Girardo, Marlene

Abstract Background Peripheral arterial disease is a marker of aggressive atherosclerosis. The ankle brachial index (ABI) is a simple and non-invasive tool to diagnose peripheral arterial disease (PAD). Patients with PAD are at increased risk for ischemic strokes and other cardiovascular diseases. Purpose To evaluate the association of abnormal ABI and poorly compressible vessels with ischemic stroke in a large patient cohort. Methods We analyzed lower extremity vascular studies of all patients with ABI measurements at a tertiary care hospital between January 1996 and August 2018. PAD is defined as ABI<1.0, and poorly or non-compressible (PC/NC) arteries as ABI>1.4 while ABI between 1.0–1.4 is normal. Association of these ABIs with new ischemic stroke events post ABI measurement were analyzed after adjusting for high risk confounders such as atrial fibrillation. Hazard ratios (HR) were calculated using multivariable Cox proportional regression with 95% confidence intervals. Results In total, 38,016 unique patients (mean age 66.1±14.8 years, female 42.3%) were included. Abnormal ABI was found to be more prevalent among elderly male patients compared to patients with normal ABI. In contrast to non-PAD patients, both PAD and PC/NC patients as defined by ABI had a statistically significant risk of ischemic stroke, with PAD conferring the greatest risk compared to PC/NC vessels. The data is summarized in Table 1. Table 1 Unadjusted HR p-value Adjusted HR p-value PAD vs. No PAD 2.77 (2.62, 2.92) <0.001 2.10 (1.98, 2.22) <0.001 PC/NC vs. No PAD 2.11 (1.95, 2.28) <0.001 1.38 (1.26, 1.51) <0.001 PAD vs. PC/NC 1.37 (1.28, 1.46) <0.001 1.37 (1.28, 1.48) <0.001 Adjusted and unadjusted hazard ratios with p-values. HR adjusted for age, sex, atrial fibrillation, ischemic stroke, transient ischemic attack, chronic heart failure, diabetes mellitus, hyperlipidemia, hypertension, and coronary artery disease. PAD = Peripheral artery disease and PC/NC = poorly compressible/non-compressible. Conclusion This study adds to the growing body of evidence that PAD and poorly-compressible vessels are independently associated with an increased risk of ischemic stroke. Given the associated risk of cerebrovascular disease, clinicians should aggressively treat to minimize risk factors in those with abnormal ABIs.

Abstract Introduction Lower extremity physiologic studies are an important non-invasive diagnostic tool in peripheral arterial disease (PAD). PAD and atrial fibrillation (AF) are associated with increased cardiovascular and all-cause mortality. Purpose To evaluate the association between PAD and new-onset AF and the risk of stroke. Methods We performed a study of all patients without AF undergoing ankle-brachial index (ABI) for any indication between January 1996 to June 2018. The ABI cut-off were as follows: abnormal ABI (0–0.99), normal ABI (1.00–1.39) and poor vessel compressibility (PC) (1.40+). Demographic, comorbidity, and outcome variables were extracted using the electronic medical record. Results Overall, 34,441 patients (mean age 66.8±14.3, 57.3% male, 88.2% white) were included in the study with a median follow-up of 7.2 years (interquartile range, 3.0–12.9 years). Multivariate Cox proportional hazard analysis showed increased risk of new-onset AF for male sex, older age, hypertension, coronary artery disease, cerebrovascular disease, chronic kidney disease stage III or greater, congestive heart failure, chronic obstructive pulmonary disease, and cancer (all p<0.0001). After adjustment, ABI results were significantly associated with new-onset AF, particularly poorly-compressible vessels (adjusted HR: 1.42 (1.30–1.55), p<0.0001) compared to abnormal ABI (adjusted HR: 1.12 (1.05–1.20), p=0.0012). Patients with atrial fibrillation were more likely to experience ischemic stroke (39.2% versus 16.1%, p<0.0001). Conclusion Abnormalities in ABI results, particularly poorly-compressible vessels, are independently associated with new-onset atrial fibrillation in a large ambulatory cohort. While the mechanism cannot be assessed, common inflammatory mechanisms and increased vascular stiffness may play an important role. Identification of AF in these at-risk patients may improve cardiovascular outcomes.

Abstract Background Based on previously published data, routine myocardial perfusion imaging in diabetics is not recommended. Selecting patients with diabetes and high risk cardiovascular features could be important to improve the yield of physiologic assessment of the coronary arteries disease and subsequently patient outcome. Purpose We posed the question whether nuclear stress testing has a better yield by selecting diabetic individuals with known vascular disease. Methods We analyzed records for 15,392 diabetics from 1996 to 2009 with and without vascular disease. Vascular disease is defined as carotid vascular disease, abdominal aortic aneurysm, or peripheral arterial disease. There was 2457 myocardial perfusion studies performed within 2 years of the vascular evaluation. We studied the results of these stress testing in each group and evaluated for the presence of myocardial ischemia. Multivariate Cox proportional regression was used to calculate hazard ratios (HR) with 95% confidence intervals after adjusting for age, gender. Results Of those who underwent myocardial perfusion studies 1819 were diabetic with vascular disease group A (mean age 67.8, 70.5% female) and 638 were diabetic without vascular disease group B (mean age 64.5 years, 67.1% female). There was at least one reversible defect suggest myocardial ischemia in 225 and 758 studies in group A and B respectively. Comparing outcome based on the presence of myocardial ischemia in group A without vascular disease, those with vascular disease did have an increased risk of myocardial infarction (adjusted HR: 1.630, 95% CI: 1.281–2.074) and death (adjusted HR: 1.646, 95% CI: 1.413–1.918). Conclusion Myocardial perfusion imaging is a reasonable test in patients with diabetes and vascular disease. The presence of myocardial ischemia is more common and is associated with worse cardiovascular outcome. Acknowledgement/Funding None

Abstract Introduction - IMIDs are critical in the treatment of multiple myeloma (MM). Unfortunately, many patients become resistant and this is a major challenge in MM therapy. IMID resistance can be caused by CRBN mutations (rarely) and by upregulation of specific antioxidative mechanisms. We hypothesized that measuring baseline antioxidative capacity might be a useful predictor of IMID sensitivity in the clinic. Methods - To develop a quantitative assay for determining cellular antioxidative capacity of MM cells we measured total cellular oxidized flavin adenine dinucleotide (FAD) after treatment with H2O2. FAD has auto-fluorescent properties that can be measured via flow cytometry. Cells with high antioxidative capacity generate more FAD, and cells with low anti-oxidative capacity generate less FAD. MM cells with an increase in FAD after H2O2 were considered IMID resistant and those with no change in FAD were considered IMID sensitive (Figure 1). Clinical IMID resistance/sensitivity was defined clinically during blinded retrospective review, with disease progression based on the IMWG criteria. After blinded review of clinical outcomes, the patient flow cytometry results were disclosed to evaluate the predictive value of the flow cytometry assay for detection of IMID resistance. Results - Of 40 patients who underwent testing, 26 were IMID resistant via flow and were considered as being clinical resistant 17 (65%). Conversely, 14 patients were IMID sensitive via flow and 12 (86%) were considered to be clinical sensitive. There was a significant correlation between clinical assessment and flow cytometry in determination of IMID resistance patterns (Table 1). The sensitivity and specificity of our assay was 89% and 57% with a positive and negative predictive value of 65% and 86% respectively. A limitation of our clinical assessment was that 16 patients (38%) were treated with combination therapy; IMIDs plus a proteasome inhibitor or a monoclonal antibody. Of the 11 patients with discordant results by flow and clinical outcome, 7 (64%) were not on therapy at the time of testing and 6 (55%) had flow testing on the bone marrow sample performed on day 100 following an autologous transplant. Two (7%) of the 29 patients with correlative results were off all therapy at the time of testing, 1 with testing on the day 100 marrow sample after transplant. Conclusions - This early testing of our assay shows promising results predicting clinical sensitivity via our flow based assay. The testing demonstrates a high sensitivity and negative predictive value, with less ability to assess for resistance. However, there were limitations to this study. The majority of patients with discordant results were off IMID therapy at the time of flow cytometry and many of these were assessed on transplant day 100 marrow samples. Depth of measureable residual disease was not readily available on all marrow samples tested. It is probable that flow testing for IMID resistance is inaccurate in patients with deeper responses to therapy, especially those who are minimum residual disease (MRD) negative. Additionally, several patients were on combination IMID, proteasome inhibitor, and monoclonal antibody. It is possible that clinical IMID resistance was not detected due to the anti-MM activity of the additional therapies. Additional larger scale prospective studies are needed to validate these findings as this method of testing could potentially provide providers with powerful information allowing them to personalize therapy for their patients. Disclosures Fonseca: Mayo Clinic: Employment; Amgen: Consultancy.

Abstract Background: Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal hemopathies characterized by burdensome symptom profiles and impaired quality of life. Treatments include pharmacologic approaches, phlebotomy, and bone marrow transplant. Outcome studies have historically focused on hematologic improvement and survival benefit. Few prospective studies have evaluated patient-reported symptoms and quality of life outcomes after standard therapy. The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify symptomatic response to standard treatments. Here we provide updated results for the prospective MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: The MEASURE trial is a prospective international cohort study evaluating responsiveness of the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10) in an anticipated 480 ET, PV, and MF patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF TSS (JCO 2012) for seven consecutive days at enrollment then again for seven days between 90 days and six months later. Patients also complete the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. Physicians report demographic, laboratory, and clinical data. Results: Demographics To date, 340 patients have enrolled and 270 have completed both study visits. Participants include ET (60%), PV (29%), and MF (12%; including 68% primary MF, 12% post-ET, 20% post-PV) patients. Enrolled patients are 51% male. The most common therapies received prior to enrollment were aspirin (34%), phlebotomy (15%), hydroxyurea (14%), and warfarin/clopidogrel/anticoagulation (6%). The most common current MPN therapies were hydroxyurea (67%), aspirin (24%), phlebotomy (9%), and ruxolitinib (8%). Information on mutational analysis was also collected; 77% of patients have a known JAK2 V617F mutation, 3% have an MPL W515 mutation. Symptom Measures On the MPN-SAF TSS, the majority of individual symptoms assessed did not change significantly between the two assessment time points while on standard therapy. Notable exceptions were a significant decrease in weight loss (mean 2.0 vs. 1.7 on a 0=absent to 10=worst imaginable scale, p=0.005) and a significant worsening in quality of life (mean 3.6 vs. 3.8 on a 0=as good as it can be to 10=as bad as it can be scale, p=0.04). No changes were seen in other symptoms including early satiety, abdominal discomfort, night sweats, fatigue, inactivity, poor concentration, bone pain, itching, or fever. Similarly, the cumulative MPN-SAF TSS score remained stable at a mean of 24.4 over the treatment period. These findings were congruent with those observed using the EORTC QLQ-C30 instrument, with no significant changes seen in emotional, physical, role, cognitive, or social functioning. Finally, the MDASI also revealed a lack of change in either symptom severity (mean 2.7) or symptom distress (mean 3.0) scores, which remained stable over the study period. Discussion: Myeloproliferative neoplasms are associated with burdensome symptoms that significantly compromise quality of life. To date, no studies have quantified symptomatic response to standard-of-care treatments. Overall, results from the MEASURE study suggest that standard treatments have limited systematic impact on patient symptomatology over time, with no improvements in overall quality of life. However, we note the relatively low proportion of patients in this cohort treated with ruxolitinib, which has been shown previously to improve symptom burden, and this may have impacted the symptom responses seen in the group as whole; detailed responses by treatment and MPN subtype will be presented. Figure. Figure. Disclosures Dueck: Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment. Ross:BMS: Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding. Tam:Janssen: Honoraria, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Travel funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Gilead: Honoraria; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding. Radia:Novartis: Speakers Bureau; Blueprint: Consultancy. Mesa:UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; NS Pharma: Research Funding; Pfizer: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy.

Abstract Coccidioidomycosis is an endemic fungal infection of the desert southwestern United States. Intact cellular immunity is critical to the control of this infection. A recently released reformulated spherulin antigen (Spherusol; Nielsen BioSciences, Inc.) was approved to detect delayed-type hypersensitivity, which implies the presence of cellular immunity, to Coccidioides species. We aimed to summarize our experience with this test in patients with primary pulmonary coccidioidomycosis. We retrospectively reviewed clinical data for all patients with primary pulmonary coccidioidomycosis who had a Coccidioides (spherulin) skin test (CST) placed at our institution between January 1, 2015, and August 31, 2017. During the study period, 172 patients had a CST placed, and 122 met our inclusion criteria for proven or probable pulmonary coccidioidomycosis. Of these 122, 88 (72.1%) had a positive CST result and 34 (27.9%) had a negative result. In the positive CST group, 74 of the 79 treated patients (93.7%) had antifungal treatment stopped, 1 of whom (1.4%) had relapsed infection. In contrast, 27 of the 33 treated patients in the negative CST group (81.8%) had their antifungal treatment stopped, and none had a relapse. Seven patients overall (5.7%), all of whom had a positive CST, experienced mild local adverse reactions to the CST. Although previous controlled studies of CST showed sensitivity and specificity greater than 98%, our real-world experience with the CST showed lower rates of positivity. Negative CST results did not predict relapse with antifungal agent withdrawal.

ObjectiveThe narrative operative report (NR) bears testimony to critical elements of patient care. Residents’ NRs also provide insights into their comprehension of the procedure. NR documentation is an informal element of surgical residency training but data regarding quality of such training are scant. We aim to evaluate the NR within a residency training program.MethodsThe quality of NRs for endoscopic sinus surgery (ESS) was evaluated through a retrospective analysis of 90 NRs for ESS. Thirty‐four elements that the attending surgeon regards as “critical” variables, or quality indicators (QIs), that should be documented, were studied to evaluate quality. A “performance metric (PM),” defined as the average percent of QIs dictated/total word count, was determined. Subgroup analysis by the level of training was additionally performed.ResultsSurgical indications, procedural steps, and immediate postoperative findings were accurately documented in 71%, 84%, and 82% of patients, respectively. The attending surgeon had the highest proportion of included key elements (89% ± 6.2%) followed by junior residents (87% ± 5.7%) and then senior residents (80% ± 14%) (P = .008). The attending surgeon also demonstrated the highest PM, followed by senior and then junior residents (P < .0001).ConclusionsThe quality of NRs was found to be high overall, but not “perfect” for either the attending or trainee surgeon. The PM among residents was expectedly lower than the attending surgeon. We propose that a synoptic reporting system that ensures inclusion of key elements may be helpful in training residents (and attendings) in creating comprehensive and efficient NRs.Level of Evidence3

AbstractBackgroundFluconazole is the most commonly used antifungal treatment for various forms of coccidioidomycosis. Although we had anecdotally observed a high proportion of patients reporting cutaneous adverse effects associated with fluconazole treatment, this observation was not well described in the medical literature, and we were unsure of the additional effect of the arid desert environment of Arizona.MethodsWe performed a one‐time, voluntary survey of patients with coccidioidomycosis and compared the responses of patients treated with fluconazole with those of untreated patients.ResultsFrom January 1, 2015, to August 22, 2017, 62 fluconazole‐treated and 35 untreated patients with coccidioidomycosis provided consent and were enrolled in the study; demographics were similar between the two groups. Among the 62 fluconazole‐treated patients, daily dosages ranged from 200 mg to 800 mg. However, most (44/62, 71%) took 400 mg daily, the typical dose for the treatment of coccidioidomycosis. The median fluconazole treatment duration at the time of study participation was 6 months. When compared with untreated patients, those taking fluconazole had more moderate to severe dry lips (74.2% [46/62] vs. 23.5% [8/34]; P < 0.001), dry skin (45.8% [27/59] vs. 22.9% [8/35]; P = 0.03), and alopecia (31.1% [19/61] vs. 11.4% [4/35]; P = 0.004).ConclusionsFor the treatment of coccidioidomycosis, patients receiving fluconazole reported significantly more severe cutaneous effects, including dry lips, dry skin, and alopecia, than untreated patients. Our findings identify an association but do not prove causality.