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Abstract The lymphocyte-to-monocyte ratio at diagnosis (LMR-D) has been reported to be a prognostic factor for clinical outcomes in both T-cell and B-cell lymphomas. However, there are no reports testing the prognostic ability of LMR-D in patients diagnosed with de novo double/triple hit diffuse large B cell lymphoma (DLBCL). Thus, we set out to investigate if the LMR-D is a prognostic factor for survival in de novo double/triple hit lymphomas. From 10/5/1998 until 1/16/2015, thirty-four patients with de novo double/triple hit DLBCL were identified for this study. Double and triple hit were defined by interphase FISH evaluating three fusion signals to identify the BCL2 translocation and IGK/MYC D-FISH probe to identify whether the partner is IG or non-IG. Interphase fluorescence in situ hybridization (FISH) was performed on paraffin sections using probes that included 8q24 (5'MYC, 3'MYC); t (2;8), IGK/MYC; t(8,14), MYC/IGH; t(8;22), MYC/IGL; 3q27 (3'BCL6, 5'BCL'6); and 18q21 (3'BCL2, 5'BCL2). The cohort included 14 females and 20 males. The median follow-up for the cohort was 9.0 months (range: 0.4-72.6 months). Using the median for the LMR-D as the cut-off value, patients with a LMR-D ≥ 1.2 experienced superior overall survival (OS) [Hazard ratio (HR) of 0.127, 95% confidence interval (CI) of 0.019-0.530, p < 0.004] and progression-free survival (PFS) [HR of 0.107, 95 CI of 0.024-0.335, p < 0.0001]. The median follow up for OS for patients with a LMR-D ≥ 1.2 was not reached with a 5-year OS rate of 82% (95% CI of 49%-95%) compared with a median follow-up of 10 months for patients with a LMR-D < 1.2 with a 0% 5 year OS rate, p < 0.003 (Figure 1A). The median PFS for patients with a LMR-D ≥ 2 was not reached with a 5 years PFS of 74% (95%CI, of 43%-91%) compared with a median follow-up of 4.7 months for patients with a LMR-D < 1.2 and 0% 5 year PFS rate, p < 0.0001 (Figure 1B). After adjusting for the International Prognostic Index, multivariate analysis showed that the LMR-D remained an independent prognostic factor for OS [HR = 0.180, 95% CI of 0.254-0.784, p < 0.02] and for PFS [HR of 0.127, 95%CI of 0.029-0.409, p < 0.0003]. In spite of the small cohort of de novo double/triple hit DLBCL, the LMR-D was identified as a prognostic factor for clinical outcomes for this specific set of aggressive lymphomas. Further studies are warranted to confirm our findings. Table.LMR-D ≥ 1.2, N = 18Events = 2LMR-D < 1.2, N = 16Events = 8P < 0.003LMR-D ≥ 1.2, N = 18Events = 3LMR-D < 1.2, N = 16Events = 14P < 0.0001Figure 1AB Figure 1. Figure 1. Disclosures Maurer: Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Off Label Use: New agent in a combination regimen..

Abstract Background Outcomes for patients with DLBCL have improved over the past decade, with the addition of rituximab to CHOP or CHOP-like multi-agent chemotherapy regimens improving the 3-year overall survival (OS) of patients by 10-16% compared to multi-agent chemotherapy alone (Coiffier 2002; Pfreundschuh 2010). However, patients with high-intermediate or high-risk disease have relatively poor outcomes with the standard RCHOP regimen (Ziepert 2010); in a recent prospective trial of intermediate- and high-risk DLBCL patients, complete response (CR) rate for RCHOP alone was 26% (Hainsworth 2011). Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising the antibody cAC10, specific for human CD30, covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Brentuximab vedotin has demonstrated compelling activity as a single agent in patients with relapsed or refractory DLBCL, even those with low CD30 expression (Bartlett 2013). This phase 2, randomized, open label study is designed to evaluate the antitumor activity and safety of brentuximab vedotin (1.2 or 1.8 mg/kg) when administered in combination with standard RCHOP chemotherapy (A+RCHOP) for the front-line treatment of patients with CD30-unselected high-intermediate/high-risk (standard IPI score 3–5 or age-adjusted IPI [aaIPI] score 2–3) DLBCL (ClinicalTrials.gov NCT01925612). Methods Patients were randomized to receive up to 6 cycles of either 1.2 or 1.8 mg/kg brentuximab vedotin administered IV on Day 1 of every 21-day cycle in combination with RCHOP; prednisone was administered orally on Days 1-5 of every 21-day cycle. Assessments included disease response per Cheson 2007, as evaluated by the investigator, surveillance of adverse events (AEs), physical examination findings, and laboratory testing. The primary endpoints for this study are the CR rate at the end of treatment (EOT) and the type, incidence, and severity of AEs. Key secondary endpoints include objective response rate (ORR), progression-free survival (PFS), and OS. Results At the time of the planned interim analysis, 33 patients were enrolled (17 patients, 1.2 mg/kg A+RCHOP; 16 patients, 1.8 mg/kg A+RCHOP). Median age for all patients was 66 years (range, 21 to 81). At baseline, 36% were high-risk (IPI 4-5, aaIPI 3) and 64% were high-intermediate risk (IPI 3, aaIPI 2). The majority of patients (73%) had Stage IV disease and 33% had an ECOG status of 2. At the time of interim analysis, a total of 12 patients (6 patients in each arm) had completed EOT. Across both dose levels, ORR was 92% (11/12), with 7 CRs (58%), 4 PRs (33%), and 1 PD. The patient with PD subsequently died. Patients with PR had a median reduction of baseline tumor size of 84% (range, 92% to 83%), as measured by SPD. The only patient with follow-up after EOT converted from PR to CR without subsequent therapy. Treatment-emergent AEs occurring in ≥30% of patients treated (26/33) were nausea, diarrhea, peripheral sensory neuropathy, fatigue, and decreased appetite. Grade 3 or higher events occurring in more than 2 patients were febrile neutropenia and neutropenia. Events of peripheral neuropathy occurred equally per arm (46%, 1.2 mg/kg A+RCHOP; 46% 1.8 mg/kg A+RCHOP) and were generally Grade 1 or 2 (15% and 23%, respectively); events were of similar grade across dose levels. The median time to onset of any grade of peripheral neuropathy was 6 weeks (range, 2 to 10 weeks). Five patients (19%) had dose reductions due to peripheral neuropathy and 3 patients (12%) had dose reductions due to febrile neutropenia. One patient who received 1.2 mg/kg A+RCHOP discontinued study drug due to an AE (thrombocytopenia). Conclusions At doses of 1.2 or 1.8 mg/kg, A+RCHOP exhibited manageable toxicity in the treatment of newly-diagnosed DLBCL; the incidence of peripheral neuropathy was similar to single-agent administration of brentuximab vedotin (Pro 2012, Younes 2012) and RCHOP alone (Rummel 2013, Flinn 2014). In 12 patients with response-assessable, high-intermediate and high-risk DLBCL, A+RCHOP showed encouraging antitumor activity, with an ORR of 92% and a CR rate of 58%. Disclosures Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. . Farber:Seattle Genetics, Inc.: Research Funding. Budde:Seattle Genetics, Inc.: Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding. Advani:Takeda Pharmaceuticals International Co.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Jansseen Pharmaceuticals: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Holkova:Seattle Genetics, Inc.: Research Funding. Halwani:Seattle Genetics, Inc.: Research Funding. Knapp:Takeda Pharmaceuticals International Co.: Research Funding; EMD Serono: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Merck: Research Funding; Heron Pharmaceuticals: Research Funding, Travel expenses, Travel expenses Other; Genentech: Research Funding, Travel expenses, Travel expenses Other; Seattle Genetics, Inc.: Research Funding; Pharmacyclics: Research Funding. Fayad:Seattle Genetics, Inc.: Consultancy, Research Funding. Kolibaba:Genentech: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Seetharam:Seattle Genetics, Inc.: Research Funding. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Bartlett:Genentech: Research Funding; ImaginAb: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Janssen: Research Funding; Astra Zeneca: Research Funding.

Abstract Abstract 689 Background: Lenalidomide was demonstrated to have significant single agent activity in relapsed aggressive B cell lymphoma (J Clin Oncol. 2008;26:4952–7, Ann Oncol. 2011;22:1622–7). In a phase I study, we previously demonstrated that Lenalidomide 25 mg day 1–10 of the cycle can be combined with RCHOP21 and this combination does not result in dose delays or increased toxicity (Leukemia 2011;12:1877–81). We now present phase 2 results of R2CHOP in treatment of patients with aggressive B-cell lymphoma. Methods: Eligible patients were adults with newly diagnosed CD20 positive diffuse large B cell (DLBCL) or grade 3 follicular lymphoma (FL). The response was evaluated using PET/CT by standard criteria (J Clin Oncol. 2007;25:579–586). The progression free survival (PFS) was defined as time from diagnosis to disease progression or death. Results: 51 patients - 6 enrolled at the MTD in phase 1 portion of the study and 45 in phase 2 portion were included in the analysis. The median age was 65 years (range, 19–87). 35% of patients were 70 and older. 63% (32/51) were males. 47 patients (92%) had DLBCL and 4 (8%) patients had FL grade 3. The international prognostic index (IPI) was low, low-intermediate, high-intermediate and high in 8 (15%), 18 (35%), 18 (35%) and 7 (14%) patients respectively. 31 patients (60%) had stage 4 disease. Hematological toxicities were: grade 3 and 4 thrombocytopenia (20% and 20% of patients respectively); grade 3 and 4 neutropenia (18% and 71% of patients respectively). Overall 27% of patients experienced a grade 3 or higher non-hematological toxicity at least possibly related to treatment. The most frequent were febrile neutropenia (10%), nausea (4%), urinary tract infection (4%), vascular access complication (4%), and dehydration (4%). 1 patient (2%) developed thrombosis. There was one death (2%) secondary to bowel perforation/sepsis. For 47 patients evaluable for response, the overall response (ORR) and complete response (CR) rates were 98% and 83% respectively. The PFS was 73% at 12 months (Figure). Since the enrolled patients represented a relatively high-risk group (49% intermediate high or high IPI, significant proportion of elderly male patients), the PFS in R2CHOP was compared to PFS in a contemporary cohort of 87 consecutive patients with DLBCL participating in Mayo Clinic Lymphoma Database and treated with standard RCHOP alone. The PFS was 62% at 12 months in this cohort and was inferior to R2CHOP (Figure). Conclusion: Lenalidomide combined with standard R-CHOP21 chemotherapy (R2CHOP) demonstrates predictable safety profile. The ORR and CR rates and PFS are encouraging in elderly high IPI patients, and compared favorably to the R-CHOP treated historical cohort with similar clinical characteristics. A randomized trial will be needed to confirm the benefits of this novel combination. Disclosures: Off Label Use: lenalidomide in treatment of NHL. Reeder:Celgene: Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding; Celgene Corporation: Consultancy.

Abstract Infused autograft absolute lymphocyte count (A-ALC) is a prognostic factor for survival post-autologous peripheral hematopoietic stem cell transplantation (APHSCT) for lymphoma. Myeloid-derived suppressor cells (MDSCs) affect tumor growth by suppression of host anti-tumor immunity. Thus, we set out to investigate if the infused autograft lymphocyte /monocyte ratio (A-LMR), as a biomarker of host immunity (i.e., lymphocytes) and MDSCs (i.e., monocytes), affects survival post-APHSCT in patients with classical Hodgkin lymphoma (cHL). Only patients that collected their stem cells through the peripheral blood were included in the study. From 1994 to 2012, 183 cHL patients qualified for the study. The 183 patients were randomly divided into a training set (n = 122) and a validation set (n = 61). Receiver operating characteristic and area under the curve (AUC) identified an A-LMR ≥ 1 as the best cut-off value (AUC = 0.8, p < 0.01) and validated by the k-fold cross-validation (AUC = 0.8) in the training set. Multivariate analysis showed A-LMR to be an independent prognostic factor for survival in the training set. Patients with an A-LMR ≥ 1.0 experienced a superior overall survival (OS) versus patients with an A-LMR < 1.0 (median OS was not reached vs 40.4 months, 5-year OS rates of 86% (95 CI, 72%-93%) vs 43% (95 CI, 28-58 %), p < 0.0001, respectively) in the training set. In the validation set, an A-LMR ≥ 1 showed a median OS of not reached vs 41.8 months for an A-LMR < 1, 5 year OS rates of 90% (95 CI, 73%-97%) vs 48% (95 CI, 29-68%), p < 0.0001, respectively. A-LMR provides a platform to engineer an immunocompetent autograft to improve clinical outcomes in cHL patients undergoing APHSCT. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 600 Background: Both MM and AL are plasma cell neoplasms. The underlying clone in both diseases appears to be different not only in terms of “tumor burden” but also in terms of their underlying biology. The overall “fitness” of patients with these two diseases is also different, with AL patients having more major organ dysfunction. Therapy for both diseases is directed at killing the underlying clone. ASCT is one method of reducing the clone size and thereby improving overall survival. Post-ASCT outcomes between the two diseases have never been formally compared. Methods: We compiled all patients with a diagnosis of AL or MM who received ASCT at the Mayo Clinic Rochester between June 1996 and January 2011 to compare outcomes. Patients were retrieved from two prospectively maintained clinical transplant data bases (M.A.G.). Differences between groups were compared using Fisher's exact and Wilcoxon tests. Survival was calculated using the method of Kaplan-Meier, and differences between survival outcomes were calculated by log rank. Cox regression modeling was done to determine how non-disease specific variables—i.e. age, time period of ASCT, number of prior regimens, time to ASCT from diagnosis and acquisition of complete response (CR)—affected outcomes. All statistical analyses were performed using JMP (SAS, NC) software. This study was approved by the Mayo IRB. Results: The data set was comprised of 454 patients with AL and 1116 patients with MM. There were significant differences between the two respective groups of patients in terms of number of prior regimens (0 vs 1, p<0.0001), time to ASCT (3.95 months vs 7.20 months, p<0.0001), intensity of conditioning regimen (non-attenuated in 69.4% vs 89.1%, p<0.0001), serum creatinine (1.1mg/dl vs 1mg/dl p<0.0001), creatinine clearance (72.5 ml/minute vs 80 ml/minute p<0.0001), albumin (2.61g/dl vs 3.50g/dl, p<0.0001) CRP (0.40mg/dl vs 0.63mg/dl p<0.0001), LDH (196 U/l vs 182U/l, p<0.0001), and bone marrow plasmacytosis at transplant (6% vs 9%, p<0.0001). Hematologic response rates were also significantly different between the groups, with higher overall hematologic response in the MM group (90.9% vs 79.5%, p<0.0001) and higher complete response (CR) rates (40.1% vs 29.4%, p<0.0001) in the AL group. With a median follow-up of surviving patients of 68 months, the respective median overall survival (OS) for the AL and MM patients was 113 and 59.5 months, p<0.0001. Notably, the 5-year OS of AL and MM patients achieving CR were 91.4% and 57.7%, respectively, p<0.0001. If only those patients who were transplanted within 1 year of their diagnosis are included in the analysis, the respective 5-year OS of AL and MM patients achieving CR were 90.4% and 61.3%, p<0.0001 (Figure 1). To correct for imbalances in non-disease specific parameters, 3 multivariate analyses were performed using: 1) all patients; 2) only those achieving CR; and 3) only those who achieved a CR and were transplanted within 12 months of their diagnosis (Table 1). Among those patients achieving CR, MM patients had nearly a 4-fold risk of death as compared to patients with AL. Conclusion: Although ASCT is not available to all patients with either AL or MM, there is a significant difference in outcomes based on the diagnosis. Patients with AL who undergo ASCT enjoy a superior survival as compared MM patients undergoing the same procedure. This difference is most notable among those patients who achieve CR suggesting very different plasma cell biology between the two diseases. Disclosures: No relevant conflicts of interest to declare.

INTRODUCTION: The association of Acute Pancreatitis and Celiac Disease (CD) has been sparingly reported in the literature. CD is known to affect approximately 1% of the western population. A Swedish national database study reported a 3-fold increased risk of developing pancreatitis in patients with CD. The exact mechanism of this is unknown, but it could be related to an untreated celiac disease affecting the major papilla causing stenosis or exocrine pancreatic insufficiency that has been reported previously. This study aimed to look at the association between acute pancreatitis and celiac disease. We also looked at whether there was any association between chronic pancreatitis and celiac disease. METHODS: We performed a retrospective cross-sectional cohort study using the 2013 National Inpatient Sample (NIS) database. We included all patients who were hospitalized with either acute pancreatitis (ICD Code 577.0) or Chronic Pancreatitis (577.1). Patients who had diagnoses of both acute and chronic pancreatitis were considered to have acute on chronic pancreatitis and combined with the chronic pancreatitis group. We then analyzed both groups for the presence or absence of celiac disease. Continuous variables were compared using t-tests, and categorical variables were compared using Rao-Scott chi-square tests. All analyses were performed using SAS Survey Procedures (version 9.4, The SAS Institute, Cary, NC). RESULTS: We analyzed more than 35 million hospitalizations in 2013 out of which 378,715 had a primary discharge diagnosis of acute pancreatitis and 155,130 had a primary discharge diagnosis of chronic pancreatitis. The mean age in the acute pancreatitis group was 53.3 yrs and in chronic pancreatitis group was 51.7 yrs. There were more males in chronic pancreatitis group (55.1%) than females (44.9%). There was significantly higher prevalence of acute pancreatitis in CD (2.3%) than non-CD patients (1.2%) (Figure 1, P = 0.001). Similarly, there was higher prevalence of chronic pancreatitis (1.2%) than the control group (0.43%) (Figure 1, P < 0.001). CONCLUSION: There is a higher prevalence of acute pancreatitis in patients with CD. Patients were also found to have much higher prevalence of chronic pancreatitis in CD. This could be related to recurrent acute pancreatitis episodes in CD patients. Further studies are needed to validate these findings.

INTRODUCTION: The association of Acute Pancreatitis and Celiac Disease (CD) has been sparingly reported in the literature. CD is known to affect approximately 1% of the western population. A Swedish national database study reported a 3-fold increased risk of developing pancreatitis in patients with CD. The exact mechanism of this is unknown but it could be related to untreated celiac disease affecting the major papilla causing stenosis or exocrine pancreatic insufficiency that has been reported previously. The aim of this study was to look at the association between acute pancreatitis and celiac disease. We also looked whether there was any association between chronic pancreatitis and celiac disease. METHODS: We performed a retrospective cross-sectional cohort study using the 2013 National Inpatient Sample (NIS) database. We included all patients who were hospitalized with either acute pancreatitis (ICD Code 577.0) or Chronic Pancreatitis (577.1). Patients who had diagnoses of both acute and chronic pancreatitis were considered to have acute on chronic pancreatitis and combined with the chronic pancreatitis group. We then analyzed both groups for presence or absence of celiac disease. Continuous variables were compared using t-tests and categorical variables were compared using Rao-Scott chi-square tests. All analyses were performed using SAS Survey Procedures (version 9.4, The SAS Institute, Cary, NC). RESULTS: We analyzed more than 35 million hospitalizations in 2013 out of which 378,715 had a primary discharge diagnosis of acute pancreatitis and 155,130 had a primary discharge diagnosis of chronic pancreatitis. The mean age in the acute pancreatitis group was 53.3 yrs and in chronic pancreatitis group was 51.7 yrs. There were more males in chronic pancreatitis group (55.1%) than females (44.9%). There was significantly higher prevalence of acute pancreatitis in CD (2.3%) than non-CD patients (1.2%) (Figure 1, P = 0.001). Similarly, there was higher prevalence of chronic pancreatitis (1.2%) than the control group (0.43%) (Figure 1, P < 0.001). CONCLUSION: There is a higher prevalence of acute pancreatitis in patients with CD. Patients were also found to have much higher prevalence of chronic pancreatitis in CD. This could be related to recurrent acute pancreatitis episodes in CD patients. Further studies are needed to validate these findings.

INTRODUCTION: Distal esophageal spasm (DES) is a motility disorder characterized by premature contraction of the esophageal body during single swallows. It is thought to be due to impairment of esophageal inhibitory pathways, but studies to support this are limited. Assessment of response to multiple rapid swallows (MRS) during high-resolution esophageal manometry (HRM) enables detection of impaired inhibition during MRS. Healthy subjects respond to MRS by deglutitive inhibition during the MRS sequence. We hypothesize that deglutitive inhibition is impaired in DES patients. Aim: compare response to MRS in DES patients and healthy controls. METHODS: Response to MRS was evaluated in 19 DES patients and 24 asymptomatic healthy controls. Demographic and symptom data were extracted from a prospectively maintained motility database. Patients with history of prior gastroesophageal surgery, endoscopic myotomy (POEM), pneumatic dilation, esophageal botulinum toxin injection within 6 months of HRM, and esophageal stricture were excluded. HRM was performed with a solid state catheter with 36 circumferential pressure sensors 1-cm apart; ten 5-ml liquid swallows were given followed by MRS sequence, analyzed with Manoview software (Medtronic). Esophagogastric junction integrated relaxation pressure (IRP), distal contractile integral (DCI), and distal latency (DL) were calculated, and Chicago Classification v3.0 was applied to diagnose DES (defined by ≥ 2 swallows with DL ≤ 4.5 sec). Response to MRS was evaluated for complete versus impaired inhibition (contractility with DCI > 100 mmHg-sec-cm during MRS), and presence of post MRS contraction augmentation (DCI post MRS greater than single-swallow mean DCI). Chi-Square and Fisher’s exact test were used for statistical analysis. RESULTS: Demographics and symptom data are shown in Table 1. Patients with DES were older and more symptomatic than controls. Impaired inhibition of peristalsis during MRS was significantly more frequent in DES compared to controls (89% vs 0%, P < 0.001, Figure 1). The proportion of subjects with augmentation post MRS was similar for both groups (37% vs 38%, P = 1.00), but mean DCI post MRS was higher in DES than controls (3788 vs 1239, P = 0.013). CONCLUSION: Impaired deglutitive inhibition during MRS is present in the majority of patients with DES, supporting impaired inhibitory pathways in the esophagus as a mechanism of action in this disorder.

INTRODUCTION: We previously showed an association between chronic opioid use and esophageal motor dysfunction characterized by esophagogastric junction outflow obstruction, distal esophageal spasm, achalasia type III, and Jackhammer esophagus. Assessment of response to multiple rapid swallows (MRS) during high-resolution esophageal manometry (HRM) enables detection of impaired inhibition during MRS. Healthy subjects respond to MRS by deglutitive inhibition during MRS followed by an augmented contraction with higher vigor than single swallows. Hypothesis: during MRS, opioids may interfere with deglutitive inhibition and may enhance post MRS contraction. Aim: compare response to MRS in opioid users, non-users and healthy controls. METHODS: Response to MRS was evaluated in 200 patients with esophageal symptoms (100 chronic opioid users on oxycodone, hydrocodone, or tramadol for ≥3 months, 100 not on opioids), and 19 asymptomatic healthy controls that underwent HRM. Patients with prior gastroesophageal surgery, pneumatic dilation, esophageal botulinum toxin injection within 6 months of HRM, esophageal stricture, achalasia type I or II, and scleroderma were excluded. Demographic and symptom data were extracted from a prospectively maintained motility database. Response to MRS was evaluated for complete versus incomplete inhibition (contractility with DCI >100 mmHg-sec-cm during MRS), and presence of post MRS contraction augmentation (DCI post MRS greater than mean DCI for single swallows). Categorical variables were analyzed by chi square. RESULTS: Patients were older than controls (Table 1). HRM indications are shown in Table 2. Incomplete inhibition during MRS was significantly more frequent in chronic opioid users compared to patients not on opioids and healthy controls (26% vs 11% vs 0% P = 0.002; Figure 1). There was a significant difference in the rate of incomplete MRS inhibition for patients on oxycodone, hydrocodone, and tramadol (27% vs 34% vs 22% P = 0.002). The proportion of patients with augmentation post MRS was similar for opioid users, non-opioid users and healthy controls ( P = 0.05). CONCLUSION: Impaired deglutitive inhibition during MRS was significantly more frequent among opioid users compared to non-opioid users and healthy controls. This was more common with stronger opioids (oxycodone and hydrocodone) compared to tramadol. These findings support our hypothesis that opioids interfere with inhibitory signals in the esophagus.

INTRODUCTION: Jackhammer esophagus (JE) is esophageal motility disorder characterized by hypercontractile peristalsis, diagnosed by high resolution manometry (HRM) showing increased contractile vigor distal contractile integral (DCI) >8000 mmHg/s/cm. Hypothesis: hypercontractile peristalsis in JE may be a compensatory mechanism for impaired EGJ relaxation, which even with normal integrated relaxation pressure (IRP), may be expressed as delayed onset of relaxation. We compare time to onset of EGJ relaxation in JE patients with normal IRP, control patients presenting for evaluation of esophageal symptoms with normal HRM, and asymptomatic healthy volunteers. METHODS: We compared time to onset of EGJ relaxation in 44 patients (24 JE, 20 with normal HRM) and 21 asymptomatic healthy volunteers who underwent HRM. Demographic characteristics and validated esophageal questionnaires (GERDQ, BEDQ, Eckardt) collected in all subjects. HRM performed by administering ten 5-ml liquid swallows, Chicago Classification v3.0 used to diagnose JE and normal esophageal motility. Time to onset of EGJ relaxation after swallow initiation was measured in seconds, from time of upper esophageal sphincter opening to EGJ opening. EGJ opening was determined at an isobaric contour of 23 mmHg, based on analysis in the healthy volunteers showing persistent EGJ effacement at this value in 100% of the volunteers. Median times to onset of relaxation for the study groups were compared by Wilcoxon rank sum test. RESULTS: Demographics, questionnaire scores, and HRM metrics in Table 1; patients were older and had higher scores compared to healthy volunteers; HRM metrics were different among the study groups with the exception of DL. Median times to onset of relaxation after swallow initiation shown in Figure 1. There was no difference in median time to onset of relaxation for volunteers compared to patient controls with normal HRM 0.20 s vs 0.90 s, P = 0.149. Median time to onset of relaxation was significantly longer in JE patients compared to volunteers and patient controls 3.30s vs 0.20 s vs 0.90 s, P = 0.001. CONCLUSION: Patients with JE and normal EGJ relaxation by IRP have significantly delayed onset of EGJ relaxation compared to healthy subjects and control patients with normal HRM. Hypercontractile peristalsis in these JE patients could be a compensatory mechanism to overcome outflow obstruction manifested as delayed EGJ relaxation. Therefore, if our findings are confirmed, therapies to address impaired EGJ relaxation could be considered.