Assessment Of Disease Burden Research Articles

Abstract IA41: Approaches for personalized medicine in lymphoma through liquid biopsies

Abstract Over the last decade, circulating tumor DNA (ctDNA) has emerged as an important biomarker across a range of cancers, including lymphomas. The potential clinical applications of ctDNA technologies are broad, including tumor mutational genotyping, detection of molecular responses and minimal residual disease, as well as early detection of relapsing disease with specific attention to mechanisms of resistance. Numerous opportunities therefore exist to apply ctDNA methodologies to tailor therapy for individual patients. By applying targeted next-generation sequencing of ctDNA via Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) in patients with lymphoma, these opportunities for precision oncology largely fall into two groups—identification of specific targetable molecular features and quantitative assessment of disease burden and risk. Here we explore these approaches in patients with diffuse large B-cell lymphoma (DLBCL) undergoing first-line or salvage therapy. Utilizing CAPP-Seq from pretreatment plasma, mutational genotyping of diverse somatic alterations is possible, including single-nucleotide variants (SNVs), translocations, and copy number alterations. By combining these mutations through an integrated Bayesian framework, identification of specific disease subtypes is possible, including activated and germinal center B-cell molecular cell-of-origin subtypes. In addition, detection of emergent mutations during and after treatment can provide insights into mechanisms of therapeutic resistance, many of which are potentially targetable. In addition to these insights into disease biology, ctDNA can serve as a quantitative handle on disease burden. By measuring ctDNA disease burden in DLBCL patients from six centers throughout North America and Europe, we demonstrate the prognostic value of ctDNA levels prior to treatment. Additionally, we found that a molecular response to treatment, as detected by the change in ctDNA after one or two cycles of therapy, is highly prognostic for patient outcomes in both front-line and later lines of therapy. Moreover, these molecular response features can be combined with additional outcome predictors, such as the IPI and interim PET/CT scans, to build a dynamic risk model termed the Continuous Individualized Risk Index (CIRI). CIRI provides a personalized probability of likely patient outcomes that updates over time as more information becomes available. Outcome prediction with CIRI significantly improved on predictions using ctDNA molecular response, interim PET/CT scans, or the IPI alone. In summary, liquid biopsies through ctDNA afford numerous opportunities for personalized medicine, ranging from mutational profiling and molecular subtyping to disease quantification and response prediction. Further studies of novel clinical approaches are likely to change treatment paradigms in the near future. Citation Format: David M. Kurtz. Approaches for personalized medicine in lymphoma through liquid biopsies [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA41.

P217 DISEASE BURDEN AND TREATMENT ADHERENCE AMONG CHILDREN AND ADOLESCENT PATIENTS WITH ASTHMA

To assess disease burden among asthma patients aged 5-17 years, and medication adherence of twice-daily ICS and ICS/LABA users in a large US claims database.

A Systematic Framework for Analyzing Observation Data in Patient-Centered Registries: Case Study for Patients With Depression.

BackgroundPatient-centered registries are essential in population-based clinical care for patient identification and monitoring of outcomes. Although registry data may be used in real time for patient care, the same data may further be used for secondary analysis to assess disease burden, evaluation of disease management and health care services, and research. The design of a registry has major implications for the ability to effectively use these clinical data in research.ObjectiveThis study aims to develop a systematic framework to address the data and methodological issues involved in analyzing data in clinically designed patient-centered registries.MethodsThe systematic framework was composed of 3 major components: visualizing the multifaceted and heterogeneous patient-centered registries using a data flow diagram, assessing and managing data quality issues, and identifying patient cohorts for addressing specific research questions.ResultsUsing a clinical registry designed as a part of a collaborative care program for adults with depression at Mayo Clinic, we were able to demonstrate the impact of the proposed framework on data integrity. By following the data cleaning and refining procedures of the framework, we were able to generate high-quality data that were available for research questions about the coordination and management of depression in a primary care setting. We describe the steps involved in converting clinically collected data into a viable research data set using registry cohorts of depressed adults to assess the impact on high-cost service use.ConclusionsThe systematic framework discussed in this study sheds light on the existing inconsistency and data quality issues in patient-centered registries. This study provided a step-by-step procedure for addressing these challenges and for generating high-quality data for both quality improvement and research that may enhance care and outcomes for patients.International Registered Report Identifier (IRRID)DERR1-10.2196/18366

Association of Cerebral Small Vessel Disease and Cognitive Decline After Intracerebral Hemorrhage.

To determine whether MRI-based cerebral small vessel disease (CSVD) burden assessment, in addition to clinical and CT data, improved prediction of cognitive impairment after spontaneous intracerebral hemorrhage (ICH). We analyzed data from ICH survivors enrolled in a single-center prospective study. We employed 3 validated CSVD burden scores: global, cerebral amyloid angiopathy (CAA)-specific, and hypertensive arteriopathy (HTNA)-specific. We quantified cognitive performance by administering the modified Telephone Interview for Cognitive Status test. We utilized linear mixed models to model cognitive decline rates, and survival models for new-onset dementia. We calculated CSVD scores' cutoffs to maximize predictive performance for dementia diagnosis. We enrolled 612 ICH survivors, and followed them for a median of 46.3 months (interquartile range 35.5-58.7). A total of 214/612 (35%) participants developed dementia. Higher global CSVD scores at baseline were associated with faster cognitive decline (coefficient -0.25, standard error [SE] 0.02) and dementia risk (sub-hazard ratio 1.35, 95% confidence interval 1.10-1.65). The global score outperformed the CAA and HTNA scores in predicting post-ICH dementia (all p < 0.05). Compared to a model including readily available clinical and CT data, inclusion of the global CSVD score resulted in improved prediction of post-ICH dementia (area under the curve [AUC] 0.89, SE 0.02 vs AUC 0.81, SE 0.03, p = 0.008 for comparison). Global CSVD scores ≥2 had highest sensitivity (83%) and specificity (91%) for dementia diagnosis. A validated MRI-based CSVD score is associated with cognitive performance after ICH and improved diagnostic accuracy for predicting new onset of dementia.

A practical method for multimodal registration and assessment of whole-brain disease burden using PET, MRI, and optical imaging

Many neurological diseases present with substantial genetic and phenotypic heterogeneity, making assessment of these diseases challenging. This has led to ineffective treatments, significant morbidity, and high mortality rates for patients with neurological diseases, including brain cancers and neurodegenerative disorders. Improved understanding of this heterogeneity is necessary if more effective treatments are to be developed. We describe a new method to measure phenotypic heterogeneity across the whole rodent brain at multiple spatial scales. The method involves co-registration and localized comparison of in vivo radiologic images (e.g. MRI, PET) with ex vivo optical reporter images (e.g. labeled cells, molecular targets, microvasculature) of optically cleared tissue slices. Ex vivo fluorescent images of optically cleared pathology slices are acquired with a preclinical in vivo optical imaging system across the entire rodent brain in under five minutes, making this methodology practical and feasible for most preclinical imaging labs. The methodology is applied in various examples demonstrating how it might be used to cross-validate and compare in vivo radiologic imaging with ex vivo optical imaging techniques for assessing hypoxia, microvasculature, and tumor growth.

Positron Emission Tomography in Merkel Cell Carcinoma.

Simple SummaryThere is currently no consensus on a widely accepted algorithm for imaging Merkel cell carcinoma (MCC) patients. Baseline, tomographic imaging is not generally recommended in early-stage disease, but its value in locally advanced and/or distant metastatic MCC has been well established. In this context, the hybrid imaging modality positron emission tomography/computed tomography (PET/CT) is increasingly applied in the workup of metastatic or unresectable MCC, providing essential information for staging, restaging, and treatment monitoring of the disease. Although the role of PET/CT in the management of loco-regional MCC is still limited and less well-defined, current evidence suggests its important contribution also in cases of localized MCC. Herein, we provide a structured literature review summarizing the most important studies on the role of PET or PET/CT with different radiopharmaceuticals in the clinical care of MCC.Merkel cell carcinoma (MCC) is a rare neuroendocrine skin malignancy usually arising as a nonspecific nodule on sun-exposed areas of the head and neck. Given the poor prognosis of this aggressive tumor, assessment of disease burden in pre- and post-treatment care may ensure an optimal management with significant implications for patient surveillance and prognosis. Although imaging has established its role in locally advanced or distant metastatic MCC, a standard imaging algorithm is yet to be determined and respective recommendations are mainly based on melanoma. Positron emission tomography/computed tomography (PET/CT) is increasingly evolving as a valuable imaging tool in metastatic or unresectable MCC, mostly utilizing the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) as a radiotracer. Despite being inferior in detecting the disease in its early stages compared to the “gold standard” of sentinel lymph node biopsy, recent evidence suggests an important role for 18F-FDG PET/CT in the routine workup of localized MCC. Moreover, 68Ga-labeled somatostatin analogues have been employed as PET tracers in the field of MCC with promising, yet comparable to 18F-FDG, results. This article provides a structured literature review of the most important studies investigating the role of PET or PET/CT in the clinical practice of MCC.

Assessment of Surgical Disease Burden in Zambia: Research Protocol for a Randomized Cross-Sectional Survey

Assessment of Surgical Disease Burden in Zambia: Research Protocol for a Randomized Cross-Sectional Survey

The incidence of postural orthostatic tachycardia syndrome in the population of Zagreb, Croatia

AimTo estimate the incidence of postural orthostatic tachycardia syndrome (POTS) in the population of Zagreb, Croatia, and to determine the patients’ demographic and clinical characteristics.MethodsFrom 2012-2017, we identified patients with POTS by a retrospective analysis of medical records at University Hospital Center Zagreb. Crude incidence rates were directly standardized by age according to the European and World Standard Population.ResultsOut of 385 patients with suspected POTS, 23 had a definitive POTS diagnosis. The annual incidence ranged from 3.3 to 14.8 per 1 000 000 for both sexes combined. The highest incidence rates were in the age groups 18-29 and 30-39 years, with female predominance. The mean age at diagnosis was 30.7 years (standard deviation ±9.2, range 18-52). The median duration of symptoms at diagnosis was 7.5 months (range 3-180 months). Regarding associated comorbidities, two patients had chronic gastritis and one patient had each of the following: epilepsy, prior subarachnoid hemorrhage, anxiety, mitral insufficiency, obstructive sleep apnea, hypothyreosis, and irritable bowel syndrome. In patients not fulfilling the criteria for POTS, the most common alternative diagnoses were autonomic dysfunction due to multiple sclerosis in 22, anxiety disorder in 17, epilepsy in 16, and orthostatic tachycardia due to deconditioning in 13 patients.ConclusionThe data obtained in this study can be used to optimize disease surveillance in population, comprehensive assessment of disease burden, and organization of health care services.

History and development of national burden of disease assessment in Australia

Australia’s 1996 national burden of disease (BoD) study was one of the first in the world and updates have continued over the following two decades with the fifth study now underway. The studies adapt the global framework most recently implemented by the Global Burden of Disease Study and the World Health Organization to suit Australia’s specific needs, producing estimates of fatal and non-fatal burden via the Disability Adjusted Life Year (DALY) metric, as well as attribution of the burden to many risk factors. Detailed Australian data are used with minimal reliance on modelling to fill data gaps. Comprehensive estimates are produced, including for the Indigenous population, for each of the eight states and territories, the five remoteness areas and five socioeconomic quintiles. A number of method developments have been made as part of these studies, including redistribution of deaths data and a detailed quality framework for describing the robustness of the underlying data and methods. Data and methods continue to be refined as part of the studies, and developments in global studies and other national studies are incorporated where appropriate.

Diagnostic limitations and considerations in the imaging evaluation of advanced multicentric infantile myofibromatosis

Infantile myofibromatosis, the most common fibrous tumor of infancy, is classified in 2 forms; as a solitary nodule or as numerous, widely-distributed multicentric lesions with or without visceral involvement. Although benign, multicentric myofibromas are still associated with a high incidence of morbidity and mortality due to the infiltration of critical structures. Herein, we present a case of an infant with aggressive PDGFRB and NOTCH3 mutation-negative myofibromas distributed throughout the vascular, respiratory, and gastrointestinal systems. The extensive disease resulted in pulmonary hypertension, respiratory failure and gastrointestinal obstruction refractory to chemotherapy and unamenable to surgical resection. Despite the presence of numerous highly invasive myofibromas, multiple imaging modalities largely underestimated, or even missed, tumors found at autopsy. This case demonstrates the limitations of radiographic imaging to assess disease burden in multicentric infantile myofibromatosis. The postmortem findings of extensive disease far exceeding what was demonstrated by multiple imaging modalities suggests that pediatricians should have a high index of suspicion for undetected tumors if clinical deterioration is otherwise unexplained.

Improving the leptospirosis disease burden assessment by including ambulatory patients from outpatient departments: a cross-sectional study.

Background: In Sri Lanka, the disease burden of leptospirosis is estimated based on a routine notification system, which is predominated by patients ill enough to be hospitalized. The notification system does not function well with ambulatory patients in outpatient departments (OPDs). The objective of this study was to determine the prevalence of leptospirosis in an OPD setting in a regional public hospital in Sri Lanka to provide further estimation of disease burden estimations Methods: This study was conducted in the OPD of the Rathnapura Provincial General Hospital from August to September 2017. Suspected leptospirosis patients were recruited based on standardized criteria and tested using the microscopic agglutination test and quantitative polymerase chain reaction. The number of OPD patients was compared with the reported patient numbers with leptospirosis from the hospital during the same period as the denominator, and the 95% confidence interval was calculated for the proportions using Poisson distribution. Results: During the study period, of 2,960 fever patients presenting to the OPD, 33 (1.1%) were suspected to have leptospirosis; 8/33 suspected (22.3%) cases were confirmed as being due to leptospirosis. There were 82 notifications of leptospirosis cases from hospital inpatients during the same period, none from the OPD. The total missing proportion from the surveillance system was 28.6% (95% CI, 19.4-40.4%). Among OPD patients, 12 (36.4%) had been given antibiotics from a primary care center prior to the OPD visit. No OPD patient was admitted to the hospital for inward care. Conclusions: More than 25% of cases of leptospirosis were not identified because they were not sick enough to be admitted nor subjected to routine leptospirosis diagnostic testing. Antibiotics given without a specific, treatable diagnosis interferes with leptospirosis disease burden assessment. These data have public health implications if the sources of leptospirosis transmission are to be controlled.

Migraine and tension-type headache in Germany. Prevalence and disease severity from the BURDEN 2020 Burden of Disease Study.

Headache disorders are widespread among women and men in Germany and are primarily associated with restrictions on quality of life. The two most common types of headache disorders are migraine and tension-type headache. In order to gain valid estimates of the prevalence of these conditions, a cross-sectional telephone-based survey was conducted among adults in Germany (N=5,009) between October 2019 and March 2020. The frequency, duration, the characteristics and comorbidities associated with headache were measured using the diagnostic criteria defined in the International Classification of Headache Disorders. 57.5% of women and 44.4% of men in Germany stated that they had had a headache in the last twelve months. 14.8% of women and 6.0% of men meet all of the diagnostic criteria for migraine. Tension-type headache affects 10.3% of women and 6.5% of men. Migraine and tension-type headache are predominantly found among people of working age and steadily decrease with age. Migraine is often accompanied by comorbidities such as depressive symptoms and anxiety disorders. People affected by headache disorders tend to receive very little professional medical care, with only a minority seeking treatment within a year. These results provide a comprehensive picture of the population-related impact of headache disorders and are used in the BURDEN 2020 study to quantify key indicators for burden of disease assessment.

18.K. Workshop: Burden of foodborne disease: methods and relevance of national studies

Abstract Despite increased political attention, foodborne diseases (FBD) still cause a substantial public health, economic and social burden worldwide. Recognizing the need to measure the burden of FBD and encourage evidence-informed policies, in 2015 the World Health Organization reported the first estimates of global and regional disease burden due to 31 foodborne hazards. Results showed that each year 1 in 10 people get ill from food contaminated with pathogens or chemicals, resulting in 600 million cases, 420,000 deaths and the loss of 33 million healthy years globally. While these estimates were crucial to raise awareness, they were the product of an enormous research initiative that faced substantial data gaps. Importantly, they did not offer the precision needed to identify priorities at national level, and were not able to make use of all data resources available. Precise national disease burden estimates are essential to identify the most important diseases and hazards in a country, the foods contributing most to these diseases, and the interventions need to effectively prevent disease. In recent years, various countries have recognized the need for studies of the national burden of FBD, and have taken steps to implement them. Despite progress, these are still a minority, and mostly representing high income countries in few regions of the world; many other countries still lack awareness, resources, and data to estimate burden and rank FBDs. Furthermore, the current burden of disease landscape remains scattered, and researchers struggle to translate their findings to decision makers. The recently established European Burden of Disease Network (burden-eu, COST Action 18218) will address these challenges by acting as a technical platform for integrating and strengthening capacity in burden of disease assessment across Europe and beyond. Burden-eu currently gathers members from 37 European countries and observers from non-European countries and international organizations, and has a working group focusing on foodborne diseases. This workshop consists of four presentations. In the first, an example of a well-established national burden of disease study is presented, and the utility of its results for policy making and establishing public health priorities are discussed. Next, main challenges to estimating burden of FBD in developing countries, and the experience and opportunities deriving from a large-scale research in this setting are presented. The fourth presentation will focus on the role of international organizations, in particularly the WHO, in supporting countries to develop capacity, implement and maintain country-level burden of disease studies. The workshop will end with ample time for discussions on current approaches and opportunities for methodological developments, challenges, possible solutions and potential for collaborations to increase implementation and utility of studies of FBD burden globally. Key messages National burden of foodborne disease studies are essential to establish food safety as a public health priority, identify the most important food safety problems, and inform prevention strategies. Different initiatives are emerging to support international collaboration across countries and public health authorities worldwide.

30.L. Workshop: European burden of disease network: strengthening the collaboration

Abstract The burden of disease (BoD) approach has become one of the foundations of descriptive epidemiology. Central to this approach is the use of the Disability-Adjusted Life Year as a comprehensive and comparable summary measure of population health. Driven by the impact of the Global Burden of Disease (BoD) study, several researchers and health institutes across the world have adopted the BoD approach to assess the health impact of diseases and risk factors, supporting a more rational allocation of available resources. Despite the increasing prominence of the BoD approach, several challenges remain. The BoD methodology is complex and highly data intensive, which has led to major disparities across researchers and nations in their capacity to perform BoD studies, to interpret the soundness of available BoD estimates, or to advocate for the use of BoD methods. Often, these disparities follow geographical boundaries–for instance, over half of all published BoD studies in Europe were set in the Netherlands, Spain and UK, while only 15% were set in eastern European countries. BoD as a generally standardized approach nonetheless requires different methodological choices, and lack of harmonization in these may hamper comparisons across studies. This is further aggravated by the fact that different BoD initiatives have remained scattered–there is for instance little interaction between infectious disease, nutritional and environmental epidemiologists, even though several methodological issues transcend the boundaries of diseases and risk factors. Finally, many BoD researchers are struggling to find optimal ways to translate their findings and communicate them adequately and comprehensively to decision makers and other stakeholders. In response to these needs, several countries and BoD researchers have set up ad hoc partnerships. In 2016, the WHO Regional Office for Europe (WHO-EURO) launched a European BoD network, aiming to intensify links between WHO, IHME and the WHO-EURO member states. In 2019, our group has launched a COST Action that aims to serve as a technical platform to integrate and strengthen capacity in BoD assessment across Europe and beyond. At the moment of writing, the “burden-eu” COST Action joins over 200 participants from 38 European countries, as well as several observers from non-European countries and international organizations. In this workshop, we give an overview of the current status and initial accomplishments of the COST Action, with a focus on the key challenges that the Action aims to address - i.e., increased interaction between existing efforts, methodological advances and technical capacity building at country level, and an actionable understanding of the process underlying knowledge translation. The different sessions will include interactions with the audience to learn about the needs and expectations of the attendees, and how these can be addressed by the COST Action. Key messages The burden of disease approach is increasingly used to generate comparable and comprehensive estimates of the health impact of diseases and risk factors. The 'burden-eu' COST Action offers a technical platform for integrating and strengthening capacity in burden of disease assessment across Europe and beyond.

Subspecialty-Level Deep Gray Matter Differential Diagnoses with Deep Learning and Bayesian Networks on Clinical Brain MRI: A Pilot Study.

To develop and validate a system that could perform automated diagnosis of common and rare neurologic diseases involving deep gray matter on clinical brain MRI studies. In this retrospective study, multimodal brain MRI scans from 212 patients (mean age, 55 years ± 17 [standard deviation]; 113 women) with 35 neurologic diseases and normal brain MRI scans obtained between January 2008 and January 2018 were included (110 patients in the training set, 102 patients in the test set). MRI scans from 178 patients (mean age, 48 years ± 17; 106 women) were used to supplement training of the neural networks. Three-dimensional convolutional neural networks and atlas-based image processing were used for extraction of 11 imaging features. Expert-derived Bayesian networks incorporating domain knowledge were used for differential diagnosis generation. The performance of the artificial intelligence (AI) system was assessed by comparing diagnostic accuracy with that of radiologists of varying levels of specialization by using the generalized estimating equation with robust variance estimator for the top three differential diagnoses (T3DDx) and the correct top diagnosis (TDx), as well as with receiver operating characteristic analyses. In the held-out test set, the imaging pipeline detected 11 key features on brain MRI scans with 89% accuracy (sensitivity, 81%; specificity, 95%) relative to academic neuroradiologists. The Bayesian network, integrating imaging features with clinical information, had an accuracy of 85% for T3DDx and 64% for TDx, which was better than that of radiology residents (n = 4; 56% for T3DDx, 36% for TDx; P < .001 for both) and general radiologists (n = 2; 53% for T3DDx, 31% for TDx; P < .001 for both). The accuracy of the Bayesian network was better than that of neuroradiology fellows (n = 2) for T3DDx (72%; P = .003) but not for TDx (59%; P = .19) and was not different from that of academic neuroradiologists (n = 2; 84% T3DDx, 65% TDx; P > .09 for both). A hybrid AI system was developed that simultaneously provides a quantitative assessment of disease burden, explainable intermediate imaging features, and a probabilistic differential diagnosis that performed at the level of academic neuroradiologists. This type of approach has the potential to improve clinical decision making for common and rare diseases.Supplemental material is available for this article.© RSNA, 2020.

Causes of morbidity and mortality among patients admitted in a tertiary hospital in southern Nigeria: A 6 year evaluation.

Data on morbidity and mortality are essential in assessing disease burden, monitoring and evaluation of health policies. The aim of this study is to describe the causes of morbidity and mortality in the wards of University of Calabar Teaching Hospital (UCTH). The study took a retrospective approach evaluating causes of morbidity and mortality from 2012-2017. Causes of death were documented based on International Classification of Disease 10 (ICD-10). Data were retrieved from health records department, UCTH. Overall, 2,198 deaths were recorded out of the 49,287 admissions during the study period giving a mortality rate of 4.5% comprising 1,152 (52.4%) males and 1,046 (47.6%) females. A greater number of males were admitted via accident and emergency. Age group 15-45 years had the highest number of admissions (57.9%) and deaths (37.7%), while age group >65 years recorded the highest number of deaths per admission (9.7% mortality rate). The broad leading causes of death were infectious and parasitic disease and diseases of the circulatory system (cardiovascular diseases) accounting for 22.7% and 15.8% of all deaths, respectively. However, diseases of the circulatory system recorded the highest number of deaths per admission (13.7% mortality rate). Overall, infectious diseases were the chief cause of mortality in adults while conditions originating from perinatal period were the major cause of death in children. Septicemia (6.0%), stroke (4.2%), liver diseases (4.1%), tuberculosis (3.7%), diabetes (3.6%) and HIV/AIDS (3.4%) were the specific leading cases of deaths. Sepsis, chronic diseases of the tonsil and adenoids and malaria were the specific leading causes of death in children, while sepsis, stroke and liver diseases were the leading cause of death in adults. Most causes of deaths in this study are preventable. This study revealed double burden of communicable and non-communicable diseases.

Abstract 719: Assessing the utility of cell-free DNA in identifying prostate cancer and characterizing tumor heterogeneity via targeted, whole exome, and whole genome multi-region sequencing

Abstract Early cancer diagnosis, especially while the disease is localized and before symptoms appear, results in significantly higher survival rates compared to late-stage diagnosis. At the time of diagnosis, it is also common to find multiple foci within the prostate in men with localized disease. Cell-free DNA (cfDNA) are short DNA fragments released into circulation by dying cells, which may reflect underlying disease biology and simultaneously allow for the identification of genetically distinct tumor subclones. The objectives of this study are to determine if cfDNA concentration can be used to distinguish between healthy individuals from patients with localized or metastatic castration-resistant prostate cancer (mCRPC), and if somatic mutations identified in tumor tissue are detectable in cfDNA. This study included samples from 277 individuals: 41 healthy donors, 112 patients with localized prostate cancer who underwent radical prostatectomy (RP) at UCSF, and 124 mCRPC patients. Whole peripheral blood was collected in EDTA tubes or PAXgene Blood ccfDNA tubes. Blood and matched tissue from adjacent normal seminal vesicles and multiple tumor regions (1-9 samples per patient) were collected from patients undergoing RP. Extraction of cfDNA was performed on double spun plasma using the Qiagen QIAamp Circulating Nucleic Acid Kits. After extraction, the concentration and fragment length distribution were measured with a Bioanalyzer 2100 Instrument. Fifty-seven samples (multiple tumor tissue foci and matched blood) from nine patients with localized disease were subjected to whole exome sequencing, and 22 samples from five patients were subjected to whole genome sequencing. All samples from 14 patients underwent targeted sequencing with a 2.5Mb panel generated via machine learning on TCGA prostate cancer sequence data. Somatic variant calling was performed with Broad Institute's Terra platform (GATK4/MuTect2) for tumor tissue and with the Curio platform for cfDNA to build consensus sequences leveraging duplex unique molecular tags. To estimate tumor fraction in cfDNA, ichorCNA was used to profile low pass whole genome sequence data. Total cfDNA concentration was able to distinguish between healthy and metastatic (p = 0.001) participants, adjusted for age; and also between localized and metastatic groups (p &amp;lt; 0.001), adjusted for age and PSA. Among the patients with localized disease, cfDNA concentration was not associated with age, PSA, Gleason score, or Decipher Score (a 22 gene metastasis risk-predicting RNA gene expression signature), suggesting the potential for this marker to be independent of factors that are commonly used to assess disease burden and risk of progression. Targeted sequencing of prostate tumors resulted in an average of 16 mutations with a range of 1 to 128 mutations per tissue region. The cfDNA allele frequencies for mutations identified in tumor tissue ranged from 0.5% to 20%. Four patients with variant detection in cfDNA also experienced biochemical recurrence. While copy number analysis identified clonal and potentially subclonal alterations in WGS tumor tissue, no alterations were found in WGS cfDNA. Further analysis of potential factors influencing variant detection in cfDNA (adverse pathology, starting amount of DNA, coverage) will be performed. Citation Format: Emmalyn Chen, Clinton L. Cario, Lancelote Leong, Karen Lopez, César Márquez, Carissa Chu, Patricia S. Li, Erica Oropeza, Imelda Tenggara, Janet Cowan, Jeffry P. Simko, Daniel K. Wells, Robin Kageyama, June M. Chan, Terence Friedlander, Rahul Aggarwal, Felix Feng, Pamela L. Paris, Peter R. Carroll, John S. Witte. Assessing the utility of cell-free DNA in identifying prostate cancer and characterizing tumor heterogeneity via targeted, whole exome, and whole genome multi-region sequencing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 719.

Systolic-to-diastolic myocardial volume ratio as a novel imaging marker of cardiomyopathy

BackgroundIn patients with normal left ventricular ejection fraction, it may be difficult to distinguish between the normal and diseased heart. Novel assessments of ventricular function, such as extracellular volume imaging, myocardial perfusion imaging and myocardial contraction fraction are emerging to better assess disease burden in these cases. This study endeavored to determine whether the ratio of myocardial volume in systole to myocardial volume in diastole (MVs/MVd), differs between normal hearts and those with disease states characterized by normal ejection fraction. MethodConsecutive patients from 2008 to 2018 with hypertrophic cardiomyopathy (HCM), cardiac amyloidosis, and heart failure with preserved ejection fraction (HFpEF) who underwent cardiac magnetic resonance imaging (MRI) were selected for inclusion, along with a sex- and age-matched cohort of normal volunteers who also underwent cardiac MRI. Manual tracings were performed on each MRI to calculate MVs/MVd, which was then compared across subgroups. ResultsIncluded were 50 patients with HCM, 50 patients with cardiac amyloidosis, 26 patients with HFpEF, and 30 normal subjects. Age was 54.1 years (SD 16.7); mean MVs/MVd was 0.88 (SD 0.04) in the normal subgroup, 1.03 (SD 0.06) in HCM patients, 1.03 (SD 0.06) in cardiac amyloidosis patients, and 0.97 (SD 0.02) in HFpEF patients, with all pathology subgroups different from the normal subgroup (p < .0001 for each). The ratio of MVs/MVd discriminated diseased from normal with c statistic 0.989 (p < .001). ConclusionsThis study suggests that a novel and easily-captured metric of ventricular function, MVs/MVd, can differentiate normal ventricular function from multiple cardiomyopathies with normal ejection fractions.

The Fatty Liver Assessment in Germany (FLAG) cohort study identifies large heterogeneity in NAFLD care.

Background & AimsNAFLD is a growing health concern. The aim of the Fatty Liver Assessment in Germany (FLAG) study was to assess disease burden and provide data on the standard of care from secondary care.MethodsThe FLAG study is an observational real-world study in patients with NAFLD enrolled at 13 centres across Germany. Severity of disease was assessed by non-invasive surrogate scores and data recorded at baseline and 12 months.ResultsIn this study, 507 patients (mean age 53 years; 47% women) were enrolled. According to fibrosis-4 index, 64%, 26%, and 10% of the patients had no significant fibrosis, indeterminate stage, and advanced fibrosis, respectively. Patients with advanced fibrosis were older, had higher waist circumferences, and higher aspartate aminotransferase and gamma-glutamyltransferase as well as ferritin levels. The prevalence of obesity, arterial hypertension, and type 2 diabetes increased with fibrosis stages. Standard of care included physical exercise >2 times per week in 17% (no significant fibrosis), 19% (indeterminate), and 6% (advanced fibrosis) of patients. Medication with either vitamin E, silymarin, or ursodeoxycholic acid was reported in 5%. Approximately 25% of the patients received nutritional counselling. According to the FibroScan-AST score, 17% of patients presented with progressive non-alcoholic steatohepatitis (n = 107). On follow-up at year 1 (n = 117), weight loss occurred in 47% of patients, of whom 17% lost more than 5% of body weight. In the weight loss group, alanine aminotransferase activities were reduced by 20%.ConclusionsThis is the first report on NAFLD from a secondary-care real-world cohort in Germany. Every 10th patient presented with advanced fibrosis at baseline. Management consisted of best supportive care and lifestyle recommendations. The data highlight the urgent need for systematic health agenda in NAFLD patients.Lay summaryFLAG is a real-world cohort study that examined the liver disease burden in secondary and tertiary care. Herein, 10% of patients referred to secondary care for NAFLD exhibited advanced liver disease, whilst 64% had no significant liver scarring. These findings underline the urgent need to define patient referral pathways for suspected liver disease.

Collagen-targeted molecular imaging in diffuse liver diseases

Liver fibrosis is a common pathway shared by all progressive chronic liver diseases (CLD) regardless of the underlying etiologies. With liver biopsy being the gold standard in assessing fibrosis degree, there is a large unmet clinical need to develop non-invasive imaging tools that can directly and repeatedly quantify fibrosis throughout the liver for a more accurate assessment of disease burden, progression, and treatment response. Type I collagen is a particularly attractive target for molecular imaging as its excessive deposition is specific to fibrosis, and it is present in concentrations suitable for many imaging modalities. Novel molecular MRI contrast agents designed to bind with collagen provide direct quantification of collagen deposition, which have been validated across animal species and liver injury models. Collagen-targeted molecular imaging probes hold great promise not only as a tool for initial staging and surveillance of fibrosis progression, but also as a marker of fibrosis regression in drug trials.