443 Chronic Cough is Associated with Large Breaks in Esophageal Peristaltic Integrity on High Resolution Manometry (HRM), With Suboptimal Therapeutic Outcome

differences in short and long term health outcomes(table 1). In a sub analysis we compared the effect of only thiopurine(and 5-asa) use on the child with children not exposed to IBD drugs or 5asa only. In total, 53 were only exposed to thiopurines(10(18.9%)with 5asa) and 80 children to 5asa(38(47.50%)) or no IBD drugs (42(52.5%)). There were no significant differences in short and long term outcomes between the two groups. For both analysis disease activity rate, folic acid use and number of mothers breastfeeding were not significantly different between the compared groups(table2). Conclusion This prospective study showed no difference in short and long term health outcomes between children with intrauterine thiopurine-exposure and children without thiopurine exposed during pregnancy.

442

Background: Physicians frequently encounter patients with immune mediated diseases and a history of malignancy. There are limited data on the safety of immunosuppressive therapy in this setting. Published studies have been small with few events, precluding robust estimates of risk. Methods: We searched Medline, EMBASE, and conference proceedings for terms related to immune mediated disease, immunosuppressive therapy and cancer recurrence from inception to April 2015. We included 16 studies (rheumatoid arthritis (RA)-8, inflammatory bowel disease (IBD)-8, psoriasis-1) and stratified studies by immunosuppressive exposure (monoclonal antibodies to tumor necrosis factor a (anti-TNF), conventional immunomodulator (IMM) or no immunosuppression (no IS)). A random effects meta-analysis was performed to calculate pooled incidence rates as well as risk differences between the various treatments. Results: Our analysis included 11,702 persons contributing 31,258 person-years (p-y) of follow up after prior cancer diagnosis. There were 1,698 instances of a new primary or recurrent cancer. Rates of cancer recurrence were similar across patient groups: anti-TNF therapy 33.8/1000py, immunomodulator therapy 36.2/1000 p-y, and no immunosuppression 37.5/1000 p-y, and was numerically higher for combination immunosuppression (54.5/ 1000 p-y) (p > 0.1 for all) ( Figure). The pooled incidence rates of new cancers were not statistically different between the no IS (24.9 / 1000 p-y; 95% CI 5.6 - 44.3), anti-TNF (28.8 / 1000 p-y; 95% CI 7.6 - 50.0) and IMM (38.4 / 1000 p-y; 95% CI 12.2 - 64.6) groups respectively though the latter had numerically the highest rates. We also observed similar rates of new or recurrent cancer with thiopurines (37.9 per 1,000 p-y, 95% CI 5.9 - 69.9) compared to methotrexate (38.9, 95% CI 14.7 - 63.0) (p=0.78). Among the two studies that included index skin cancer alone, the risk of new or recurrent cancers was statistically significantly greater with IMM (71.6 per 1000 p-y, 95% CI 58.9 - 84.2) when compared to no IS (50.8 per 1,000 p-y, 95% CI 43.7 - 57.8) and numerically (but not statistically) higher with anti-TNF therapy (55.5 per 1,000 p-y, 95% CI 44.7 - 66.3). In contrast, excluding studies with skin cancer as the index malignancy yielded similar rates of new or recurrent cancer with IMM (26.3 per 1,000 p-y, 95% CI 13.3 - 39.3), anti-TNF (24.3 per 1,000 p-y, 95% CI 16.0 - 32.5) or no IS (31.2 per 1,000 p-y, 95% CI 7.9 - 54.5). Conclusion: Similar rates of cancer recurrence in individuals with prior cancer were observed with no immunosuppression, anti-TNF, immunomodulator or combination therapy in this meta-analysis.

441 Live Birth and Adverse Birth Outcomes in Women With Ulcerative Colitis Receiving Assisted Reproduction - A 20 Year Nationwide Cohort Study Bente M. Nørgård, Pia V. Larsen, Jens Fedder, Punyanganie S. de Silva, Sonia Friedman Objective The incidence of ulcerative colitis (UC) is increasing and coincides with the childbearing years. Denmark has one of the highest incidence rates worldwide (23 per 100,000 annually), especially among women and men aged 15-29. Fertility in women with UC is affected by surgery, particularly the ileoanal pouch anastomosis, and may also be affected by increased disease activity. There is little evidence of the impact of UC on the efficacy of assisted reproductive technology (ART). In this study, we examine the efficacy of ART in women with UC compared to women without UC and also examine the effect of UC on birth outcomes following ART. We also assess the impact of prior UC surgery. Design We performed a nationwide cohort study based on the Danish health registries during the period from January 1 1994 to December 31 2013. Our primary outcome was live birth; the exposed cohort comprised all ART treatment cycles in women with UC and the unexposed cohort comprised all ART treatments in women without UC. ART treatments consisted of in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and/or frozen embryo replacement (FER). Our secondary outcome was adverse birth outcomes; the exposed cohort comprised all children conceived via ART treatment by women with UC and the unexposed cohort comprised all children conceived through ART treatment by women without UC. We adjusted for comorbidities, age, type of treatment (IVF, ICSI, FER), fertility factor and the lifestyle factors of BMI, partner's age, smoking, and alcohol. Results In all, 1,360 transfers were performed in 432 UC women and 149,094 transfers in 52,661 nonUC women. The median age of UC women at embryo transfer was 33 years and the median disease duration was 8 years. Surgery had been performed prior to the transfer in 34.5% of UC women. The chance of having a live birth was significantly decreased in UC women (crude odds ratio (OR) = 0.79, 95% CI: 0.67-0.93). The ORs were virtually unchanged across two different models of adjustment (in the full model, OR = 0.73, 95% CI: 0.580.92). The risk of preterm birth was OR=5.00 (95% CI: 2.30-10.88) in analyses including both singletons and multiple births, and the OR was 1.83 (95% CI: 0.51-6.54) when restricted to singleton births. The OR for live birth per cycle in UC women with prior surgery compared to UC women with no prior surgery was close to unity (OR=0.97, 95% CI: 0.59-1.61). Conclusion In this first population-based study of ART in women with UC, we find that the chance of a live birth per embryo transfer in women with UC receiving ART is significantly decreased and the risk of preterm birth increased. UC surgery before ART treatment did not negatively impact the chance of live birth. This negative impact of UC on the success of ART should help guide treatment decisions regarding timing of attempts at conception.

Forest Plot of Risk of recurrence of cancer or development of new primary by type of immunosuppression in individuals with a prior history of cancer

443 Chronic Cough is Associated with Large Breaks in Esophageal Peristaltic Integrity on High Resolution Manometry (HRM), With Suboptimal Therapeutic Outcome Michael Bennett, Amit Patel, Nitin Sainani, Dan Wang, Gregory S. Sayuk, C. Prakash Gyawali Background: Breaks in the peristaltic contour predict bolus retention in the esophagus, and can potentially prolong reflux exposure. Limited data suggest a relationship between cough and long breaks, but this is incompletely characterized. We evaluated the relationship between esophageal symptoms, reflux exposure, and peristaltic breaks on high resolution manometry (HRM) in a large prospective cohort. Methods: Patients undergoing both pHimpedance testing and esophageal HRM for persisting reflux symptoms over a 5-yr period were prospectively evaluated. Demographics, symptom presentation, antisecretory treatment status on testing, acid exposure time (AET), symptom association probability (SAP), and symptom burden assessed with dominant symptom intensity (DSI, product of symptom severity and frequency on 5-point Likert scales) and global symptom severity (GSS, global

S-93

AGA Abstracts

AGA Abstracts

Cancer Recurrence With Immunosuppressive Therapy in Immune Mediated Diseases: A Systematic Review and Meta-Analysis Edward Shelton, David Laharie, Frank I. Scott, Ronac Mamtani, James Lewis, JeanFrederic Colombel, Ashwin N. Ananthakrishnan

AGA Abstracts

esophageal symptoms on 100-mm visual analog scales) were collected. Patients were prospectively contacted for follow-up; outcomes were assessed using changes in DSI and GSS. A blinded author reviewed HRM studies for the presence and length of breaks in the peristaltic contour of individual swallows; breaks ‡5 cm were considered large (Chicago Classification v3.0). Relationships between breaks, reflux parameters, presenting symptoms, and outcomes were assessed. Results: 218 patients (53.2±0.9 yr, 68.3% F) were included; presenting symptoms, allowing for overlaps, included heartburn (140, 64.2%), regurgitation (106, 48.6%), chest pain (67, 30.7%), cough (78, 35.8%), dysphagia (38, 17.4%), and ENT symptoms (24, 11.0%). The presence of large breaks was not associated with age, gender, race, PPI status on testing, elevated AET, positive SAP, or changes in symptom metrics (p‡0.1 for all comparisons). However, patients with large breaks were more likely to have cough as a presenting symptom than those without (43.4% vs. 28.6%, OR 1.9, 95% CI 1.1-3.4, p=0.02); this association was not significant for any of the other symptoms (p ‡0.3). The presence of small breaks £5 cm was not associated with any symptom (p ‡0.3). Numbers of swallows with large breaks were higher in patients with cough (median=1, IQR 0-4.3) compared to those without (0, IQR 0-2; p=0.02); differences were not found with other symptoms (p‡0.4). 159 patients were successfully contacted to assess symptom outcome. Independent of reflux parameters, the presence of large breaks with cough as a presenting symptom predicted less profound decline in DSI with antireflux therapy (4.9±0.9) compared to absence of large breaks (8.9±1.4, p=0.02); this did not hold true for other symptoms (p‡0.2). Conclusions: Chronic cough frequently associates with large breaks on esophageal peristaltic contours, which predicts suboptimal response to antireflux therapy when present. We speculate proximal esophageal stimulation from luminal content as a mechanism.

Fig 2. EndoFLIP derived mCSA in patients with/without strictures.

445 Quantifying the LES and Crural Diaphragm Elements of the Esophagogastric Junction (EGJ) in GERD Patients With Novel 3D-HRM Metrics Yinglian Xiao, Zhiyue Lin, John Pandolfino, Min-hu Chen, Peter Kahrilas

444 Direct Versus Indirect Methods for Detecting Pharyngeal Outflow Obstruction in Dysphagia Following Head and Neck Cancer Peter Wu, Michal Szczesniak, Maclean Julia, Harry Quon, Jolyne O'Hare, Peter Graham, Lennart Choo, Teng G. Zhang, Taher Omari, Ian J. Cook

Background: Dysfunction of anti-reflux barrier is a primary mechanism of GERD. However, the EGJ is complex with contractile elements attributable to both the crural diaphragm (CD) and lower esophageal sphincter (LES) and, apart from the condition of hiatus hernia, their contributions to EGJ pressure cannot be resolved with conventional manometry, highresolution or not. 3D-HRM potentially improves on this by providing a 360° representation of the EGJ in which the diaphragmatic hiatus (DH) has a distinct pressure signature characterized as an inverted V with the apex of the V (DHA) corresponding to maximal CD contact. We developed two novel 3D-HRM metrics to quantify the LES and CD elements of EGJ pressure. This study aimed to compare these novel metrics in GERD patients and controls. Methods: Twenty healthy subjects (13F) and 14 patients (3F) with GERD defined by either esophagitis on upper endoscopy or pathologic acid exposure during 24-hour pH monitoring were studied. All subjects underwent pH monitoring and HRM using a 3D-HRM catheter with 32 standard HRM sensors and a 9-cm 3D segment composed of 12 rings of 8 radially independent pressure sensors spaced 7.5 mm apart straddling the EGJ (Given Imaging). Two novel 3D-HRM metrics of the EGJ, 3D-DHA and 3D-LESP, were calculated during three consecutive respiratory cycles at rest. 3D-DHA was a contractile integral value for a square box centered on DHA that is 180° (4 radial sectors) x 2.25 cm and referenced to intragastric pressure (IGP). After dividing by 2.25 cm and 4 sectors, the resultant 3D-DHA value was expressed as mmHg.cm.sector. The 3D-LESP value, calculated at each time as the maximum of the minimal radial pressure at each of 3D axial levels was also referenced to IGP as the best approximation of the LES component at each time (Figure 1). Median 3D-DHA and 3D-LESP values during three respiratory cycles were reported for each study. These two metrics were computed by exporting data and applying a custom MATLAB program. Variable differences between two groups were compared using Wilcoxon rank sum tests. Results: Representative 3D-HRM panoramic snapshots of the EGJ in both GERD and healthy controls are shown in Figure 1. Shown in Table 1, both the median 3D-LESP and the median 3D-DHA were significantly lower in GERD patients than in healthy subjects (p<0.05). Conclusions: We have devised novel 3D-HRM metrics to quantify the LES (3DLESP) and CD (3D-DHA) elements of EGJ contractility at rest. Both the median 3D-LESP and 3D-DHA values were significantly lower in well-defined GERD patients than in control subjects. These two novel 3D-HRM metrics may provide a better scheme to interrogate EGJ functional integrity and classify mechanisms of dysfunction. Further studies are required to validate these metrics in other patient populations. Table 1 Comparison of median (IQR, interquartile range) of 3D-HRM metrics of the EGJ in 14 patients with GERD and 20 healthy subjects

Background: Chemo-radiotherapy in the treatment of Head and Neck Cancer (HNC), with/ without laryngectomy, commonly causes dysphagia. Pharyngo-Esophageal Junction (PEJ) stricture is an important contributor. While video fluoroscopy (VF) is the standard diagnostic test, its diagnostic accuracy in detecting PEJ stricture has never been systematically evaluated. Aim: To evaluate and compare the diagnostic accuracy of videofluoroscopy and Endolumenal Functional Lumen Imaging Probe (EndoFLIP) in detecting PEJ strictures in patients with dysphagia following HNC therapies. Methods: We prospectively studied 33 consecutive patients with persistent (>12 months) dysphagia following radiotherapy for HNC who were undergoing endoscopic dilatation for suspected PEJ strictures. In this study, our gold standard for PEJ stricture was the identification of a mucosal tear at the PEJ upon re-inspection following endoscopic dilatation (Savary-Gilliard). All patients underwent VF before dilatation and radiographic data were analysed in 2 ways: 1) presence of a stricture was determined by three experienced blinded investigators; 2) a blinded observer objectively measured the narrowest diameter of the PEJ in sagittal projection when the pharynx was maximally distended during VF. In 22/33 (67%) of patients EndoFLIP measurements were performed under sedation pre- and post-dilatation at the index endoscopy. EndoFLIP utilises impedance to determine the narrowest cross-sectional areas (mCSA) across an 8-cm long fluid-filled bag during distension within the PEJ. Results: The concordance among the 3 observers in identification of strictures was very poor with an intra-class correlation of 0.06, 95% CI [0.13, 0.29] (p=ns), with complete agreement achieved in only 10 of 33 patients. The radiologically-defined mean narrowest sagittal PEJ diameter did not differ between patients with and without strictures (6.5mm vs. 7.9mm; p=0.09) (Fig 1). The optimal diagnostic sensitivity and specificity of VF in detecting strictures at a cut-off of 8.2mm was 0.76 and 0.58 respectively. EndoFLIP measured mCSA was significantly lower in patients with stricture than those without (66.4mm2 vs. 176.6mm2; p<0.01) (Fig 2). Diagnostic accuracy of the mCSA at the PEJ assessed using ROC analysis gave an area under the curve of 1. A cut-off of 118mm2 (12.3mm diameter) yields a sensitivity and specificity both at 100%. In patients with strictures, a single dilatation session resulted in an average 54% increase in the mCSA (p<0.01). In patients without strictures (ie no demonstrable mucosal tear), dilatation caused no change in the mCSA (0%; p=ns). Conclusions: Videofluoroscopy has very poor accuracy in detecting PEJ strictures in HNC survivors with dysphagia. EndoFLIP is a highly accurate technique for the detection of PEJ strictures and sufficiently sensitive to detect changes following a single dilatation.

IGP, intragastric pressure; LESP, lower esophageal sphincter pressure; 3D-DHA, contractile integral value for DHA component referenced to IGP.

Fig 1. VF derived sagittal PEJ diameter in patients with/without strictures. Figure 1 Representative 3D-HRM panoramic snapshots of the EGJ in a GERD patient (left panel) and in a healthy control (right panel). The dashed red box is the area for calculating

AGA Abstracts

S-94