Sheila Kumar

High Prevalence of BRCA1 and BRCA2 Germline Mutations With Loss of Heterozygosity In a Series of Resected Pancreatic Adenocarcinoma and Other Neoplastic Lesions

PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is associated with the breast ovarian cancer syndrome (BRCA1/BRCA2) mutations. It is unknown if this association is causal. EXPERIMENTAL DESIGN This is a single-site study of patients who underwent surgical pancreatic tumor resection and self-identified as Ashkenazi Jewish. DNA from normal pancreatic tissue was genotyped for the three Ashkenazi Jewish BRCA1/2 founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, and loss of heterozygosity (LOH) was determined by sequencing DNA from microdissected tumor. When additional tumor tissue was available, p53 immunohistochemistry (IHC) was conducted. RESULTS Thirty-seven patients underwent surgery for PDAC, seven for intraductal papillary mucinous neoplasm (IPMN), and 19 for other diseases. A high prevalence of BRCA1/2 mutations was found in the surgical cohort (12/63; 19.0%; P < 0.001), PDAC cohort (8/37; 21.6%; P < 0.001), and IPMN cohort (2/7; 28.6%; P = .01) compared with published control mutation frequency. A high prevalence of BRCA1 185delAG (8.1%; P < 0.001) and BRCA2 6174delT (10.8%; P < 0.001) in Ashkenazi Jewish patients with PDAC was shown. BRCA1/2 LOH was found in 2 of 4 BRCA1-associated PDACs and 3 of 4 BRCA2-associated PDACs. Positive p53 IHC was found in 5 of 8 BRCA1/2 PDACs. CONCLUSIONS We show a high prevalence of BRCA1/2 mutations with LOH in an Ashkenazi Jewish cohort of surgically resected PDAC and neoplastic lesions, suggesting that these germline mutations are causal in selected individuals.

Optical biopsy of sessile serrated adenomas: do these lesions resemble hyperplastic polyps under narrow-band imaging?

BACKGROUND Serrated colorectal lesions include hyperplastic polyps (HPs) and sessile serrated adenomas (SSAs). Optical biopsy could misclassify SSAs as unimportant if they resemble HPs. OBJECTIVE To explore the narrow-band imaging (NBI) features of SSAs. We hypothesized that SSAs resemble HPs under NBI. DESIGN Retrospective analysis of data from our prospective study of NBI in routine practice. SETTING Single specialty group. PATIENTS Patients undergoing colonoscopy. INTERVENTION Colonoscopy. MAIN OUTCOME MEASUREMENTS Polyp histology prediction by community gastroenterologists. Features of SSAs versus HPs and adenomas by using the Narrow-Band Imaging International Colorectal Endoscopic (NICE) Classification. RESULTS Among 2388 lesions, 141 were diagnosed on pathology as SSAs, 465 as HPs, and 1546 as adenomas. Each individual NICE feature of HPs was found in 38% to 42% of SSAs, 66% to 67% of HPs, and 15% to 20% of adenomas (P < .001 for each). Each individual NICE feature of adenomas was found in 57% to 62% of SSAs, 33% to 34% of HPs, and 80% to 84% of adenomas (P < .001 for each). Compared with HPs, SSAs were less likely (odds ratio [OR] 0.74; 95% confidence interval [CI], 0.69-0.79) and adenomas were even less likely (OR 0.62; 95% CI, 0.59-0.64) to have all 3 NICE features of HPs. SSAs >5 mm were more likely than smaller SSAs to have all 3 NICE features of adenomas. SSA location did not predict NBI features. Analyses restricted to high-confidence lesions showed similar results. LIMITATIONS The endoscopists were not NBI experts. CONCLUSION Community gastroenterologists observed a profile of NICE features among SSAs that was intermediate to the profiles observed for HPs and adenomas. These results require confirmation by NBI experts.

BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high‐risk pancreatic cancer screening and pancreatic cancer cohorts

Approximately 10% of pancreatic ductal adenocarcinoma (PDAC) is due to a genetic predisposition, including the breast and ovarian cancer syndrome germline mutations BRCA1 and BRCA2. Knowledge of specific genetic mutations predisposing to PDAC may enable risk stratification, early detection, and the development of effective screening and surveillance programs. In the current study, the authors attempted to determine the diagnostic yield of testing for BRCA1/2 germline mutations in a PDAC screening cohort and a PDAC cohort referred for genetic testing.

Absence of pancreatic intraepithelial neoplasia predicts poor survival after resection of pancreatic cancer.

Objectives Pancreatic intraepithelial neoplasia (PanIN), thought to represent the dominant precursor of pancreatic adenocarcinoma (PDAC), is often found synchronously adjacent to resected PDAC tumors. However, its prognostic significance on outcome after PDAC resection is unknown. Methods A total of 342 patients who underwent resection for PDAC between 2005 and 2010 at a single institution were identified and stratified according to highest grade of PanIN demonstrated surrounding the tumor. Clinical and pathologic characteristics of each patient and tissue were recorded and analyzed. The primary outcome was length of survival after resection. Results An absence of PanIN lesions was identified in 32 patients (9%), low grade PanIN without synchronous high grade lesions was identified in 52 patients (15%), and high grade PanIN was found in 258 patients (75%). Median survival were 12.8 months for the non-PanIN group, 26.3 months for the low-grade PanIN group, and 23.8 months for the high-grade PanIN groups (P = 0.043). In multivariable analysis, absence of PanIN was independently associated with poor survival (P = 0.002). Conclusions The patients who demonstrate an absence of PanIN in the pancreatic tissue adjacent to the resected PDAC tumor have shorter postresection survival compared with those who demonstrate a PanIN lesion.

The Association Between Helicobacter pylori Infection and Nonalcoholic Fatty Liver Disease

Purpose of ReviewHelicobacter pylori (HP) infection is known to be a significant risk factor in the development of certain gastric conditions, such as ulcers, gastritis, and malignancy. Recently, however, the systemic effect of HP infection on other organ systems has come to be appreciated. In this review, we will explore the association between HP infection and nonalcoholic fatty liver disease (NAFLD), the hepatic component of metabolic syndrome.Recent FindingsThe possible association between HP infection and NAFLD initially stemmed from the isolation of HP bacteria in the livers of patients with NAFLD. Although there have been conflicting results, several subsequent clinical trials have demonstrated a higher rate of fatty liver and NASH in HP-positive patients compared to HP-negative patients; in addition, small trials examining the effect of HP eradication have shown improvement in markers of NAFLD activity, further supporting a link between these two conditions. The pathophysiology behind the possible association between HP infection and NAFLD has yet to be fully elucidated; several possible mechanisms include induction of a pro-inflammatory state that shifts the body toward a more lipogenic profile, and a hormonal shift that favors progression toward insulin resistance and fibrosis.SummaryThe association between HP infection and NAFLD has been demonstrated in several clinical trials, including small trials evaluating the effect of HP eradication on NAFLD. Future studies examining the pathophysiology behind this association are the next step in characterizing the relationship between these two conditions.

Self-Reported Questionnaire Detects Family History of Cancer in a Pancreatic Cancer Screening Program.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death; approximately 5–10% of PDAC is hereditary. Self-administered health history questionnaires (HHQs) may provide a low-cost method to detail family history (FH) of malignancy. Pancreas Center patients were asked to enroll in a registry; 149 with PDAC completed a HHQ which included FH data. Patients with FH of PDAC, or concern for inherited PDAC syndrome, were separately evaluated in a Prevention Program and additionally met with a genetic counselor (GC) to assess PDAC risk (n = 61). FH obtained through GC and HHQ were compared using Wilcoxon signed-rank sum and generalized linear mixed models with Poisson distribution. Agreement between GC and HHQ risk-assessment was assessed using kappa (κ) statistic. In the Prevention Program, HHQ was as precise in detecting FH of cancer as the GC (all p > 0.05). GC and HHQ demonstrated substantial agreement in risk-stratification of the Prevention Program cohort (κ = 0.73, 95% CI 0.59–0.87.) The sensitivity of the HHQ to detect a patient at elevated risk (i.e., moderate- or high-risk) of PDAC, compared to GC, was 82.9% (95% CI 67.3–92.3%) with a specificity of 95% (95% CI 73.1–99.7%). However, seven patients who were classified as average-risk by the HHQ were found to be at an elevated-risk of PDAC by the GC. In the PDAC cohort, 30/149 (20.1%) reported at least one first-degree relative (FDR) with PDAC. The limited sensitivity of the HHQ to detect patients at elevated risk of PDAC in the Prevention Program cohort suggests that a GC adds value in risk-assessment in this population. The HHQ may offer an opportunity to identify high-risk patients in a PDAC population.

229 A Prospective, Randomized Trial of Adenoma Miss Rates At Colonoscopy Associated With 3-Minute vs. 6-Minute Withdrawal Time

Introduction: A minimum withdrawal time for screening colonoscopy of 6 minutes has been proposed, based on an observational study. The 6-minute withdrawal time remains controversial and has not been compared in a standardized fashion to alternate withdrawal times. Aim: To perform a prospective, randomized trial to compare adenoma miss rates (AMR) associated with withdrawal times of 6 minutes vs. 3 minutes. Methods: Consecutive patients undergoing colonoscopy at Stanford University and Palo Alto Veterans Administration Hospital were randomized to undergo either a 3-minute or 6-minute withdrawal (1st pass), followed immediately by a tandem 6-minute withdrawal (2nd pass). AMR was defined as the number of adenomas detected on the 2nd pass divided by total number of adenomas found. A chi-square statistic was used to directly compare AMR. A z-statistic was used to determine effect of polyp size/location on AMR. A mixed-effects logistic regression model was then created to compare AMR, controlling for endoscopist, size/location of adenoma, and patient. Finally, a Cochrane-Armitage test for trend was used to evaluate the trend of adenoma detection associated with increasing withdrawal time. Results: 200 subjects were enrolled (99 in the 3-minute group, 101 in the 6-minute group). Demographics and indications for colonoscopy were similar between the two groups (Table 1). AMR was significantly higher in the 3-minute withdrawal group compared to the 6-minute withdrawal group (48.5% vs 21.8%; p≤0.0001). Adenomas were significantly more likely to be missed in the 3-minute withdrawal group in all 3 locations of the colon (right, transverse and left colon). AMR was higher in the 3-minute withdrawal group among adenomas that were ≤5mm; there was no significant difference in AMR for adenomas that were 6-9mm or ≥10mm. After controlling for endoscopist, size/location of the polyp/adenoma, and the patient, AMR remained significantly higher in the 3-minute withdrawal group compared to the 6-minute withdrawal group (OR 2.92, 95% CI=1.54-5.55) (Table 1). Adenoma detection rate (ADR) was similar between both 3 and 6 minute withdrawal groups (38.4% vs 40.6%, p=0.75); however, this study was not powered to detect differences in ADR. There was a significant trend towards higher total number of adenomas detected as withdrawal time increased (52 at 3 minutes, 87 at 6 minutes, 101 at 9 minutes, and 111 at 12 minutes; p<0.001) (Figure 1). Conclusions: A 3-minute withdrawal time leads to an unacceptably high AMR. A 6minute withdrawal time is more appropriate for colorectal cancer screening. Location did not affect AMR; however, adenomas that were ≤5mm were more likely to be missed in the 3-minute withdrawal group. Further research into the optimal withdrawal time, including evaluation of withdrawal times longer than 6 minutes, is warranted.

Understanding the Interpretation of Disease Incidence and Prevalence

One of the main goals in epidemiology is to describe the disease of interest, quantify the frequency of the disease, and study the risk factors and potential causes of the disease. “Measures of occurrence,” which are used to describe frequency of diseases, are the descriptive values in clinical epidemiology that describe events or outcomes, such as mortality or morbidity. Two of the main measures of occurrence that are used in the field of epidemiology are “incidence” and “prevalence.” These types of measures of occurrence are used in different ways by experts from various backgrounds. Clinicians can use incidence and prevalence in direct patient care to describe the frequency of a disease of interest, to help predict the course of a patient, and to estimate an individual’s risk for a disease and its complications. Public health professionals can use incidence and prevalence to describe the conditions and burden of a disease of interest, to identify the areas/conditions/disease where resources should be directed, and to compare between patients, subgroups of population, and finally, health care systems. Finally, researchers can use incidence and prevalence to compare diseases and define clinical outcomes in studies. In this chapter, we will discuss the basics of incidence and prevalence, which are essential to the comprehension and interpretation of different indices of disease frequency.

Su1817 EUS Features of Chronic Pancreatitis Do Not Correlate With Pathologic Findings of Abnormal Parenchyma in High-Risk Pancreas Cancer Patients Undergoing Pancreatic Resection

Background: The success of pancreatic cancer (PC) surveillance depends to a large extent on the commitment of participants to adhere to the repeated follow-up investigations. Though the results of our recently conducted retrospective study showed that the burden of PC surveillance is acceptable, a prospective assessment was warranted to document the mental and psychological impact of PC screening. We aimed to investigate possible changes in cancer worries and levels of anxiety and depression in high-risk individuals participating in a PC surveillance program. Methods Eligible for this prospective questionnaire study were high-risk individuals participating in our multicenter nationwide endoscopic ultrasound (EUS)-MRI-based PC-surveillance study. High-risk individuals were those with a strong family history of PC or carriers of PC-prone gene mutations. Questionnaires, administered both before (pretest) and after (posttest) the baseline PC screening investigations, assessed concerns about developing cancer (CancerWorry Scale), and levels of anxiety and depression (Hospital Anxiety and Depression scale). Results Of the 54 high-risk individuals, 47 (87%) completed both the pretest and posttest questionnaires (38% male, mean age= 52 yr., range 20-74 yrs.). Of these, 44 participated in the PC screening and 3 declined. All participants underwent both EUS and MRI. Prior to undergoing PC screening, 36% of the participants reported being fearful about undergoing EUS, whereas 5% was fearful about the MRI. After screening, 2.3% of all participants feared the next EUS (p<.001) and 2.3% the next MRI. The mean level of depression was significantly higher prior to screening as compared to after screening (p<.001). However, the number of participants with clinical levels of anxiety and/ or depression was low (n=5) and remained stable over time. Prior to, as well as after screening the most frequently reported worries were about the possibility of developing cancer themselves (29% at both time points) and the chance that relatives would develop cancer (19% and 21%, respectively). The 3 individuals who did not undergo screening indicated that they were not very fearful of the MRI or EUS. They also had low levels of anxiety, depression and cancer worries. Conclusion: The results of this prospective study indicate that: (1) the expected burden of EUS is higher than the actual experienced burden; and that (2) mean levels of anxiety, depression and cancer worries are not significantly influenced by participating in the PC screening program. This finding is of great importance for this group that is at high risk of developing pancreatic cancer and might benefit from participation in a life-long repeated PC surveillance program.