area under the receiver operating characteristic curve of 0.87 for predicting clinical outcome. Using a cut‐off of 10.5 kPa, TE has a sensitivity, specificity, positive predictive value and negative predictive value (NPV) of 94.7%, 63.0%, 19.3% and 99.2%, respectively. A predictive model for clinical events was developed using generalized cross‐validation for clinical endpoints considering TE, liver biopsy results and multiple other predictors. Individually, TE performed better than biopsy, or any other variable, for predicting clinical outcome [Harrell’s C Statistic 0.86 for TE, 0.78 for stage]. Patients with a TE score of >12.5 kPa were found to have a relative hazard for clinical event of 18.99 compared with patients with TE score <10.5. A combined variable model including TE, aspartate aminotransferase/alanine aminotransferase ratio and model for end‐stage liver disease (MELD) yielded the highest predictive accuracy with Harrell’s C value of 0.93. In the subset of patients with cirrhosis, TE was not found to be independently associated with clinical outcomes in univariate or multivariate analysis although it retained a high sensitivity and NPV of 97.5% and 92.3%, respectively, at a kPa cut‐off of 10.5. TE can successfully identify patients with chronic liver disease who are at low risk of clinical decompensation over a time period of 2 years.

Robotics in endoscopy.

Purpose of review The increasing complexity of intralumenal and emerging translumenal endoscopic procedures has created an opportunity to apply robotics in endoscopy. Computer-assisted or direct-drive robotic technology allows the triangulation of flexible tools through telemanipulation. The creation of new flexible operative platforms, along with other emerging technology such as nanobots and steerable capsules, can be transformational for endoscopic procedures. In this review, we cover some background information on the use of robotics in surgery and endoscopy, and review the emerging literature on platforms, capsules, and mini-robotic units. Recent findings The development of techniques in advanced intralumenal endoscopy (endoscopic mucosal resection and endoscopic submucosal dissection) and translumenal endoscopic procedures (NOTES) has generated a number of novel platforms, flexible tools, and devices that can apply robotic principles to endoscopy. The development of a fully flexible endoscopic surgical toolkit will enable increasingly advanced procedures to be performed through natural orifices. Summary The application of platforms and new flexible tools to the areas of advanced endoscopy and NOTES heralds the opportunity to employ useful robotic technology. Following the examples of the utility of robotics from the field of laparoscopic surgery, we can anticipate the emerging role of robotic technology in endoscopy.

Narcotic Independence After Pancreatic Duct Stenting Predicts Narcotic Independence After Lateral Pancreaticojejunostomy for Chronic Pancreatitis.

Objective This study aimed to determine if the improved pain response to endoscopic retrograde cholangiopancreatogrphy (ERCP) and pancreatic stent placement (EPS) predicts pain response in patients with chronic pancreatitis after modified lateral pancreaticojejunostomy (LPJ). Methods A multi-institutional, retrospective review of patients who underwent successful EPS before LPJ between 2001 and 2010 was performed. The primary outcome was narcotic independence (NI) within 2 months after ERCP or LPJ. Results A total of 31 narcotic-dependent patients with chronic pancreatitis underwent successful EPS before LPJ. Ten (32%) achieved post-LPJ NI (median follow-up, 8.5 months; interquartile range [IQR], 2–38 months). Eight (80%) of 10 patients with NI post-ERCP achieved NI post-LPJ. Two (10%) without NI post-ERCP achieved NI post-LPJ. Narcotic independence post-EPS was associated strongly with NI post-LPJ with an odds ratio of 38 (P = 0.0025) and predicted post-LPJ NI with a sensitivity, specificity, positive predictive value, and negative predictive value of 80%, 90.5%, 80%, and 90.5%, respectively. Conclusions Narcotic independence after EPS is associated with NI after LPJ. Failure to achieve NI post-ERCP predicts failure to achieve NI post-LPJ. These results support the need for larger studies to confirm the predictive value of pancreatic duct stenting for better selection of chronic pancreatitis patients who will benefit from LPJ.

The effect of neoadjuvant chemoradiation on pancreatic cancer-associated diabetes mellitus.

Objectives Pancreatic cancer-associated diabetes mellitus (PaCDM) occurs in approximately 50% of patients. In patients with new-onset PaCDM undergoing neoadjuvant chemoradiation therapy before surgical resection, we hypothesized that pancreatic tumor destruction would lead to improvement in fasting glucose levels. Methods A retrospective chart review was performed on patients with newly diagnosed pancreatic adenocarcinoma without a history of DM treated with neoadjuvant therapy at our center. All patients underwent combined modality neoadjuvant chemoradiation therapy, followed by surgical excision of the primary tumor. Results Sixty-nine patients (31 with PaCDM) met inclusion criteria for the study; 18 had Evans grade II tumor kill response, 10 had grade III response, and 3 had grade IV response. In patients with grade IV response, the odds ratio (OR) for achieving a normal preoperative glucose was 5.0 (95% confidence interval [CI], 0.4–63.2), compared with grade III (OR, 0.5; 95% CI, 0.1–3.0) and grade II (OR, 1.1; 95% CI, 0.2–5.2). When adjusted for percent kilogram weight loss and tumor size in a multivariable regression model, the grade IV response became significant to an OR of 6.5 (95% CI, 1.2–77.3). Conclusions In patients with new-onset PaCDM undergoing neoadjuvant chemoradiation therapy, fasting glucose response may mirror the extent of tumor destruction.

Rectal Indomethacin for the Prevention of Post-ERCP Pancreatitis: A Valuable Tool to Keep in Your Back Pocket

CDH1 mutations and the development of undifferentiated adenocarcinomas. It is unclear how the genetic alterations in cell adhesion-related genes, including FAT4, could contribute to the development of intestial-type gastric cancer, and it is thus important to valuate the phenotype of the animal model with stomch-specific deletion of these genes. Chromatin remodeling is essential for various biologic steps, such as DNA replication, transcription, and DNA damage repair. ARID1A (AT-rich interactive domain-conaining protein 1A) is an integral member of the SWI/SNF hromatin-remodeling complex. Increasing evidence suggests that dysfunction of the chromatin-remodeling complex promotes chromosomal instability and thus could contribute to tumorigenesis. Mutations in the ARID1A gene are reported in a variety of human cancers, including endometriosis-associated ovarian, uterine, breast, pancreatic, and liver cancers (Nat Rev Cancer 2011;11:481-492). The present study revealed a collective 8% ARID1A mutation rate in gastric cancer. imilar findings are reported in a previous study in hich resequencing of all coding exons led to the deection of ARID1A somatic mutations in 32 of 109 astric cancer specimens (Nat Genet 2011;43:1219223). The results obtained with deep sequencing were onsistent with previous analyses of immunostaining ndicating the loss of ARID1A protein expression in 1%–14% of gastric cancer tissues (J Pathol 2011;224: 28-333; Am J Surg Pathol 2011;35:625-632). These ndings suggest that ARID1A has critical tumor-supressing potential in the development of gastric caners. Interestingly, ARID1A mutations and TP53 mutaions were mutually exclusive in tumor tissues. Thus, it s possible that dysfunction of the chromatin-remodelng complex by an ARID1A mutation causes the epigenetic instability that drives tumorigenesis without the presence of genetic instability caused by TP53 mutation. In addition, mutations in an epigenetic regulatory gene, ARID1A, were frequently detectable in MSI tumors, suggesting the close association between genetic and epigenetic aberrations in gastric cancers. Zhang et al identified several candidate genes that could play a role as a tumor driver for human gastric carcinogenesis. Identification of the driver genes that directly trigger malignant transformations provides the opportunity to determine novel targets for cancer therapy. Thus, it is hoped that the rapid advances in sequencing technologies will contribute to uncover the cause of gastric cancer resulting from genetic and epigenetic alterations.

The Clinical Relevance of Rising IPMN Incidence in the United States

Background: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has been recognized as an important precursor to pancreatic cancer. Since the WHO established a consensus in 1996 for grading IPMNs, numerous studies have characterized genetic mutations associated with these various histologic grades. However, the molecular basis for progression into cancer remains poorly understood. We hypothesize that malignant transformation of IPMN reflects a progression in molecular changes. To determine the risk of malignant transformation associated with specific genetic abnormalities, we performed themost comprehensive meta-analysis to date of genetic associations with IPMN grade. Methods: We conducted a meta-analysis reviewing Pubmed, Cochrane Library, and Embase databases from January 1996 thru October 2010. We included only studies that adhered to 1996 WHO guidelines for distinguishing adenoma and borderline IPMNs (IPM-A, IPM-B) vs. carcinoma in situ and invasive carcinoma (IPM-C) based on surgically resected specimens. Quantitative meta-analysis was performed of gene candidates using both fixedand random-effects models. The I2 test was used to evaluate study heterogeneity. Results: We identified 178 studies that satisfied the inclusion criteria (1,343 IPMN samples). In pooled analysis there was an overall positive association for IPM-C with MUC-1 expression (OR 5.90; 95% C.I. 2.5413.70), k-Ras mutations (OR 1.90; 95% C.I. 1.04-3.47), and p53 mutations (OR 2.00; 95% C.I. 0.80-4.98). The strongest positive association for IPM-C vs. IPM-A/B was with telomerase mutations (OR 15.95; 95% C.I. 6.32-40.25), consistent with this genetic abnormality occurring relatively later in the histologic progression of IPMN into cancer. Expression of MUC5AC was not associated with IPM-C vs. IPM-A/B (OR 0.71; 95% C.I. 0.23-2.23). We further summarize associations with 91 additional genes including Shh, Cox2, Smad4, APC, and S100A4 as well as findings from cyst and pancreatic fluid assays. Conclusion: This metaanalysis identifies MUC-1 expression and mutations in telomerase, p53 and k-Ras genes as molecular changes associated with IPMN progression to cancer. These associations provide a basis for the use of molecular markers in diagnostic grading of IPMNs as well as a basis for therapeutic targets.

Su1346 Prophalactic Hemoclip Application At ERCP to Prevent Post-ES Bleeding in Patients Receiving Anticoagulation or Antiplatelet Therapy

Patient characteristics Mean age (SD) 59.4 (16.4) 64.0 (16.2) 0.12 1.00 (0.97, 1.02) 0.88 % female sex 49.2 (40.2, 58.1) 56.8 (42.2, 71.5) 0.39 % jaundice 7.5 (2.8, 12.2) 15.9 (5.1, 26.7) 0.11 0.56 (0.17, 1.86) 0.35 Clinical presentation Incidental finding 82.9 (71.2, 94.7) 17.1 (5.3, 28.8) 0.023 FAP surveillance 75.6 (62.8, 88.3) 24.4 (11.7, 37.2) Abnormal liver function tests 42.9 (15.8, 70.0) 57.1 (30., 84.2) 0.26 (0.07, 0.91) 0.035