Faculty Bibliography

OBJECTIVES/OBJECTIVE:Our aim was to identify baseline characteristics associated with disease progression and malignant transformation in low-risk suspected intraductal papillary mucinous neoplasms (IPMNs). METHODS:This is a retrospective cohort study of prospectively maintained databases of pancreatic cysts at 3 international, academic institutions. Five hundred fifty-nine adult patients with clinically suspected asymptomatic IPMN evaluated by radiologic studies or endoscopic ultrasound between 2003 and 2013 without worrisome features and under surveillance for 12 months or longer were included. We evaluated the relationship of baseline demographics and cyst features to disease progression (size increase, development of worrisome features, or high-grade dysplasia/cancer). RESULTS:After a median of 44 months follow-up, 269 (48%) patients experienced cyst size increase, 68 (12%) developed worrisome features, and 11 (2%) developed high-grade dysplasia/cancer. In multivariable Cox-regression analysis, no baseline characteristics were associated with size increase. An initial cyst size of 2 cm or greater, multifocality, history of prostate cancer, and smoking were the strongest predictors of development of new worrisome features. Univariable analysis found male sex, diabetes, and recent weight loss associated with development of high-grade dysplasia/cancer. CONCLUSIONS:Our study demonstrates that low-risk suspected IPMNs carry a small but clinically relevant risk of disease progression and provides data on baseline characteristics that may help in risk stratification.

BACKGROUND AND AIMS/OBJECTIVE:Our goal was to compare the diagnostic accuracy of FISH in the detection of malignancy compared with other standard diagnostic modalities, including brush cytology and biopsy specimens over a 10-year period of prospective data collection. METHODS:We conducted a review of all consecutive biliary strictures evaluated between 2006 and 2016. Patients with a final pathologic diagnosis or conclusive follow-up were included. We evaluated the performance of FISH polysomy (CEP 3, 7, and 17) and 9p21 deletion as well as cholangioscopic biopsy (CBx) and EUS-FNA. Statistical analysis was performed with the Mann-Whitney U and Fisher's exact tests. RESULTS:Of 382 patients with indeterminate strictures, 281 met inclusion criteria. Forty-nine percent were malignant. Cytology, FISH polysomy, and FISH polysomy/9p21 showed a specificity of 99.3%. FISH polysomy/9p21 as a single modality was the most sensitive at 56% (p < 0.001). The sensitivity of FISH polysomy/9p21 and cytology was significantly higher than cytology alone at 63 versus 35% (p < 0.05). EUS-FNA for distal strictures and CBx for proximal strictures increased sensitivity from 33 to 93% (p < 0.001) and 48-76% (p = 0.05) in cytology-negative strictures. CONCLUSIONS:The high specificity of FISH polysomy/9p21 suggests that a positive result is sufficient for diagnosing malignancy in indeterminate strictures. The significantly higher sensitivity of FISH polysomy/9p21 compared to cytology supports the use of FISH in all non-diagnostic cases. Although both EUS-FNA and CBx were complimentary, our results suggest that distal strictures should be evaluated by EUS initially. Proximal strictures may be evaluated by FISH first and then by CBx if inconclusive.

BACKGROUND & AIMS/OBJECTIVE:It is a challenge to detect malignancies in biliary strictures. Various sampling methods are available to increase diagnostic yield, but these require additional procedure time and expertise. We evaluated the combined accuracy of fluorescence in situ hybridization (FISH) and polymerase chain reaction-based DNA mutation profiling (MP) of specimens collected using standard brush techniques. METHODS:We performed a prospective study of 107 consecutive patients treated for biliary strictures by endoscopic retrograde cholangiopancreatography from June 2012 through June 2014. We performed routine cytology and FISH analyses on cells collected by standard brush techniques, and analyzed supernatants for point mutations in KRAS and loss-of-heterozygosity mutations in tumor-suppressor genes at 10 loci (MP analysis was performed at Interpace Diagnostics). Strictures were determined to be nonmalignant based on repeat image analysis or laboratory test results 12 months after the procedure. Malignant strictures were identified based on subsequent biopsy or cytology analyses, pathology analyses of samples collected during surgery, or death from biliary malignancy. We determined the sensitivity and specificity with which FISH and MP analyses detected malignancies using the exact binomial test. RESULTS:Our final analysis included 100 patients; 41% had biliary malignancies. Cytology analysis identified patients with malignancies with 32% sensitivity and 100% specificity. Addition of FISH or MP results to cytology results increased the sensitivity of detection to 51% (P < .01) without reducing specificity. The combination of cytology, MP, and FISH analyses detected malignancies with 73% sensitivity (P < .001). FISH identified an additional 9 of the 28 malignancies not detected by cytology analysis, and MP identified an additional 8 malignancies. FISH and MP together identified 17 of the 28 malignancies not detected by cytology analysis. CONCLUSIONS:Addition of FISH and mutation analyses to cytology analysis significantly increased the level of sensitivity with which we detected malignancy in biliary strictures, with 100% specificity. These techniques can be performed using standard brush samples collected during endoscopic retrograde cholangiopancreatography, with mutations detected in free DNA in supernatant fluid of samples. The tests are complementary and therefore should be used sequentially in the diagnostic evaluation of biliary strictures.

Background and Study Aims: Fluorescent in-situ hybridization (FISH) performed on brush specimens is one of the most accurate and widely used second line diagnostic modalities. Our goal was to compare the diagnostic accuracy of FISH in the detection of malignancy compared with other standard diagnostic modalities, including brush cytology and biopsy specimens over a ten year period of prospective data collection. Patients and methods: We conducted a review of a prospectively maintained database of biliary strictures between 2006 and 2016. Patients with a final pathologic diagnosis or a conclusive follow-up were included. Cytology and biopsy results were considered positive for malignancy when suspicious or malignant cells were identified. We evaluated the performance of FISH polysomy (CEP 3, 7, and 17) and 9p21 deletion. Statistical analysis was performed with the Chi square and Fisher exact tests. Results: Of 382 who underwent evaluation for biliary strictures, 277 met inclusion criteria. 119 patients (42.8%) were found to have malignancy (58.0% pancreatic cancer, 37.0% cholangiocarcinoma, 5.0% other malignancies). Benign etiology included inflammatory strictures (63.9%), PSC (19.6%), post-operative (6.3%) or other benign etiologies (10.2%). The sensitivities for FISH and cytology were found to be 55.4% and 39.0%. Both cytology and FISH showed a very high specificity of 99.4%. The accuracy and AUC of FISH polysomy and cytology (AUC=.789) was significantly higher than cytology alone (AUC=.688; p<0.05). The addition of detection of 9p21 deletion led to no additional false positives but an additional diagnosis of 11/119 (9.2%) malignant cases, however there was a nonsignificant difference in the accuracy and AUC of FISH polysomy versus FISH polysomy plus 9p21 deletion. The combination of brush cytology, FISH polysomy and 9p21 deletion and any additional sampling (i.e. biopsy) taken during ERCP showed a sensitivity of 70.0% that was not significantly higher than cytology plus FISH polysomy. There were 36 (30.3 %) patients who had malignancies that were undetected by any of the diagnostic modalities studied. Conclusion: This is the largest prospective cohort of patients with biliary strictures evaluated by FISH. The very high specificity of FISH polysomy and 9p21 deletion suggests that a positive result is sufficient for the diagnosis of biliary malignancy. A limitation of our data is the relatively small number of PSC patients where specificity may be lower. The significantly higher sensitivity of both FISH polysomy and polysomy or 9p21 deletion compared to cytology and the non-significant improvement in sensitivity when combing further sampling methods supports the use of FISH as first line in the evaluation of cytology negative strictures. (Table Presented)

LEARNING OBJECTIVE #1: Recognize the inciting factors of orthodeoxia with a patent foramen ovale. CASE: An 82 year-old presented with acute onset hypoxia upon extubation after a laparoscopic gastrectomy. She had positional episodes of desaturation to 79% when sitting up, with other vitals signs normal and no dyspnea. Her oxygen saturation was 91% on 2L nasal cannula when supine. Her lungs were clear to auscultation bilaterally. PaO2 was 45mmHg on roomair and increased to only 74 mmHg with 100% O2. Initial transthoracic echocardiogram with bubble study demonstrated a patent foramen ovale (PFO) with normal right atrial and pulmonary artery pressures and function. She had a stable 4.1 cm ascending thoracic aortic aneurysm and multiple, stable hepatic cysts. She was diagnosed with Platypnea-Orthodeoxia Syndrome (POS) due to PFO and underwent successful percutaneous transfemoral closure of the defect. Upon discharge, she was saturating 97% on room air, regardless of position. IMPACT: While PFOs can be seen in up to 29% of the general population, orthodeoxia is much more rare, with less than 200 cases described in the literature. With the elderly population increasing, the incidence of aortic aneurysms and other cardiovascular conditions distorting previously silent PFOs may increase as well, so it is important to maintain a high index of suspicion and perform the gold standard diagnostic test early: echocardiography with bubble study. DISCUSSION: Orthodeoxia, or the arterial deoxygenation that accompanies the positional change from supine to erect, requires two conditions to coexist: an anatomical component (interatrial communication such as a patent foramen ovale [PFO] or atrial septal defect [ASD]) and a functional component that redirects shunted blood flow through the atrial septum. These functional defects can either preferentially direct blood flow through the anatomical defect or cause a transient increase in right atrial pressure, reversing the leftright gradient. The former can be caused by conditions that direct the jet of deoxygenated blood through the interatrial communication by repositioning the atrial septum, such as an ascending aortic aneurysm, intracardiac lipoma, hepatic cyst distorting the right atrium, or aortic valve replacement. Conditions which transiently increase right sided pressures include pulmonary embolism, pulmonary hypertension, pericardial effusion, pneumonectomy, chronic obstructive pulmonary disease and constrictive pericarditis. Measured right sided pressures are typically normal in POS. The pathophysiology in our patient is likely due to her thoracic aortic aneurysm, elongating in the erect position and stretching the interatrial septum and PFO. While a possibility, it is unlikely her hepatic cysts contributed to her presentation as they were small and there has only been one case report of a large liver cyst causing this presentation

Introduction: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that carry a risk of malignant transformation to pancreatic ductal adenocarcinoma (PDAC). Guidelines have been evolving to best identify which criteria should qualify a patient for resection and which cysts can safely remain under surveillance. Our aim was to understand which baseline cyst and patient features predict disease progression and malignant transformation. Aims & Methods: Patients with clinically suspected IPMN who did not meet consensus criteria for resection at diagnosis and were surveyed for at least 12 months or underwent surgery after a minimum surveillance of 3 months were included. All patients evaluated by radiologic studies or endoscopic ultrasound between 1998 and 2015 were included. We defined progression as either an increase in size of the dominant cyst >=20% or >=2mm or the development of worrisome features (mural nodule or mass, thick septations, main duct involvement or high grade dysplasia or cancer on cytology or surgical pathology). Statistical analysis was performed with the Chi square and Fisher exact tests for categorical variables and Mann-Whitney U test for continuous variables. All covariates of interest with p<0.05 in the univariate analysis were included in the logistic regression model. Result: male gender, a history of prostate cancer and diabetes, weight loss and initial cyst size >2 cm. A history of prostate cancer, diabetes, weight loss, elevated cyst fluid CEA and cyst size >2 cm were associated with development of worrisome features. In logistic regression analysis, a history of prostate cancer (OR 2.9; 95% CI 1.7-7.7) and weight loss (OR 2.47; 95% CI 1.18-6.1) were associated with development of worrisome features (p<0.05). There were no baseline predictors of cyst size increase alone. Baseline characteristics such as race, smoking or alcohol use, a strong family history of PDAC, multifocality and location of cysts were not associated with increased disease progression. Conclusion: In the largest multicenter surveillance study of low risk IPMNs to date, we showed that 41% of suspected IPMNs increased in size only, 9% developed worrisome features and 2% developed high-grade dysplasia or cancer. Among baseline characteristics, none were predictive of size increase. A personal history of prostate cancer and weight loss were the strongest predictors of the development of worrisome features. (Table Presented)