Citations

Abstract Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for esophageal motility disorders using metrics from high‐resolution manometry (HRM). Fifty‐two diverse international experts separated into seven working subgroups utilized formal validated methodologies over two‐years to develop CCv4.0. Key updates in CCv.4.0 consist of a more rigorous and expansive HRM protocol that incorporates supine and upright test positions as well as provocative testing, a refined definition of esophagogastric junction (EGJ) outflow obstruction (EGJOO), more stringent diagnostic criteria for ineffective esophageal motility and description of baseline EGJ metrics. Further, the CCv4.0 sought to define motility disorder diagnoses as conclusive and inconclusive based on associated symptoms, and findings on provocative testing as well as supportive testing with barium esophagram with tablet and/or functional lumen imaging probe. These changes attempt to minimize ambiguity in prior iterations of Chicago Classification and provide more standardized and rigorous criteria for patterns of disorders of peristalsis and obstruction at the EGJ.

Background Peripheral microvascular endothelial dysfunction (PMED) has been linked to an increased risk of cardiovascular events, but there is a lack of information characterizing the predictive value of PMED for future risk of ischemic stroke (IS). Methods and Results This retrospective observational cohort study enrolled 637 patients who underwent non‐invasive microvascular endothelial function assessment using reactive hyperemia peripheral arterial tonometry. Reactive hyperemia peripheral arterial tonometry index ≤2 was defined as PMED. Of 280 patients with PMED, 12 (4.3%) patients developed IS, compared with only 4 (1.1%) of 357 patients without PMED during a median follow‐up of 5.3 years. Patients with PMED had lower IS‐free survival compared with patients without PMED (log‐rank P =0.03). Cox proportional hazard ratio (HR) analyses showed that PMED predicted the incidence of IS, with a HR of 3.43, 95% CI, 1.10–10.63 ( P =0.03); adjusted HR of 3.70, 95% CI, 1.18–11.59 ( P =0.02) after adjusting for sex, smoking history, and atrial fibrillation; adjusted HR of 3.45, 95% CI, 1.11–10.72 ( P =0.03) after adjusting for CHA 2 DS 2 ‐VASc score; adjusted HR of 5.70, 95% CI, 1.40–23.29 ( P =0.02) after adjusting for revised Framingham Stroke Risk Score. Reactive hyperemia peripheral arterial tonometry index improved discrimination of risk for IS after adding reactive hyperemia peripheral arterial tonometry index to CHA 2 DS 2 ‐VASc score and revised Framingham Stroke Risk Score. Conclusions PMED was associated with a >3‐fold increased risk of IS. These findings underscore the concept of the systemic nature of endothelial dysfunction, which could act as a potential marker to predict future risk of IS.

Heart failure is a common debilitating illness, associated with significant morbidity and mortality, rehospitalisation and societal costs. Current guidelines and position statements emphasise the management of patients with overt symptomatic disease, but the increasing prevalence of congestive heart failure underscores the need to identify and manage patients with early left ventricular dysfunction prior to symptom onset. Asymptomatic left ventricular systolic dysfunction (ALVSD), classified as stage B heart failure, is defined as depressed left ventricular systolic function in the absence of clinical heart failure. Early initiation of therapies in patients with presumed ALVSD has been shown to lead to better outcomes. In this article, the authors clarify issues surrounding the definition and natural history of ALVSD, outline clinical tools that may be of value in identifying patients with ALVSD and highlight potential opportunities for future investigations to better address aspects of our understanding of this complex syndrome.

6542 Background: Adjuvant chemotherapy (ACT) and postoperative radiotherapy (PORT) are used in the treatment of resected NSCLC to reduce risk of relapse, but guideline-based recommendations for these treatment modalities have varied over time. ACT is now recommended for stage II-IIIA NSCLC following resection based on phase III trial results which, starting in 2003, showed improved survival. Conversely PORT recommendations have been rescinded due largely to a 1998 Lancet meta-analysis. In this study we explore the rates of these two adjuvant treatment modalities across areas over time. Methods: Using SEER-Medicare data we identified 18,410 patients diagnosed 1992-2007 with resected NSCLC. Adjuvant treatment was defined as the first treatment received within 4 months of surgery. The study period was divided into 3 eras: 1992-1998, 1999-2003, and 2004-2007. Area treatment rates were calculated using the 50 patients closest to each zip code, adjusting for patient and area characteristics. Areas were then ranked and divided into quintiles. Percent differences were calculated to measure the variation between the highest and lowest quintiles. Results: Between 1992-1998 when the results of the phase III ACT trials were still unknown and utilization of ACT was low, areas with the highest treatment rates were 35 times more likely than areas with the lowest rates to administer ACT. After 2003 ACT use increased swiftly and geographic variation fell. In contrast, PORT utilization rates have declined and become more geographically dispersed since 1998. Receiving no adjuvant treatment was highest between 1999-2003, after the Lancet PORT meta-analysis and before the major ACT trials. Conclusions: NSCLC adjuvant treatment has been shifting from PORT to ACT. The positive results of the ACT trials and publication of treatment guidelines have increased usage and reduced geographic variation in ACT use. Geographic variation in PORT use however has increased over time, although overall usage has decreased. [Table: see text]

e19065 Background: Treatment decisions for patients with advanced stage (stages IIIB and IV) non-small cell lung cancer (AS NSCLC) are influenced by comorbidity at time of diagnosis. We studied the effects of comorbidity on survival and whether effects differ for short-term (120 days) vs. for long-term (>120 days) survival. Methods: Data were from surveys and medical records of 1498 patients withnewly diagnosed AS NSCLC in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS). Respiratory disease severity and comorbidities at diagnosis were measured from the Adult Comorbidity Evaluation (ACE-27) index and model fitting used the Akaike Information Criteria. The log-rank test was used for univariable survival models, and Cox proportional hazards regression for multivariable survival models. Results: Five comorbidities were significantly associated with survival and 437 (29.2%) patients had one or more of these. Survival to 120 days was significantly poorer for patients with a baseline diagnosis of stroke [hazard ratio (HR) 1.92; 95% confidence interval (CI) 1.26–2.93], diabetes (HR 1.33, 95% CI 1.08–1.65), or congestive heart failure (HR 1.45, 95% CI 1.07–1.96), controlling for age, gender, smoking status, stage, severe respiratory disease, and brain metastases. Given survival to 120 days (885 pts, 59%), survival beyond that was significantly poorer only for patients with baseline arrhythmia (HR 1.47, 95% CI 1.15–1.87) or end stage renal disease (HR 1.82, 95% CI 1.09–3.04), controlling for the covariates above. Adjustment for chemotherapy use had no effect on these associations. Conclusions: Several comorbidities present at diagnosis affected survival for AS NSCLC, with some comorbidities having a more immediate relationship to survival than others. Our finding provides information that could be used to tailor treatment decisions to patients’ comorbidities at diagnosis.

Background The presence of a durable left ventricular assist device ( LVAD ) is associated with increased risk of vasoplegia in the early postoperative period following heart transplantation ( HT ). However, preoperative predictors of vasoplegia and its impact on survival after HT are unknown. We sought to examine predictors and outcomes of patients who develop vasoplegia after HT following bridging therapy with an LVAD . Methods and Results We identified 94 patients who underwent HT after bridging with continuous‐flow LVAD from 2008 to 2018 at a single institution. Vasoplegia was defined as persistent low vascular resistance requiring ≥2 intravenous vasopressors within 48 hours after HT for >24 hours to maintain mean arterial pressure >70 mm Hg. Overall, 44 patients (46.8%) developed vasoplegia after HT . Patients with and without vasoplegia had similar preoperative LVAD , echocardiographic, and hemodynamic parameters. Patients with vasoplegia were significantly older; had longer LVAD support, higher preoperative creatinine, longer cardiopulmonary bypass time, and higher Charlson comorbidity index; and more often underwent combined organ transplantation. In a multivariate logistic regression model, older age (odds ratio: 1.08 per year; P =0.010), longer LVAD support (odds ratio: 1.06 per month; P =0.007), higher creatinine (odds ratio: 3.9 per 1 mg/dL; P =0.039), and longer cardiopulmonary bypass time (odds ratio: 1.83 per hour; P =0.044) were independent predictors of vasoplegia. After mean follow‐up of 4.0 years after HT , vasoplegia was associated with increased risk of all‐cause mortality (hazard ratio: 5.20; 95% CI, 1.71–19.28; P =0.003). Conclusions Older age, longer LVAD support, impaired renal function, and prolonged intraoperative CPB time are independent predictors of vasoplegia in patients undergoing HT after LVAD bridging. Vasoplegia is associated with worse prognosis; therefore, detailed assessment of these predictors can be clinically important.

Aims Cardiovascular health metrics predict the risk not only of cardiovascular diseases but also of several types of cancers. Microvascular endothelial dysfunction can predict future cardiovascular adverse events, but the predictive value of microvascular endothelial dysfunction for future risk of solid-tumor cancer has not been characterized. Methods A total of 488 patients who underwent microvascular endothelial function assessment using reactive hyperemia peripheral arterial tonometry were included in this study. Microvascular endothelial dysfunction was defined as a reactive hyperemia peripheral arterial tonometry index ≤2.0. Results Of 221 patients with a baseline reactive hyperemia peripheral arterial tonometry index ≤2.0, 21 patients (9.5%) were diagnosed with incident solid-tumor cancer during follow-up, whereas of 267 patients with a baseline reactive hyperemia peripheral arterial tonometry index >2.0, 10 patients (3.7%) were diagnosed with incident solid-tumor cancer during follow-up ( p = 0.009). Patients with a reactive hyperemia peripheral arterial tonometry index ≤2.0 had lower solid-tumor cancer-free survival compared to patients with a reactive hyperemia peripheral arterial tonometry index >2.0 (log-rank p = 0.017) (median follow-up 6.0 (3.0–9.1) years). Cox proportional hazard analyses showed that a reactive hyperemia peripheral arterial tonometry index ≤2.0 predicted the incidence of solid-tumor cancer, with a hazard ratio of 2.52 (95% confidence interval 1.17–5.45; p = 0.019) after adjusting for age, sex, and coronary artery disease, 2.83 (95% confidence interval 1.30–6.17; p = 0.009) after adjusting for diabetes mellitus, hypertension, smoking status, and body mass index >30 kg/m2, 2.79 (95% confidence interval 1.21–6.41; p = 0.016) after adjusting for fasting plasma glucose, systolic blood pressure, smoking status (current or former), and body mass index, and 2.43 (95% confidence interval 1.10–5.34; p = 0.028) after adjusting for Framingham risk score. Conclusion Microvascular endothelial dysfunction, as defined by a reactive hyperemia peripheral arterial tonometry index ≤2.0, was associated with a greater than two-fold increased risk of solid-tumor cancer. Microvascular endothelial dysfunction may be a useful marker to predict the future risk of solid-tumor cancer, in addition to its known ability to predict cardiovascular disease. Further research is necessary to develop adequate cancer screening strategies for patients with microvascular endothelial dysfunction.

Abstract Background Patients with type 2 diabetes are at an increased risk of cardiovascular events compared to individuals without diabetes. The role glycemic control plays in reducing cardiovascular risk remains uncertain. Coronary microvascular dysfunction (CMD) is more frequent in women compared to men, is prevalent in patients with type 2 diabetes and is linked to adverse cardiovascular events. We compared the association between CMD and glycemic control across sexes in patients with chest pain and non-obstructive coronary artery disease (CAD). Methods Patients with chest pain who were found to have non-obstructive CAD (stenosis <40%) at angiography underwent an invasive assessment of endothelial-independent and endothelial–dependent coronary microvascular function. Using a Doppler guidewire, endothelial-independent microvascular function was assessed by measuring the coronary flow velocity in response to intracoronary adenosine and comparing this to baseline to calculate the coronary flow reserve ratio (CFRAdn). A CFRAdn ≤2.5 was considered abnormal. Endothelial-dependent microvascular function was assessed by measuring the percent change in coronary blood flow in response to intracoronary infusions of acetylcholine (%ΔCBFAch), with a %ΔCBFAch ≤50% considered abnormal. Patients were classified as having normal versus abnormal CFRAdn and %ΔCBFAch. Measurements of HbA1c and fasting serum glucose were obtained at the time of catheterization and compared between groups after stratification by sex. Results Between 1993 and 2012, 1,469 patients (mean age 50.4 years, 35% male) underwent coronary angiography and invasive testing for CMD, of which 129 (8.8%) had type 2 diabetes. Fifty one (39.5%) had an abnormal %ΔCBFAch and 49 (38.0%) had an abnormal CFRAdn. Conventional cardiovascular risk factors did not vary significantly between groups. Females with an abnormal CFRAdn or abnormal %ΔCBFAch had a significantly higher HbA1c compared to those with a normal CFRAdn or %ΔCBFAch respectively: HbA1c % (standard deviation) 7.4 (2.1) vs. 6.5 (1.1), p=0.035 and 7.3 (1.9) vs. 6.4 (1.2), p=0.022, respectively. Females with an abnormal CFRAdn had significantly higher fasting serum glucose concentrations compared to those with a normal CFRAdn: fasting serum glucose mg/dL (standard deviation) 144.4 (55.6) vs. 121.9 (28.1), p=0.035. These effects were not observed in men. Amongst female diabetics, a higher HbA1c was significantly associated with any CMD after adjusting for covariates: odds ratio (95% confidence interval) 1.69 (1.01 – 2.86) p=0.049; and a fasting serum glucose >140 mg/dL was significantly associated with an abnormal CFRAdn, 4.28 (1.43–12.81). Conclusion Poor glycemic control is associated with CMD in females with diabete who present with chest pain and non-obstructive CAD. These findings highlight the importance of sex-specific risk stratification models and treatment strategies when managing cardiovascular risk in diabetics. Acknowledgement/Funding Mayo Foundation

Abstract Background: Multiple myeloma (MM) is characterized by the invasion of malignant plasma cells into the bone marrow. While first line treatment options result in significant clinical benefit to patients, spatiotemporal clonal evolution results in disease relapse and mortality. Advances in genomics have armed clinicians with unprecedented insight into the molecular architecture of MM cells, however, the clinical benefit derived by genomics-guided intervention has been limited. We present a novel computational biology modelling (CBM) tool, which takes into account the combined effect of individual mutations, gene copy number abnormalities and large scale chromosomal changes in order to predict the salient molecular pathways utilized by the MM cell for survival. By reverse-engineering MM cell architecture in silico, the CBM tool is able to predict drug response and resistance mechanisms. Thus, our aim was to determine the accuracy of the CBM tool in predicting treatment response of relapsed/refractory MM patients for future management of their disease, in a more individualized manner. Methods: Cytogenetics and somatic mutations (by targeted NGS) for 15 MM patients were input into the CBM model to predict responses to different therapeutic combinations. All patients were relapsed to prior treatment. CBM uses PubMed and other online resources to generate patient-specific protein network maps of activated and inactivated disease pathways. We simulated the specific combinations of the drugs per patient and measured the quantitative drug effect on a composite MM disease inhibition score (i.e., cell proliferation, viability, apoptosis and paraproteins). The actual clinical outcome of the treatments was compared with predicted outcomes. Results: Fifteen patients were analysed using CBM for prediction of treatment response after NGS was performed. 13/15 were clinically evaluable, of which 1 was a responder and 12 were non-responder. 6/13 patients were treated on clinical trial and 7/13 were on drug combinations per physician decision. CBM correctly predicted 1 responder and 11 non-responder with a PPV of 50%, NPV 100%, specificity 91.67%, sensitivity 100%. The accuracy of CBM prediction was 92.30%. CBM also predicted the response of prior drug therapies for its non-response at relapse. For prior drug treatment options, 14 patients were evaluable. All the 14 patients were clinically non-responders and CBM correctly predicted for 13 patients with NPV 100%, Specificity 92.85% and overall accuracy of 92.85%. The majority of patients did not respond to therapies recommended at relapse. As an example, the operative molecular pathways from 2 patients who did not respond to combination treatment, either pre-NGS or post-NGS profiling, are shown in Fig. 1 and Table 1. CBM identified amplification (AMP) of chromosome (chr) 1 (WNT3A, IL6R, CKS1B, MCL1, PIK3C2B, USF1), chr 3 (HES1, PIK3CA, CTNNB1, WNT7A, FANCD2), chr 5 (IL6ST, IRF1, GLRX, SKP2), chr 7 (CDK5, EZH2, IL6, CAV1, ABCB1), chr 9 (NOTCH1, HSPA5, FANCC, FANCG), chr 15 (DLL4, FANCI, ALDH1A2), chr 19 (ERCC1, ERCC2, USF2); deletion(DEL) of chr 13 (CUL4A) , chr 16 (AXIN1, CDH1) and TP53 mutation in different combinations, which confer resistance to therapies at relapse. Conclusions: The CBM technology represents a potential means to identify therapeutic options for MM patients based on the patients individual tumor-genome profile and which can also be deployed for uncovering drug resistance mechanisms. This tool may aid clinicians in decision making for recommending the most appropriate therapy based on standard of care agents or clinical trials; thus improving patient outcomes and reducing unnecessary costs or drug-related toxicities. Disclosures Singh: Cellworks Research India Private Limited: Employment. Sauban:Cellworks Research India Private Limited: Employment. Husain:Cellworks Research India Private Limited: Employment. Kumar:Cellworks Research India Private Limited: Employment. Kumari:Cellworks Research India Private Limited: Employment. Tyagi:Cellworks Research India Private Limited: Employment. Abbasi:Cell Works Group Inc.: Employment. Vali:Cell Works Group Inc.: Employment. Ailawadhi:Pharmacyclics: Research Funding; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy.