ASCO, Author Interviews, Biomarkers, Breast Cancer, Chemotherapy, Genetic Research, Journal Clinical Oncology / 03.03.2016 Interview with: Oleg Gluz, MD West German Study Group Breast Center Niederrhein Evangelical Hospital Bethesda Moenchengladbach, Germany What is the background for this study? Dr. Gluz: PlanB trial is a Phase III chemotherapy study performed in patients with clinically high risk HER2 negative breast cancer. After early amendement, Recurrence Score (Oncotype Dx) as a selection criterion for or against chemotherapy together with central pathology review were included into the study. Patients with very low RS of below 12 and up to 3 positive lymph nodes were recommended to omit chemotherapy based on the low genomic recurrence risk. Chemotherapy was omitted in about 15% of all patients. For the first time we present prospective data comparing a genomical tool (Oncotype Dx) and an independent central pathology review for grade, ER, PR, and Ki-67 from a large phase III study combined with an exploratory analysis on early relapse risk. What are the main findings? Dr. Gluz: The study has two major findings: We have found a significant discordance in risk assessment between prognostic tools (grade by local and central lab, Oncotype Dx, Ki-67). Patients treated by endocrine therapy alone based on very low Recurrence Score had an excellent disease free survival of 97% after 3 years of follow up. (more…)
Author Interviews, Biomarkers, Brain Injury / 03.03.2016 Interview with: Mr. Jim Joyce Chairman and CEO of Aethlon What is the background for this study? What are the main findings? Mr. Joyce: Our research into the neurodegenerative disease Chronic Traumatic Encephalopathy (CTE), was inspired by the death of Tom McHale, who was a former teammate and the second person diagnosed with CTE by our colleagues at the Boston University CTE Center. CTE is characterized by exposure to repetitive head trauma and at present, can only be diagnosed post-mortem, thus creating a significant need for a non-invasive method to diagnose and monitor CTE in living individuals. The aim of our study was to examine exosomal tau levels in plasma as a potential CTE biomarker. Our research team originally discovered the presence of exosomal tau in circulation and then established methods to quantify exosomal tau, which we refer to as a TauSome™, which we believe to be the first potential blood test to detect CTE living individuals. For this study, researchers examined 78 former National Football League players and 17 former athletes of non-contact sports, with preliminary findings suggesting that exosomal tau in plasma may be a noninvasive, accurate biomarker for CTE. The study results, published in the journal of Alzheimer’s disease, can be accessed here: (more…)
Author Interviews, Biomarkers, Cancer Research, Melanoma, Ophthalmology / 01.03.2016 Interview with: J. William Harbour, MD Professor & Vice Chairman Dr. Mark J. Daily Endowed Chair Director, Ocular Oncology Service Bascom Palmer Eye Institute Interim Associated Director for Basic Research Leader, Eye Cancer Site Disease Group Sylvester Comprehensive Cancer Center Member Interdisciplinary Stem Cell Institute University of Miami Miller School of Medicine Biomedical Research Building, Room 824 Miami FL 33136 Medical Research: What is the background for this study? What are the main findings? Dr. Harbour: Gene expression profiling has become the predominant means of molecular prognostic testing in uveal melanoma, with primary tumors being divided into Class 1 (low metastatic risk, about two thirds of cases) and Class 2 (high metastatic risk, about one third of cases).  In this study, we identified a new biomarker for uveal melanoma that subdivides Class 1 tumors based on the mRNA expression of the oncogene PRAME. Class 1 tumors not expressing PRAME have an extremely low metastatic risk, whereas those expressing PRAME have an intermediate metastatic risk. (more…)
Author Interviews, Biomarkers, Heart Disease, Lipids / 19.02.2016 Interview with: Lorenz Räber, MD, PhD Director Division CAD and MI INSELSPITAL, Bern University Hospital Bern, Switzerland Medical Research: What is the background for this study? Response: Inflammation is a key player in the pathobiology of atheorsclerosis. Inflammatory markers and specifically C-reactive protein (CRP) associate with statin-mediated clinical event reduction and plaque burden reduction in patients with stable CAD. Whether CRP correlates with changes in plaque composition, ie. an important presumed substrate of plaque vulnerability, remains unknown. We thought to assess compositional atheroma changes by means of virtual histology IVUS in relation to levels of hs-CRP in STEMI patients. For this purpose, we performed intracoronary imaging using virtual histology IVUS in the proximal part of the two non-infarct related coronary arteries of STEMI patients at baseline and 13 months follow-up (IBIS-4 study). A total of 44 patients with 80 vessels had serial imaging and hsCRP measurements available. Medical Research: What are the main findings? Response: This is the first study to show that serial changes and on-treatment levels of hs-CRP correlate with virtual histology IVUS-defined necrotic core content in patients with STEMI receiving high-intensity statin therapy. Patients with a low inflammatory activity are more likely to achieve a reduction in necrotic core, which represents a presumed substrate of plaque vulnerability. These findings may provide the basis for assessing inflammation at follow-up to monitor disease activity in STEMI patients. (more…)
Author Interviews, Biomarkers, Heart Disease, JACC / 29.01.2016 Interview with: Joseph Yeboah MD, MS Heart and Vascular Center of Excellence Assistant Professor, Cardiology Maya Angelou Center for Health Equity Epidemiology & Prevention Wake Forest University School of Medicine  Medical Research: What is the background for this study? What are the main findings? Dr. Yeboah: In 2013 the American College of Cardiology/American Heart Association introduced a new way of atherosclerotic cardiovascular disease (ASCVD) risk assessment. The document also recommended the use of additional risk markers including coronary artery calcium (CAC), ankle brachial index, high sensitivity C-reactive protein, family history of ASCVD, to refine ASCVD risk assessment for primary prevention. The goal of this study was to assess the utility of these recommended additional risk markers for primary ASCVD risk assessment in the most ethnically diverse prospective cohort in the USA. We found that among the additional risk markers considered in this analysis, only coronary artery calcium modestly improved primary ASCVD risk assessment. (more…)
Annals Internal Medicine, Author Interviews, Biomarkers, Colon Cancer, Kaiser Permanente / 27.01.2016 Interview with: Douglas A. Corley, MD, PhD Gastroenterologist and Research Scientist III Division of Research Kaiser Permanente Oakland, CA  Medical Research: What is the background for this study? What are the main findings? Dr. Corley: Colorectal cancer is a leading cause of cancer death in the United States, so understanding how cancer screening tests for this cancer are used and if they are effective is extremely important. There are two commonly used tests for colorectal cancer screening in the United States: colonoscopy and fecal immunochemical tests (also known as "FIT"). Colonoscopy requires a bowel preparation to clean you out and is invasive but, if normal, it is done infrequently (every ten years). FIT is simple to do at home but, to be most effective, needs to be done every year. This has the advantage of potentially picking up cancers that grow between tests. There are few studies that have looked at how well FIT picks up cancers when used year after year. If a test picks up most cancers, it is said to be very "sensitive" for picking up cancer. Most studies only looked at 1 or 2 years of use for how well FITdetected cancers. It is possible that the first year of use may "clear out" most of the easily detectable cancers and that FIT might not work as well in subsequent years. This very large study over several years at Kaisier Permanente, where we use both colonoscopy and FIT for colorectal cancer screening, looked at whether FIT worked as well at detecting cancer in years 3 and 4 as it did the first time someone used it. We found that the sensitivity was highest in the first year, likely from clearing out cancers that were there for a while and easily detected, but that in subsequent years the sensitivity, though 5-10% lower, remained high. Also, most people who started with FIT continued doing it, suggesting that it is both feasible and effective for colorectal cancer screening. (more…)
Author Interviews, Biomarkers, Mayo Clinic, Prostate, Prostate Cancer, Urology / 12.01.2016 Interview with: R. Jeffrey Karnes MD Department of Urology, Mayo Clinic, Rochester, MN 55905   MedicalResearch: What is the background for this study? What are the main findings? Dr. Karnes: Cancer recurrence following radical prostatectomy is a concern for men undergoing definitive surgical treatment for prostate cancer. Approximately 20-35% of patients develop a rising prostate specific antigen following radical prostatectomy for clinically localized prostate cancer. PSA monitoring is an important tool for cancer surveillance; however, a standard PSA cutpoint to indicate biochemical recurrence has yet to be established. Over 60 different definitions have been described in literature. This variation creates confusion for the patients and clinicians. By studying a large group of patients who underwent radical prostatectomy at Mayo Clinic, we found that a PSA cutpoint of 0.4 ng/mL is the optimal definition for biochemical recurrence. (more…)
Author Interviews, Biomarkers, NEJM, OBGYNE / 06.01.2016 Interview with: Stefan Verlohren, MD, PhD Consultant and Senior Lecturer Maternal-Fetal Medicine Klinik für Geburtsmedizin / Department of Obstetrics Charité Campus Mitte Berlin  Medical Research: What is the background for this study? What are the main findings? Dr. Verlohren: Preeclampsia affects 2–5% of pregnancies worldwide, and is a potentially life threatening syndrome for both mother and child. Treatment options for preeclampsia are very limited, with delivery being the only ‘cure’; however, early detection and monitoring are beneficial for improving maternal and fetal outcomes. Development of preeclampsia is very difficult to predict: its clinical presentation is variable and its signs and symptoms overlap with other conditions. There has been an unmet medical need for improved prediction of preeclampsia, i.e. predicting which women will develop preeclampsia and which will not. Women with suspected preeclampsia are often hospitalized until preeclampsia and related adverse outcomes are ruled out. Others who require hospitalization may be overlooked because their symptoms were nonspecific (e.g. headache). Preeclampsia has been linked with impaired function of the placenta. Placental development is highly dependent on blood vessel formation; before and during preeclampsia, levels of molecules involved in blood vessel inhibition or growth are altered in the maternal bloodstream. In particular, soluble fms-like tyrosine kinase-1 (sFlt-1) (a molecule that inhibits blood vessel growth) is increased and placental growth factor (PlGF) (a molecule that encourages blood vessel growth) is decreased. This study has established that the ratio of these two molecules (sFlt-1:PlGF) can be used to predict whether preeclampsia will develop or not. The sFlt-1:PlGF ratio can be calculated with a blood test (the Elecsys® sFlt-1 immunoassay and Elecsys® PlGF immunoassay). PROGNOSIS has validated the sFlt-1:PlGF ratio cutoff level of 38 for prediction of preeclampsia. For women with suspected preeclampsia, the Elecsys® immunoassay sFlt-1:PlGF ratio of 38 or below has a high negative predictive value to rule out preeclampsia or adverse fetal outcomes in the next week. A Elecsys® immunoassay sFlt-1:PlGF ratio of more than 38 indicates that preeclampsia or fetal adverse outcomes may develop in the next four weeks. In conjunction with other diagnostic and clinical information, the Elecsys® immunoassay sFlt-1:PlGF ratio can be used to guide patient management. (more…)
Author Interviews, Biomarkers, Emergency Care, Heart Disease / 21.12.2015 Interview with: Florence Leclercq, MD, PhD Department of Cardiology Arnaud de Villeneuve Hospital University hospital of Montpellier Montpellier,France Medical Research: What is the background for this study? What are the main findings? Response: Patients with history of coronary artery disease (CAD) are considered as a population with high risk of further coronary eventsHowever, frequent pre-existing ECG changes observed in these patients result in difficulty interpreting new ECG aspects in case of chest discomfort. Furthermore, anxiety frequently induced non-cardiac causes of chest pain in these patients, leading to unjustified admission to cardiology units.  Moreover, levels of troponin are usually higher in patients with previous CAD compared to patients without history of angina, resulting in difficulty interpreting baseline values in this population.  Conversely, copeptin may be influenced by the severity of myocardial ischemia and resulting endogenous stress, and could be a useful additional marker to exclude severe coronary stenosis in high-risk patients with recent chest pain. This propective monocentric study evaluates the incremental value of copeptin associated with high-sensitivity cardiac T troponin (hs-cTnT) to exclude severe coronary stenosis in 96 patients with coronary artery disease  (CAD) and acute chest pain.   Mean age of patients was 60 +/- 13.8 years and the mean time between chest pain onset and blood samples of copeptin was 4.2 +/-2.7 hours. According to clinical decision, coronary angiography was performed in 71 patients (73.9 %) and severe stenosis diagnosed in 14 of them (14.6%). No ischemia was detected on SPECT imaging (n=25). Among the 69 patients with a negative kinetic of hs-cTnT and a negative baseline copeptin, 5 (7.4%) had a severe stenosis (NPV 0.93; 95% CI: 0.87-0.99), 4 of them related to in-stent restenosis (NPV for exclusion of native coronary stenosis: 0.98; 95% CI: 0.93-1). We can conclude that in patients with preexisting CAD, and once Acute Myocardial Infarction (AMI) is excluded, copeptin increases the NPV of  hs-cTnT  to rule out severe coronary stenosis or significant myocardial ischemia. Coronary stenosis not detected with this strategy concerned exclusively in-stent restenosis or stenosis related to infarcted -related  coronary artery without myocardial viability. (more…)
Author Interviews, Biomarkers, Emergency Care, Heart Disease / 10.12.2015 Interview with: Justin A. Ezekowitz, MBBCh MSc Associate Professor, University of Alberta Co-Director, Canadian VIGOUR Centre Cardiologist  and Director, Heart Function Clinic Nariman Sepehrvand, MD Research Fellow & Graduate Student Mazankowski Alberta Heart Institute University of Alberta Edmonton, Canada  Medical Research: What is the background for this study? Dr. Ezekowitz: Major practice guidelines recommend the use of natriuretic peptide (NP) testing for diagnosing acute heart failure (HF) in emergency departments (ED). Despite these guidelines, the majority of healthcare regions all around the world (except for the United States and New Zealand) have restricted access to NP testing due to concerns over cost to healthcare systems. In the province of Alberta, Canada, however, a province-wide access to NP testing was provided for all EDs in 2012. This study investigates the factors that are related to the utilization of NP testing in EDs. Medical Research: What are the main findings? Dr. Ezekowitz: There was a substantial geographic variation in testing for NPs, despite having a single payer system and the universal availability of NP testing in Alberta. Several factors (including male sex, some comorbidities like prior heart failure, urban residence, type of care provider and ED clinical volume) influenced the utilization of testing for NPs in routine ED practice. Interestingly, patients with heart failure who were tested for NPs at ED, had a higher rate of hospital admission and lower 7 day and 90 day repeat ED visit rates compared to those who were not tested. (more…)
Author Interviews, Biomarkers, Infections, PLoS, Technology / 10.12.2015 Interview with: Leo McHugh, Ph.D. Director, Bioinformatics Immunexpress Seattle, Washington  Medical Research: What is the background for this study? What are the main findings? Dr. McHugh: Sepsis is the leading cause of child mortality in the world, and in developing countries kills more adults than breast cancer, prostate cancer and HIV combined. Approximately 30% of people admitted to ICU have sepsis, and up to 50% of these patients die. It’s a major cost burden also, costing the US health system $17 billion per year. The best way to reduce costs and improve patient outcomes is to detect sepsis early and with confidence, so that appropriate treatments can be applied. Each hour delay in the detection of sepsis has been reported to correspond to an 8% increase in mortality. So the need for a rapid and accurate diagnostic is recognized. Traditional methods rely on detection of the specific pathogen causing the infection, and these methods often take more than 24 hours, and find a pathogen in only 30% of clinically confirmed cases because they’re trying to detect a minuscule amount of pathogen or pathogenic product in the blood. Our approach was to use the host’s own immune system, which is highly tuned to respond to the presence of pathogens. Around 30% of all genes are dysregulated in sepsis, so there is a huge signal base to draw from. The trick with using multi marker host response is to pick out the specific combination of gene expression patterns that cover the broad range of patients that present with sepsis and who may present either early or late in the episode, thus with different gene activation patterns. This paper describes a simple combination of such genes that can be used to detect sepsis and performs over the full range of patients irrespective of stage of infection or severity of infection. In it’s current format, the test is manual and takes 4-6 hours, and is a great advance on the current tools, however the methods we’ve used are specifically designed to meet requirements to port this assay onto a fully automated Point of Care platform that could deliver a result in under 90 minutes. (more…)
Author Interviews, Biomarkers, Kidney Disease, University of Michigan / 07.12.2015 Interview with: Wenjun Ju, Ph.D., M.S. Research Assistant Professor, Internal Medicine Matthias Kretzler, M.D. Professor, Internal Medicine, Nephrology Research Professor, Computational Medicine and Biology University of Michigan Health System  Medical Research: What is the background for this study? What are the main findings? Response: Chronic kidney disease (CKD) is a global health issue that affects approximately 15% of the global population.. While not all patients with CKD will progress to end-stage kidney disease (ESKD), those that do tend to advance quickly and require dialysis or kidney transplant. They are also at an increased risk of death from cardiovascular disease. According to the International Society of Nephrology, treatment of CKD, including medical management, dialysis and kidney transplant, is very costly.  In the U.S. alone, therapy for CKD is likely to exceed $48 billion per year, and the ESKD program consumes 6.7 percent of the total Medicare budget to care for less than 1 percent of the covered population. In China, the disease will cost the economy the equivalent of $558 billion in the U.S. over the next decade. Early identification of patients that are more likely to experience end-stage kidney disease is an urgent, unmet clinical need. Currently, kidney biopsy is required to determine diagnosis and prognosis of kidney disease. This procedure is costly, carries a low, but significant health risk, and has limited ability to predict the future course of kidney disease. Together with the European Renal cDNA Bank and the Peking University Institute of Nephrology, the University of Michigan team identified epidermal growth factor (EGF) as a promising candidate for prediction of kidney function loss while analyzing transcriptomic data derived from kidney tissue biopsies of CKD patients across Europe and the U.S. We then validated the findings in urine samples from more than 940 patients in North America, Europe and China, and found that a decrease in urinary EGF protein concentration is an early sign of diminishing kidney function and pinpoints the at-risk patient population. (more…)
Author Interviews, Biomarkers, Heart Disease / 29.11.2015 Interview with: Lori Daniels, MD, MAS, FACC Professor of Medicine Director, Coronary Care Unit UCSD Division of Cardiology Sulpizio Cardiovascular Center La Jolla, CA  Medical Research: What is the background for this study? Dr. Daniels: A large number of individuals who are at risk for developing cardiovascular disease (CVD) may not be identified as “at risk” by traditional screening methods. Blood-based biomarkers provide a possible way, in conjunction with traditional risk factor screening, to assess risk in individuals. Two such biomarkers which are gaining widespread attention are NT-proBNP and cardiac troponin T (TnT). NT-proBNP is secreted by cardiac muscle cells in response to stretch, while TnT is consider a marker of cardiac cellular damage. Previous studies have shown that each of these markers is associated with long-term risk of cardiovascular outcomes in the general population. Race and ethnicity have been shown to affect the levels of these markers, and whether these markers are equally predictive of future cardiovascular risk in various ethnic groups has not been well studied. The Multi-Ethnic Study of Atherosclerosis (MESA) is an NIH-funded, multicenter, prospective, population-based study of white, black, Hispanic, and Chinese individuals without clinical CVD at baseline. Participants had blood drawn at a baseline study visit in 2000-2002, and again several years later, in 2004-2005. They have been followed for the development of CVD since then. The purpose of this study was to learn whether NT-proBNP (single and serial measures) and TnT are predictive of incident cardiovascular disease in a diverse cohort of 5592 participants from the MESA. We also wanted to learn whether the addition of these biomarkers to established CVD risk prediction scores, including the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Pooled Cohort Risk Equation and the Framingham Risk Score, could improve performance of the risk score. (more…)
Author Interviews, Heart Disease, Lipids / 20.11.2015 Interview with: Dr. Héctor González-Pacheco MD Coronary Care Unit, National Institute of Cardiology Mexico City, Mexico Medical Research: What is the background for this study? Dr. González-Pacheco: Epidemiological studies have provided robust evidence for an inverse correlation between plasma levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular risk. At hospital admission, a high percentage of patients with an acute coronary syndrome (ACS) have low HDL-C levels. Currently, the association of very low levels of HDL-C with early mortality in patients with ACS is still a topic of considerable interest. However, the possible mechanisms are not clear. Since an acute coronary syndrome induces an inflammatory response, and several chronic systemic diseases and acute critical illnesses with clear pro-inflammatory components have been associated with significantly reduced HDL-C levels, and investigators have shown an inverse correlation between HDL-C levels and the levels of pro-inflammatory cytokines, we hypothesized that reduced HDL-C levels in acute coronary syndrome might be associated to inflammatory mediators. We therefore sought to evaluate the correlation between HDL-C levels and biomarkers of inflammation available in routine laboratory screenings (high-sensitivity C-reactive protein (hs-CRP), white blood cell (WBC) count, and serum albumin) in a retrospective cross-sectional study of patients with ST-elevation myocardial infarction (STEMI) or non-ST-elevation ACS (NSTE-ACS). Medical Research: What are the main findings? Dr. González-Pacheco: We found that approximately one-fifth of patients had very low HDL-C levels (<30 mg/dL). Baseline levels of hs-CRP were significantly higher in these patients than in those with low (30–39.9 mg/dL) and normal (≥40 mg/dL) HDL-C levels. In contrast, serum albumin values were lower in patients with very low HDL-C levels. WBC count did not differ significantly. Accordingly, hs-CRP levels ≥ 10 mg/L and serum albumin levels ≤ 3.5 mg/dL, were two strong independent predictors of very low HDL-C levels. We observed that patients with STEMI had higher expression of biomarkers of inflammation and lower levels of HDL-C, compared with NSTE-ACS patients, as well as a lack of significant difference in the extent of coronary disease among the categories of HDL-C levels. These findings suggest that the fall in HDL-C levels is in accordance with the severity of the inflammatory response and the extent of the myocardial damage. Our findings are consistent with previous studies, in which patients with very low HDL levels had a higher rate of in-hospital mortality compared with those of other HDL-C levels. (more…)
Author Interviews, Biomarkers, Rheumatology / 13.11.2015 Interview with: Ron Rogers Executive Vice President, Corporate Communications Spokesman, Myriad Genetics, Inc. Salt Lake City, Utah 84108 Medical Research: What is the background for the MBDA test? What types of biomarkers are included in the score? Response: Vectra DA is an advanced blood test for adults with rheumatoid arthritis (RA). It helps you and your doctor better understand your rheumatoid arthritis disease activity.  Vectra DA blood test for RA gives physicians a more complete look at your disease activity by measuring 12 markers of RA disease activity. Some other tests, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR or “sed rate”), only measure one marker. Vectra DA test scores can help track your disease activity over time with an objective measure that complements your doctor’s exam and your own assessment.  Patients with high Vectra DA scores have 7-fold higher risk for rheumatoid arthritis-related joint damage than patients with low or moderate Vectra DA scores. You can learn more about the specific biomarkers at: (more…)
AACR, Author Interviews, Biomarkers, Chemotherapy, Colon Cancer, MD Anderson / 10.11.2015 Interview with: Van K. Morris,  M.D. Assistant Professor, GI Medical Oncology University of Texas – M.D. Anderson Cancer Center Houston, TX 77030  Medical Research: What is the background for this study? What are the main findings? Dr. Van K Morris: BRAF V600E mutations are associated with poor clinical outcomes for patients with metastatic colorectal cancer.  Patients were enrolled in a phase I clinical trial with the BRAF inhibitor vemurafenib, the anti-EGFR antibody cetuximab, and irinotecan.  Blood  samples were collected every two weeks with each dose, and plasma was analyzed for changes in the fraction of mutant BRAF V600E allele relative to wild-type BRAF allele with time.  Trends in circulating free DNA (cfDNA) changes were compared with radiographic changes by RECIST 1.1 criteria to examine this technique as a marker for response to therapy. For patients who had a response radiographically, drastic reductions in the BRAF V600E allele fraction were observed even after two weeks of starting therapy, well before the first restaging scan.  Patients who did not have responses radiographically had less  dramatic changes relative to baseline in the BRAF V600E allele fraction.  This technique analyzing cfDNA from plasma was validated using two different approaches – digital droplet PCR and next-generation sequencing by Guardant Health.  Sequencing of cfDNA was also compared in pretreatment and post-progression samples, and novel mutations in MEK1 and GNAS were observed uniquely in post-progression samples. (more…)
Author Interviews, Biomarkers, Lyme, Rheumatology / 10.11.2015 Interview with: Robert B. Lochhead PhD Clinical Fellow in Medicine  Division of Rheumatology, Allergy & Immunology Massachusetts General Hospital Harvard Medical School, Boston, MA Medical Research: What is the background for this study? What are the main findings? Dr. Lochhead: Lyme arthritis (LA), caused by the tick-borne spirochete Borrelia burgdorferi, usually resolves appropriately with antibiotic treatment, called antibiotic-responsive Lyme arthritis. However, in some patients, arthritis persists for months or years after spirochetal killing with oral and IV antibiotic therapy, called antibiotic-refractory Lyme arthritis. Synovial lesions in these patients show marked synovial proliferation, inflammation, and vascularization, accompanied by autoimmune T and B cell responses. MicroRNAs (miRNAs) regulate many biological processes including inflammation, immune responses, and cell proliferation, and are effective biomarkers that may reveal molecular mechanisms of disease. Our objective here was to identify extracellular miRNAs (ex-miRNAs) in synovial fluid (SF) that distinguish regulated (responsive) from dysregulated (refractory) immune responses in Lyme arthritis, thereby providing insights into underlying biological processes and potential diagnostic biomarkers to distinguish between  these disease courses. (more…)
Author Interviews, Cancer Research, JAMA, MD Anderson / 05.11.2015 Interview with: William N. William Jr., MD Associate Professor Chief, Head and Neck Section Department of Thoracic / Head and Neck Medical Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX Medical Research: What is the background for this study? What are the main findings? Dr. William: Oral pre-malignant lesions are often characterized as white and/or red patches in the mouth and are considered risk factors for oral cancer. This is why it might be best for people to go get oral cancer screening done if they suspect that there might be a problem. However, not all oral pre-malignant lesions will turn into cancer, but when this happens, surgery is usually recommended, many times leading to serious speech and swallowing dysfunction. Chemoprevention is the use of compounds to prevent cancers from happening before they occur. One of the greatest challenges in developing chemopreventive agents is to identify the population at highest cancer risk. The Erlotinib Prevention of Oral Cancer (EPOC) trial involved 379 patients at five sites across the country. All had premalignant lesions in their mouths. Following study enrollment, participants were evaluated for LOH, a chromosomal abnormality characterized by the loss of chromosomal regions, which include tumor suppressor genes. Patients who tested positive for LOH were considered to be at high risk for oral cancer and were randomized to receive either erlotinib (an EGFR inhibitor drug) or a placebo for one year. The study’s primary endpoint was to determine if fewer patients treated with erlotinib would develop oral cancer, compared to those that received placebo. The EPOC study demonstrated that LOH predicted a higher oral cancer risk. LOH-negative patients had a three-year cancer-free survival rate of 87 percent compared to 74 percent for the LOH-positive group. However, patients who took erlotinib showed no statistical difference in terms of cancer-free survival rates after three years: 74 percent for participants given erlotinib compared to 70 percent for those taking placebo. Patients with both LOH and EGFR copy number gains had the highest incidence of cancer, but still did not benefit from erlotinib. (more…)
Author Interviews, Cancer Research, Personalized Medicine / 04.11.2015

Timothy Humphrey DPhil. CRUK/MRC Oxford institute for Radiation Oncology University of Oxford, Interview with Timothy Humphrey DPhil. CRUK/MRC Oxford institute for Radiation Oncology University of Oxford, UK Medical Research: What is the background for this study? What are the main findings? Response: Multiple mutations resulting in loss of a particular histone mark (H3K36me3) are frequently found in a number of cancer types. These include mutations resulting in loss of the tumour suppressor SETD2 (which trimethylates H3K36) and over-expression of the oncogene KDM4A (which demethylates H3K36me3), which together are observed in more than 10% of a number of cancer types. Notably, loss of H3K36me3 has been reported in more than 50% of pediatric high-grade gliomas. While loss of this histone mark is associated with poor prognosis, there is no targeted therapy yet. Following observations made in fission yeast, we have found a new way to selectively target H3K36me3-deficient cancers using the WEE1 inhibitor, AZD1775. Surprisingly, treatment of H3K36me3-deficient cancer cells with the WEE1 inhibitor resulted in S-phase arrest. Further analysis revealed ribonucleotide reductase to be the target of this synthetic lethal interaction, thereby leading to dNTP starvation, replication fork collapse and cell death. (more…)
Author Interviews, Biomarkers, Brigham & Women's - Harvard, Cancer Research / 03.11.2015 Interview with: Bakhos A. Tannous, Ph.D Associate Professor of Neurology Harvard Medical School Director, Experimental Therapeutics and Molecular Imaging Lab Director, Interdepartmental Neuroscience Center Director, MGH Viral Vector Development Facility Massachusetts General Hospital Charlestown, MA 02129 Medical Research: What is the background for this study? What are the main findings? Dr. Tannous: In recent years, it has become apparent that, in addition to their role in promoting blood clotting, platelets take up protein and RNA molecules from tumors, possibly playing a role in tumor growth and metastasis. Working with our collaborators Dr. Thomas Wurdinger and Pieter Wesseling at the VU Medical Center, Amsterdam, the Netherlands, we found that the RNA profiles of tumor-educated platelets – those that have taken up molecules shed by tumors – can (1) distinguish healthy individuals and patients with six different types of cancer, (2) determine the location of the primary tumor and (3) identify tumors carrying mutations that can guide therapeutic decision making and personalized medicine. (more…)
Author Interviews, Biomarkers, Infections / 24.10.2015 Interview with: Dr. Johannes Kettunen Computational Medicine, Institute of Health Sciences, University of Oulu National Institute for Health and Welfare, Helsinki NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio Finland   Medical Research: What is the background for this study? What are the main findings? Dr. Kettunen: The initial discovery of the mortality biomarkers was made 1.5 years ago when we published the first paper describing four biomarkers indicative of 5-year mortality in two cohorts totaling over 17 000 population based samples ( We wanted to understand the molecular background of the strongest mortality predictor and this is how the current study was started. Here,  The network was enriched with defense response genes and we had an idea to test if the biomarker was predictive of future severe infections. We were able to show that chronic inflammation creates extra stress to immune system and predisposes to future infections. (more…)
Author Interviews, Baylor University Medical Center Dallas, Biomarkers, BMJ, Cancer Research / 20.10.2015

Ajay Goel, Ph.D. Investigator/Professor Director, Center for Gastrointestinal Research Director, Center for Epigenetics, Cancer Prevention and Cancer Genomics Baylor Research Institute and Charles A. Sammons Cancer Center Baylor University Medical Center Dallas, TX Interview with: Ajay Goel, Ph.D. Investigator/Professor Director, Center for Gastrointestinal Research Director, Center for Epigenetics, Cancer Prevention and Cancer Genomics Baylor Research Institute and Charles A. Sammons Cancer Center Baylor University Medical Center Dallas, TX 75246 Medical Research: What is the background for this study? What are the main findings? Dr. Goel: Colorectal cancer (CRC) remains one of the most common and lethal malignancies worldwide, and is the second leading cause of cancer-related deaths in the United States. Although there are some improvements in cancer treatments, such as development of novel chemotherapeutic drugs and technical advances in invasive treatment for metastatic lesion, there is a clear need for prognostic biomarkers that can identify high-risk patients, who can benefit from intensive post-treatment surveillance protocols for early detection of recurrence. Small nucleolar RNAs (snoRNAs) are one of the largest groups of single-stranded small ncRNAs, and in the past, snoRNAs were recognized for housekeeping functions due to their roles in rRNA maturation, while causing a relatively low impact on cellular homeostasis. However, recent evidence has revealed a new and previously unrecognized role of snoRNAs in the control of cell fate and oncogenesis in various cancers. The main finding of this study is to firstly demonstrate the clinical impact of snoRNA expression as a predictive biomarker of recurrence and poor prognosis in patients with Colorectal cancer. This study for the first time showed that higher levels of SNORA42 were associated with overall and disease-free survival, and emerged as a risk factor for the return of cancer in another part of the body. It was also correlated with high risk of recurrence and shorter survival in a smaller sample of bowel cancer patients in early stages of their disease. (more…)
Author Interviews, Biomarkers, Cleveland Clinic, Heart Disease, JACC, Kidney Disease / 12.10.2015

Dr. Wilson Tang MD Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Director of the Center for Clinical Genomics Cleveland Interview with: Dr. Wilson Tang MD Professor of Medicine Cleveland Clinic Lerner College of Medicine Case Western Reserve University Director of the Center for Clinical Genomics Cleveland Clinic  Medical Research: What is the background for this study? What are the main findings? Dr. Tang: Renal impairment has long been associated with worse outcomes in acute heart failure. Administration of diuretic therapy often obscures accurate assessment of renal function by urine output.  Despite extensive literature suggesting the poor outcomes in those with a rise in creatinine following treatment, recent data has suggested that in the presence of effective diuresis, this phenomenon likely represents hemoconcentration and azotemia rather than acute kidney injury.  We observed that using a novel and sensitive biomarker that identified acute kidney injury, specific to tubular injury, we can identify those at higher risk of adverse outcomes in patents admitted for acute heart failure.   However, after adjusting for standard risk factors, the prognostic value was clearly attenuated. (more…)
Author Interviews, Biomarkers, OBGYNE, Rheumatology / 30.09.2015

Jane E. Salmon, MD Division of Rheumatology Hospital for Special Surgery, and Weill Cornell Medical College, New York, NY Interview with: Jane E. Salmon, MD Division of Rheumatology Hospital for Special Surgery, and Weill Cornell Medical College, New York, NY  Medical Research: Background on lupus and antiphospholipid antibodies - what are they? Dr. Salmon: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease that predominantly affects women and presents during their childbearing years. In SLE, the immune system which normally protects one from infection, turns reacts against the self and can cause damage of multiple organs. Antiphospholipid antibodies (APL) occur in some people with SLE and some without SLE. They are autoantibodies that can damage the placenta and cause arterial and venous thromboses. Patients with APL can have fetal deaths, miscarriages, preeclampsia and/or growth restricted babies. Pregnancy in patients with SLE, particularly those with antiphospholipid antibodies (APL), and in patients with APL alone, is associated with an increased risk for maternal and fetal morbidity due to preeclampsia (PE) and insufficient placental support of the developing fetus. PE and placental insufficiency are, in turn, associated with adverse pregnancy outcomes (APOs), including maternal complications of PE, intrauterine fetal death, and fetal growth restriction, as well as indicated preterm delivery. Given that APOs affect over one fifth of pregnancies in SLE and/or APL, the ability to identify patients early in pregnancy who are destined for poor outcomes would significantly impact care of this high risk population. Medical Research: Two bullets about your PROMISSE study: Dr. Salmon: The PROMISSE Study (Predictors of pRegnancy Outcome: bioMarker In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus). PROMISSE is the largest multi-center, multi-ethnic and multi-racial study to prospectively assess the frequency of APO, clinical, laboratory and biomarker variables that predict APO, in women with SLE and/or APL with inactive or mild/ moderate activity at conception. Pregnant patients with SLE and/or APL were enrolled at <12 weeks gestation into PROMISSE between September 2003 and August 2013 at 7 sites (n=497) along with matched healthy controls (n=207) and followed every month of pregnancy.  (more…)
Accidents & Violence, Technology / 18.09.2015

Dr. Xiaohu Xia Ph.D. Assistant Professor Department of Chemistry Michigan Technological University Houghton, MI Interview with: Dr. Xiaohu Xia Ph.D. Assistant Professor Department of Chemistry Michigan Technological University Houghton, MI 49931 Medical Research: What is the background for this study? What are the main findings? Xiaohu Xia, Jingtuo Zhang, Ning Lu, Moon J. Kim, Kushal Ghale, Ye Xu, Erin McKenzie, Jiabin Liu, Haihang Ye. Pd–Ir Core–Shell Nanocubes: A Type of Highly Efficient and Versatile Peroxidase Mimic. ACS Nano, 2015; 150910154147007 DOI: 10.1021/acsnano.5b03525Dr. Xia: Peroxidases, a family of enzymes that catalyze the oxidation of certain compounds with peroxides, have found widespread use in areas such as biomedicine and environmental protection. Over the past several years, researchers have found that certain inorganic nanomaterials (such as nanoparticles made of metal, metal oxides, and carbon) possess intrinsic peroxidase-like activities. As the major advantage over their natural counterparts, these peroxidase mimics are much more stable because they are less vulnerable to denaturation and protease digestion. In spite of the superior stability of the mimics, improvement in their catalytic efficiency has been met with limited success. The catalytic efficiencies for most of the previously reported peroxidase mimics with sizes 1-100 nm are limited to the range of 101-104 s-1 in terms of catalytic constant (Kcat, which measures the maximum number of chemical conversions of substrate molecules per second per enzyme/mimic). Our research team have recently developed a new type of peroxidase mimic with a record high efficiency that was engineered by coating ~18 nm palladium (Pd) nanocubes with ultrathin iridium (Ir) skins of a few atomic layers (i.e., Pd-Ir core-shell cubes, see Figure). The catalytic efficiency of our Pd-Ir cubes could reach a level of Kcat = 106 s-1. In view of the substantially enhanced efficiency, we applied our Pd-Ir cubes to the colorimetric enzyme-linked immunosorbent assay (ELISA) of human prostate surface antigen (PSA) by functionalizing their surface with antibodies. The detection limit of the Pd-Ir cubes-based ELISA of PSA was determined to be 0.67 pg/mL, which is over 100-fold lower than that of the conventional horseradish peroxidase(HRP)-based ELISA using the same set of antibodies and the same procedure (see Figure). (more…)
Author Interviews, Biomarkers, Mayo Clinic, Melanoma / 17.09.2015

Dr. Roxana S. Dronca, M.D Assistant Professor of Oncology Assistant Program Director of Hematology-Oncology Fellowship Mayo Clinic College of Medicine Rochester, Minnesota Interview with: Dr. Roxana SDronca, M.D Assistant Professor of Oncology Assistant Program Director of Hematology-Oncology Fellowship Mayo Clinic College of Medicine Rochester, Minnesota  Medical Research: What is the background for this study? What are the main findings? Dr. Dronca: We previously showed that Bim (BCL-2-interacting mediator of cell death ) is a downstream signaling molecule of PD-1 pathway reflecting the degree of PD-1 interaction with its ligand PD-L1 (unpublished data). In the current study we found that patients who experienced clinical benefit (CR/PR/SD) after 4 cycles of anti-PD1 therapy had higher frequency of Bim+ PD-1+ T-killer cells in the peripheral blood at baseline compared to patients with radiographic progression, likely reflecting an abundant PD-1 interaction with its tumor-associated ligand PD-L1 (B7-H1). In addition, the frequencies of Bim+ PD-1+ CD8 T cells decreased significantly after the first 3 months of treatment in responders compared to nonresponders, indicating tumor regression and therefore less PD-1 engagement with tumor-associated PD-L1. (more…)
Author Interviews, Biomarkers, Cancer Research / 03.09.2015

Kenneth R. Shroyer, MD, PhD The Marvin Kuschner Professor and Chair Department of Pathology Stony Brook Medicine Stony Brook, NY Interview with: Kenneth R. Shroyer, MD, PhD The Marvin Kuschner Professor and Chair Department of Pathology Stony Brook Medicine Stony Brook, NY     Medical Research: What is the background for this study? What are the main findings? Dr. Shroyer: Patients that appear to have the same type of cancer often respond very differently to treatment; while some patients appear to go into long-term regression or are cured, others follow a rapid downhill course and ultimately die of their disease. This suggests that there are fundamental differences between tumors at the biologic level that are not detected by current clinical measures. In this study, we report the unexpected finding that cancer patients that have high levels of a protein called Keratin 17 (K17) have decreased long-term survival when compared to patients that express little to no K17 in their tumors. In addition, we found that K17 enters the nucleus of tumor cells to mediate the degradation of the master regulator of cell division and tumor growth key tumor suppressor protein, p27. Furthermore, we identified that K17 increases the resistance of tumor cells to chemotherapy. These are critical findings because this is the first report that a keratin is an oncoprotein that can enter the nucleus to promote the development of cancer and resistance to chemotherapy. (more…)
Author Interviews, Biomarkers, Pancreatic / 28.08.2015

Jenny Permuth Wey, PhD, MS Assistant Member Departments of Cancer Epidemiology and Gastrointestinal Oncology Moffitt Cancer Cente Interview with: Jenny Permuth Wey, PhD, MS Assistant Member Departments of Cancer Epidemiology and Gastrointestinal Oncology Moffitt Cancer Center   Medical Research: What is the background for this study? What are the main findings? Dr. Wey: Pancreatic cancer is one of the deadliest cancers world-wide. It is currently the fourth leading cause of cancer-related deaths in the United States, and is predicted to become the second leading cause by 2030. Currently there are no accurate methods to diagnose pancreatic cancer early when a patient may be eligible for surgery to remove the tumor and hopefully survive longer. To beat this disease, early detection is key, and our team has dedicated efforts to studying pancreatic cancer in its ‘precancerous’ state because we and other researchers believe that the identification and treatment of precancerous pancreatic lesions offers a promising strategy to reduce the number of people losing their lives to this disease. Similar to how colon polyps can progress into colon cancer, we now know that certain types of pancreatic cystic lesions can progress into pancreatic cancer. Pancreatic cancer precursors/pre-cancers known as intraductal papillary mucinous neoplasms (IPMNs) account for nearly one-half of the estimated 150,000 asymptomatic pancreatic cysts detected as ‘incidental findings’ on computed tomography (CT) scans or magnetic resonance imaging (MRI) scans each year during the clinical work-up for an unrelated condition.  Imaging alone cannot reliably distinguish between benign, pre-cancerous, and cancerous cysts, and cannot differentiate ‘low-risk’intraductal papillary mucinous neoplasms' (defined as low- or moderate-grade disease) that can be monitored from ‘high-risk’ IPMNs (defined as high-grade or invasive disease) that should be surgically removed.  The decision to undergo pancreatic surgery is not trivial for the patient and medical team since pancreatic surgery can be associated with an estimated 40% chance of complications and a 4% chance of death. Noninvasive tests are needed to accurately detect precancerous lesions of the pancreas so that personalized risk assessment and care can be provided. microRNAs (miRNAs) are small molecules that act as ‘master-regulators’ of cancer-related processes in the body. One of the main purposes of our ‘proof of principle’ study was to measure miRNAs in the blood and determine whether a set of miRNAs could distinguish patients with IPMNs from healthy individuals. We then sought to determine whether a set of miRNAs could distinguish patients known to have ‘low-risk’ IPMNs from those with ‘high-risk’ IPMNs.  We show that new, relatively inexpensive digital technology could reliably measure miRNAs in blood plasma (the pale yellow liquid component of blood) from individuals newly-diagnosed with pancreatic cancer precursors (IPMNs) and healthy individuals.  Thirty miRNAs out of 800 tested showed higher levels in IPMN patients compared to healthy individuals, providing a preliminary ‘miRNA signature’ that may be found only in people with early pancreatic disease, suggesting it could serve as an early diagnostic tool.  Furthermore, we also provide preliminary data to suggest that a 5-miRNA signature can partially distinguish high-risk IPMNs that warrant resection from low-risk IPMNs that can be watched.  This is important clinically because it would be opportune to personalize care such that high-risk IPMNs that warrant resection are properly identified while individuals with low-risk IPMNs are spared the substantial  risks of mortality and morbidity associated with overtreatment from unnecessary surgery. (more…)
Author Interviews, Biomarkers, Pancreatic / 17.08.2015

Tatjana Crnogorac-Jurcevic MD PhD Reader Centre for Molecular Oncology Barts Cancer Institute, Queen Mary, University of London London Interview with: Tatjana Crnogorac-Jurcevic MD PhD Reader Centre for Molecular Oncology Barts Cancer Institute, Queen Mary University of London London UK  Medical Research: What is the background for this study? What are the main findings? Dr. Crnogorac-Jurcevic: Pancreatic adenocarcinoma (PDAC) is one of the most difficult cancers to detect. More than 80% of patients usually present at a late stage, with either locally advanced or with already metastatic disease. This is one of the major reasons for a bleak prognosis of this malignancy, which is typically 3-6 months and with <5% five-year survival. However, if patients are diagnosed with stage II disease, the survival rate is 20%, and at stage I, in patients with very small tumours, the five-year survival can increase up to 60%. In order to find biomarkers for early detection of this disease, we have performed in depth GeLC/MS/MS (SDS-PAGE-liquid chromatography-tandem mass spectrometry) analysis of 18 proteomes of urine samples collected from healthy controls, chronic pancreatitis, and patients with Pancreatic adenocarcinoma and obtained around 1500 non-redundant proteins. From these, three proteins, LYVE-1, REG1A, and TFF1, were selected for further analysis based on their known biological functions and statistical difference in comparisons of the experimental groups. These biomarkers were subsequently validated using ELISA assays in a multicenter cohort of urine samples: 87 from healthy people, 92 from patients with chronic pancreatitis, and 192 from PDAC patients. Multiple logistic regression was then applied: when comparing Pancreatic adenocarcinoma with healthy urine specimens, the resulting areas under the receiver-operating characteristic curves (AUC) of the three biomarkers combined into a panel were 0.89 (95% confidence interval: 0.84–0.94) in the training dataset (70% of the data) and 0.92 (95% confidence interval: 0.86–0.98) in the validation dataset (30% of the data). When the results from the analysis of PDAC stage I–II (n=71) urine samples were compared with the healthy urine specimens, the panel achieved AUCs of 0.90 (95% confidence interval: 0.84–0.96) and 0.93 (95% confidence interval: 0.84–1.00) in the training and validation datasets, respectively. In comparison to matching plasma CA19.9 values, the only Pancreatic adenocarcinoma biomarker in widespread clinical use (albeit mostly for monitoring of the disease), the panel achieved a higher AUC of 0.97 (95% confidence interval: 0.94–0.99) than CA19.9 (AUC 1/4 0.88; 95% confidence interval: 0.81–0.95, P=0.005). When combined with CA19.9, increased AUC of 0.99 (95% confidence interval: 0.97–1.00, P=0.04) was achieved, but this was not seen in a panel combined with plasma CA19.9 in stage I–IIA PDAC (n =17) vs. healthy sample comparison. (more…)
Author Interviews, Biomarkers, Dermatology, JAMA, Pulmonary Disease, University of Pennsylvania / 12.08.2015

Misha A. Rosenbach, MD Assistant Professor of Dermatology at the Hospital of the University of Pennsylvania Assistant Professor of Dermatology in Interview with: Misha A. Rosenbach, MD Assistant Professor of Dermatology at the Hospital of the University of Pennsylvania Assistant Professor of Dermatology in Medicine Medical Research: What is the background for this study? What are the main findings? Dr. Rosenbach: Sarcoidosis is an inflammatory disease of unknown etiology where genetically susceptible patients develop multi-organ granulomatous inflammation in response to an as-yet unidentified stimulus.  Patients with sarcoidosis typically have granulomatous inflammation in their lungs, but the second most commonly affected organ is the skin; the eyes, lymph nodes, liver, heart, brain, and other organs can be affected as well.  Patients with sarcoidosis can experience a few disease trajectories; some spontaneously recover, while others have persistent, active inflammation, whereas another group can experience inflammation which leads to scarring and fibrosis.  It can be challenging to distinguish these cohorts of patients based on their lungs alone. The skin is much easier to evaluate, as it is right there on the surface, and can be examined by physicians without resorting to invasive tests or radiography.  At Penn, we developed a novel cutaneous sarcoidosis assessment tool, called the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI), which is designed to accurately measure how inflamed skin sarcoid lesions are in a given patient, as well as describing which type of cutaneous lesion patients’ have.  The CSAMI has in previously studies been shown to be reliable when used by dermatologists, with excellent inter-rater and intra-rater reproducibility. In this study, we had a group of Pulmonologists, Rheumatologists, and Dermatologists (representing the groups of physicians who most commonly care for patients with sarcoidosis, especially if there is skin involvement) evaluate a group of patients with cutaneous sarcoidosis, using the CSAMI and another sarcoidosis activity instrument, the SASI, which has also previously been used to measure skin sarcoidosis activity in a number of settings.  We were able to demonstrate that these cutaneous scoring tools are reliable and reproducible and able to accurately measure cutaneous sarcoidosis disease activity in a variety of patients with a range of skin disease severity.  We also compared the physician scores to patients’ own evaluations of their disease, and showed that the CSAMI (physician impression of disease) correlated well with patients’ own perception of their disease activity and severity. (more…)