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 MedicineMedicalResearch.com 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…)
Author Interviews, Biomarkers, Breast Cancer / 11.08.2015

Dr Stephen Chan DM, FRCR, FRCP Consultant Oncologist Breast and Gynaecological Cancers Nottingham University Hospitals Trust Honorary Professor at the University of Nottingham Visiting Professor of Cancer Medicine at Nottingham Trent UniversityMedicalResearch.com Interview with: Dr Stephen Chan DM, FRCR, FRCP Consultant Oncologist Breast and Gynaecological Cancers Nottingham University Hospitals Trust Honorary Professor at the University of Nottingham Visiting Professor of Cancer Medicine at Nottingham Trent University MedicalResearch: What is the background for this study? What are the main findings? Dr. Chan: Worldwide each year 1.68 million women are diagnosed with breast cancer and more than half a million die from the disease. Of these new cases around 12% will be classified as triple negative breast cancer (TNBC), meaning that tumour cells from these patients do not show any of the three established clinical markers that can be treated with targeted therapies. These drugs are used in addition to standard chemotherapy to improve the chance of a good treatment response, leading to prolonged disease free survival. Without these additional treatment options triple negative patients are forced to depend entirely on chemotherapy to treat their cancer. Traditionally the sensitivity of a cancer to different types of chemotherapy has been categorised is based on a tumours tissue of origin and stage. There is currently no predictive marker of response that would allow chemotherapy treatment to be tailored to individual patients. With this information a clinician can predict which patients would benefit most from a particular chemotherapy and switch any who would do poorly to an alternative. The result would be a shift to increased treatment efficacy, while avoiding toxicity from ineffective treatment, which would in turn also reduce the cost to the health service. This need is particularly acute in triple negative breast cancer cases where chemotherapy is the cornerstone of treatment. In collaboration with researchers based at Nottingham Trent University our group has been successful in finding new markers, which can predict how a patient will respond to chemotherapy treatment. One of these is HAGE (DDX43), a DEAD box RNA helicase. We have found that high HAGE expression predicts good respond to one of the main first line chemotherapy drugs, called anthracycline (Tarek MA Abdel-Fatah et al, April 2014). Our recent work (Tarek MA Abdel-Fatah, 2015) has shown that the predictive value is strong in triple negative breast cancer cases. (more…)
Anemia, Author Interviews, Biomarkers, Kidney Disease, Mineral Metabolism / 10.08.2015

MedicalResearch.com Interview with: Lac Tran, MD Division of Nephrology and Hypertension Kaiser Permanente Los Angeles Medical Center Los Angeles, CA Medical Research: What is the background for this study? What are the main findings? Dr. Tran: Abnormal serum phosphorus levels have been associated with adverse cardiovascular outcomes and progression to renal failure.  Given phosphorus’s important biological roles in cellular replication and bone mineral metabolism, we sought to investigate the association between phosphorus levels and anemia in normal kidney function and early chronic kidney disease. Our study is a population-based study among a large racially/ethnically diverse population within the Kaiser Permanente Southern California health system. Among 155, 974 individuals, 4.1% had moderate anemia and 12.9% had mild anemia.  We found that phosphorus levels greater than 3.5 mg/dL and less than 2.0 mg/dL showed a greater likelihood for moderate anemia.  Every 0.5 mg/dL phosphorus level increase demonstrated a 16% greater likelihood for moderate anemia.  The highest phosphorus tertile of our population had a 26% greater likelihood for anemia compared to the middle tertile.  We also found that female sex, Asian race, diabetes, low albumin, and low iron saturation were risk factors for anemia. (more…)
Author Interviews, Biomarkers, Brain Injury / 31.07.2015

Dr. Heinrich Thaler Trauma Hospital Meidling Vienna AustriaMedicalResearch.com Interview with: Dr. Heinrich Thaler Trauma Hospital Meidling Vienna Austria Medical Research: What is the background for this study? Dr. Thaler:  An increased prevalence of minor head injuries in elderly patients combined with the frequent use of platelet aggregation inhibitors resulted in increased hospital admissions and cranial computed tomography. We undertook the study with the aim to reduce the workload of medical staff and costs as well as the radiation burden in the management of patients with mild head injuries. Medical Research: What are the main findings? Dr. Thaler:  S 100B is a reliable negative predictor in elderly patients and/or in patients on platelet aggregation inhibitors to rule out an intracranial hemorrhage after minor head injury (S100B is an astroglial derived protein detectable in serum in the case of cerebral tissue damage). The negative predictive value of S100B is 99,6%. We conclude that S100B levels below 0.105 µg/L can accurately predict a normal cranial computed tomography after minor head injury in older patients and those on antiplatelet medication. Additionally we found no increased risk for intracranial hemorrhage in older patients or in patients receiving antiplatelet therapy. (more…)
Author Interviews, Biomarkers, Breast Cancer / 30.07.2015

Karla M. Gonye, MBA President, sphingotec LLC Cambridge, MassachusettsMedicalResearch.com Interview with: Karla M. Gonye, MBA President, sphingotec LLC Cambridge, Massachusetts MedicalResearch: What is the background for this study? Response:
  • Met- and Leu-Enkephalin: are endogenous pentapeptides of the family of opioid peptides known as opiod-growth factors (OGF)
  • Enkephalins have been widely studied and play a major role in a variety of physiological processes
    • Perception of pain
    • Regulation of stress
    • Regulation of cardiovascular function
    • Regulation of bone formation
    • Regulation of immune responses
  • Alcohol and pain relievers reduce synthesis of Enkephalins
  • Met-Enkephalin (opioid growth factor) inhibits tumor progression and metastasis and enhances natural killer cell activity1,2
  • Mechanisms3-7:
    • Opioids can directly interact with tumor cells to cause a cytotoxic or antiproliferative effect
    • Opioids can modulate host antitumor immune mechanisms
  • Opiods can also induce apoptosis
  • We need enkephalins to help inhibit tumor progression
  • At sphingotec, it was hypothesized that disease progression begins earlier than symptoms are present and that reduced enkephalins in the blood would be an indicator of future breast cancer; measurement of this hormone peptide was possible with the company’s expertise, and that test could be developed to precisely measure enkephalin.
  • This method is published in a separate publication by Ernst et al (2006) in Peptides.
  • To test this hypothesis, Sphingotec measured enkephalin levels in the MDC and MPP study populations to determine if an association could be made between lower enkephalins and risk of breast cancer: We related proenkephalin (P-ENK) in fasting plasma from 1929 healthy women (mean age 58±5.9 years) of the population based Malmö Diet and Cancer Study (MDCS) to incidence of breast cancer (n=123) using multivariate Cox proportional hazards models during 14.8 years of follow-up. For replication, P-ENK was related to risk of breast cancer (n=130) in an older independent sample from the Malmö Preventive Project (MPP) consisting of 1569 women (mean age 70.0±4.4 years), using multivariate logistic regression.
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Author Interviews, Biomarkers, Breast Cancer / 29.07.2015

Karla M. Gonye, MBA President, sphingotec LLC Cambridge, MassachusettsMedicalResearch.com Interview with: Karla M. Gonye, MBA President, Sphingotec LLC Cambridge, Massachusetts MedicalResearch: What is the background for this study? Response:
  • In experimental studies, Neurotensin and neurotensin expression was highly associated to breast cancer tissue
    • Dupouy et al (2009) investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal carcinomas (IDCs) and found that NTS is expressed in ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade 3 (p<0.05), larger tumor size (p<0.01), and the number of metastatic lymph nodes (p<0.05).
    • It was concluded from this paper that NTS/NTSR1 is a contributor to breast cancer progression.
    • Souaze et al (2006)also studied IDCs and found 34% of all tumors were positive for neurotensin and 91% positive for the NT1 receptor, suggesting the contribution of neurotensin’s involvement in the signaling cascade within breast cancer progression.  In this study, it was found that disruption of neurotensin receptor signaling by silencing RNA or using a specific NT1 antagonist in nude mice xenografted with an aggressive cell line SR48692, caused the reversion of transforming functions that lead to tumor growth.
    • These findings support the contribution of neurotensin to breast cancer progression.
    • Wu, Z. et al (2013) reviewed the contribution of the neurotensinergic system to cancer progression, as well as the regulation and mechanisms of the system in order to highlight its potential as a therapeutic target, and its prospect for its use as a treatment in certain cancers.
    • This summarizes nicely the oncogenic effects of neurotensin after stimulation signaling proliferation, survival, migration, invasion and neoangeogeneis.
    • Several other papers published demonstrate the effects of neurotensin in cancers including breast cancer.
    • New studies such as Roselli et al (2015) further demonstrate the role of neurotensin in aggressive breast cancer.
    • At sphingotec, it was hypothesized that disease progression begins earlier than symptoms are present and that elevated expression of neurotensin in the blood would be an indicator of future breast cancer; measurement of this hormone peptide was possible with the company’s expertise, and that test could be developed to precisely measure neurotensin.
    • This method is published in Ernst et al (2006) in Peptides.
    • To test the hypothesis, the first clinical study was conducted in a cohort of normal healthy population that was indentified from the Malmo Diet and Cancer study, a prospective epidemiological study of 28,449 men and women. Of this group, a subset of 4632 randomly selected subjects were identified and neurotensin was measured in all subjects. Subjects were adjusted for known breast cancer risk factors such as age, age of menarche, heredity of cancer (all), hormone status, etc. (see Table 3, Melander et al JAMA 2012) so that the factors did not influence outcomes. On a 10-15 follow up period, of these subjects, 123 breast cancer events were found to be associated with higher levels of neurotensin, with the highest quartile associated with the highest levels of neurotensin and the lowest quartile associated with the lowest levels of neurotensin. The association of elevated neurotensin was found to be statistically significant for prediction of breast cancer.
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Author Interviews, Biomarkers, Melanoma / 09.07.2015

MedicalResearch.com Interview with: Mario Mandalà, MD Department of Oncology and Haematology Papa Giovanni XXIII Hospital Bergamo, Italy Medical Research: What is the background for this study? Dr. Mandalà: In addition to their established molecular mechanism of action, growing evidence suggests that the therapeutic efficacy of BRAFi relies on additional factors that affect the tumor–host interactions, including the enhancement of melanoma antigen expression and the increase in immune response against tumor cells.  Preclinical data show that oncogenic BRAF contributes to immune evasion, and that targeting this mutation may increase the melanoma immunogenicity. Data in vitro or from animal models propose PD-L1 as a potential mechanism that favors BRAFi resistance through the modulation of host immune responses. However, demonstration of this hypothesis in the clinical setting is lacking. Medical Research: What are the main findings? Dr. Mandalà: In the present study, we have evaluated, in a homogeneous series of MMP treated with BRAFi, the association of tumoral PD-L1 IHC expression and the density of TIMC with RR, PFS and OS. Results provide the first proof-of-principle clinical evidence of the predictive and prognostic relevance of PD-L1 IHC expression and density of immune cell infiltration in BRAFV600 mutated MMP receiving BRAFi. (more…)
Author Interviews, Nature, OBGYNE / 08.07.2015

Shawn L. Chavez, Ph.D Assistant Scientist/Professor Oregon National Primate Research Center OHSU | Oregon Health & Science UniversityMedicalResearch.com Interview with: Shawn L. Chavez, Ph.D Assistant Scientist/Professor Oregon National Primate Research Center OHSU | Oregon Health & Science University Medical Research: What is the background for this study? Dr. Chavez: This study builds upon a previous study also published in Nature Communications in 2012, which demonstrated that chromosomally normal and abnormal 4-cell human embryos can be largely distinguished by combining the timing intervals of the first three cell divisions with the presence or absence of a dynamic process called cellular fragmentation. The current study further combines time-lapse imaging of embryo development and full chromosome analysis with high throughout single-cell gene expression profiling to assess the chromosomal status of human embryos up to the 8-cell stage. Medical Research: What are the main findings? Dr. Chavez: The key findings of this research were that by measuring the duration of the first cell division, one can identify which embryos are chromosomally normal versus abnormal even earlier in development. By examining gene expression at a single-cell level, we were able to correlate the chromosomal make-up of an embryo to a subset of 12 genes that are activated prior to the first cell division. These genes likely came from either the egg or sperm and can be used to predict whether an embryo will be chromosomally normal or abnormal within the first 30 hours of development. (more…)
Author Interviews, Biomarkers, Cancer Research / 02.07.2015

MedicalResearch.com Interview with: Chao Cheng, Ph.D. Assistant Professor Department of Genetics Institute for Quantitative Biomedical Sciences Geisel School of Medicine at Dartmouth Hanover NH, 03755 Medical Research: What is the background for this study? Dr. Cheng: Bladder cancer is a common tumor type, with non-muscle-invasive bladder cancer (NMIBC) representing the majority of cases. Bacillus Calmette-Guerin (BCG) treatment is an effective immunotherapy that is commonly used to treat cancers of this subtype. However, this treatment fails to suppress tumor recurrence in up to 40% of patients. For this reason, biomarkers that predict the recurrence/progression of bladder cancer and patient response to BCG therapy are needed to tailor treatment strategies to individual patients. Medical Research: What are the main findings? Dr. Cheng: We had previously developed an E2F4 signature that consisted of the E2F4 transcription factor and its target genes identified by ChIP-seq and ChIP-chip experiments. Here, we found that the E2F4 signature is predictive of the progression of both non-muscle-invasive and muscle-invasive bladder cancer. Furthermore, this signature is also predictive of patient responsiveness to intravesical BCG immunotherapy. Our results suggest that patients with positive E2F4 scores (indicating high E2F4 activity) benefit significantly from BCG therapy, while the progression of patients with negative E2F4 scores (indicating low E2F4 activity) does not show significant difference from untreated patients. (more…)
Author Interviews, Biomarkers, Melanoma / 25.06.2015

Mitchell S. Stark Senior Research Assistant/PhD Student Oncogenomics Group QIMR Berghofer Medical Research Institute Herston, Brisbane, AustraliaMedicalResearch.com Interview with: Mitchell S. Stark Senior Research Assistant/PhD Student Oncogenomics Group QIMR Berghofer Medical Research Institute Herston, Brisbane, Australia Medical Research: What is the background for this study? What are the main findings? Response: Melanomas are among the most commonly occurring cancers with the number of new cases rising each year. Melanoma is currently is listed as the 4th and 6th most common cancer in Australia and the USA with >11,000 and >76,000 news diagnoses each year.  The overall 5-year survival for melanoma is 91%, which is largely due to curative surgery for early stage disease. However, cure rates are <15% if distant metastasis occurs (stage IV). We now have evidence that current therapeutic options for late stage disease are more effective if the disease is treated with a lower disease burden.  2010). Hence, melanoma must be treated in earlier stages to maximize the chances of patient survival. Therefore, the ability to identify signs of melanoma progression sooner would be a valuable clinical tool. The use of melanoma progression markers have been used for many years however it is clear from the survival rates that melanoma must be detected before disease progresses thus highlighting that the current methods of progression detection are inadequate. We have identified a seven-microRNA panel (MELmiR-7) that has the ability to detect the presence of melanoma with high sensitivity and specificity which is superior to currently used markers for melanoma progression, recurrence, and survival. This panel may enable more precise measurement of disease progression and may herald an increase in overall survival. (more…)
Author Interviews, Biomarkers, Breast Cancer / 21.06.2015

MedicalResearch.com Interview with: Kristian Pietras, Ph.D. Göran & Birgitta Grosskopf Professor of Molecular Medicine Strategic Director of Cancer Research Lund University Dept of Laboratory Medicine Lund Div of Translational Cancer Research Lund, Sweden Medical Research: What is the background for this study? What are the main findings? Dr. Pietras: Breast cancer is the largest malignant disease among women with 1.7 million new cases worldwide each year (25% of all new cancer cases for women). The prognosis for breast cancer patients is relatively good when the disease is detected at early stages (close to 90% of patients are still alive 5 years after diagnosis). Nevertheless, metastatic disease is the cause of 90% of all cancer-related deaths. Thus, learning more about the metastatic process and finding new cures for widespread disease is justifiably at the center of clinical attention. The current study is part of our ongoing efforts to map support functions performed by the various cell types comprising the tumor stroma with the premise that decisive treatment benefit can only be achieved by targeting multiple, but distinct, cell types and pathways that collectively sustain the growth of tumors. The development of a rich vascular supply  is recognized as a key hallmark of a growing tumor necessary for the development into a clinically relevant disease. Our focus is the role of the tumor vasculature in preventing or promoting metastatic dissemination from the primary tumor. For a metastasis to form, a cancer cell must, 1) detach from its neighboring cells in the mother tumor, 2) traverse the vascular wall to escape into the blood stream, 3) exit the vasculature to enter the metastatic site, and 4) colonize the metastatic site. Recent evidence points to that the transmigration into and out of the vasculature is a regulated process of previously unrecognized importance for the metastatic process. Importantly, the fact that the process of escape into/from the vasculature is regulated also implies that it is possible to use drugs to block this process. In the present study, we have combined functional studies in advanced models of cancer and computational biology approaches to investigate the specific contribution to the metastatic process of a molecular signaling pathway emanating from the ALK1 protein expressed by endothelial cells in the vasculature. Using information from 2 different patient cohorts including a total of  nearly 2000 breast tumors, we found that patients specifically having high levels of ALK1 in the vasculature of their tumor were much more likely to develop metastatic/recurrent disease. Accordingly, therapeutic administration of a drug (dalantercept) blocking the action of ALK1 prevented metastatic dissemination in multiple mouse models of breast cancer to a large degree. In addition, combination therapy of dalantercept and a commonly used chemotherapeutic drug (docetaxel) was exceedingly effective in preventing spread of the primary tumor to the lungs. Our results suggest that the molecular features of the tumor vasculature are important to consider as potential determinants of breast cancer dissemination and that metastatic spread can be delayed by targeting the tumor vasculature. (more…)
Author Interviews, Biomarkers, Kidney Disease, University of Pittsburgh / 14.06.2015

MedicalResearch.com Interview with: Raghavan Murugan MD, MS, FRCP, FCCP Associate Professor of Critical Care Medicine and Clinical and Translational Science Core Faculty, Center for Critical Care Nephrology, CRISMA Center, Raghavan Murugan MD, MS, FRCP, FCCP Associate Professor of Critical Care Medicine and Clinical and Translational Science Core Faculty, Center for Critical Care Nephrology, CRISMA Center, John Kellum, MD Professor and Vice Chair for Research Director, Bioengineering and Organ Support Program, CRISMA Center Director, Center for Assistance in Research using eRecord (CARe)John Kellum, MD Professor and Vice Chair for Research Director, Bioengineering and Organ Support Program, CRISMA Center Director, Center for Assistance in Research using eRecord (CARe) Department of Critical Care Medicine University of Pittsburgh Pittsburgh, PA Medical Research: What is the background for this study? What are the main findings? Response: In our prior studies, we found that nearly one-half of critically ill patients in the intensive care unit who receive dialysis die by 2 months after acute illness and more than one-third of surviving patients are dialysis dependent. We sought to examine whether simple patient characteristics and inflammatory biomarkers predicted death and non-recovery of kidney function after severe acute kidney injury. We found that a combination of four simple and readily available patient characteristics including older age, lower mean arterial pressure, need for mechanical ventilation, and higher serum bilirubin levels predicted death and dialysis dependence. Higher plasma concentration of interleukin (IL)-8 in combination with the clinical characteristics also increased risk prediction. To our knowledge, this study is the first large study to examine risk prediction for outcomes after severe acute kidney injury using a panel of biomarkers in a large cohort of critically ill patients receiving dialysis. (more…)
Author Interviews, Biomarkers, Lung Cancer, Wistar / 11.06.2015

MedicalResearch.com Interview with: Qihong Huang, M.D., Ph.D. Associate professor in the Tumor Microenvironment and Metastasis Program The Wistar InstituteQihong Huang, M.D., Ph.D. Associate professor in the Tumor Microenvironment and Metastasis Program The Wistar Institute Medical Research: What is the background for this study? What are the main findings? Dr. Huang: Lung cancer is the leading cause of cancer deaths in both men and women in the United States and results in more deaths globally than breast, prostate and colon cancers combined. While the five year survival rate for early stage non-small cell lung cancer (NSCLC) is above 50%, it is less than 5% in patients with metastatic disease.  Clearly, early detection can save lives, but accurate screening tests for high-risk individuals are still lacking. Although low dose computed tomography (LDCT) has been successfully used for screening in high-risk populations, multiple negative factors are associated with recurrent LDCT screening, including false-positives and false-negatives, unnecessary invasive procedures, radiation exposure, global availability of the technology and cost. Although several non-invasive tests for lung cancer using body fluids such as blood, urine or sputum are under investigation, none are currently available. When low dose computed tomography is used for screening, patients who are 50 years old or older are frequently diagnosed with pulmonary nodules.  However, only a small fraction of the nodules detected are subsequently diagnosed as lung cancer.  In cases where it is difficult to differentiate malignant from benign nodules, it is recommended that patients with these indeterminate nodules be followed with serial LDCT, which increases radiation exposure and financial cost. A simple, inexpensive blood test that differentiates malignant from benign nodules would fill an important clinical need. In this study, we validated AKAP4 as a highly accurate biomarker in a cohort of 264 blood samples from patients with known non-small cell lung cance and 135 controls samples from two different sites including a subset of controls with high risk lung nodules.   When all 264 lung cancers were compared with all 135 controls, the area under the ROC curve (AUC) was 0.9714. When 136 stage I NSCLC lung cancers were compared with all controls, the AUC is 0.9795, and when all lung cancer patients were compared to 27 controls with histologically confirmed benign lung nodules – a comparison of significant clinical importance – the AUC was 0.9825. AKAP4 expression increases significantly with tumor stage but independently of age, gender, smoking history or cancer subtype. Follow-up studies in a small number of resected NSCLC patients revealed a decrease of AKAP4 expression post-surgical resection that remained low in patients in remission and increased with tumor recurrence. AKAP4 is a highly accurate biomarker for the detection of early stage lung cancer, lung cancer recurrence, and distinguishing malignant from benign lung nodules. (more…)
Author Interviews, Biomarkers, Chemotherapy, JAMA, Johns Hopkins, Prostate Cancer / 08.06.2015

Emmanuel S. Antonarakis, M.B.B.CH Department of Urology and Oncology Johns Hopkins University School of Medicine Baltimore, MarylandMedicalResearch.com Interview with: Emmanuel S. Antonarakis, M.B.B.CH Department of Urology and Oncology Johns Hopkins University School of Medicine Baltimore, Maryland Medical Research: What is the background for this study? What are the main findings? Dr. Antonarakis: In a previous publication, we reported that detection of the androgen receptor splice variant 7 (AR-V7; an abnormal version of the androgen receptor) in circulating tumor cells from patients with advanced prostate cancer was associated with resistance to hormonal therapies such as abiraterone and enzalutamide. Here, we aimed to explore the role of AR-V7 in the context of chemotherapy treatment. We showed that detection of AR-V7 was not associated with resistance to the chemotherapy drugs docetaxel or cabazitaxel, and that AR-V7-positive patients could still derive benefit from these chemotherapies. (more…)
Author Interviews, Biomarkers, Breast Cancer / 03.06.2015

Daniel F. Hayes, M.D. Stuart B. Padnos Professor of Breast Cancer Research University of Michigan Comprehensive Cancer Center Ann Arbor MIMedicalResearch.com Interview with: Daniel F. Hayes, M.D. Stuart B. Padnos Professor of Breast Cancer Research University of Michigan Comprehensive Cancer Center Ann Arbor MI Medical Research: What is the background for this study? What are the main findings? Dr. Hayes: We have developed a circulating tumor cell endocrine therapy index that we hypothesize will identify patients with estrogen receptor positive metastatic breast cancer but who will not benefit from endocrine (anti-estrogen) therapy. We can now semi-quantifiably measure er as well as bcl2, her2, and ki67 in a highly accurate and reproducible fashion.  We are now conducting a multi-institutional prospective trial in North America (the Circulating Tumor Cell-Endocrine Therapy COMETI study) to determine if our hypothesis is correct. (more…)
Author Interviews / 01.06.2015

Yuyuan Li, PhD Liaoning Provincial Key Laboratory of Brain Diseases Institute for Brain Disorders, Dalian Medical University College of Basic Medical Sciences, Dalian Medical University Dalian ChinaMedicalResearch.com Interview with: Yuyuan Li, PhD Liaoning Provincial Key Laboratory of Brain Diseases Institute for Brain Disorders, Dalian Medical University College of Basic Medical Sciences, Dalian Medical University Dalian China Medical Research: What is the background for this study? What are the main findings? Dr. Li: Traumatic brain injury (TBI) will become the leading cause of death and lifelong disability in the general population by the year 2020. Early determination of prognosis based on epidemiological data is the key to inform care of these patients. Neurobiochemical markers, like Ubiquitin C-terminal Hydrolase-L1 (UCH-L1) have shown a prognostic value for outcome prediction. Recently, several studies have investigated the correlation between serum UCH-L1 concentrations and TBI, however the results thus far have been inconsistent. In the present study, we conducted a systematic review and meta-analysis to evaluate the prognostic value of serum UCH-L1 concentrations after traumatic brain injury. Five studies (including 673 TBI and 1004 controls) were included in the meta-analysis and the overall results reveal that the serum UCH-L1 level was significantly higher in patients with traumatic brain injury compared to those of the control group. Importantly, there was no statistical evidence of a publication bias among the contributing studies from the result of Egger’s test either. (more…)
Author Interviews, Biomarkers, Technology / 31.05.2015

R. Kenneth Marcus, FRSC & FAAAS Professor of Chemistry Clemson UniversityMedicalResearch.com Interview with: R. Kenneth Marcus, FRSC & FAAAS Professor of Chemistry Clemson University Medical Research: What is the background for this study? What are the main findings? Prof. Marcus: We had previously shown that chromatographic columns formed from aligned capillary-channeled polymer (C-CP) fibers were highly effective in analytical scale and preparative separations of proteins from diverse media.  The C-CP fibers are extracted from commodity fibers such as polyester, nylon, and polypropylene.  The key aspects in using the C-CP fibers are very high bed porosity and rapid protein-surface mass transfer, this allows for very rapid separations.  Packing of the fibers in narrow-bore polymer tubing (0.8 mm id x 1 cm long) allows them to be fixed to the end of a micropipette tip.  Urine samples of 10 microliter-to-milliliter volumes can be spun through on a microcentrifuge, washed with DI-water, and then eluted with a solvent.  Thus the proteins are isolated and pre-concentrated on the fiber surface.  The elution solvent can be chosen based on the analytical method employed (e.g., MALDI- or ESI-MS).   (more…)
Author Interviews, Biomarkers, Transplantation / 29.05.2015

MedicalResearch.com Interviews with: Dr. Sunil M. Kurian Ph.D.Lead- Biomarker Discovery at the Laboratory of Functional Genomics and Cell Therapy The Scripps Research Institute and Transplant Genomics Inc.Dr. Sunil M. Kurian Ph.D. Lead- Biomarker Discovery at the Laboratory of Functional Genomics and Cell Therapy The Scripps Research Institute and Transplant Genomics Inc. and   Dr. John J. Friedewald, MDAssociate Professor of Medicine and Surger Northwestern University’s Feinberg School of Medicine and a transplant nephrologist at Northwestern Memorial Hospital and the Kovler Organ Transplant CenterDr. John J. Friedewald, MD Associate Professor of Medicine and Surgery Northwestern University’s Feinberg School of Medicine and a transplant nephrologist at Northwestern Memorial Hospital and the Kovler Organ Transplant Center Editor’s note: These interviews are based on two abstracts presented at the American Transplant Congress 2015. MedicalResearch: What is the background for these studies? Response: Previous studies by the scientific founders of Transplant Genomics Inc. helped lay the groundwork for the company’s development of genomic biomarker tests for kidney transplant graft status and demonstrated feasibility as noninvasive monitoring tools that could enable differential diagnosis of graft status in kidney transplant recipients.1-3 These included a study involving five transplant centers published in the American Journal of Transplantation.4 In that study, peripheral blood gene expression profiling was used to classify kidney graft recipients into three key categories of graft status based on gene expression signatures – clinical acute rejection, acute dysfunction no rejection, and stable graft performance - with very high predictive accuracy. STUDY A: Validation of Blood and Biopsy Gene Expression-Based Molecular Diagnostics for Subclinical Acute Rejection: Comparing DNA Microarrays vs. Next-Generation RNA Sequencing  MedicalResearch: What are the main findings? Response: The current study presented recently at the 2015 American Transplant Congress5 validated that gene expression signatures as indicators of kidney graft status can be detected as robustly with RNA sequencing as with microarrays, with implications for reduced cost of analysis, faster turnaround times and improved throughput for sample processing. In this study, we substantiated RNA sequencing as an alternative data generation platform for analyzing gene expression profiles in peripheral blood and tissue from kidney transplant recipients. The data validated that gene expression signatures for subclinical acute rejection (a histological acute cellular rejection in the presence of a normal or stable serum creatinine that is associated with decreased graft survival), clinical acute rejection and stable graft performance can be detected as robustly with RNA sequencing as with microarrays. MedicalResearch: What should clinicians and patients take away from your report? Response: The key point of this study is that gene expression profiles generated and validated using microarray technology have been successfully translated to a technology platform based on RNA sequencing. Sequencing has the potential to offer advantages such as reduced cost of analysis, faster reporting back to the clinician and improved throughput for sample processing. In addition, it could facilitate development of kits enabling standardized assay performance on local lab-based sequencing systems and expansion of test use worldwide. (more…)
Author Interviews, Biomarkers, Nature, Prostate Cancer, Technology / 27.05.2015

Gabriel Popescu PhD Associate Professor Department of Electrical and Computer Engineering & Bioengineering University of Illinois at Urbana-Champaign Beckman Institute for Advanced Science and Technology Urbana, IL 61801MedicalResearch.com Interview with: Gabriel Popescu PhD Associate Professor and Shamira Sridharan, Ph.D. candidate Quantitative Light Imaging Laboratory, Department of Bioengineering, Beckman Institute for Advanced Science and Technology University of Illinois at Urbana Champaign Urbana, IL Medical Research: What is the background for this study? What are the main findings? Dr. Popescu: We developed a new optical tool that can identify patients at high risk for recurrence of prostate cancer after undergoing radical prostatectomy as treatment.  Early identification of risk for recurrence can allow early treatment of disease. Our main finding was that among individuals with worse disease outcomes, the tissue is more disorganized.  This manifests as a decrease in anisotropy, or light scattering angle, which reports on nano-scale differences in tissue architecture. (more…)
Author Interviews, Biomarkers, Colon Cancer / 22.05.2015

Dr. Jeanne Tie Medical Oncologist | Royal Melbourne and Western Hospital Research Fellow Walter and Eliza Hall Institute of Medical Research Parkville, VICMedicalResearch.com Interview with: Dr. Jeanne Tie Medical Oncologist | Royal Melbourne and Western Hospital Research Fellow Walter and Eliza Hall Institute of Medical Research Parkville, VIC Medical Research: What is the background for this study? Dr. Tie: The increasing number of active agents available to treat metastatic colorectal cancer has resulted in an ever-improving life expectancy in this group of patients. However, the ability to expose patients with metastatic colorectal cancer to all effective anti-cancer treatment, particularly 3rd line treatment and beyond, is increasingly challenging in routine practice as some patients’ condition deteriorate too rapidly and do not live long enough to enjoy the benefit of these additional therapies. This is partly due to the current imaged-based method of assessing treatment response with the Response Evaluation Criteria in Solid Tumors (RECIST), which is usually performed every 8-12 weeks during the course of treatment. This means that for non-responders to treatment, several weeks to months will elapse before a switch to alternative therapy will be made. Conceptually, if a patient’s response to treatment could be made earlier, such as with a blood test,  then an earlier switch to an alternative treatment can be made, minimizing the side-effects of the ineffective therapy and providing the opportunity for a more effective one. Currently, blood biomarkers add little to imaging-based assessment, with CEA lacking sensitivity and specificity. Colorectal cancer is characterised by several recurrently mutated genes and advances in genomics and molecular technologies have now enabled rapid detection and quantification of these cancer-specific mutations in patient’s circulation (circulating tumor DNA - ctDNA). Previous studies have demonstrated that ctDNA can be detected in a high proportion of patients with advanced cancer. In this study, we describe the potential role of ctDNA as an early predictor of treatment response in patients with treatment naïve metastatic colorectal cancer (mCRC) undergoing chemotherapy and as a marker of disease bulk that could complement RECIST measurement. (more…)
Author Interviews, Biomarkers, Breast Cancer / 19.05.2015

Lao Saal, M.D. Ph.D.MedicalResearch.com Interview with: Lao Saal, M.D. Ph.D. Head, Translational Oncogenomics Unit Assistant Professor Department of Oncology and Pathology Lund University Cancer Center Lund, Sweden Medical Research: What is the background for this study? Dr. Saal: About a quarter of women diagnosed with primary (non-metastatic) breast cancer will unfortunately progress and later be found to have metastatic spread, which can occur many years to even a decade or more after the first diagnosis. At this point, the prognosis after identification of metastatic breast cancer is very poor. Metastatic disease is typically diagnosed only after it has grown large enough to cause symptoms, be noticed on exam, or be detectable by imaging. It is thought that early detection of metastasis has the potential to lead to better outcomes because therapies could be modified when the metastasis is still very small. Moreover, a very sensitive and specific test that could identify patients who appear "cancer-free" could also be useful. Essentially all cancers have unstable genomes, where chromosomes physically break and are reassembled incorrectly and thus the normal sequence is altered. Importantly, DNA material from cancer cells can be found in the blood circulation and therefore this circulating tumor DNA has the potential to be a cancer biomarker. Medical Research: What are the main findings? Dr. Saal: Eleonor Olsson, a PhD student in my lab who defends her thesis next week, and Christof Winter, a postdoc bioinformatician in my group, were the first authors of the paper. In our study we tested whether periodic monitoring of circulating tumor DNA (ctDNA) in blood plasma samples, taken before surgery for primary breast cancer and at multiple timepoints after surgery, could identify the metastastic spread, and whether the quantity of ctDNA was associated to patient outcome. We analyzed a retrospective cohort of 20 patients, who had enrolled many years ago in a separate epidemiological study run by Helena Jernström in our department, wherein the appropriate blood plasma samples had been biobanked and tumor tissue was available and we had long-term clinical follow-up information. As far as we are aware, our study is the first to show the potential for serial ctDNA monitoring in the context of primary breast cancer. We found that our ctDNA blood tests could discriminate patients with eventual metastasis from those with long‐term disease‐free survival with 93% sensitivity and 100% specificity. Furthermore, ctDNA‐based detection of metastatic disease preceded clinical detection for 86% of patients by an average 11 months and in some cases by 3 years. In all of the patients who had long-term disease-free survival, we did not detect any ctDNA in any timepoints after surgery. Lastly, the measured quantity of ctDNA was a significant predictor of outcome: for each doubling of the ctDNA level, the odds ratio for metastasis was 2.1 and the odds ratio for death was 1.3. An interesting anecdote -- one patient we studied had bilateral breast cancer and we found that it was the right-side tumor (which actually had more favorable clinical characteristics) that gave rise to the metastasis and not the left-side tumor. (more…)
Author Interviews, Biomarkers, Brain Injury / 13.05.2015

MedicalResearch.com Interview with: Pashtun Shahim, MD Departement of Neurosurgery, University Hospital, Linköping, Sweden Clinical Neurochemistry Laboratory Institute of Neuroscience and Physiology Sahlgrenska University Hospital Mölndal Sweden Medical Research: What is the background for this study? What are the main findings? Response: Visinin-like protein-1 (VLP-1 or VILIP-1) is a neuronal calcium-sensor protein, originally studied as a stroke marker and identified as a marker of neuronal injury in brain injury models. Increased plasma and cerebrospinal fluid (CSF) VILIP-1 hase been reported in Alzheimer’s disease, where CSF VILIP-1 correlates with CSF total tau (T-tau) and with brain volume. Recently, using a novel ultrasensitive method to measure tau in plasma, increased levels of plasma T-tau were found in concussed professional ice hockey players, where the levels correlated with the resolution of post-concussive symptoms and the players returning to play. The main findings of this study were that VILIP-1 did not increase significantly in serum after sports-related concussion. However, the serum levels of VILIP-1 increased after a friendly game without concussion, signaling extracerebral expression. (more…)
Author Interviews, Biomarkers, UCSF / 10.05.2015

Alan H.B. Wu, PhD, DABCC Professor Laboratory Medicine Chief, Clinical Chemistry Laboratory University of California San Francisco, CAMedicalResearch.com Interview with: Alan H.B. Wu, PhD, DABCC Professor Laboratory Medicine Chief, Clinical Chemistry Laboratory University of California San Francisco, CA Medical Research: What is the background for this study? What are the main findings? Response: Clinical trials are conducted for validation of novel biomarkers.  There is considerable heterogeniety in the quality design and documentation of findings. This can have a major impact on the conclusions rendered. (more…)
Author Interviews, Biomarkers, Lancet, Lymphoma, NIH / 06.04.2015

MedicalResearch.com Interview with: Dr. Mark Roschewski, MD and Dr Wyndham H Wilson MD-PhD Lymphoma Therapeutics Section Lymphoid Malignancies Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda, MD 20892 Medical Research: What is the background for this study? What are the main findings? Response: Monitoring patients with diffuse large B-cell lymphoma (DLBCL) has relied on computed tomography (CT) scans which are imprecise, expensive and include radiation. We investigated the ability of a blood-based assay to monitor patients with DLBCL during and after their initial therapy. The assay we studied amplifies and quantifies small amounts of circulating tumor DNA from the patient’s blood. We showed that this assay effectively predicts which patients will relapse and identifies recurrence 3.5 months before CT scans. (more…)
Author Interviews, Biomarkers, Infections / 03.04.2015

Wikipedia mosquitoMedicalResearch.com Interview with: Amalia Z. Berna CSIRO Food and Nutrition Flagship Acton ACT 2601 MedicalResearch: What is the background for this study? What are the main findings? Response: Globally an estimated 3.2 billion people in 97 countries are at risk of malaria and, in 2013, an estimated 198 million cases and 584,000 deaths were attributed to this infection. Accurate diagnosis of malaria is important to provide adequate treatment, conserve valuable drugs, and help prevent the emergence of resistant strains of the parasite. It is becoming important to be able to diagnose low level and asymptomatic cases, to support the drive towards local and/or global eradication. Detection of volatile chemicals in expired breath has been used to diagnose or monitor a small number of diseases, including Helicobacter pylori infection, diabetes and lung inflammation but, if breath analysis is to be more broadly useful, we need to identify reliable biomarkers for a wider range of diseases and to develop more robust methods for breath analysis. In collaboration with Professor James McCarthy of the QIMR Berghofer Institute and Associate Professor Kevin Saliba of the ANU, we found:
  1. Four specific thioether biomarkers in the breath of volunteers with experimentally induced blood stage Plasmodium falciparum
  2. That the levels of the volatiles strongly correlate with the levels of malaria parasitaemia.
  3. That the thioethers are not produced by in vitro cultures of falciparum.
  4. That although we do not know the metabolic origin of the thioethers, our results suggest that interplay between host and parasite metabolic pathways is involved in their production.
We think it is important to emphasise that no volunteer was infected with malaria primarily for the purpose of this study. Our research was entirely piggy-backed on pre-existing trials of malaria therapeutics. (more…)
Author Interviews, Biomarkers, Emergency Care, Heart Disease / 02.04.2015

MedicalResearch.com Interview with: Anne Vorlat MD Department of Cardiology Antwerp University Hospital Department of Cardiology, Edegem, Belgium MedicalResearch: What is the background for this study? What are the main findings? Dr. Vorlat: Early diagnosis of myocardial infarction is critical for optimal treatment and prognosis of the patient. The third universal definition of myocardial infarction states that a rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit is mandatory with symptoms and or ST segment changes on the ECG. Since the development of more sensitive assays for cardiac troponins, myocardial injury can be detected earlier. This has permitted to shorten the timing of the second sampling of cardiac biomarkers from 6h to 3h after the first sampling. Recent studies have tested biomarker protocols with a very short delay (e.g., 1 hour) or with a single measurement of troponin and copeptin (a marker of endogenous stress, not cardiac specific) to rule in or to rule out myocardial injury in a population with chest pain. Although these newer protocols appear to be promising, early presenters (chest pain for less than 2 hours) are underreported. The present study evaluated the usefulness of early rule-in and rule-out biomarker protocols to estimate ischemia-induced myocardial injury in an early presenter model. The “early presenter” model was tested in 107 stable patients after a short period of myocardial ischemia, induced by stenting of a significant coronary artery stenosis. High-sensitivity troponin T (hsTnT), hsTnI and copeptin were measured at the start, and 90, 180 and 360 minutes after stent implantation. We confirmed our hypothesis that short biomarkers protocols underestimate myonecrosis in early presenters. (more…)
Author Interviews, Biomarkers, Colon Cancer / 28.03.2015

MedicalResearch.com Interview with: Professor Massimiliano Mazzone and Professor Hans Prenen Lab of Molecular Oncology and Angiogenesis VIB Vesalius Research Center University of Leuven Leuven Belgium Medical Research: What is the background for this study? What are the main findings? Response: Monocytes are circulating cells with patrolling behaviour. In case of harmful situations, they go to the site of injury rapidly to ensure immune and wound-healing functions. Once in the inflammation site, they differentiate into macrophages which are versatile cells adopting different phenotypes according to the stimuli they are subjected to. We hypothesized that cancer cells might release signals and soluble factors that educate and change monocytes already when in circulation. In this work, we proved our hypothesis and found that soluble molecules released by colorectal cancer cells imprint a specific signature in the circulating monocytes. Now, by collecting these monocytic cells from the blood, we are able to determine if colorectal cancer cells are present in the body, either at the primary site (in the colon) or in distant organs (where cancer cells give rise to metastases). (M. Mazzone). (more…)
Author Interviews, Biomarkers, Rheumatology / 24.03.2015

Dr Naila Rabbani Reader of Experimental Systems Biology Protein Damage and Systems Biology Research Group, Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick, Clinical Sciences Research Laboratories, University Hospital U.K.MedicalResearch.com Interview with: Dr Naila Rabbani Reader of Experimental Systems Biology Protein Damage and Systems Biology Research Group, Division of Metabolic & Vascular Health, Warwick Medical School, University of Warwick, Clinical Sciences Research Laboratories, University Hospital  U.K. Medical Research: What is the background for this study? What are the main findings? Dr Rabbani: We performed a study to investigate biochemical markers indicative of early-stage decline in joint health and development of early-stage osteoarthritis OA), rheumatoid arthritis (RA) and other inflammatory joint disease. The main finding was that by combining measures of three substances in blood - citrullinated protein (CPs), antibodies to CPs and hydroxyproline we could detect and discriminate between early-stage osteoarthritis and rheumatoid arthritis. (more…)
Author Interviews, Biomarkers, Melanoma, NYU, Personalized Medicine / 24.02.2015

Iman Osman, MD Professor, Departments of Dermatology, Medicine and Urology Associate Director, NYU Cancer Institute Director, Interdisciplinary Melanoma Program New York University Langone Medical Center New York, NY 10016MedicalResearch.com Interview with: Iman Osman, MD Professor, Departments of Dermatology, Medicine and Urology Associate Director The Laura and Isaac Perlmutter Cancer Center Director, Interdisciplinary Melanoma Program New York University Langone Medical Center New York, NY 10016 MedicalResearch: What is the background for this study? What are the main findings? Dr. Osman: We were interested in exploring molecules that could be biomarkers or functional regulators of metastasis in melanoma in early-stage tumor lesions on the skin. Though these tumors are treated largely the same (by surgical removal ), patients with these tumors have vastly different outcomes (apparent cure vs. metastatic spread of the disease). The reasons for these disparities are unclear and we have little ability to identify or predict the patients that will be cured and those that won’t. We also don’t have much data to know even if these tumors have differences at the molecular level. Our findings indicate that there are molecular differences in these tumors and that some of these differences contribute to tumor spread.  (more…)