Author Interviews, Genetic Research, Melanoma, Nature / 25.01.2015

MedicalResearch.com Interview with: Prof Lukas Sommer. Ph.D. Cell and Developmental Biology University of Zurich Institute of Anatomy Zurich Switzerland MedicalResearch: What is the background for this study? What are the main findings? Prof. Lukas Sommer:   Melanoma, the most aggressive of all skin cancers, is often fatal for patients due to the pronounced formation of metastases. Up to date, a melanoma’s rampant growth was mainly attributed to genetic causes, such as mutations in certain genes. However, we now reveal that so-called epigenetic factors also play a crucial role in the formation of metastases in malignant skin cancer. Epigenetic factors do not influence the gene sequence directly, but rather cause certain genes and chromosomal segments to be packed in different densities – and thus make them accessible for reading. In our study we identified “EZH2” as an epigenetic control protein found very frequently in malignant melanoma cells compared to normal cells. In these cells, “EZH2” controls genes that govern both tumor growth and genes that are important for the formation of metastases. We exploited this central position of EZH2 to combat the cancer by using a pharmacological inhibitor to suppress the activity of EZH2. As a result, we were able to prevent the growth and malignant spread of the cancer in an animal model and in human melanoma cells. (more…)
Author Interviews, Breast Cancer, Scripps / 25.01.2015

Dr. Patrick Griffin PhD Professor and Chairman Department of Molecular Therapeutics Director of the Translational Research Institute Scripps Research Institute, Jupiter, FloridaMedicalResearch.com Interview with: Dr. Patrick Griffin PhD Professor and Chairman Department of Molecular Therapeutics Director of the Translational Research Institute Scripps Research Institute, Jupiter, Florida MedicalResearch.com: What is the background for this study? What are the main findings? Dr. Griffin: We identified a novel synthetic compound known as SR1848 that sharply inhibits the activity and expression of “liver receptor homolog-1” or LRH-1, a protein that plays an important role in the progression of breast and pancreatic cancers. Our new study shows that SR1848 removes LRH1 from DNA, shutting down expression of LRH-1 target genes, and halts cell proliferation. It’s a novel compound that appears to be a promising chemical scaffold for fighting tumors that are non-responsive to standard therapies. (more…)
Author Interviews, Colon Cancer / 22.01.2015

Jason A. Zell, D.O., M.P.H. Program Director, Hematology/Oncology Fellowship Program Division of Hematology/Oncology Department of Medicine UC Irvine HealthMedicalResearch.com Interview with: Jason A. Zell, D.O., M.P.H. Program Director, Hematology/Oncology Fellowship Program Division of Hematology/Oncology Department of Medicine UC Irvine Health Medical Research: What is the background for this study? What are the main findings? Dr. Zell: Colorectal cancer incidence (CRC) has been declining in the U.S. since 1975, due largely to screening for premalignant polyps. Screening in the U.S. begins at age 50 for average risk individuals, and so the vast majority of Young Adults in the U.S. (defined as age 20-39 in our study) are unscreened. Recently, several studies have reported an increased risk of colorectal cancer among U.S. individuals under age 50. In our analysis of 231,544 CRC cases in California over a 22 year period, we identified 5617 cases among Young Adults (age 20-39). As expected, the overall risk of colorectal cancer in Young Adults is low. However, colorectal cancer is increasing among Young Adults as observed in this population-based study, and certain groups remain at particularly high risk. For example, Hispanic Females age 20-29 were observed to have nearly a 16% increase in colorectal cancer risk when comparing the Biannual Percent Change over the course of the study period.   Also concerning was the observation that Young Adults were more likely to be diagnosed with colorectal cancer at an advanced stage than adults in the “screened population” (ie, those age 50 and over). (more…)
Author Interviews, Coffee, JNCI, Melanoma, NIH, Yale / 21.01.2015

MedicalResearch.com Interview with: Erikka Loftfield Doctoral student at the Yale School of Public Health Fellow at the National Cancer Institute Medical Research: What is the background for this study? What are the main findings? Response: Previous studies have reported conflicting results on the association between coffee drinking and melanoma. We sought to clarify this relationship using data from the large NIH-AARP Diet and Health Study. We followed over 400,000 retirees aged 50 to 71 years at study entry for an average of 10 years. Participants were asked to report typical coffee intake. During the course of follow-up nearly 3,000 cases of malignant melanoma occurred. In our study, we observed that individuals who reported the highest total coffee intake (4 cups/day) had about 20% lower risk of malignant melanoma compared with those who did not consume coffee. (more…)
Author Interviews, Breast Cancer, Nutrition / 19.01.2015

Cecilia Cesa Schiavon Department of Nutrition, Federal University of Santa Catarina Florianópolis, Santa Catarina, BrazilMedicalResearch.com Interview with: Cecilia Cesa Schiavon Department of Nutrition, Federal University of Santa Catarina Florianópolis, Santa Catarina, Brazil Medical Research: What is the background for this study? What are the main findings? Response: The study was based on a nutritional intervention for patients undergoing treatment for breast cancer. The intervention took place right after the surgical procedure and lasted about a year, until the end of chemotherapy. The patients were submitted to a special methodology of intervention, aimed at increasing fruit and vegetable intake and reducing red and processed meat, following the World Cancer Research Fund and the American Institute for Cancer Research in the document entitled Food, Nutrition, Physical Activity and the prevention of Cancer: A Global Perspective”. The main findings show that women undergoing breast cancer treatment may benefit from immediate, individualized, and detailed nutrition monitoring through appropriate nutrition education. (more…)
Author Interviews, Brigham & Women's - Harvard, Cancer Research, Science / 19.01.2015

Lee Zou, Ph.D. Professor of Pathology, Harvard Medical School The Jim & Ann Orr MGH Research Scholar Associate Scientific Director, MGH Cancer CenterMedicalResearch.com Interview with: Lee Zou, Ph.D. Professor of Pathology, Harvard Medical School The Jim & Ann Orr MGH Research Scholar Associate Scientific Director, MGH Cancer Center Medical Research: What is the background for this study? What are the main findings? Dr. Lee Zou: Cancer cells must rely on telomerase or the alternative lengthening of telomere (ALT) pathway to maintain telomeres and bypass replicative senescence. The ALT pathway is active in about 10-15% of human cancers, and it is particularly prevalent in specific cancer types, such as osteosarcoma, glioblastoma, and neuroendocrine pancreatic tumors. ALT is a recombination-mediated process. Whether the reliance of cancer cells on  alternative lengthening of telomere can be exploited therapeutically was not known. In our study, we discovered that the ATR kinase is a key regulator of alternative lengthening of telomere. We found that ATR inhibitors disrupt ALT effectively. Furthermore, we found that ATR inhibitors selectively kill ALT-positive cancer cells in a panel of caner cell lines. These findings have suggested the first rational therapeutic strategy for the treatment of ALT-positive cancer. (more…)
Author Interviews, Breast Cancer, Inflammation / 16.01.2015

Dr. Jorge Morales-Montor Departamento de Inmunología Instituto de Investigaciones Biomédicas Universidad Nacional Autónoma de México México City MéxicoMedicalResearch.com Interview with: Dr. Jorge Morales-Montor Departamento de Inmunología Instituto de Investigaciones Biomédicas Universidad Nacional Autónoma de México México City México MedicalResearch: What is the background for this study? Dr. Morales-Montor: Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped in several protein families referred as tumour necrosis factors, interleukins, interferons and colony stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis and metastasis, all phenomena in which cytokines are prominent players. The data we have hitherto let us suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancer related disorders. (more…)
Author Interviews, Prostate, Prostate Cancer, Urology / 16.01.2015

MedicalResearch.com Interview with: Mufaddal Mamawala, MBBS, MPH, CPH Biostatistician Johns Hopkins School of Medicine Brady Urological Institute Medical Research: What is the background for this study? What are the main findings? Dr. Mamawala: Twenty years after prostate-specific antigen (PSA) was FDA approved for the diagnosis of prostate cancer, its use remains highly controversial. There has been an ‘over- diagnosis’ and ‘over-treatment’ of low-risk prostate cancers that would have never progressed to a more lethal form of the disease during one’s life. Active surveillance (AS) is an alternative to immediate treatment, which allows for monitoring of favorable risk patients with selective delayed intervention among those with disease progression. However  ‘misclassification’ is a cause of concern for patients in the initial years of been in AS. The initial biopsy may have missed an area of prostate with an aggressive cancer, due to under-sampling of cores or due to randomness, such that this patient could get misclassified as having a low-risk disease and by the time the follow-up biopsy shows an aggressive cancer the window of curability is lost. However with more sampling of the prostate there is more likelihood to find an aggressive cancer. As such if the patient is compliant with their biopsies, and more prostate is sampled under the microscope, better are the chances of finding a higher risk cancer. Conversely if the patient has more biopsies that show no high-risk cancer then they are less likely to have a high-risk cancer on future biopsies. Thus we wanted to evaluate the risk of reclassification, from a low-risk disease to a high-risk disease (higher Gleason score, or increase in extent of the disease), over a period of time in compliant active surveillance patients.  The length of time under Active surveillance without reclassification has not been evaluated as a predictor of future reclassification. Biopsies are invasive procedures, and the fact that patient has to undergo this invasive procedure regularly is a deterrent from been in Active surveillance. This study would help to make informed decisions about the need for doing frequent biopsies in light with other clinical factors especially in older patients who had many non-reclassifying biopsies before. We found that the risk of reclassification was not equally distributed across time. As a result of ‘under sampling’ of prostate at diagnostic biopsy we had highest rates of reclassification in the first two years of been in Active surveillance with more than 50% of total reclassifications happening during those two years. The ‘low-risk’ and the ‘very-low-risk’ groups, determined by the Epstein criteria, had similar rates of reclassification in the first two years. After first two years the ‘low-risk’ group were 2.4 times as likely to have a higher risk of reclassification than the ‘very-low-risk’ group. In both the groups the risk of reclassification declined over time significantly by at least 30% with each biopsy that did not show reclassification. (more…)
Author Interviews, Melanoma / 14.01.2015

Keiran Smalley, PhD. Scientific Director, The Comprehensive Melanoma Research Center Associate Professor The Moffitt Cancer Center & Research Institute, Tampa, FLMedicalResearch.com Interview with: Keiran Smalley, PhD. Scientific Director, The Comprehensive Melanoma Research Center Associate Professor The Moffitt Cancer Center & Research Institute, Tampa, FL   Medical Research: What is the background for this study? What are the main findings? Dr. Smalley: Although many patients with BRAF mutant melanoma respond very well to BRAF inhibitors and the BRAF/MEK inhibitor combination, resistance is commonplace and the majority of those treated ultimately fail therapy. Most studies to date have focused upon the genetic changes that are associated with acquired BRAF and BRAF/MEK inhibitor resistance. We decided to take a different approach and to use proteomics to comprehensively map all of the signaling changes associated with resistance. Our study showed that melanoma cells with resistance to BRAF and BRAF/MEK inhibition were highly invasive and aggressive. This aggressive phenotype was driven through a cell surface receptor called EphA2, and this became upregulated in both melanoma cell cultures and in patient tumors following BRAF inhibitor treatment. As this suggested that the resistant cells would be more metastatic, we then performed animal experiments and analyzed tumors from melanoma patients receiving BRAF inhibitor. These studies showed an increase in EphA2 expression in the metastatic tumors that was lacking in the primary tumors. When we looked at cohorts of melanoma patients who received either a BRAF inhibitor or an older chemotherapy drug, we found that more of the BRAF inhibitor treated patients seemed to develop disease at new sites. Together this suggested that BRAF inhibition may switch the cancer cells to being more metastatic. (more…)
Author Interviews, Breast Cancer, JAMA / 14.01.2015

Javaid Iqbal, MD, MSC (Candidate) Institute of Medical Sciences, and Women’s College Research Institute/Women’s College Hospital University of Toronto, Toronto CanadaMedicalResearch.com Interview with: Javaid Iqbal, MD, MSC (Candidate) Institute of Medical Sciences, and Women’s College Research Institute/Women’s College Hospital University of Toronto, Toronto Canada What is the background for this study? What are the main findings? Dr. Iqbal: A woman’s racial/ethnic background predicts her participation in breast cancer control program (i.e., awareness and screening). The ultimate objective of breast cancer control program is to detect cancer at an optimal stage, which is stage I, because women with stage I breast cancer survive longer. Given the racial/ethnic diversity of North America, this poses questions such as “what predicts stage I breast cancer in the multiethnic North American population?”, “what predicts its survival?”, and “does a woman’s ethnic background plays a role in predicting an early stage, and survival?” We studied 373,563 women diagnosed with invasive breast cancer in the United States between 2004 and 2011. We followed these women for 7 years and recorded whether or not they died of breast cancer, or whether they are still alive. We then divided all women into different ethnic groups, in particular white, black, Chinese, Japanese, and Indian/Pakistani (South Asian). For each racial/ethnic group, we estimated proportions of women who were diagnosed with stage I breast cancer, and risk of death at 7 years. Our aim was to determine if the racial/ethnic differences in early stage breast cancer, and its survival were better explained by intrinsic biological differences in tumor characteristics, or by differences in early-detection of breast cancer. We found that a woman’s racial/ethnic background predicted the diagnosis of stage I breast cancer, as well as her risk of dying at 7 years after breast cancer. A black woman was less likely than a white woman to be diagnosed with stage I breast cancer. A black woman was also more likely than a white woman to die of stage I breast cancer 7 years after her diagnosis. The Japanese and Chinese women were more likely than white women to be diagnosed with stage I breast cancer. The risk of death at 7 years was lowest for Indian or Pakistani (South Asian) women. Furthermore, even for small sized (2.0) breast cancers the risk of death at 7 years was higher for black women (9%), compared to white women (5%). Compared to white women, small sized breast cancers in black women were more aggressive at diagnosis, and had spread to lymph nodes and other organs. (more…)
Author Interviews, Melanoma / 13.01.2015

MedicalResearch.com Interview with: Razieh Soltani-Arabshahi, MD, MSci Department of Dermatology, University of Utah, Salt Lake City, Utah MedicalResearch.com: What is the background for this study? Dr. Soltani-Arabshahi: The incidence of melanoma is rapidly rising. Dermatologists are the leading specialty group to diagnose melanoma. While ABCD cirteria for diagnosis of melanoma have been used by many dermatologists, there are few studies of it's predictive value. MedicalResearch.com: What are the main findings? Dr. Soltani-Arabshahi: We showed that at an academic dermatology center, nearly 16 clinically suspicious lesions need to be biopsied to find one case of melanoma. Biopsies of lesions larger than 6 mm in diameter on older male patients had the highest yield. (more…)
Author Interviews, Cancer Research, Dermatology / 13.01.2015

MedicalResearch.com Interview with : Cédric Blanpain, MD, PhD Professor of Stem Cell and Developmental Biology WELBIO, Interdisciplinary Research Institute (IRIBHM) Université Libre de Bruxelles Belgium MedicalResearch.com : What is the background for this study? What are the main findings? Dr. Blanpain: Squamous cell carcinoma (SCC) represents the second most frequent skin cancer with more than half million new patients affected every year in the world. Cancer stem cells (CSCs) are a population of cancer cells that have been described in many different cancers including skin SCCs and that feed tumor growth. These cells could be resistant to therapy thus being responsible for tumor relapse after therapy. However, still very little is known about the mechanisms that regulate Cancer stem cells functions. In a new study published and making the cover of Cell Stem Cell, researchers led by Pr. Cédric Blanpain, MD/PhD, professor and WELBIO investigator at the IRIBHM, Université libre de Bruxelles, Belgium, report the mechanisms regulating the different functions of Twist1 controlling skin tumour initiation, cancer stem cell function and tumor progression. Benjamin Beck and colleagues used state of the art genetic mouse models to dissect, the functional role and molecular mechanisms by which Twist1 controls tumor initiation, cancer stem cell function and tumor progression. In collaboration with Dr Sandrine Rorive and Pr Isabelle Salmon from the department of Pathology at the Erasme Hospital, ULB and the group of Jean-Christophe Marine (VIB, KUL Leuven), they demonstrated that while Twist1 is not expressed in the normal skin, Twist1 deletion prevents skin cancer formation demonstrating the essential role of Twist1 during tumorigenesis. The authors demonstrate that different levels of Twist1 are necessary for tumor initiation and progression. Low level of Twist1 is required for the initiation of benign tumors, while higher level of Twist1 is necessary for tumor progression. They also demonstrate that Twist1 is essential for tumor maintenance and the regulation of cancer stem cell function. The researchers also uncovered that the different functions of Twist1 are regulated by different molecular mechanisms, and identified a p53 independent role of Twist1 in regulating cancer stem cell functions. (more…)
Author Interviews, Cancer Research, Technology / 12.01.2015

Oleh Taratula, Ph. D. Assistant Professor of Pharmaceutics Department of Pharmaceutical Sciences College of Pharmacy Oregon State University Corvallis, OR 97331-3507MedicalResearch.com Interview with: Oleh Taratula, Ph. D. Assistant Professor of Pharmaceutics Department of Pharmaceutical Sciences College of Pharmacy Oregon State University Corvallis, OR 97331-3507 Medical Research: What is the background for this study? What are the main findings? Dr. Taratula: Our research group is focused on the development of novel nanotechnology-based approaches to treat different cancers, including ovarian cancer. For many cancers, surgery is a first choice of treatment. For example, only optimal surgical resection of most abdominal metastases can significantly reduce ovarian cancer recurrence and, therefore, improve patient survival. However, it is challenging to remove most of the cancer tumors and residual cancer cells eventually may lead to cancer relapse. Therefore, our aim is to develop a nanomedicine platform, which could help surgeons achieve maximal tumor resection, using the intraoperative guidance with real-time near infrared (NIR) fluorescence signal. Moreover, we expect that the same nanoplatform could further enhance surgical outcomes by combinatorial phototherapy to be performed intraoperatively after tumor resection to eradicate unresected cancer cells. Our data published in Nanoscale is the first step towards our main goal. At this point, by utilizing naphthalocyanine, we have developed a single-agent-based nanomedicine platform capable of both NIR fluorescence imaging and combinatorial phototherapy. Naphthalocyanine is a commercially available compound, but its potential clinical application is limited by low water solubility and aggregation. Especially, aggregation diminishes the imaging ability and phototherapeutic efficacy of this compound. To address these shortcomings, we discovered that the loading of naphthalocyanine into the dendrimers significantly enhances water solubility, prevents aggregation and preserves imaging and therapeutic abilities. Our data demonstrated that naphthalocyanine-based nanoplatform can generate a NIR fluorescence signal in the cancer tumors, required for elimination of autofluorescence from healthy tissue and body fluids. Furthermore, our results also indicated that the developed nanoplatform is an efficient therapeutic agent which, upon exposure to NIR light, destroys chemotherapy-resistant ovarian cancer tumors by producing both heat and toxic reactive oxygen species. Finally, many organic fluorophores, including naphthalocyanine, can undergo photobleaching under exposure to light, which could be misinterpreted as a lack of fluorescence signal during the surgery. We demonstrated that the dendrimer encapsulated naphthalocyanine exhibits extremely high photostability and could overcome the above mentioned issue. (more…)
Author Interviews, Leukemia, Social Issues / 12.01.2015

Professor Eleni Petridou Preventive Medicine & Epidemiology, Department of Hygiene Epidemiology and Medical Statistics, Athens University Medical School Athens GreeceMedicalResearch.com Interview with: Professor Eleni Petridou Preventive Medicine & Epidemiology, Department of Hygiene Epidemiology and Medical Statistics, Athens University Medical School Athens Greece Medical Research: What is the background for this study? What are the main findings? Prof. Petridou: Impressive gains in survival from childhood leukemia have been achieved during the last decades mainly on account of advancements in treatment of the disease. Yet, these big improvements do not seem to be equally shared by all sick children. Disparities in the survival of children suffering leukemia who live in high versus low-income countries, as well as among different racial groups pointed to socio-economic status (SES) of the family as a factor that might adversely affect the outcome. SES, however, is a multifaceted variable comprising economic, social and professional components, which cannot be easily assessed. Therefore, an array of area of residence- and individual family- based proxy indices have been used in order to investigate the association between SES and overall or event-free survival from childhood leukemia. We have intensively searched for published articles around the globe and also analyzed primary data kindly provided by the US National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) for the period 1973-2010 as well as the Nationwide Registry for Childhood Hematological Malignancies (NARECHEM) in Greece for the period 1996-2011. This study is the first meta-analysis summing up the findings of 29 individual studies and quantifying the adverse effect in the survival due to SES differentials among 60 000 afflicted children. According to the findings, lower socio-economic status children suffering, at least, the more common Acute Lymphoblastic Leukemia (ALL) type have nearly two fold higher death rates compared to those of high socio-economic status. Of note, the SEER data show that the survival gap was wider in the USA with increased risk of death from ALL in the lower SES children (by 20-82%) and widening during the last 40 years time period. (more…)
Author Interviews, Breast Cancer, Genetic Research, Nature / 11.01.2015

MedicalResearch.com Interview with: Dr. Pentao Liu PhD and Dr. Walid Khaled PhD Wellcome Trust Sanger Institute Cambridgeshire United Kingdom Medical Research: What is the background for this study? What are the main findings? Dr. Pentao Liu: The significance of this research is that it aims to tackle the worst type of breast cancer. Triple Negative Breast Cancer (TNBC) has the poorest patient survival rate compared to other forms of breast cancer.  At present there are no targeted therapies available for TNBC, leaving the non-specific chemotherapy as the only treatment option. In this study we identify a new key gene in  Triple Negative Breast Cancer which could potentially be inhibited for the targeted treatment of TNBC. In this study we report the identification of a novel gene for Triple Negative Breast Cancer. By analyzing genomics data from 3,000 patients we find BCL11A to be highly expressed in TNBC. We then demonstrate experimentally that upregulation of BCL11A drives tumour development while its downregulation leads to reduction in tumour size. In the experimental mouse model, inactivation of this gene completely abolishes breast tumour development. (more…)
Author Interviews, Breast Cancer, JNCI / 11.01.2015

https://medicalresearch.com/category/hepatitis-liver-disease/page/2/MedicalResearch.com Interview with: Hazel B. Nichols, PhD Assistant Professor, Department of Epidemiology University of North Carolina Gillings School of Global Public Health MedicalResearch:What is the background for this study? Dr. Nichols: Tamoxifen, a drug that is often used to treat breast cancer, has also been approved to prevent breast cancer in women who may be at high risk for developing the disease. Taking tamoxifen for 5 years can lower breast cancer risk by up to 48%. The United States Federal Drug Administration (FDA) approved tamoxifen for breast cancer prevention more than 15 years ago (in 1998) for women ages 35 and older who are at high risk of breast cancer and who are at low risk for serious side effects. National estimates show that <1% of women who are eligible to use tamoxifen actually use it for breast cancer prevention. While tamoxifen lowers breast cancer risk it does cause hot flashes and may lead to serious side effects such as cataract, stroke, and uterine cancer. Women who start taking may also stop taking it before the recommended 5-years due to side effects. We used a tool developed by scientists at the National Cancer Institute (NCI) to calculate whether the benefits of tamoxifen outweighed the risks for women in the Sister Study, a study of more than 50,000 U.S. and Puerto Rican women with a family history of breast cancer. The tool uses information on a woman’s age, race, breast cancer risk, menopausal status, and whether she had a hysterectomy (surgical removal of the uterus) to estimate whether there is no, moderate or strong evidence that the benefits of tamoxifen will outweigh the risks. (more…)
Author Interviews, Breast Cancer, Genetic Research / 10.01.2015

Dr. Chao Cheng PhD Department of Genetics Geisel School of Medicine at Dartmouth Hanover 03755, NHMedicalResearch.com Interview with: Dr. Chao Cheng PhD Department of Genetics Geisel School of Medicine at Dartmouth Hanover 03755, NH   MedicalResearch: What is the background for this study? What are the main findings? Dr. Chao Cheng: Cancer survival prognosis—“How long do I have, Dr.?” is a topic of great importance to cancer patients and their families. While clinical and pathological variables, such as cancer type, stage, grade, and patient demographics, have long been used to predict survival outcomes, only recently have molecular signatures become incorporated into survival prediction. A molecular approach holds great promise for improving prediction accuracy and additionally elucidating mechanisms of disease, however it is fraught with difficulty due to assay “noise” and “big data” statistical issues, such as the multiple comparisons problem In this study, we began by analyzing transcription factor binding profiles across available cell lines. By restricting our analysis to transcription factors, DNA expression regulators known to be involved in tumor genesis, we reasoned that we could avoid many of the “big data” issues and achieve results that would make mechanistic and biological sense. We first employed a statistical method we described previously to calculate which genes were the major downstream targets of our transcription factors. With these targets identified, we then analyzed gene expression data using a bioinformatics method to infer the relative activity of each transcription factor based upon the overall expression levels of their gene targets. From here, we incorporated cancer survival data and examined how each transcription factor’s regulatory activity did, or did not, correlate with survival. The most prognostic transcription factor was E2F4, a member of the E2F family and a known regulator of the cell cycle. We therefore restricted our analysis to E2F4 and examined how its activity level impacted survival in breast cancer patients. We found that tumors with high E2F4 regulatory activity as compared to low E2F4 regulatory activity had much worse survival outcomes. These results were stable even after controlling for tumor stage, grade, patient age, and treatment, and were based on data from over 1900 patients across eight independent datasets. These results demonstrate that E2F4 is an independent and enhancing predictor of survival above the currently examined variables. (more…)
Author Interviews, Prostate Cancer, Vaccine Studies / 10.01.2015

Dr. Robert S. DiPaola Director, Rutgers Cancer Institute of New Jersey New Brunswick, NJ 08901MedicalResearch.com Interview with: Dr. Robert S. DiPaola Director, Rutgers Cancer Institute of New Jersey New Brunswick, NJ 08901   Medical Research: What is the background for this study? What are the main findings? Dr. DiPaola: Despite significant recent improvements in the treatment of advanced castration-resistant prostate cancer, there remains a need for a standard therapy for those patients who have an early relapse with PSA progression after local therapy.  Immune therapy with poxvirus vaccines are optimal, because they can induce potent immune responses by mimicking natural infection, have great flexibility regarding antigen composition and are easily administered. ECOG-ACRIN Cancer Research Group investigators conducted a Phase II clinical trial examining adult patients from member institutions with advanced prostate cancer (as evidenced by two rising prostate-specific antigen or PSA values and no visible metastasis) who had prior surgery or radiation. We explored two different experimental treatment options. In step one, patients were treated with PROSTVAC-V/TRICOM and PROSTVAC-F/TRICOM. PROSTVAC-V is derived from a vaccinia virus that was used for many years to vaccinate against smallpox. This virus is modified to produce a PSA protein that helps focus the body’s immune response to the PSA in the prostate tumor. In addition, it is modified to produce three other proteins that help increase an immune cell’s ability to destroy its target (TRICOM). PROSTVAC-F is made from the fowlpox virus, which is found in birds and not known to cause any human disease.  It contains the same genetic material as PROSTAC-V, but is given multiple times to further boost the body’s immune system. Patients in the study were given one cycle of PROSTVAC-V/TRICOM followed by PROSTVAC-F/TRICOM for subsequent cycles in combination with a drug known as GM-CSF. GM-CSF is a protein normally made by the body to increase the amount of certain white blood cells and make them more active. When in drug form, it is used to boost the body’s immune system to fight off disease.  After six months from first treatment, 25 of 40 eligible patients (63 percent) were found to have no disease progression and experienced minimal toxicity.  The rate of rise of PSA also decreased.  The second part of the study included the addition of hormone therapy (androgen ablation) to the PROSTVAC-VF/TRICOM combination. In the 27 patients eligible for this step, 20 patients (74 percent) experienced a significant response at seven months. (more…)
Author Interviews, Breast Cancer, Geriatrics / 07.01.2015

MedicalResearch.com Interview with: Pamela Vacek, PhD Research Assistant Professor Department of Pathology Medical Biostatistics Unit, College of Medicine University of Vermont,  Burlingon, Vermont Medical Research: What is the background for this study? What are the main findings? Dr. Vacek: Clinical trials to evaluate the effectiveness of screening mammography have focused primarily on women under age 70 and, consequently, its benefit for older women is uncertain. However, many believe that the benefit of screening mammography diminishes as women age and acquire other health problems, because they are less likely to live long enough for any detected breast cancer to have a clinical impact. To gain insight into this, we followed approximately 20,000 women aged 70 and older for an average of 10 years to examine their mammography use, cancer detection and survival. We found that screening mammography use declined steadily (9% per year) after age 70, but this was not accompanied by decline in the incidence of invasive breast cancer. Hence, as the women aged breast cancer was more likely to be detected clinically than by screening. The clinically detected tumors were significantly larger and of more advance stage and were associated with poorer overall survival, for all but the oldest and most infirm women. We also found that the use of breast conserving surgery as the only treatment for early stage cancer increased markedly with age and was associated with shorter survival compared to women receiving radiation or mastectomy. (more…)
Author Interviews, Colon Cancer, Compliance / 07.01.2015

Dr Siu Hing Lo Research Associate in Health Psychology UCL Research Department of Epidemiology and PublicMedicalResearch.com Interview with: Dr Siu Hing Lo Research Associate in Health Psychology UCL Research Department of Epidemiology and Public Medical Research: What is the background for this study? What are the main findings? Dr. Lo: Most types of population-based cancer screening – such as the Faecal Occult Blood (FOB) test – require repeat participation to be effective. The Faecal Occult Blood test is a stool test that typically needs to be self-completed every two years. This study investigated predictors of repeat participation in the NHS Bowel Cancer Screening Programme (BCSP). Late kit return, a definitive abnormal [FOB test] result and failure to comply with a follow-up colonoscopy in a previous screening episode were consistently and independently associated with lower repeat uptake. (more…)
Author Interviews, Lung Cancer, Medical Imaging / 05.01.2015

Joao R. Inacio, MD Cardiothoracic Radiologist Director Visiting Professor Program Assistant Professor of Radiology, University of Ottawa Medical Imaging, The Ottawa Hospital Ottawa, ONMedicalResearch.com Interview with: Joao R. Inacio, MD Cardiothoracic Radiologist Director Visiting Professor Program Assistant Professor of Radiology, University of Ottawa Medical Imaging, The Ottawa Hospital Ottawa, ON Medical Research: What is the background for this study? What are the main findings? Dr. Inacio: Lung cancer is the most common and most lethal cancer worldwide. Its prognosis remains poor with a 5-year survival rate of 6–18%. Adenocarcinoma has surpassed squamous cell carcinoma as the leading histologic type. The presence of metastases carries the worst prognosis in lung cancer and is the most important in determining staging and management. Hematogenous spread (i.e., carried by blood) is the most common mechanism of intrapulmonary metastasis. Cumulative evidence suggests that intrapulmonary aerogenous spread may exist and is under recognized. Deriving from our clinical experience, we performed a literature review that supports the hypothesis that lung cancer, particularly adenocarcinoma, may spread through the airways. With aerogenous metastases, it has been postulated that cancer cells growing along the alveolar septa at the primary site detach from the basal membrane, spread through the airways and re-attach and grow along alveolar septa away from the primary focus. Radiology-pathology correlation studies, using Chest Computed Tomography (CT), have documented the radiological evolution from focal adenocarcinoma to multifocal airspace disease and demonstrated cytologic and histologic findings supportive of aerogenous spread. (more…)
Author Interviews, Breast Cancer, Mayo Clinic, NEJM / 03.01.2015

MedicalResearch.com Interview with: Dr. Lynn C. Hartmann MD Professor of Oncology, Mayo Clinic Associate Director for Education of the Mayo Clinic Cancer Center. Medical Research: What is the background for this study? What are the main findings? Dr. Hartmann: Women with atypical hyperplasia of the breast – which is defined via breast biopsy that was done to evaluate findings on a mammogram or a palpable concern – have been considered a “high risk” group of women, but the extent of their risk has not been clearly defined. As a consequence, practice guidelines for high-risk women (eg for screening MRI) do not include them. Mayo Clinic has developed a cohort of women with atypical hyperplasia who have been followed long-term for later breast cancers and we show that their risk of developing breast cancer is about 30% at 25 years of follow-up. This same level of risk was confirmed in the other large cohort of women with atypical hyperplasia, based at Vanderbilt University (Nashville Breast Cohort). This level of risk meets the current criterion for screening MRI and should also encourage the use of anti-estrogen drugs, such as tamoxifen, which have already been shown to be efficacious in this population of women. Medical Research: What should clinicians and patients take away from your report? Dr. Hartmann: There are about 100,000 US women each year diagnosed with atypical hyperplasia via breast biopsy. Although strictly speaking, atypical hyperplasia is a benign finding, it is associated with a sizable risk of a later breast cancer. Physicians from numerous disciplines care for women with high-risk benign breast issues, including gynecologists, family physicians, internists, surgeons and oncologists. These practitioners, and the patients themselves, need information about the absolute risk of breast cancer occurring over time after a diagnosis of atypical hyperplasia. This information is provided in the NEJM report. Also, current guidelines should be updated to include this high-risk population and specifics about their absolute risk, and that the risk level qualifies these patients for screening MRI. Moreover, from the standpoint of risk reduction, four previously conducted breast cancer prevention trials included women with atypical hyperplasia. These trials used hormonal therapies (anti-estrogens) and showed that, in women with atypical hyperplasia, the use of such medications could lower the risk of a later breast cancer by 50% or more. Yet, other research has shown that women are quite reluctant to take such medications, primarily because of fear of side effects. In the NEJM report, we detail specific numbers of side effects that actually occurred in women who used these anti-estrogens (as opposed to the number of side effects seen in women taking placebo) and show that most of the side effects occurred quite uncommonly. Thus, we hope that the combination of information provided in this report on (i) actual risks of breast cancer and (ii) actual risks of side effects will help patients and practitioners make informed decisions on the best treatment approaches for women with atypical hyperplasia. Medical Research: What recommendations do you have for future research as a result of this study? Dr. Hartmann: First, women with atypical hyperplasia should be included in future prospective trials of novel imaging strategies (they were not included in trials of MRI, which had been limited to women with hereditary risk). Second, efforts should continue to predict which women with atypical hyperplasia are at highest risk, especially in the first 5-10 years after their biopsy, so they can be cared for optimally. Our research team, and others, continue to study the underlying molecular pathways that drive the progression from atypical hyperplasia to cancer; identifying such processes would not only aid in risk prediction but also identify driving pathways that could be blocked pharmaceutically. Citation: upcoming NEJM publication discussing: Women with Atypical Hyperplasia are at Higher Risk of Breast Cancer MedicalResearch.com Interview with: Dr. Lynn C. Hartmann MD Professor of Oncology, Mayo Clinic Associate Director for Education of the Mayo Clinic Cancer Center. Medical Research: What is the background for this study? What are the main findings? Dr. Hartmann: Women with atypical hyperplasia of the breast – which is defined via breast biopsy that was done to evaluate findings on a mammogram or a palpable concern  – have been considered a “high risk” group of women, but the extent of their risk has not been clearly defined.  As a consequence, practice guidelines for high-risk women (eg for screening MRI) do not include them.  Mayo Clinic has developed a cohort of women with atypical hyperplasia who have been followed long-term for later breast cancers and we show that their risk of developing breast cancer is about 30% at 25 years of follow-up.  This same level of risk was confirmed in the other large cohort of women with atypical hyperplasia, based at Vanderbilt University (Nashville Breast Cohort).  This level of risk meets the current criterion for screening MRI and should also encourage the use of anti-estrogen drugs, such as tamoxifen, which have already been shown to be efficacious in this population of women. (more…)
Author Interviews, Journal Clinical Oncology, Lung Cancer, Radiation Therapy, UT Southwestern / 03.01.2015

MedicalResearch.com Interview with: Dr. Puneeth Iyengar, MD, PhD. Assistant Professor Director of Clinical Research Dept of Radiation Oncology Co-leader, Thoracic Disease Oriented Team Harold Simmons Cancer Center UT Southwestern Medical Center  Dallas, TX Medical Research: What is the background for this study? What are the main findings? Response: Stage IV Non-small cell lung cancer (NSCLC) remains a disease of limited survival, in the range of one year for a majority of patients who historically have gone on to receive systemic therapy only. Disease in this patient population most often recurs in the sites of original gross disease. With greater understanding of the biology and patterns of failure that occur in stage IV NSCLC, it is becomingly increasingly obvious that there are subsets of patients, those with limited sites of metastatic disease, who may benefit with more aggressive local therapy in addition to systemic agents to effectuate longer progression free survival (PFS) and potentially overall survival (OS). Since failures of treatment occur most commonly in original gross deposits, local non-invasive therapy in the form of stereotactic body radiation therapy (SBRT) may offer a means to curtail the recurrences, perhaps as a way to shift the time to and patterns of failure. To address these concepts, a multi institutional single arm phase II study was conducted at UT Southwestern Medical Center in Dallas and University of Colorado Medical Center. Twenty-four patients with limited metastatic NSCLC (fewer than or equal to six sites of disease including the primary) who had progressed through at least one systemic therapy regimen were treated with SBRT to all sites of gross disease and the EGFR inhibitor erlotinib with progression free survival the primary end point. The results of the study were very significant, with a PFS in this study cohort of 14.7 months, compared to historical ranges of 2-4 months, and an OS of 20.4 months, compared to historical ranges of 6-9 months for this same patient population. The SBRT treatments were found to be very safe and efficacious – only 3 out of 47 measurable lesions irradiated recurred with a concomitant shift in failure patterns from local to distant sites. As importantly, EGFR status was evaluated in 13 patient tumors, with none harboring the most common mutations. One could, therefore, predict that with a mutation enriched population, the combination of EGFR inhibitor and SBRT may have offered even greater PFS and OS benefits. Our observations also suggest that the SBRT treatments probably contributed the most to the dramatic PFS and OS outcomes. These findings were published in the Journal of Clinical Oncology in the December 1, 2014 print issue with an accompanying editorial. (more…)
Author Interviews, Cancer Research, PNAS, UCSD / 31.12.2014

MedicalResearch.com Interview with: Annie Samraj and Ajit Varki MDDr. Annie Samraj MD Postdoc Fellow Varki Lab and Ajit VAjit Varki MD Distinguished Professor of Medicine and Cellular & Molecular Medicine Co-Director, Center for Academic Research and Training in Anthropogeny (CARTA) Co-Director, Glycobiology Research and Training Center (GRTC) University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0687.arki MD Distinguished Professor of Medicine and Cellular & Molecular Medicine , Co-Director, Center for Academic Research and Training in Anthropogeny, Co-Director, Glycobiology Research and Training Center University of California, San Diego, La Jolla, CA Medical Research: What is the background for this study? What are the main findings? Dr. Varki: For the past decade, there has been increasing evidence that people who consume red meat (beef, pork, lamb) are at a higher risk for certain kinds of cancers. Although red meat is a high quality source of protein, iron and vitamins, too much consumption may be harmful to humans. While there are other hypotheses under consideration, we focused on a non-human sugar molecule called Neu5Gc in red meat that could explain the link to cancer risk. We extensively studied various foods and concluded that red meat (particularly beef) is rich in Neu5Gc. In contrast poultry, fish steaks and hen eggs have little or no Neu5Gc. From previous studies, we knew that animal-derived Neu5Gc could be incorporated into human tissues. In this study, we hypothesized that eating red meat could lead to inflammation if the body’s immune system targets the foreign Neu5Gc. Chronic inflammation is also known to instigate or promote tumor progression. To test this hypothesis, we used mice engineered to be similar to humans in that they lacked Neu5Gc, and also produced antibodies against it. When these mice were fed Neu5Gc, they developed systemic inflammation. Tumor formation increased fivefold and Neu5Gc accumulated in the tumors, proving the hypothesis. None of the various control groups of mice showed this effect. (more…)
Author Interviews, Cancer Research / 30.12.2014

Paul Dent PhD Massey Cancer Center, Departments of Biochemistry and Molecular Biology Virginia Commonwealth University, Richmond, VA 23298MedicalResearch.com Interview with: Paul Dent PhD Massey Cancer Center, Departments of Biochemistry and Molecular Biology Virginia Commonwealth University, Richmond, VA 23298 Medical Research: What is the background for this study? What are the main findings? Dr. Dent: I have worked on understanding how the drug OSU-03012 (AR-12) kills cancer cells since 2005. The drug was originally advertised as an inhibitor of PDK1 in the PI3 kinase pathway. We found that PDK1 inhibition could not be the major way in which the drug worked. We found that the drug killed brain cancer cells through endoplasmic reticulum stress signaling. And in 2012 we published that OSU-03012 destabilized the chaperone protein GRP78, without significantly altering its transcription. Loss of GRP78 was responsible for the prolonged intense endoplasmic reticulum stress signal, that was toxic. In 2014 we published that OSU-03012 + Viagra / Cialis synergized to kill brain cancer cells. We hypothesized that Viagra / Cialis might enhance the anti-GRP78 effect of OSU-03012; and this was proven to be true. We discovered that the OSU-03012 + Viagra combination, but not OSU-03012 alone, reduced expression of other chaperone proteins, such as HSP70, GRP94. In mice, the combination was not toxic to "normal" tissues, but was toxic to tumor cells. In human patients the drug was found to be safe in a phase I trial, with plasma levels of up to 8 microM, and patients on trial for up to 9 months. (more…)
Annals Internal Medicine, Author Interviews, Colon Cancer, Race/Ethnic Diversity, University of Pennsylvania / 30.12.2014

Jeffrey H. Silber, M.D., Ph.D. The Nancy Abramson Wolfson Endowed Chair in Health Services Research Director, Center for Outcomes Research The Children's Hospital of Philadelphia Professor of Pediatrics, Anesthesiology & Critical Care The Perelman School of Medicine Professor of Health Care Management, The Wharton SchoolMedicalResearch.com Interview with: Jeffrey H. Silber, M.D., Ph.D. The Nancy Abramson Wolfson Endowed Chair in Health Services Research Director, Center for Outcomes Research The Children's Hospital of Philadelphia Professor of Pediatrics, Anesthesiology & Critical Care The Perelman School of Medicine Professor of Health Care Management, The Wharton School The University of Pennsylvania  Philadelphia, PA 19104 Medical Research: What is the background for this study? What are the main findings? Response: Differences in colon cancer survival by race is a well recognized problem among Medicare beneficiaries. We wanted to determine to what extent the racial disparity in survival is due to a racial disparity in presentation characteristics at diagnosis (such as advanced stage and the presence of chronic diseases) versus a disparity in subsequent treatment by surgeons and oncologists. To answer this question, we compared black colon cancer patients to three matched white groups: (1) “Demographics” match controlling age, sex, diagnosis year, and Survey, Epidemiology, and End Results (SEER) site; (2) “Presentation” match controlling demographics plus comorbidities and tumor characteristics including stage and grade; and (3) “Treatment” match including presentation variables plus details of surgery, radiation and chemotherapy. We studied Medicare patients 65 years of age and older diagnosed between 1991-2005 in the SEER-Medicare database. There were 7,677 black patients and 3 sets of 7,677 matched white controls. We found that difference in 5-year survival (black-white) was 9.9% in the demographics match. This disparity remained unchanged between 1991-2005. After matching on presentation characteristics, this difference fell to 4.9%. Finally, after additionally matching on treatment, this same difference hardly changed, moving to only 4.3%. So the disparity in survival attributed to treatment differences comprised only an absolute 0.6% of the overall 9.9% survival disparity. (more…)
Author Interviews, Cancer Research, Radiology / 29.12.2014

Ulas Sunar, Ph.D. Research Assistant Prof. Dept of Biomedical Engineering SUNY-University at BuffaloMedicalResearch.com Interview with: Ulas Sunar, Ph.D. Research Assistant Prof. Dept of Biomedical Engineering SUNY-University at Buffalo Medical Research: What is the background for this device? What are the main implications? Dr. Sunar: Most of ovarian cancer cases are not diagnosed until after the disease has spread in the abdominal cavity. A major challenge is to detect and remove dozens or hundreds of metastatic tumor nodules within the abdominal cavity. Fluorescence endoscopy can utilize the high sensitivity and specificity of fluorescence contrast and high resolution of endoscopic imaging. We are developing a clinically-relevant, fiber-based endoscopy system that allows both accurate fluorescence imaging and for projecting adaptive-shaped light for light-induced chemodrug delivery. The system can provide high contrast for improved demarcation and trigger drug release to destroy micrometastases. The system utilizes a highly sensitive camera and structured light illumination scheme with a projector for accurate fluorescence imaging of drug distribution, as well as allows light-triggered drug release and adaptive light delivery for optimized treatment of micrometastases. We expect that our novel illumination and drug release strategy will permit lower doxorubicin doses to be administered while simultaneously achieving more specific drug delivery in order to destroy the micrometastases and improve survival rates. (more…)
Author Interviews, Breast Cancer / 29.12.2014

Dr. SikovMedicalResearch.com Interview with: William M. Sikov, MD Associate Chief of Clinical Research Program in Women's Oncology Women & Infants Rhode Island Associate professor of Medicine The Warren Alpert Medical School of Brown University Medical Research: What is the background for this study? What are the main findings? Dr. Sikov: The data presented at San Antonio this year are the first results from correlative studies performed on pretreatment tissue samples from patients treated on CALGB 40603, a 2 x 2 factorial randomized phase II study which tested the addition of carboplatin or bevacizumab to a standard neoadjuvant chemotherapy regimen consisting of weekly paclitaxel followed by dose-dense AC in patients with stage II-III triple breast cancer. Last year at San Antonio (and subsequently published in the JCO) we presented the primary endpoint of the study - pathologic complete response (pCR) - and reported that the addition of either carboplatin or bevacizumab significantly increased pCR rates compared to the control regimen. This year we reported results of a preplanned analysis which assessed the impact of intrinsic subtype (based on mRNA expression analysis) - especially the basal-like subtype - on the impact of the two agents on pCR rates. We also reported the effects of a number of previously published mRNA expression signatures on pCR rates and the benefits of adding carboplatin or bevacizumab. The findings reported were as follows: We had a higher percentage of basal-like cancers than we anticipated when the study was designed (87% vs. 70-80% expected), which we hypothesize is due to improvements in the ways we assess hormone receptor and HER2 status, and thus define triple-negative breast cancer, compared to 10-15 years ago. When we limit our analysis to the subset of patients with basal-like cancers, we continue to see a statistically significant increases in pCR rates with both carboplatin and bevacizumab. However, while the 13% of patients with non-basal-like cancers get essentially the same increase in pCR rates with carboplatin as do the basal-likes, non-basal-likes actually had a reduction in their pCR rates with the addition of bevacizumab - thus, there was a significant interaction between subtype and pCR benefit for bevacizumab but not for carboplatin. Among the mRNA signatures we assessed, higher expression of immune signatures  (indicating more tumor-infiltrating lymphocytes) correlated with higher pCR rates, but not greater pCR increments with either carboplatin or bevacizumab. Higher proliferation, lower estrogen, and higher TP53 mutation signaturss also correlated with higher pCR rates overall, and also with greater pCR increments with bevacizumab, but not carboplatin. (more…)
Author Interviews, Breast Cancer, Johns Hopkins, Journal Clinical Oncology, Leukemia / 28.12.2014

MedicalResearch.com Interview with: Dr. Judy Karp, Dr. Antonio Wolff and  Dr. Kala Visvanathan Breast Cancer Program Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Baltimore, MD 21287 Medical Research: What is the background for this study? What are the main findings? Response: The background for this study was the clinical observation from the Johns Hopkins Leukemia Program that a significant number of women with newly diagnosed acute myeloid leukemia had a personal history for breast and/or ovarian cancers.  This observation led to our examination of the large NCCN breast cancer database in a multidisciplinary and multi-institutional study.  The overarching finding in our study is that the risk of developing some form of leukemia following chemotherapy with or without radiation therapy, while small, continues to increase over at least 10 years without a plateau and is roughly twice what we thought it to be from previous breast cancer studies. (more…)