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LINKED CONTENTThis article is linked to Sebastian et al papers. To view these articles, visit https://doi.org/10.1111/apt.15456 and https://doi.org/10.1111/apt.15498.

Abstract Context Prognosis of metastatic pheochromocytoma/paraganglioma following 131-Iodine metaiodobenzylguanidine (MIBG) is incompletely characterized due to small samples and shorter follow-up in these rare, often indolent tumors. Objective To describe long-term survival, frequency, and prognostic impact of imaging, biochemical, and symptomatic response to 131-I MIBG. Design Retrospective chart and imaging review at a tertiary referral center. Patients Six hundred sixty-eight person-years of follow-up in 125 patients with metastatic pheochromocytoma/paraganglioma with progression through prior multimodal treatment. Intervention Median 18 800 MBq 131-I MIBG. Main Outcome Measures Overall survival, Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) imaging response, symptomatic response per chart review, and biochemical response (20% change over 2 consecutive assays of catecholamines, vanillylmandelic acid, metanephrines, or chromogranin A). Results Median survival standard deviation [SD] from diagnosis was 11.5 years [2.4]; following metastasis, 6.5 years [0.8]; post treatment, 4.3 years [0.7]. Among 88 participants with follow-up imaging, 1% experienced complete response, 33% partial response, 53% stability, and 13% progression. Fifty-one percent showed subsequent progression, median progression-free survival [SD] of 2.0 years [0.6]. Stability/response vs progression at first imaging follow-up (3–6 months) predicted improved survival, 6.3 vs 2.4 years (P = 0.021). Fifty-nine percent of 54 patients demonstrated biochemical response. Fifty percent of these relapsed, with median time to laboratory progression [SD] of 2.8 years [0.7]. Biochemical response did not predict extended survival. Seventy-five percent of 83 patients reported improvement in pretreatment symptoms, consisting primarily of pain (42%), fatigue (27%), and hypertension (14%). Sixty-one percent of these patients experienced subsequent symptomatic progression at median [SD] 1.8 years [0.4]. Symptomatic response did not predict extended survival. Conclusions Imaging, symptomatic, and laboratory response to multimodal treatment including high-dose 131-I MIBG were achieved on long-term follow-up in metastatic pheochromocytoma or paraganglioma. Imaging response at 3 to 6 months was prognostic.

Abstract Abstract 3165 Background: Accrual to large oncology group studies in the United States is often slower than planned, especially in less common malignancies such as Multiple Myeloma (MM). To improve the treatment of patients with MM, it is essential that we address the barriers to accrual (BtA) to national clinical trials. The NCI Myeloma Steering Committee (MYSC) formed the Accrual Working Group (AWG), charged to analyze this problem. Methods: The members of the MYSC have developed a list of 10 potential BtA to NCI MM-CT under the leadership of the AWG at meetings conducted in person and by monthly telephone conference. This list was distributed via Survey Monkey among investigators and research staff of the SWOG, ECOG/ACRIN and Alliance research bases for the purpose of ranking the perceived importance of the 10 selected BtA. Responses based on a 0–5 Likert Scale were analyzed as continuous and categorical. For the latter, responses were grouped: Impedes Accrual – No (0,1), Yes (2–5); Significantly Impedes Accrual – No (0–3), Yes (4,5). Results: 246 survey responses were received. 50 participants who indicated that they had never attempted to or actually never enrolled a patient into a MM-CT were excluded. Of 196 responders, 61% had enrolled at least 5 patients, 43% practiced in academic centers (A) and 57% in community centers (C). 26% identified themselves as research staff, 74% as primarily physician investigators including Principal Investigators (12%). 78% have current access to NCI MM-CT. 46% identified their research base affiliation with SWOG, 20% with ECOG/ACRIN, 17% with Alliance, 17% as CTSU, NRG and other. The majority of survey responders confirmed agreement in the perception that all 10 identified BtA impede accrual, ranging from 60–84% depending on the specific barrier identified, while significant impediment to accrual ascribed to these BtA ranged from 22–47%. The perceived barriers most often cited as impeding accrual were (1) spectrum of available treatment options, (2) level of reimbursement for clinical trial related expenses and (3) patient‘s need for prompt treatment intervention (84%, 80%, 76% respectively). The first two barriers along with the requirement that patients receive their treatment exclusively at the NCI designated treatment site were rated most often as significantly impeding accrual (37%, 47%, 34% respectively). The first two were also identified most often as perceived BtA independent of practice setting (A, C), type of research engagement (physician investigator, research staff) and level of experience with MM-CT. Interestingly, the perception that patients must receive their treatment at the NCI designated treatment site and competing industry sponsored clinical trials were substantially more often cited as impeding accrual in academic centers compared to community centers and by physician investigators compared to research staff. The complexity of required diagnostic work up and the complexity of the treatment protocol and follow up testing were substantially more often cited as BtA in the community setting and by research staff compared to their peers in the academic setting and by physician investigators. The NCI MYSC AWG has proposed specific solutions to potentially lower perceived BtA. These include guidelines to allow protocol specific administration of commercially available agents by the patient‘s local oncologist, a simplified diagnostic work up and treatment plan and eligibility inclusion of patients who have received up to one cycle of specified urgent therapy prior to enrollment in MM-CT. Conclusions: We have queried experienced clinical investigators and research staff on 10 potential MM-CT specific BtA and found substantial consensus among responding participants in this survey. There are apparent differences in perceived BtA between the respondents from academic and community centers as well as between research staff and physician investigators. These data suggest that a structured approach to identification of BtA to clinical trials is feasible and creates opportunities to overcome them. This may have application to clinical trials across other diseases and may also lead to improvements in accrual. Disclosures: Barlogie: Celgene, IMF, MMRF, Millennium, Genzyme: Consultancy; Celgene, IMF, Millennium: Honoraria; Celgene, Novartis, NCI, Millennium, Onyx, Icon: Research Funding; GEP: Patents & Royalties.

Abstract Background: Anemia is an extremely prevalent disease and contributes to a substantial percentage of worldwide years lived with disability. Clinicians generally agree that investigation of the gastrointestinal (GI) tract with colonoscopy and/or endoscopy is warranted in the presence of either overt clinical evidence of GI bleeding or in the presence of documented iron deficiency. However, little is known about the appropriateness of these procedures in the evaluation of patients without either overt GI bleeding or iron deficiency. Additionally, while a large number of colonoscopies and endoscopies are performed each year, the proportion of such procedures performed in the absence of suspect history or findings has not been characterized. Methods: We performed a retrospective review of all patients at Mayo Clinic Rochester who underwent endoscopy, colonoscopy, or both procedures between July 1, 2014 and June 30, 2015 for an indication of either "anemia" or "iron deficiency anemia." Sources of data included provider notes, laboratory values, procedure notes, and pathology reports. Information including patient demographic characteristics, medical comorbidities, laboratory values related to anemia, findings at the time of gastrointestinal procedure, and procedure-related complications was collected. Data was entered into an electronic database and data analysis was performed using Microsoft Excel. Results: 999 procedures were included, including 224 colonoscopies, 306 endoscopies, and 469 combined colonoscopy/endoscopies. Of the 999 total procedures, 78 (8%) had no documented pre-procedure hemoglobin value, 666 (67%) were performed after documented anemia (defined as hemoglobin ≤12 g/dL), and 255 (26%) were performed after a documented hemoglobin of >12 g/dL. Of the 675 procedures performed for "iron deficiency anemia," 462 (68%) patients had documented anemia and documented ferritin prior to the procedure, including only 237 (35%) with both hemoglobin ≤12 and ferritin ≤ 20. 388 (39%) had a documented pre-procedure patient and/or provider report of blood in the stool, and 111 (11%) had a documented pre-procedure positive hemoccult test. 365 (37%) of the 999 procedures identified a probable benign source of bleeding, 54 (5.4%) identified a probable malignant source, and 580 (58%) had no findings consistent with a bleeding source. Patients with documented anemia were more likely to have a probable bleeding source identified than those without documented anemia [46% versus 34%, p<.001]. Of the 83 patients with hemoglobin >12 and ferritin >20, only 1 procedure in 83 demonstrated a malignant finding, and this patient did have blood in the stool at the time of the procedure. There were 46 patients who underwent a procedure without any "warning signs" (either anemia and/or blood in the stool and/or positive hemoccult). Of these patients, 0 had a malignant finding. Conclusions: A large number of procedures performed for either "anemia" or "iron deficiency anemia" were done without pre-procedure documentation of anemia and/or iron deficiency. Documentation of anemia is associated with an increased chance of finding a source of bleeding during the procedure. There were no missed diagnoses of malignancy among patients undergoing procedures without anemia, blood in the stool, and/or positive hemoccult. Careful attention to documentation should be encouraged, and quality improvement initiatives requiring appropriate documentation prior to performing these procedures may be helpful. Disclosures No relevant conflicts of interest to declare.

Abstract Background. A recent meta-analysis of 9 case-control and 5 cohort studies reported a positive association of transfusion history with risk of NHL (RR=1.20; 95% CI 1.07-1.35), which was only evident in cohort (RR=1.25) and not case-control (RR=1.05) studies (Castillo et al., Blood 2010;116:2897-2907). Risk was similar in men and women, and for transfusions before or after 1992. In subset analyses, elevated risk was only apparent for chronic lymphocytic leukemia (CLL) and not diffuse large B-Cell lymphoma (DLBCL) or follicular lymphoma, but power was low. To further investigate these findings, particularly from studies conducted after 1990, better assess confounding, and address heterogeneity by NHL subtypes, we conducted an individual-level, pooled analysis of 13 case-control studies in the InterLymph Consortium (including 11 studies conducted after 1990; 8 studies were not included in the published meta-analysis). Methods. There were a total of 10,805 cases and 14,026 controls with transfusion data from 13 studies conducted in Europe, North America, and Australia. Transfusion history and other risk factors were self-reported in interviewer-administered or self-administered questionnaires. All risk factor data were harmonized centrally, and cases were grouped into NHL subtypes according to the WHO classification using guidelines from the InterLymph Pathology Working Group. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression, adjusted for age, sex, and study center. Results. The median age at diagnosis was 60 years for cases (range, 18-97) and 59 years for controls (range, 16-97). The overall prevalence of a history of any transfusion in controls was 15.5%, was higher in women (18.6%) than men (13.0%), and increased with age, but was not associated with race/ethnicity (Asian, Black, Hispanic, White, other) or geographic region after adjusting for age and sex. Among whites, history of any transfusion was inversely associated with NHL risk among men (OR=0.74; 95% CI 0.65-0.83) but not women (OR=0.92; 95% CI 0.83-1.03); there were no significant results for other race/ethnicity groups, and ORs were highly variable and imprecise due to small sample sizes. Thus analyses were restricted to white men, where there was no trend with the number of transfusions, time since first transfusion, age at first transfusion, or decade of first transfusion. Further adjustment for socioeconomic status, body mass index, smoking, alcohol use or hepatitis C virus (HCV) seropositivity did not alter these results. The associations were stronger in hospital-based (OR=0.56; 95% CI 0.45-0.70) than population-based (OR=0.84; 95% CI 0.72-0.98) studies, and were stronger in studies from Southern Europe (OR=0.53; 95% CI 0.36-0.79) than northern Europe (OR=0.67; 95% CI 0.53-0.83) or North America (OR=0.82; 95% CI 0.70-0.98). For NHL subtypes, statistically significant inverse associations were observed for follicular lymphoma (OR=0.70; 95% CI 0.56-0.88), DLBCL (OR=0.72; 95% CI 0.59-0.87), and CLL/SLL (OR=0.67; 95% CI 0.52-0.87), whereas weaker and non-statistically significant associations were observed for mantle cell (OR=0.81; 95% CI 0.54-1.23), marginal zone (OR=0.78; 95% CI 0.54-1.15), lymphoplasmacytic (OR=0.82; 95% CI 0.47-1.42) and peripheral T-cell (OR=0.83; 95% CI 0.49-1.40) lymphomas. Conclusion. Contrary to earlier results, transfusion history was inversely associated with risk of NHL and the common subtypes of follicular lymphoma, DLBCL and CLL/SLL among white men, whereas associations were null among white women and other racial/ethnic groups. These results were not explained by confounding by lifestyle factors or HCV seropositivity, era of first transfusion, hospital versus population-based study design, or geographic location. Despite dramatic changes in transfusion practice over the past 40 years, results were similar for decade of first transfusion, suggesting secular trends are a less likely explanation. Our results are unexpected and bias cannot be ruled out. Further studies, particularly cohort studies, are needed to clarify the role of transfusion history in NHL risk. Disclosures No relevant conflicts of interest to declare.

INTRODUCTION: Gastroparesis is defined as delayed gastric emptying in the absence of mechanical obstruction. Diabetes and medication side effects are common causes. AL amyloidosis is a systemic disease due to extracellular fibril deposition that can affect multiple organs. Gastro-intestinal (GI) involvement is less common than in other organ systems but can present in many different ways, including gastroparesis. CASE DESCRIPTION/METHODS: A 77 year old non-diabetic man from Mississippi presented with a one year history of intermittent abdominal distention, nausea and bloating. In addition, he had increasing dyspnea on exertion and lower extremity edema. Outside work-up consisted of multiple imaging studies demonstrating marked gastric distention as well as delayed gastric emptying (Figures 1 and 2). Outside colonoscopy was unrevealing and EGD was negative except for a distal esophageal ulcer and focal active duodenitis. He was started on a PPI and trialed on an alternating regimen of metoclopramide and erythromycin, without symptomatic relief. He was referred to our hospital for further diagnostic work-up. Repeat colonoscopy showed congested distal ileal mucosa and friable ascending colonic mucosa. Biopsies from both sites revealed amyloid deposits by Congo red stain (Figure 3). Serum protein electrophoresis noted a monoclonal IgG lambda peak with M-spike of 1.5 g/dL and bone marrow biopsy revealed approximately 70% of marrow cellularity consisting of plasma cells. Echocardiogram confirmed severely increased concentric left ventricular wall thickening consistent with cardiac amyloidosis. Interestingly, neither fat pad biopsy nor bone marrow biopsy showed presence of amyloid. The patient was diagnosed with myeloma and AL amyloidosis with gastro-intestinal and cardiac involvement. DISCUSSION: This case highlights the broad differential for gastric distention and dysmotility. When the ‘usual suspects’ such as diabetes, medication, post-surgery and neurological disease have been ruled out, rarer causes like an infiltrative process should be considered. Common manifestations of GI tract amyloidosis include GI bleeding, malabsorption, protein-losing enteropathy and chronic dysmotility. The diagnosis of amyloidosis is based on positive tissue diagnosis. While the combination of a fat pad and a bone marrow biopsy has a high sensitivity (89%) for diagnosing AL amyloidosis, negative results do not rule out amyloid elsewhere and tissue sampling from the affected organ site is essential, as demonstrated in this case.

INTRODUCTION: Double balloon enteroscopy (DBE) is an important tool for evaluation of obscure GI bleeding but is a limited resource given time and expertise required. Patient selection is important to help optimize diagnostic yield and subsequent successful management of small bowel bleeding. To maximize the efficiency of DBE performed, our endoscopy group established a screening protocol (Figure) prior to approval of any procedure. We developed a quality improvement project to assess the efficacy of this screening protocol and to evaluate which components of screening were most predictive for procedural success. METHODS: A retrospective chart review was performed on all patients who underwent anterograde or retrograde double balloon enteroscopy for suspected GI bleeding from January 2016 to December 2017. Our screening protocol was implemented on February 1 st , 2017. Data was obtained on patient demographics, clinical presentation, laboratory evaluation, and prior investigation for bleeding evaluation. Endoscopy outcomes were separated into procedural success, defined as lesion identified, and clinical success, defined as resolution of bleeding. Success rates were compared pre and post intervention. Regression analysis was performed to evaluate which components best predicted a successful procedure. RESULTS: We reviewed 114 DBE procedures in 89 patients, 53.5% male (n = 61) with a mean age of 62.8 + 13.3 years. Of these, 86% (n = 98) were performed prior to initiation of the screening protocol. Overall, there was no significant difference in procedural success pre and post intervention as defined by presence of recurrent bleeding, persistent anemia, or transfusion need (Table 1). On univariate analysis of clinical success, defined as lack of recurrent bleeding, gender, anticoagulation use, and presence of lesion on CE were significant (Table 2). Identification and intervention on a lesion during the balloon endoscopy did not impact future anemia, bleeding, or transfusion requirements. CONCLUSION: The patient screening protocol was successful in decreasing the number of procedures performed but did not improve our lesion detection rate on endoscopy and did not improve clinical outcomes as measured by rebleeding. Patients on anticoagulation and those who had prior lesions identified on capsule endoscopy had higher odds of rebleeding, indicating clinical failure. This data may help modify patient selection to maximize success of DBE procedures in the future.

AbstractEpidemiologic studies show an increased risk of non‐Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen‐stimulation in one disease leads to another. Here we assess shared genetic risk in genome‐wide‐association‐studies (GWAS).Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B‐cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta‐analysis.Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta‐analysis (combing AD with NHL) implicated genes of apoptosis and telomere length.This GWAS‐based analysis four NHL subtypes and three ADs revealed few weakly‐associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Abstract Aims Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve. Methods and results Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P &lt; 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P &lt; 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P &lt; 0.0001) and inversely correlated with PA compliance (r = −0.52 and −0.43, both P &lt; 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s′ and e′ tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e′, r = −0.59 and −0.67, both P &lt; 0.001), reduced cardiac output responses to exercise (r = −0.59 and −0.61, both P &lt; 0.0001), and more severely impaired peak VO2 (r = −0.60 and −0.67, both P &lt; 0.0001). Conclusion Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype. Clinical trial registration NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search