AACR, Author Interviews, Biomarkers, Cancer Research, Colon Cancer, Technology / 27.04.2016

MedicalResearch.com Interview with: Dr. Elodie Sollier PhD Chief Scientific Officer at Vortex Biosciences MedicalResearch.com: What is the background for this study? What are the main findings? Response: Vortex Biosciences has developed a fast and simple way to isolate and collect intact circulating tumor cells (CTCs) directly from whole blood in less than an hour using a process based on microfluidics. To better understand the utility of the technology for the clinical setting, PCR-based Sanger sequencing was used to profile the mutations of CTCs isolated from blood from metastatic Colorectal cancer patients. The mutations were compared to primary tumor biopsies, secondary tumor biopsies and ctDNA. There are 3 primary take-aways:
  1. The Vortex technology captures CTCs with enough purity to perform sensitive and accurate PCR-based Sanger sequencing.
  2. Mutations present in primary and secondary tumors can be identified in both CTCs and ctDNA making liquid biopsies a valuable alternative to tissue biopsies.
  3. While there is general consistency of mutations identified, some mutations are only identified in CTCs while others only in ctDNA demonstrating how these are indeed complimentary.
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Author Interviews, Cancer Research, Cost of Health Care, Radiology / 20.04.2016

MedicalResearch.com Interview with: Dr. Christine Fisher MD, MPH Department of Radiation Oncology University of Denver MedicalResearch.com: What is the background for this study? Dr. Fisher: Screenable cancers are treated by oncologists every day, including many in invasive, advanced, or metastatic settings.  We aimed to determine how health insurance status might play into this, with the hypothesis that better access to health care would lead to presentation of earlier cancers.  While this sounds intuitive, there is much debate over recent expansions in coverage through the Affordable Care Act and how this may impact health in our country. MedicalResearch.com: What are the main findings? Dr. Fisher: The findings confirm that those without health insurance present with more advanced disease in breast, cervix, colorectal, and prostate cancers, including tumor stage, grade and elevated tumor markers.  That is to say, all else being equal for risk of cancer, lack of health insurance was an independent risk factor for advanced presentation.  (more…)
Author Interviews, Cancer Research, PLoS, Vitamin D / 15.04.2016

MedicalResearch.com Interview with: Sharon L. McDonnell MPH GrassrootsHealth Encinitas, California Medical Research: What is the background for this study? What are the main findings? Response: Higher vitamin D levels in the blood have been associated with a lower risk of multiple cancer types including colorectal and breast. Using data from two study cohorts of women aged 55 years and older (N=2,304), we investigated the association between serum 25(OH)D concentration, the marker of vitamin D in the blood, and risk of all non-skin cancers combined across a broad range of 25(OH)D concentrations. We found that women with 25(OH)D concentrations ≥40 ng/ml had a 67% lower risk of cancer compared to women with concentrations <20 ng/ml. We also found that the greatest decrease in risk occurred between ~10-40 ng/ml. These findings suggest that increasing 25(OH)D concentrations to a minimum of 40 ng/ml could substantially reduce  cancer incidence and associated mortality in the population. (more…)
Author Interviews, BMJ, Cancer Research, Education / 08.04.2016

MedicalResearch.com Interview with: Dr Alex Ghanouni Research Associate UCL Research Department of Epidemiology and Public Health Health Behaviour Research Centre London MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Ghanouni: This study comes out of growing concern among academics, doctors, and policymakers about the unintended harms of healthcare interventions. One prominent issue in the ongoing debate is ‘overdiagnosis’, that is detection of disease that would not have caused symptoms or death if it had remained undetected. There are many contexts in which overdiagnosis can occur but one of the most prominent is cancer screening, in which asymptomatic individuals undergoing testing may have slow-growing cancers detected that would never have otherwise come to light. However, because it is impossible to be sure which cancers are slow-growing and which are aggressive, most are treated. This means that overdiagnosis can lead to harm through the anxiety caused by a disease label and the negative effects of treatment (e.g. surgery) that is actually unnecessary. Despite professional concern about overdiagnosis, previous research has found that the public is mostly unaware that it exists. One study that was particularly relevant to our research was an Australian survey in which members of the public were asked whether they had encountered the term before and what they thought it meant. Although around half the sample stated that they had heard or seen the term before, only 41% were able to provide a definition that was approximately correct. We tested the extent to which this was true as part of an online survey of adults aged 50-70 years in the UK. We found that recognition of the term was very low (only 30%) and almost no-one (3%) gave an answer that was strictly accurate. Responses often indicated misconceptions (e.g. “misdiagnosis”, “false positive diagnosis”, or being “overly health conscious”). (more…)
Author Interviews, Cancer, Cancer Research, End of Life Care / 06.04.2016

MedicalResearch.com Interview with: Holly G. Prigerson, Ph.D. Irving Sherwood Wright Professor in Geriatrics Professor of Sociology in Medicine Director, Center for Research on End of Life Care Weill Cornell Medicine New York Presbyterian Hospital New York City, New York 10065  MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Prigerson: Patients need to know their prognosis to be informed consumers of end-stage cancer care. We found that most patients have an overly optimistic view of their life-expectancy and that few patients base their life expectancy estimate on communications with their healthcare providers. It was striking that 0% of black patients said their prognostic estimate was based on a medical professional. (more…)
Author Interviews, Cancer Research, Technology, UCLA / 26.03.2016

MedicalResearch.com Interview with: Dr. David Wong D.M.D, D.M.S.C Professor Associate Dean for Research Director for UCLA Center for Oral/Head & Neck Oncology Research (COOR) Felix and Mildred Yip Endowed Chair in Dentistry UCLA MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Wong: The EFIRM technology is an electrochemical technology developed for the optimal detection of saliva targets for molecular diagnostics. It is a multiplexible platform (nucleic acid and proteins) that has sensitivity and specificity that comparable with PCR and luminex-based assays. It permits direct target detection in bio-samples without processing. (more…)
Author Interviews, Cancer Research, JAMA, Pediatrics / 25.03.2016

MedicalResearch.com Interview with: Lee J. Helman, MD Senior Investigator Pediatric Oncology Branch Head, Molecular Oncology Section Acting Director, Center for Cancer Research and CCR Scientific Director for Clinical Research National Cancer Institute Bethesda, Maryland MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Helman: It was known that most gastrointestinal stromal tumors (GISTS) that occur in children and young adults do not contain cKIT or PDGFRA mutations that drive more than 90% of adult GIST tumors.  Since GISTs are quite rare in the pediatric and young adult population, we decided to establish a clinic at NIH that would allow us to study the most patients to try to define these tumors both clinically and molecularly. We were able to bring both patients and physicians interested in pediatric GIST from around the country to the NIH to begin to collect and study these patients. Of the 95 patients in this cohort study that lacked cKIT or PDGFRAmutations, 84 were found to have succinate dehydrogenase (SDH) deficient (SDH-deficient) GIST (75% due to SDH A, B, C, or D mutations, and 25% due to SDHC promoter hypermethylation. Since these tumors are driven by SDH loss and not due to KIT or PDGFR mutations, they do not generally respond to standard treatments for GIST that target these kinases. The mechanism of SDH-deficiency is important, since SDH mutations are commonly germ line and therefore require genetic counseling and family testing, while the SDHC promoter methylation is not a germ line alteration and therefore does not require genetic counseling.  Finally, any patient with SDH-deficient GIST is also at risk for development of paraganglioma and should be screened on a regular basis for these tumors.  (more…)
Author Interviews, Cancer Research, Imperial College / 21.03.2016

MedicalResearch.com Interview with: Dr Olivier E Pardo PhD Team Leader Imperial College Division of Cancer Hammersmith Hospital London UK  MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Pardo: Metastatic dissemination, the ability of tumour cells to go and colonise organs distant from the primary disease site, is the principal cause for failing to cure patients with cancer. This is particularly true in the case of breast cancer where resection of local disease offers good chances of cure but metastatic dissemination that may appear at a later stage carries very poor prognosis. Surgical resection is also the only true curative strategy for localised lung cancer. Hence, a better understanding of the mechanisms controlling the dissemination of tumour cells is likely to propose novel targets for combination therapy that will improve the survival of cancer patients. Here, we showed that an enzyme, named MARK4, controls the ability of lung and breast cancer cells to move and invade. When we lower MARK4 levels, it prevents cancer cells from moving by changing their internal architecture, making them unfit to invade. Consequently, these cells were unable to efficiently form metastasis in mouse cancer models. Confirming the role of this enzyme in cancer, we show that breast and lung cancer patients with increased levels of MARK4 in their tumours have poorer prognosis. We found that what controls the levels of MARK4 in cells is miR-515-5p, a small oligonucleotide sequence called a microRNA. When present in the cells, miR-515-5p prevents the expression of MARK4. Incidentally, the loss of miR-515-5p correlates with increased metastasis and poorer prognosis in mouse cancer models and patients, respectively. (more…)
Author Interviews, Cancer Research / 19.03.2016

MedicalResearch.com Interview with: Douglas.A. Lauffenburger PhD Ford Professor of Biological Engineering, Chemical Engineering, and Biology Head, Department of Biological Engineering Massachusetts Institute of Technology Cambridge, MA 02139  MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Lauffenburger: We aimed to advance understanding concerning causes of tumor resistance to kinase inhibitor drugs, which limits effectiveness for many therapeutics even when indicated by specific genetic mutations in the new ‘personalized medicine’ paradigm.  We discovered a new mechanism underlying this resistance at least for a number of otherwise promising drugs currently in clinical use as well as further clinical trials.  Our discovery was based on realizing that the same oncogenic signaling driving tumor cell proliferation and invasiveness at the same time activates proteolytic shedding of receptor tyrosine kinases not involved in the targeted oncogenic pathway, shutting down additional signaling inputs.  Thus, when the targeted pathway is inhibited by the intended drug, this shedding is concomitantly diminished — now permitting “bypass" pathways to be activated downstream of these alternative receptor inputs.  Moreover, we showed that measurement of a set of key shed receptors (primarily AXL and MET, in our examined case of MEK pathway inhibitors for melanoma and triple-negative breast tumors) in patient blood serum samples could predict effectiveness of these inhibitors: when the shed levels were high, the drugs were less effective because of the correspondingly great potential for bypass signaling upon drug treatment.  In follow-up mouse experiments, we demonstrated increased effectiveness of a MEK inhibitor when combined with either an AXL inhibitor or a proteolysis inhibitor, thereby confirming the mechanism and proving an avenue for overcoming it. (more…)
Author Interviews, Cancer, Cancer Research, Cost of Health Care / 14.03.2016

MedicalResearch.com Interview with: Hrishikesh Kale School of Pharmacy Virginia Commonwealth University MedicalResearch.com: What is the background for this study? What are the main findings? Response: The cost of cancer care in the United States is extremely high and escalating every year. Because of increased cost sharing, patients are paying higher out-of-pocket costs for their treatments. Along with high medical expenses, cancer survivors face problems such as loss of employment and reduced productivity. It has been well-established in the literature that because of high out-of-pocket costs, many cancer survivors forgo or delay medical care and mental health-related services and avoid filling prescriptions. This puts their physical and mental health at risk. A related issue is the growing number of cancer survivors in the U.S. As of January 2014, there were approximately 14.5 million cancer survivors in the U.S. By 2024, this number is expected to reach 19 million as a result of improved survival among patients with cancer along with an aging population. Therefore, we decided to investigate the prevalence and sources of financial problems reported by a nationally representative sample of cancer survivors from the 2011 Medical Expenditure Panel Survey. We also studied the impact of cancer-related financial burden on survivors’ health-related quality of life and psychological health. (more…)
Author Interviews, Cancer Research, JAMA / 11.03.2016

MedicalResearch.com Interview with: Joseph Unger, PhD, MS SWOG Statistical Center Assistant Member, Public Health Sciences Division, Fred Hutchinson Cancer Research Center Affiliate Assistant Professor, Health Services Research, University of Washington Seattle, WA  98109-1024 MedicalResearch.com: What is the background for this study? Dr. Unger: The rate at which trials are positive has previously been examined, and the relationship between trial results and publication rates in the context of publication bias has also been studied. But the comparative scientific impact of positive vs negative clinical trials using citation data has not been investigated We used the phase III trial database of SWOG, a major national cooperative clinical trials group, in combination with its trial publication database and citation data from Google Scholar, to compare the scientific impact of positive vs negative phase III cancer clinical treatment trials. (more…)
Author Interviews, BMJ, Cancer Research, Colon Cancer, Psychological Science / 09.03.2016

MedicalResearch.com Interview with: Benedicte Kirkøen, PhD candidate Bowel Cancer Screening in Norway – a pilot study Cancer Registry of Norway (Kreftregisteret) MedicalResearch.com: What is the background for this study? Response: Randomised controlled trials have demonstrated that screening for colorectal cancer (CRC) can reduce CRC related mortality, but the total benefit and harm of national cancer screening programmes are under debate. Saving relatively few lives requires a large number of people to be screened. Most people who attend screening will never develop cancer, but may be exposed to potential psychological stress by participation. Cancer is one of the largest threats to peoples’ health, and participating in screening for cancer might therefore cause anxiety. In Norway, colorectal cancer incidence has nearly tripled since the 1950s, and currently a large randomised pilot study of a national screening programme (Bowel Cancer Screening in Norway) is investigating the effect of screening on reduction in CRC incidence and mortality. As part of an evaluation of the benefits and harms of the pilot, we investigated the psychological effect of screening participation in a large group of participants. Of particular interest to us were participants who received a positive screening result and were referred to colonoscopy. (more…)
Author Interviews, Chemotherapy, Pancreatic, Vanderbilt / 07.03.2016

MedicalResearch.com Interview with: Alexander A. Parikh, M.D., M.P.H. Associate Professor of Surgery Director of Hepatobiliary, Pancreatic and GI Surgical Oncology Director, Vanderbilt Pancreas Center Vanderbilt University Medical Center Nashville, TN MedicalResearch.com: What is the background for this study? Dr. Parikh: Although adjuvant chemotherapy has been proven to increase survival after successful resection of pancreatic cancer and has become the standard of care worldwide, the use of adjuvant chemoradiation is more controversial. The vast majority of randomized trials have failed to show a significant improvement in survival with the use of chemoradiation after pancreatic cancer resection. Furthermore, our own report from the multi-institutional Central Pancreatic Consortium (CPC) published several years ago failed to show a benefit in the use of chemoradiation except in high-risk groups such as lymph node positive disease. The purpose of the current study was to investigate the patterns of recurrence with the use of adjuvant chemotherapy or chemoradiation in hopes of explaining some of these differences. It was our hypothesis that systemic chemotherapy would prevent distant recurrence (and perhaps local) while chemoradiation would only prevent local recurrence and thereby have less impact on overall survival. MedicalResearch.com: What are the main findings? Dr. Parikh: The main findings demonstrated that adjuvant chemotherapy led to an improvement in both local and distant recurrence with a corresponding improvement in overall survival while chemoradiation only led to an improvement in local recurrence but not distant nor overall survival. (more…)
Author Interviews, Dental Research, Esophageal, Infections / 02.03.2016

MedicalResearch.com Interview with: Dr. Huizhi Wang Assistant Professor Department of Oral Immunology and Infectious Diseases University of Louisville School of Dentistry Louisville, KY  MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Wang: Esophageal cancer is the eighth most frequent tumor and sixth leading cause of cancer death worldwide, characterized by rapid development and poor prognosis, including high mortality. Whereas the majority of cases occur in Asia, particularly in central China, recent data suggest that the frequency of new cases is rising in Western Europe and the USA. Mounting evidence suggests a causal relationship between specific bacterial infections and the development of certain malignancies. However, the possible role of the keystone periodontal pathogen, Porphyromonas gingivalis, in esophageal squamous cell carcinoma (ESCC) was unknown before our study. We found P. gingivalis infects epithelium of cancerous tissues up to 61%, as compared with 12% of adjacent tissues and non-infected in normal esophageal mucosa. A similar distribution of lysine-specific gingipain, a catalytic endoprotease uniquely secreted by P. gingivalis, and P. gingivalis DNA was observed. Moreover, we found infection of P. gingivalis was positively associated with the multiple clinicopathologic characteristics, including differentiation status, metastasis, and overall survival rate.  (more…)
Author Interviews, Cancer Research, Diabetes, Diabetologia / 01.03.2016

MedicalResearch.com Interview with: Bendix Carstensen Department of Clinical Epidemiology Steno Diabetes Center Gentofte Medical Research: What is the background for this study? What are the main findings? Response: It has long been known that all diabetes patients have elevated risk of cancer (10-15%). Patients on insulin slightly more (20-25%). Type 1 patients is only a small fraction (10%) of all diabetes patients, but they ALL take insulin. If insulin has a role in cancer occurrence it would be expected to be particularly pronounced in type 1 patients, and increasing by duration. But it is not, the risk of cancer is 15% elevated (if we disregard prostate, breast and other cancers only occurring in one of the sexes), and there is no increase in the excess risk by duration of insulin use. Breast cancer risk is 10% lower and prostate cancer risk some 40% lower. Overall there is very little increased cancer risk - 1% for men 7% for women. (more…)
Author Interviews, Cancer Research, Colon Cancer, Journal Clinical Oncology, Radiation Therapy / 26.02.2016

MedicalResearch.com Interview with: Dr Guy van Hazel Clinical Professor of Medicine, School of Medicine and Pharmacology, University of Western Australia  Medical Research: What is the background for this study? What are the main findings? Dr. van Hazel: The SIRFLOX study is based on original work by Dr Bruce Gray and myself almost two decades ago, when we studied the combination of Selective Internal Radiation Therapy (SIRT) with Y-90 resin microspheres – which was absolutely new at the time – with hepatic artery chemotherapy. This study showed an increase in liver control with the addition of SIRT [Gray B et al. Ann Oncol 2001; 12: 1711–1720.]. We then proceeded to initiate a trial comparing systemic SIRT plus 5-FU/LV according to the Mayo Clinic regimen compared to the Mayo Clinic regimen alone, but unfortunately this had to be abandoned because new chemotherapy became available which made it unethical to offer the control arm. However, in those patients who were treated up to that point with SIRT plus 5-FU/LV [van Hazel G et al. J Surg Oncol 2004; 88: 78–85.] we did see a very high response rates compared to the control arm, with an impressive survival of 29 months. We subsequently did a phase l/ll study of modified FOLFOX6 with or without SIRT and again found very high response rates [Sharma R et al. J Clin Oncol 2007; 25: 1099–1106.].  This led us to launch the SIRFLOX study in 2007. (more…)
Author Interviews, Cancer Research, Esophageal, Lung Cancer, Radiology, Surgical Research, University of Michigan / 25.02.2016

MedicalResearch.com Interview with: Mark A. Healy, MD Department of Surgery Center for Healthcare Outcomes & Policy, University of Michigan Ann Arbor, MI   Medical Research: What is the background for this study? What are the main findings? Dr. Healy: In our study, we found high overall use of PET as a primary study for recurrence detection in lung and esophageal cancers, with substantial hospital-based variation in the use of PET. Despite this, there was not a significant difference in survival for patients across high and low PET use hospitals. (more…)
Author Interviews, BMJ, Cancer Research, OBGYNE / 24.02.2016

MedicalResearch.com Interview with: Jiangrong Wang PhD Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm, Sweden Medical Research: What is the background for this study? What are the main findings? Dr. Wang: Cervical screening has been proved to effectively suppress the occurrence of cervical cancer, since it detects not only cervical cancer at early stages, but also precursor lesions that can be treated before progressing to invasive cancers. However, cervical screening has mainly reduced the occurrence of squamous cell cervical cancer, the most common type of invasive cervical cancer, but not adenocarcinoma of the cervix which originates from glandular cells. Although there is a well-known connection between adenocarcinoma in situ and invasive adenocarcinoma, questions remain on the magnitude of the cancer risk after detection of the glandular intraepithelial lesion-atypical glandular cells (AGC). We also wanted to study whether the current clinical management after detection of glandular abnormalities reduced the cancer risk as much as the standard management for squamous intraepithelial lesions does. Our findings show that 2.6% of women with  intraepithelial lesion-atypical glandular cells as the first abnormality developed invasive cervical cancer after 15 years of follow up and 74% of the cancers were adenocarcinoma. A moderately high proportion of women with AGC had prevalent cancer (diagnosed within 6 months from AGC), while there was considerably high incidence of cervical cancer within 0.5-6.5 years after a detection of AGC. The incidence of cervical cancer following AGC was significantly higher than for high-grade squamous intraepithelial lesions, and this increased risk remained even after having histology assessment in the initial half year.

The high risk of cervical cancer associated with AGC implies that the current clinical management following AGC does not prevent cervical cancer as sufficiently as the management for squamous intraepithelial lesions does.

 

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Author Interviews, Cancer Research, Cost of Health Care, End of Life Care / 19.02.2016

MedicalResearch.com Interview with: Melissa Garrido, PhD Assistant Professor / Research Health Science Specialist GRECC, James J Peters VA Medical Center, Bronx, NY Brookdale Department of Geriatrics & Palliative Medicine Icahn School of Medicine at Mount Sinai, New York, NY Medical Research: What is the background for this study? What are the main findings? Response: Medical costs for people with serious illnesses are rapidly rising in the United States. Concerns about medical debt and bankruptcy are especially relevant when deciding whether to begin or maintain a treatment that may have limited benefit to a patient’s survival or quality of life. Among patients with advanced cancer, one such decision is the choice of whether to use additional chemotherapy when the disease has not responded to an initial line or lines of chemotherapy. In this study, we used data from a prospective study of patients with advanced cancer and their caregivers to examine the relationship between chemotherapy use at study entry (median of four months before death) and estimated costs of healthcare other than chemotherapy in the last week of life. Medical Research: What is the background for this study? What are the main findings? Dr. Garrido: Among patients with end-stage cancer, those who received chemotherapy in the months before death had higher estimated costs of care in the last week of life.  We did not find evidence that this relationship was explained by patients’ preferences for care, do-not-resuscitate orders, or discussions of care preferences. (more…)
Author Interviews, Cancer Research, Columbia, Genetic Research / 19.02.2016

MedicalResearch.com Interview with: Jeanine D'Armiento, M.D., Ph.D. Associate Professor of Medicine in Anesthesiology Director of the Center for Molecular Pulmonary Disease in Anesthesiology and Physiology and Cellular Biophysics Director, Center for LAM and Rare Lung Disease New York, NY 10032 Medical Research: What is the background for this study? What are the main findings? Dr. D'Armiento: I am the Director of the Center for Lymphangiomyomatosis (LAM) and Rare Lung Disease at Columbia University; the Center focuses on this proliferative lung disease, which arises spontaneously or as the pulmonary manifestation of the Tuberous Sclerosis Complex (TSC). We have one of the largest cohorts of these patients in the country. Through an understanding of the pathogenesis of LAM our research aims to identify novel therapeutic targets of the disease to improve the care of these patients. Building on our previous research we demonstrated that the HMGA2 gene and its signaling pathway (the route of information which begins an action within cells), are required to produce tumors in the lung and kidneys in individuals with Tuberous Sclerosis Complex. (more…)
Author Interviews, Cancer Research, Geriatrics, Lung Cancer, Nature / 12.02.2016

MedicalResearch.com Interview with: Chiara Ambrogio, PhD Experimental Oncology Group CNIO-Centro Nacional de Investigaciones Oncológicas (Spanish National Cancer Research Centre) Melchor Fernández Almagro nº3 Madrid Spain  Medical Research: What is the background for this study? Dr. Ambrogio: The majority of preclinical studies aimed at discovering new therapeutic strategies for lung adenocarcinoma have been conducted so far in full-blown tumors. We wanted to try a new approach by studying early lung lesions in a KRasG12V mouse model in order to bypass the problems imposed by tumor heterogeneity in later stages of the disease. We reasoned that the analysis of the first steps of lung adenocarcinoma development would help us in identifying valuable targets for therapeutic intervention.  Medical Research: What are the main findings? Dr. Ambrogio: 1) We performed gene expression analysis of KRasG12V-driven mouse lung hyperplasias (≤ 500 cells) and we compared it to the gene expression profile of full-blown lung adenocarcinoma. We found that the aggressive nature of this tumor type is determined earlier than what predicted by histopathological criteria. 2) The analysis of transcriptional changes in early lesions allowed us to identify DDR1 as a drugable target in KRasG12V-driven lung adenocarcinoma. We validated its potential as a therapeutic target both genetically and pharmacologically by means of a selective DDR1 inhibitor. We demonstrated that the co-inhibition of DDR1 and NOTCH pathway, a key player in DDR1-mediated survival, exerted additive therapeutic effect. 3) We confirmed these results in human lung adenocarcinoma by reporting, for the first time, the development of an orthotopic Patient-Derived Xenograft (PDX) model as the ideal platform for the preclinical evaluation of new therapeutic strategies. (more…)
Author Interviews, Cancer Research, Radiation Therapy, Stem Cells / 11.02.2016

MedicalResearch.com Interview with: Erina Vlashi, PhD Assistant Professor Department of Radiation Oncology David Geffen School of Medicine at UCLA Los Angeles, CA 90095-1714 Medical Research: What is the background for this study? What are the main findings? Dr. Vlashi: It has been known for quite some time that head and neck squamous cell carcinomas (HNSCC) that test positive for human papilloma virus (HPV) respond to radiation therapy more favorably than HPV-negative HNSCCs. Our team reviewed a cohort of 162 patients with a head and neck squamous carcinoma diagnosis over a two-year period, and confirmed that the outcomes were correlated with the patient's HPV status. The work that followed was prompted by a discovery we had made earlier in breast cancer suggesting that breast cancer cells that manage to survive radiation therapy have the capacity to convert into more de-differentiated, therapy-resistant cells with characteristics of cancer stem cells, and that the degree of this conversion depended on the type of breast cancer: the more aggressive types of breast cancer being more prone to the therapy-induced phenotype conversion. So, we hypothesized that this therapy-induced conversion phenomenon may especially be at play in  head and neck squamous cell carcinomas given the clinical observation that HPV-positive HNSCCs respond to radiation therapy much more favorably than HPV-negative HNSCCs, despite optimum treatment modalities. And indeed, that is what we found: tumor cells derived from a panel of  head and neck squamous cell carcinomas cell lines that do not respond well to radiation therapy have an enhanced ability to convert the cells that survive radiation into more aggressive cells, cancer stem-like cells that will resist the next round of radiation therapy.  (more…)
Author Interviews, Cancer Research, Dermatology, Transplantation / 09.02.2016

MedicalResearch.com Interview with: Claire M. Vajdic, PhD Center for Big Data Research in Health University of New South Wales Australian Graduate School of Management Bldg, Sydney Australia on behalf of the authors. Medical Research: What is the background for this study? Dr. Vajdic: Lip cancer is one of the most common cancers in solid organ transplant recipients. Iatrogenic immunosuppression is a strong risk factor for lip cancer but the dose-related association between individual immunosuppressive agents and risk of lip cancer has not been examined. Therefore, we investigated the association between the type, dose and duration of immunosuppressive therapy and lip cancer risk in Australian liver, heart and lung transplant recipients. (more…)
Author Interviews, Cancer Research, Heart Disease, Journal Clinical Oncology / 07.02.2016

MedicalResearch.com Interview with: Saro H. Armenian, DO, MPH Associate Professor Departments of Pediatrics and Population Sciences City of Hope Comprehensive Cancer Center Director of the Childhood Cancer Survivorship Clinic Duarte, CA     Medical Research: What is the background for this study? What are the main findings? Dr. Armenian: There are an estimated 14 million cancer survivors living in the U.S. today, and this number is expected to reach 19 million by 2024. Among these cancer survivors, nearly two-thirds will have survived more than five years beyond their cancer diagnosis, and two out of every five will be considered a ten-year survivor, contributing to a growing population of aging cancer survivors. Until now, very little was known about the cardiovascular health of adult long-term cancer survivors. For the current study, we relied on diagnosis/procedures routinely recorded in a large integrative healthcare system that includes racially/ethnically and socioeconomically diverse members who are broadly representative of the residents in Southern California. Cardiovascular outcomes were captured from a wide variety of healthcare delivery settings (inpatient and outpatient, primary and sub-specialty care). Importantly, cancer survivors included in the current study continued to receive their primary and subspecialty care within this system well-beyond their initial cancer diagnosis (5- and 10-year retention rate: 81% and 70%, respectively), providing us with reliable population-based estimates of long-term cardiovascular disease (CVD) risk. We found an up to 70% higher risk of CVD (ischemic heart disease, stroke, or cardiomyopathy/ heart failure) in patients diagnosed with breast, kidney, lung/bronchus, multiple myeloma, non-Hodgkin lymphoma, and ovarian cancer when compared with an age- sex- and zip-code matched non-cancer controls. Cancer survivors who had multiple modifiable risk factors such as hypertension, diabetes, dyslipidemia were at highest risk of developing cardiovascular disease  later in life, irrespective of cancer diagnosis. Importantly, cancer survivors who developed CVD were significantly more likely to die from all causes when compared to cancer survivors who did not develop CVD. While the reasons for these findings are not clear, it is possible that the presence of CVD can markedly diminish treatment options or planned duration of therapy at the time of cancer recurrence, thus compromising the optimal long-term management of a cancer patient. (more…)
Author Interviews, Cancer Research, Heart Disease, JAMA, Pharmacology / 06.02.2016

MedicalResearch.com Interview with: Jonathan Douxfils Pharm.D. - Ph.D. Research assistant Faculty of Medicine - Department of Pharmacy NAmur Research Institute for LIfe Sciences (NARILIS) Namur Thrombosis and Hemostasis Center (NTHC) Medical Research: What is the background for this study? What are the main findings? Dr. Douxfils: We decided to perform this study based on the release of the FDA regarding the risk of arterial occlusive events associated with ponatinib. We then hypothesize that the risk was not only restricted to ponatinib but also to other TKIs. This study shows that dasatinib, nilotinib and ponatinib increase the risk of vascular occlusive events compared to imatinib. Medical Research: What should clinicians and patients take away from your report? Dr. Douxfils: We suggest that patients treated with these molecules should be more frequently monitored, i.e. by an intensive support of associated comorbidities. In addition, even if they appear to have a better efficacy in terms of molecular response, new generation TKIs does not improve the overall survival at one year. As we have not access to individual data, it was impossible to clearly identify categories of patients for whom the risk of cardiovascular occlusive events is predominant. Therefore, the intensive monitoring proposed should be applied to all patients treated with these molecules. Regarding the choice of the therapy, the physician should certainly consider the goals of the treatment. For elderly patients, improving survival is the main objective and in this context, imatinib remains an excellent choice. For patients with a life expectancy greater than 10 years in whom we aim to achieve a deep molecular response to potentially reach a point of treatment cessation, dasatinib and nilotinib could be preferred. However, the choice of dasatinib or nilotinib as first-line treatments should involve a screening for potential risk factors such as diabetes, prior vascular occlusive events or any risk that could increase these adverse events. For second- and third-line treatments, the choice of the treatment has to be based on mutational analysis, previous adverse events, and the medical condition of the patient. Thus, in case of intolerance or resistance, the switch to one of the other TKIs approved for first-line therapy is an option. If treatment failure still occurs, a more potent TKI, i.e. bosutinib, is preferred. Importantly, ponatinib is reserved to patients with the T315I mutation and must be avoided in patients with good prognosis. (more…)
Author Interviews, Brain Cancer - Brain Tumors, Genetic Research, Pediatrics, University of Pennsylvania / 04.02.2016

MedicalResearch.com Interview with: Dr. Adam C. Resnick, Ph.D Assistant Professor of Neurosurgery Faculty, Abramson Cancer Center Director of Children's Brain Tumor Tissue Consortium Division of Neurosurgery Director, CHOP/PENN Department of Neurosurgery Brain Tumor Tissue BiorepositoryDirector for Neurosurgical Translational Research, Division of Neurosurgery Children's Hospital of Philadelphia   Payal Jain, PhD Candidate Division of Neurosurgery, Children's Hospital of Philadelphia Department of Neurosurgery Cell and Molecular Biology Graduate Group Gene Therapy and Vaccines Program Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania   Medical Research: What is the background for this study? What are the main findings? Response: This study originates from our long-standing interest in studying pediatric low-grade gliomas (PLGGs), which are the most commonly diagnosed brain tumor in children. While several PLGGs have been found to harbor mutations/gene fusions driving the mitogen-associated protein kinase (MAPK) pathway leading to clinical trials testing MAPK inhibitors, these tumors remain poorly categorized and not enough is known about specific genetic mutations driving different tumor sub-types and the potential for specific targeted therapeutics. Our current study encompasses analysis of the largest combined genomic dataset of pediatric low-grade gliomas samples.  In doing this we, identified the MYB-QKI gene fusion, a non-MAPK related event, as the common genetic event driving a rare PLGG sub-type, called angiocentric gliomas. We have reported a novel tri-partite mechanism by which MYB-QKI mediates its oncogenic effect, this being the first report of a single gene rearrangement utilizing three different paths to cause cancer.
  • First, this gene rearrangement activates MYB, which is a proto-oncogene that is normally not expressed in the developed brain.
  • Second, we found that the rearrangement leads to translocation of QKI-related enhancers close to MYB’s promoters, thereby driving MYB-QKI expression in these tumors. Furthermore, MYB-QKI can also regulate its expression in a positive feedback loop.
  • Third, the tumor suppressor activities of QKI are disrupted in MYB-QKI. Such collaboration of genetic and epigenetic dysregulation in a single genetic rearrangement has previously not been reported.
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Cancer Research / 03.02.2016

MedicalResearch.com Prof. Norbert Stefan, MD Department of Molecular Epidemiology German Institute of Human Nutrition Potsdam-Rehbruecke Nuthetal, Germany MedicalResearch: What is the background for this study? Prof. Stefan: Cardiovascular disease, type 2 diabetes, and cancer are among the most important causes of morbidity and mortality worldwide. Although the body mass index and waist circumference are established variables that help to predict the risk of these disease, adult height also predicts mortality independently of adiposity measures. However, compared to these risk factors, it has been somewhat neglected in clinical practice. Based on the finding that in recent decades the height of children and adults has steadily increased throughout the world, the question arises whether this secular trend in height might be a marker of a yet not well understood mechanism that affects not only stature, but also the development of cardiometabolic disease and cancer.  MedicalResearch: What are the main findings? Prof. Stefan: We summarized and interpreted data from different areas of research and also could provide some novel data to better understand the causes of the worldwide increase in height and its relationships with cardiometabolic disease and incidence of cancer. There is strong epidemiological evidence that tall people, in comparison to short people, have a lower risk of cardiovascular disease and type 2 diabetes but have a higher cancer risk. Per 6.5 cm in height the risk of cardiovascular mortality decreases by six percent, but cancer mortality, by contrast, increases by four percent. We suspect that the increase in body height is a marker of overnutrition of high-calorie food rich in animal protein during different stages of growth. Thus, already in utero, lifelong programming might take place that until now has mainly been established for the insulin-like growth factor 1 and 2 and the IGF-1/2 system. Among other consequences, activation of this system causes the body to become more sensitive to insulin action, thus positively influencing the lipid metabolism. Accordingly, our new data show that tall people are more sensitive to insulin and have lower fat content in the liver, which may explain their lower risk for cardiovascular disease and type 2 diabetes. However, this activation of the IGF-1/2 system and other signaling pathways may be related to an increased risk of certain cancers, especially breast cancer, colon cancer, and melanoma because cell growth is permanently activated. (more…)
Author Interviews, Brigham & Women's - Harvard, Cancer Research, Lancet, Pediatrics, Radiation Therapy / 02.02.2016

MedicalResearch.com Interview with: Dr. Torunn Yock, MD Director, Pediatric Radiation Oncology Associate Professor, Harvard Medical School Radiation Oncology Quality Assurance Massachusetts General Hospital, Proton Center Boston, MA Medical Research: What is the background for this study? Dr. Yock: Proton radiotherapy is a highly targeted form of radiation therapy that can spare normal tissues better than standard x-ray/photon based radiotherapy. Because, all side effects from radiotherapy come from radiation dose to normal healthy tissues, it is widely believed that proton radiotherapy has great potential to mitigate the side effects of treatment, both acute and long term side effects. There have been many planning studies that show that proton radiation can achieve a more highly conformal dose distribution and appear to spare 50% or more normal tissue from unnecessary irradiation.  However, there have been only a handful of retrospective studies that report disease control and side effects of treatment. While the technology looked promising, the definitive clinical data has been lacking to date. Because of this lack of clinical outcome data, the role and benefit of proton radiotherapy has been a subject of great debate in the oncology community.  Critics assert that proton radiotherapy is expensive and unproven and therefore a leading culprit in escalating costs of oncologic health care. Proponents assert that when used in the appropriate patient setting, the margin of benefit in terms of improved health outcomes, outweighs the increased cost of treatment. We embarked on this study to answer help answer the call for prospectively collected clinical outcome data to better define the most appropriate role for proton radiotherapy. Importantly, this study addresses both disease control and side effects of treatment in a pediatric medulloblastoma cohort of children. Medical Research: What are the main findings? Dr. Yock: This study shows that disease control in the pediatric medulloblastoma population is very much the same as that which is achieved by photon based radiotherapy treatments. However, more importantly, late side effects commonly attributed to radiotherapy such as neurocognitive decline over time and hearing loss appear to be improved compared with published photon treated cohorts of pediatric medulloblastoma patients.  Additionally, adverse late side effects on the cardiopulmonary, GI, and reproductive systems were essentially eliminated. (more…)