MedicalResearch.com Interview with:
Catterina Ferreccio, MD, MPH
School of Medicine
Pontificia Universidad Católica de Chile
Santiago, Chile
Medical Research: What is the background for this study? What are the main findings?
Dr. Ferreccio: In Chile, gallbladder cancer (GBC) is the 2nd highest cause of cancer death in women. Other than gallstones no other causal factors have been identified. We conducted a pilot case-control study of gallbladder cancer to evaluate its association with aflatoxin B1 (AFB1) exposure. Aflatoxins are toxics products of the fungis Aspergillus flavus and Aspergillus parasiticus and are contaminants of food; AFB1 is carcinogenic. Usually they are found in areas closer to the Equator than Chile.
Main findings were the high proportion (35%) of study subjects carrying aflatoxins adducts and the particularly high exposure among the Gallbladder cancer (GBC) cases (64%) compared with gallstones controls (18%) or with population controls (23%).
Difference of gallbladder cancer vs controls were statistically significant and suggests aflatoxins may be a significant risk factor for gallbladder cancer; hypothesis never tested before.
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MedicalResearch.com Interview with:Professor Ramsey Cutress
Associate Professor in Breast Surgery
University of Southampton
Medical Research: What is the background for this study? What are the main findings?Response: The main finding is that in young women with breast cancer, a breast cancer family history of breast cancer did not affect recurrence rates.
This work forms part of the Prospective Outcomes in Sporadic versus Hereditary breast cancer (POSH) study, which included 2850 women under age 41 years who were diagnosed with breast cancer and treated in the UK. The study, led by principal investigator Professor Diana Eccles, recorded patients’ personal characteristics, tumour characteristics, treatment, and family history of breast/ovarian cancer over a 15-year period.
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MedicalResearch.com Interview with: Mr Matthew Nankivell
MRC Clinical Trials Unit at University College London
Institute of Clinical Trials and Methodology
Aviation House, London
UK
Medical Research: What is the background for this study? What are the main findings?
Response: Ovarian cancer is diagnosed in over 7000 women each year in the UK. Over 75% of these already have advanced disease, for which the standard treatment is surgery followed by platinum based chemotherapy. The prognosis for these patients remains poor however, with less than 25% surviving for 5 years. There is consistent evidence that achieving optimal debulking (meaning less than 1cm of residual tumour after surgery) is key to increasing survival. The theory tested in Chorus is that giving the chemotherapy before surgery (neo-adjuvantly) would be as least as effective as giving it post-operatively, and may in fact increase the chance of achieving optimal debulking, and subsequently living for longer.
In Chorus we randomised 552 women to receiving either the current standard of immediate surgery followed by chemotherapy, or chemotherapy followed by surgery. The trial met its primary aim of showing that neo-adjuvant chemotherapy was no worse than post-operative chemotherapy, with median survival times of 24.1 and 22.6 months respectively. The proportion of women achieving optimal debulking increased from 41% in the post-operative chemotherapy group to 73% in the neo-adjuvant chemotherapy group. Additionally we saw that fewer women experienced serious post-operative complications having had neo-adjuvant chemotherapy (14% vs 24%), and fewer women died within 28 days of surgery (<1% vs 6%).
There is a planned meta-analysis, to combine the data from Chorus with those from a similar European trial, which will allow further investigations to take place, and may allow the identification of groups of women who are more likely to benefit from one or other of the approaches.
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MedicalResearch.com Interview with:
Dr. Jeanne Tie
Medical Oncologist | Royal Melbourne and Western Hospital
Research Fellow
Walter and Eliza Hall Institute of Medical Research
Parkville, VIC
Medical Research: What is the background for this study?
Dr. Tie: The increasing number of active agents available to treat metastatic colorectal cancer has resulted in an ever-improving life expectancy in this group of patients. However, the ability to expose patients with metastatic colorectal cancer to all effective anti-cancer treatment, particularly 3rd line treatment and beyond, is increasingly challenging in routine practice as some patients’ condition deteriorate too rapidly and do not live long enough to enjoy the benefit of these additional therapies. This is partly due to the current imaged-based method of assessing treatment response with the Response Evaluation Criteria in Solid Tumors (RECIST), which is usually performed every 8-12 weeks during the course of treatment. This means that for non-responders to treatment, several weeks to months will elapse before a switch to alternative therapy will be made. Conceptually, if a patient’s response to treatment could be made earlier, such as with a blood test, then an earlier switch to an alternative treatment can be made, minimizing the side-effects of the ineffective therapy and providing the opportunity for a more effective one. Currently, blood biomarkers add little to imaging-based assessment, with CEA lacking sensitivity and specificity.
Colorectal cancer is characterised by several recurrently mutated genes and advances in genomics and molecular technologies have now enabled rapid detection and quantification of these cancer-specific mutations in patient’s circulation (circulating tumor DNA - ctDNA). Previous studies have demonstrated that ctDNA can be detected in a high proportion of patients with advanced cancer. In this study, we describe the potential role of ctDNA as an early predictor of treatment response in patients with treatment naïve metastatic colorectal cancer (mCRC) undergoing chemotherapy and as a marker of disease bulk that could complement RECIST measurement. (more…)
MedicalResearch.com Interview with:
Lao Saal, M.D. Ph.D.
Head, Translational Oncogenomics Unit
Assistant Professor
Department of Oncology and Pathology
Lund University Cancer Center
Lund, Sweden
Medical Research: What is the background for this study?
Dr. Saal: About a quarter of women diagnosed with primary (non-metastatic) breast cancer will unfortunately progress and later be found to have metastatic spread, which can occur many years to even a decade or more after the first diagnosis. At this point, the prognosis after identification of metastatic breast cancer is very poor. Metastatic disease is typically diagnosed only after it has grown large enough to cause symptoms, be noticed on exam, or be detectable by imaging. It is thought that early detection of metastasis has the potential to lead to better outcomes because therapies could be modified when the metastasis is still very small. Moreover, a very sensitive and specific test that could identify patients who appear "cancer-free" could also be useful. Essentially all cancers have unstable genomes, where chromosomes physically break and are reassembled incorrectly and thus the normal sequence is altered. Importantly, DNA material from cancer cells can be found in the blood circulation and therefore this circulating tumor DNA has the potential to be a cancer biomarker.
Medical Research: What are the main findings?
Dr. Saal: Eleonor Olsson, a PhD student in my lab who defends her thesis next week, and Christof Winter, a postdoc bioinformatician in my group, were the first authors of the paper. In our study we tested whether periodic monitoring of circulating tumor DNA (ctDNA) in blood plasma samples, taken before surgery for primary breast cancer and at multiple timepoints after surgery, could identify the metastastic spread, and whether the quantity of ctDNA was associated to patient outcome. We analyzed a retrospective cohort of 20 patients, who had enrolled many years ago in a separate epidemiological study run by Helena Jernström in our department, wherein the appropriate blood plasma samples had been biobanked and tumor tissue was available and we had long-term clinical follow-up information.
As far as we are aware, our study is the first to show the potential for serial ctDNA monitoring in the context of primary breast cancer. We found that our ctDNA blood tests could discriminate patients with eventual metastasis from those with long‐term disease‐free survival with 93% sensitivity and 100% specificity. Furthermore, ctDNA‐based detection of metastatic disease preceded clinical detection for 86% of patients by an average 11 months and in some cases by 3 years. In all of the patients who had long-term disease-free survival, we did not detect any ctDNA in any timepoints after surgery. Lastly, the measured quantity of ctDNA was a significant predictor of outcome: for each doubling of the ctDNA level, the odds ratio for metastasis was 2.1 and the odds ratio for death was 1.3. An interesting anecdote -- one patient we studied had bilateral breast cancer and we found that it was the right-side tumor (which actually had more favorable clinical characteristics) that gave rise to the metastasis and not the left-side tumor.
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MedicalResearch.com Interview with: Michael Fenstermaker MD
NYU School of Medicine | MD, MS | Class of 2015
Northwestern University | BA | Biochemistry, Psychology
Medical Research: What is the background for this study? What are the main findings?
Dr. Fenstermaker: The benefits of using prostate-specific antigen (PSA) testing to screen for prostate cancer are uncertain. In response to this, many medical societies have recently scaled back their recommendations for PSA screening. One common thread among these groups is that shared decision-making should guide whether or not men get tested. Shared decision-making is a process by which physicians and patients work together to make a medical decision that aligns with the patient’s values and follows the best available medical evidence.
Several studies have shown a decline in PSA testing since new guidelines have been published. While a decrease in screening is not necessarily problematic itself, it could be an issue if this is the result of fewer physicians discussing screening with their patients. Some experts worry that disparities in screening could develop, such that only informed patients go on to speak with their physicians and receive PSA testing. By analyzing data from a national survey, we had the chance to investigate just how much men know about the controversies leading to these guidelines changes and whether this knowledge influences PSA usage.
Our findings show that the majority of U.S. males of screening age report that they were not informed of many key facts important to understanding the risks and controversies surrounding PSA testing. Of particular concern, certain vulnerable populations, such as those without regular healthcare providers were less likely to be informed of these facts. Surprisingly, those men who had more awareness of the controversies about PSA testing were more likely to undergo testing. (more…)
MedicalResearch.com Interview with:
Jennifer R. Rider, ScD, MPH
Assistant Professor of Medicine
Channing Division of Network Medicine
Brigham and Women's Hospital and Harvard Medical School
Department of Epidemiology
Harvard T.H. Chan School of Public Health
Boston, MA 02115
Medical Research: What is the background for this study? What are the main findings?
Dr. Rider: Numerous studies have investigated the potential role of sexual activity on the development of prostate cancer. However, most of these studies have been small and retrospective, making them more prone to bias. In addition, previous studies often relied on proxies of exposure for sexual activity (number of sexual partners, age at first marriage, etc.), which may not adequately measure the aspects of sexual activity that are most important for prostate health. The current study is the largest prospective study to date on ejaculation frequency and prostate cancer. It includes 18 years of follow up of almost 32,000 healthy men, 3839 of whom later were diagnosed with prostate cancer. We asked men about their average monthly frequency of ejaculation between the ages of 20-29, 40-49, and in the year prior to the questionnaire (1991). We find that frequency of ejaculation throughout life course is inversely associated with risk of prostate cancer at all three of these time points. For instance, men who have an average monthly ejaculation frequency of 21 or more times/moth at ages 40-49 have a statistically significant 22% reduction in risk of developing prostate cancer compared to men with a frequency of 4-7 times/month, adjusting for multiple dietary and lifestyle factors, and prostate cancer screening history.
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MedicalResearch.com Interview with:
Ryan P. Terlecki, MD, FACS
Director, Men's Health Clinic
Director, Fellowship in Urologic Reconstruction, Prosthetic Urology, and Infertility
Director, Medical Student Education
Associate Professor of Urology
Wake Forest Baptist Health
Medical Research: What is the background for this study? What are the main findings?
Response: In recent years, the value of generalized screening for prostate cancer (PCa) in adult men has been questioned, with several national associations recommending against the practice in men without recognized risk factors. Screening, when performed, often consists of a blood test for prostate specific antigen (PSA) and a digital rectal exam (DRE). Once PSA was developed as a screening tool, we witnessed a stage migration such that observing a locally advanced cancer that would be initially found via DRE became a rarer event. In practice, we have noticed that some men will actually avoid a clinic visit because of the DRE. Additionally, the digital rectal exam has limitations and is often poorly reproducible among providers. We chose to review a large body of data to shed some light on the utility of the digital rectal exam exam. We analyzed data from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening trial, to determine the ability of the digital rectal exam to result in a diagnosis of clinically significant PCa in the setting of a normal PSA. We found that if PSA is normal and digital rectal exam is considered abnormal, the chance of detecting a clinically significant cancer is similar to a situation of normal DRE and normal PSA. Also, 1,372 men would need to undergo a digital rectal exam to identify a single case of clinically significant prostate cancer not detected by PSA.
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MedicalResearch.com Interview with:
Michael Brawer, M.D.
Vice president of Medical Affairs
Myriad Genetic Laboratories
Editor’s Note: Dr. Brawer spoke with MedicalResearch.com regarding two studies...
MedicalResearch.com Interview with:
Katherine Aird, Ph.D.Gene Expression and Regulation Program
The Wistar Institute, Philadelphia, PA
MedicalResearch: What is the background for this study? What are the main findings?Dr. Aird: Senescence is considered an important tumor suppressor mechanism. In normal cells, activation of certain oncogenes decreases the levels of dNTPs (the building blocks of DNA), leading to replication stress. We previously found that loss of the rate-limiting enzyme in dNTP synthesis, ribonucleotide reductase M2 (RRM2), is the cause of this replication stress. Restoration of RRM2 expression could rescue the loss of dNTPs and replication stress, which overcame the senescence-associated growth arrest. Indeed, RRM2 is highly expressed in many cancer types, including melanoma and ovarian cancer. Therefore, we found that increased dNTP levels can overcome senescence and potentially lead to transformation of cells and cancer.
We next wanted to further our understanding of replication stress in the context of senescence. In the current study, we suppressed nucleotide metabolism by decreasing RRM2 expression as a model for replication stress and then determined what proteins are necessary for the induction of senescence. We found that loss of ATM could overcome replication stress-induced senescence. This was due to increased dNTP levels. dNTPs were increased due to a coordinated inactivation of p53 and activation of c-MYC by loss of ATM. These changes at the molecular level correlate with reprogramming of cellular metabolism by generating dNTPs. Thus, loss of ATM in the context of replication stress can change cellular metabolism to a more cancer-like phenotype.
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MedicalResearch.com Interview with:
Melinda L. Telli, M.D. Assistant Professor of Medicine Stanford University Division of Medical Oncology Stanford, CA 94305-5826Medical Research: What is the background for this study? What are the main findings?
Response: A major goal of this study was to explore a DNA damaging chemotherapy regimen in patients with newly diagnosed early-stage triple-negative or BRCA1/2 mutation-associated breast cancer. This was based on the hypothesis that these types of tumors are more responsive to DNA damaging therapeutics. A second major goal was to identify predictors of response to this platinum-based therapy among patients with sporadic triple-negative breast cancer (TNBC).
Overall, this study demonstrated that the non-anthracycline and non-taxane neoadjuvant regimen of gemcitabine, carboplatin and iniparib resulted in a 36% pathologic complete response rate (pCR). This compares favorably to pCR rates commonly observed with anthracycline and taxane-based regimens in this group of patients. The response rate was higher among triple-negative breast cancer patients with a germline BRCA1 or BRCA2 mutation (56%).
Given the hypothesis of underlying DNA repair defects in sporadic triple-negative breast cancer, we also evaluated a novel measure of genomic instability to detect the accumulation of changes in the genomic landscape of a tumor attributable to defective homologous recombination DNA repair. Homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies. Very importantly, we found that the HRD-LOH assay was able to identify patients with sporadic TNBC lacking a BRCA1 or BRCA2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. (more…)
MedicalResearch.com Interview with:
Bernadette A.M. Heemskerk-Gerritsen, Ph.D.
Department of Medical Oncology
Erasmus MC Cancer Institute
Roterdam, the NetherlandsMedical Research: What is the background for this study? What are the main findings?
Dr. Heemskerk-Gerritsen: Women with a BRCA1 or BRCA2 mutation have substantially higher risks of developing both primary and contralateral breast cancer (BC) and ovarian cancer than women from the general population. Options to reduce these increased cancer risks include risk-reducing mastectomy (RRM) and/or risk-reducing salpingo-oophorectomy (RRSO). The latter intervention obviously reduces the risk of developing ovarian cancer, but has been reported also to reduce the risk of developing a subsequent breast cancer with approximately 50%. However, studies on the efficacy of risk-reducing surgery in BRCA1/2 mutation carriers are confined to observational studies, thus challenging several methodological issues. Consequently, previous studies on breast cancer risk-reduction after RRSO may have been influenced by bias associated with selection of study subjects, bias associated with start of follow-up, or by confounding, and breast cancer risk-reduction may have been overestimated.
In the current study, we revisited the association between risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1/2 mutation carriers, focusing on the impact of different analytical methods and potential types of bias.
First, we replicated the analyses of four previously performed studies, to examine if our Dutch cohort was comparable with the cohorts used in the previous studies. We replicated the approximately 50% breast cancer risk reduction after RRSO in the Dutch cohort.
Second, we estimated the effect of RRSO on breast cancer risk in the Dutch cohort using a revised analytical approach for observational studies in BRCA1/2 mutation carriers in order to minimize bias as much as possible. Using this method of analysis, we found no evidence of first BC risk-reduction after RRSO in BRCA1/2 mutation carriers.
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MedicalResearch.com Interview with:
Ahmad M. Khalil, PhD
Assistant professor, Department of Genetics and Genome Sciences
Case Western Reserve University School of Medicine
MedicalResearch: What is the background for this study? What are the main findings?Dr. Khalil: This study aimed to identify other genes that work synergistically with the oncogene HER2 in HER2positive (HER+) breast cancer. The gene HER2 is amplified in those patients, which results in excess activities that promote uncontrolled cell growth. There are drugs that target HER2 and diminish its activity. However, these drugs can work initially, but patients relapse; or sometimes, the drugs don't work at all in some patients.
Thus, by identifying other genes that work synergistically with the HER2 gene, we now have more genes to target by various drugs or compounds to destroy the tumor. The challenge was how to identify the key genes that work synergistically with HER2, especially in human subjects. To that end, we used clinical samples from a clinical trial of a drug that is known to inhibit HER2 activity to identify those genes. To further refine our list, we used cell culture models of the disease to also inhibit HER2. By combining those data sets, we identified 44 protein-coding genes.
Next, we wanted to make sure that those genes stand a third independent filter. For that part, we interrogated those 44 genes in HER2+ tumors vs matched normal tissues from The Cancer Genome Atlas database — a collection of hundreds of tumors and normal tissues. Of the 44 genes, 35 genes passed this third filter. By examining the known functions of those genes, we can deduce that those genes work cooperatively with HER2 to promote carcinogenesis.
There are currently known drugs that target some of those genes. We will use these drugs in combination with a drug that target HER2 to determine if the combination works better at destroying the tumor entirely.
Lastly, we found that a special type of genes that we previously discovered, called lincRNAs, could also affect the oncogenic activity of HER2. These lincRNAs can also be targeted with HER2 to eliminate the tumor. (more…)
MedicalResearch.com Interview with:
Matthias Eiber, MD
Department of Nuclear Medicine
Munich, Germany
Medical Research: What is the background for this study? What are the main findings?
Dr. Eiber: The background of the study is the investigation of a novel 68Ga-PSMA ligand using PET/CT in the workup of patients with recurrent prostate cancer after radical prostatectomy. Hereby, we found substantial higher detection rate compared to other methods. In total 222 (89.5%) patients showed pathological findings in 68Ga-PSMA-ligand PET/CT. Stratified by PSA-level the detection rates were 96.8%,93.0%,72.7% and 57.9% of ≥2,1-<2, 0.5-<1 and 0.2-<0.5ng/mL, respectively.
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MedicalResearch.com Interview with:
Robert J Canter MD
Associate Professor of Clinical Surgery
Division of Surgical Oncology
University of California at Davis
Medical Research: What is the background for this study?
Dr. Canter: Our data suggest that surgeons are improving in their ability to select patients for surgical intervention in cancer patients near their end of life. Our research suggests that surgeons may be operating on healthier patients who are anticipated to have a better recover from a palliative operation. These are patients who can perform activities of daily living without assistance, for example.
Our interest in the appropriate surgical care of people with late-stage cancer grew from observing terminally ill patients whose acute problems were addressed through surgery, and who then suffered complications resulting in lengthy stays in intensive care units, and even in death.
Unfortunately, it is quite common that this group of disseminated malignancy patients end up dying in the intensive care unit instead of being managed with less invasive interventions with hopes of returning home with their families, including with hospice care.
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MedicalResearch.com interview with
Dr. Victoria L. Chiou, MD
Medical Oncology Fellow
Women’s Malignancies Branch
National Cancer Institute
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Chiou: We studied the effects of different treatments in ovarian and breast cancer cell lines with and without BRCA1 mutation in the laboratory. Our discovery that olaparib pretreatment before carboplatin led to decreased carboplatin-induced DNA damage in tumor cells carrying BRCA1 mutation led us to a novel clinical question. We wanted to further understand whether there was an optimal way to deliver a combination of the new tablet formulation of olaparib with carboplatin chemotherapy in women with gynecologic and breast cancers.
We launched our clinical trial to test this important question. Overall, we are pleased that the drug combination of olaparib and carboplatin chemotherapy can be given safely together, with preliminary activity in women with breast and ovarian cancer associated with germline BRCA mutations. We are excited to report the findings of this study, which is the first to report preclinical and clinical data on sequence specificity for this drug combination in this patient population. (more…)
MedicalResearch.com Interview with:
Dr. Alec (Chengcheng) Zhang
Michael L. Rosenberg Scholar in Medical Research
Associate Professor of Physiology and Developmental Biology, Member of the Harold C. Simmons Comprehensive Cancer Center
UT Southwestern Medical Center
Medical Research: What is the background for this study? What are the main findings?
Response:Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. Treatments for AML yield poor outcomes, especially for the typical senior patients. The medical need for new therapies for AML is underscored by the fact that no new therapies for AML have been approved in over 30 years. There are over 50 experimental agents in clinical trials for the treatment of AML today, although only a few agents have promising data to date. New molecular targets and therapeutic strategies are needed for AML treatment.
In 2012, we published a paper showing that we cloned the human leukocyte immunoglobulin-like receptor B2 (LILRB2) as a receptor for several angiopoietin-like proteins (Angptls) (Zheng et al 2012 Nature 485:656-660). The LILRB family receptors contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and are classified as inhibitory receptors because ITIM motifs can recruit phosphatases SHP-1, SHP-2, or SHIP to negatively regulate immune cell activation. Surprisingly, in that work, we showed that PirB, the mouse ortholog of LILRB2, is expressed by AML stem cells (AML-SCs) and supports AML development. Although counterintuitive, this result is consistent with the generally immune-suppressive and thus tumor-promoting roles of the inhibitory receptors in the immune system.
In the current paper, we continued the research and report that a number of receptors containing the ITIMs are crucial for the development of AML. We mainly focus on studying the function and downstream signaling of LAIR1 as a representative ITIM-containing receptor. We found that the deletion of LAIR1 does not affect normal hematopoiesis but abolishes leukemia development in several different mouse leukemia models. We also identified a mechanism by which LAIR1 supports AML development, showing that the LAIR1/SHP-1/CAMK1/CREB pathway sustains the survival and self-renewal of AML cells. Importantly, our findings are well supported by bioinformatics analysis of AML patient databases and experimental results of human leukemia cells. Since certain ITIM-containing receptors are essential for AML cells but not critical for normal hematopoiesis, and blocking their signaling can boost immunity, these ITIM-containing receptors including LAIR1 represent ideal targets for treating AML.
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MedicalResearch.com Interview with:
Terry Boyle, PhDCIHR Fellow, MSFHR Trainee, Honorary UBC Killam Fellow
Cancer Control Research, BC Cancer Agency
School of Population and Public Health, The University of British Columbia
Australian NHMRC Early Career Fellow
The University of Western Australia
Cancer Control Research, BC Cancer Agency
Vancouver BC Canada
Medical Research: What is the background for this study? What are the main findings?
Dr. Boyle: Little is known about what causes non-Hodgkin lymphoma (NHL), so trying to identify risk factors is particularly important for the prevention and control of this cancer. There is really good evidence that people who are physically active have a lower risk of some cancers (such as colon and breast cancers), but not many studies have investigated whether being physical active is associated with the risk of non-Hodgkin lymphoma.
The key finding of this case-control study was that study participants who were in the higher (second, third, and fourth) quartiles of vigorously intense physical activity performance in their lifetimes had about 25 percent to 30 percent lower risk for NHL, compared with those who were in the lowest (first) quartile of vigorously intense physical activity.
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MedicalResearch.com Interview with:
Dr. Stephen Wank MD
Digestive Diseases Branch, NIDDK
National Institutes of Health, Bethesda, Maryland
MedicalResearch: What is the background for this study?Dr. Wank: Small intestinal carcinoids are rare and difficult to diagnose because symptoms may be absent or mistaken for more common diseases. Because carcinoids usually grow slowly over several years before spreading or causing symptoms, patients often seek medical attention late with advanced, incurable disease. However, when diagnosed at an early stage, carcinoid can be surgically cured. Presently, there are no long-term effective therapies for surgically non-resectable disease. Although carcinoids occur sporadically, there have been reports of family clusters (more than one blood relative with carcinoid). Hereditary small intestinal carcinoid has not been recognized as a disease and causative genetic factors have not been identified in either sporadic cases or families with multiple affected members.
If small intestinal carcinoid occurs in families on a hereditary basis, we hypothesized that asymptomatic relatives in families with carcinoid are at a high risk of harboring an undiscovered tumor. To test this, we established a clinical research protocol at the National Institutes of Health in Bethesda, Maryland to screen asymptomatic relatives in families with at least two cases of small intestinal carcinoid in the hope of detecting their tumors at an early surgically curable stage. If successful in our endeavor, we would improve the outcome of the disease in these asymptomatic relatives and position ourselves to discover the genetic basis for their disease. Understanding the gene mutations causing small intestinal carcinoid would allow us to screen for the disease with a blood test, help us understand what causes the disease, and treat the disease with specific targeted therapies.
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MedicalResearch.com Interview with: Jacqueline Hirth, PhD, MPH
Assistant Professor and
Dr. Abbey B. Berenson MD, MMS, PhD
Center for Interdisciplinary Research in Women's Health
Obstetrics and Gynecology
The University of Texas Medical Branch at Galveston Texas
Medical Research: What is the background for this study? What are the main findings?
Response: In this sample of young women, vaccination was effective at reducing prevalence of vaccine-type HPV (6,11,16,18) compared to women who were unvaccinated. We also found a dose response, with young women who received at least 2 doses of the 3 dose vaccine series having a lower rate of vaccine-type HPV compared to those who only received one dose (8.6% compared to 16.9%, respectively).
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MedicalResearch.com Interview with:
Lisa M. Nyberg, MD, MPH
Transplant Hepatologist
Director, Hepatology Research
Kaiser Permanente, Garfield Specialty Center
San Diego, CA 92111
Medical Research: What is the background for this study? What are the main findings?
Dr. Nyberg: The overall cancer rates were higher in patients with Hepatitis C (HCV) vs those without HCV. Of note, though, the HCV cohort had higher rates of alcohol abuse, tobacco use, cirrhosis and diabetes mellitus (DM). However, even after stratification for the variables alcohol abuse, tobacco use, body mass index (BMI) and DM; the increased cancer rates remained significant for total cancer sites, liver cancer and NHL.
Note that this study does not establish a cause and effect relationship between Hepatitis C and cancer. A strength of this study is that it is an evaluation of a large patient population (n=35,712 with HCV and 5,297,191 without HCV). Limitations of the study are those inherent in epidemiological studies using large databases. For example, confounders may not be accurately recorded in automated databases (smoking and alcohol abuse may be under-recorded).
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MedicalResearch.com Interview with:Nasim Mavaddat M.B.B.S. MPhil PhD PhD
Centre for Cancer Genetic Epidemiology
Department of Public Health and Primary Care
University of Cambridge, Cambridge, UK
MedicalResearch:What is the background for this study?
What are the main findings?Dr. Mavaddat: Recent large-scale genome wide association analyses have led to the discovery of genetic variation- called single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Individually these variants confer risks that are too small to be useful for risk prediction. But when combined as a single score, called a polygenic risk score (PRS), this score may be used to stratify women according to their risk of developing breast cancer. This stratification could guide strategies for screening and prevention.
Our study was a large international collaboration involving 41 research groups from many different countries and included 33,673 breast cancer patients and 33,381 controls. We found that the genetic variants act more or less independently, and that the more risk variants a woman has the higher her risk of breast cancer. When women were ranked according to their PRS, women with scores in the top 1% had a threefold increased risk of breast cancer. This translates into an absolute risk of breast cancer of 29% by age 80. By contrast, women with the lowest 1% scores had a risk of 3.5%.
The PRS was effective in stratifying women with and without a family history of breast cancer, so that highest risk was for women with a family history and a high PRS. Finally, we showed that the PRS was better at predicting the risk of ER-positive breast cancer (potentially relevant to the application of risk stratification to chemoprevention for example, with tamoxifen, raloxifene or aromatase inhibitors).
There has been much debate as to whether genomic profiles are useful for individual risk prediction, especially in the context of the preventative strategies available at the present time. The estimates provided in this study will help inform these debates.
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MedicalResearch.com Interview with:
Joanna Kitlinska, PhD
Assistant Professor
Georgetown University Medical Center
Department of Biochemistry and Molecular & Cellular Biology
Washington, DC 20057
MedicalResearch: What is the background for this study? What are the main findings?Dr. Kitlinska: Neuroblastoma is a pediatric malignancy with extremely heterogeneous phenotypes, ranging from spontaneously regressing to aggressive, untreatable tumors. Consequently, treatment strategies vary significantly between patients, depending on the initial risk assessment. Given the severe late effects of anti-cancer treatment administered to infants and children, proper disease stratification is of utmost importance for neuroblastoma patients.
Due to their neuronal origin, neuroblastomas secrete neuropeptide Y (NPY), a small protein normally released from mature nerves. This, in turn, may result in elevated NPY levels in blood of neuroblastoma patients. We have found that serum NPY is particularly high in patients with aggressive, metastatic disease. Consequently, patients with elevated NPY levels have significantly worse survival. This finding is in agreement with our previous data indicating crucial role for NPY in stimulation of neuroblastoma tumor growth.
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MedicalResearch.com Interview with:
Joanna Kitlinska, PhD
Assistant Professor
Georgetown University Medical Center
Department of Biochemistry and Molecular & Cellular Biology
Washington, DC 20057
MedicalResearch: What is the background for this study? What are the main findings?Dr. Kitlinska: Neuroblastoma is a pediatric tumor which arises due to defects in normal fetal neuronal development. Although the disease is associated with genetic changes, there are also clinical and experimental data implicating non-genetic factors in its etiology. We hypothesized that maternal stress during pregnancy can be one such factor, as it leads to fetal hypoxia and elevated cortisol levels – the two factors known to alter normal neuronal development and increase aggressiveness of neuroblastoma. Indeed, using an animal model of neuroblastoma, we have found that offspring of mothers which have been subjected to stress during pregnancy develop tumors twice as frequently as those from intact pregnancies. Moreover, tumors developing in prenatally-stressed mice were spreading more often to distant organs.
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MedicalResearch.com Interview with:
Neel S. Madhukar
Graduate student in the lab of
Olivier Elemento, PhD, Associate Professor
Head, Laboratory of Cancer Systems Biology
Department of Physiology and Biophysics
Institute for Computational Biomedicine
Weill Cornell Medical College
Medical Research: What is the background for this study? What are the main findings?Response: It takes on average 2.6 billion dollars and 10-15 years to develop a single new drug. Despite massive investment in drug discovery by pharmaceutical companies, the number of drugs obtaining FDA approval each year has remained constant over the past decade. One of biggest bottlenecks in the process of developing a new drug is to understand precisely how a drug works, that is, what it binds to in cells, how it binds, and what it does when it is bound. This process is collectively called target identification and characterization of mechanisms of action. At present, target identification is a slow and failure-prone process, driven by laborious experimentation. Every time we seek to develop a new drug, such laborious experimentation needs to be redone from scratch. We are not learning from data acquired from our past successes and failures.
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MedicalResearch.com Interview with:
Pedram Gerami, M.D.
Associate Professor of Dermatology
Director, Melanoma Research
Northwestern Skin Cancer Institute
Northwestern University
MedicalResearch: What is the basis and background for performing this study?Dr. Gerami: Most of the existing literature shows that Sentinel Lymph Node Biopsy (SLNB) will identify 25 to 35 percent of patients who will ultimately die of metastatic melanoma. Hence while SLNB is reported to be the strongest predictor of outcome for melanoma, the vast majority of patients who ultimately die of metastatic melanoma have a negative Sentinel Lymph Node Biopsy result. Hence in this study we aimed to determine whether a GEP assay developed by Castle bioscience could be used independently or in conjunction with SLNB to better detect those patients who are at high risk for developing metastatic disease and dying from melanoma.
MedicalResearch: What are the findings of the study?Dr. Gerami: Our study, which examined the use of a Gene Expression Profile (GEP) assay developed by Castle Biosciences and Sentinel Lymph Node Biopsy alone and in combination in a multi-center cohort of 217 patients, demonstrated that the use of the GEP identified more than 80 percent of patients who develop melanoma
Combining the two methods showed that patients predicted to be high risk based on the GEP test alone had similar rates of disease progression whether they were SLNB positive or negative. Patients who were SLNB negative and predicted to be low risk using the GEP test had lower rates of disease progression than the SLNB negative group as a whole.
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MedicalResearch.com Interview with:
Daniel C. Beachler, PhD Postdoctoral fellow
Infections and Immunoepidemiology Branch of the
National Cancer Institute (NCI)Medical Research: What is the background for this study? What are the main findings?Dr. Beachler: HPV is a common sexually transmitted infection. Individuals can acquire HPV infections in the epithelium of their cervical, anal and oral sites, and occasionally these infections lead to cancer. There are three prophylactic HPV vaccines on the market that can protect against HPV at these sites among those not been previously exposed to HPV.
This study examined the effect of HPV vaccination of 18-25 year old women at all three anatomic sites. The combined multi-site HPV vaccine efficacy has not been reported previously. It was unknown whether the vaccine may protect non-infected sites against HPV infection or re-infection in women exposed to HPV prior to vaccination.
We observed that the HPV vaccine provides the strongest protection at all three sites among women unexposed to HPV before vaccination. Additionally, we observed some protection at the non-infected sites in women who were previously infected with HPV.
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MedicalResearch.com Interview with:Timothy Yap, MD, PhD, NIHR BRC
The Institute of Cancer Research and
The Royal Marsden NHS Foundation Trust
London, United Kingdom.Medical Research: What is the background for this study? What are the main findings?
Dr. Yap: This is a novel phase I trial assessing for the first time if the PARP inhibitor olaparib can be combined with the AKT inhibitor AZD5363. The study was undertaken at the Royal Marsden and The Institute of Cancer Research in London, England. This targeted combination was based on strong preclinical rationale demonstrating synergy between both drugs in BRCA positive tumors and also antitumor activity in non-BRCA positive tumors. Although olaparib was recently approved by the FDA for treating advanced ovarian cancer associated with defective BRCA genes, antitumor efficacy in different non-BRCA tumors is yet to be established.
The key finding for this study was that it was indeed possible to combine both drugs safely, with multiple patients with different cancers responding, including patients with and without BRCA1/2 mutations. We also assessed a new intrapatient dose escalation phase I trial design in this study, and demonstrated that the novel design could be successfully implemented, with completion of the dose escalation phase in 2 schedules of the combination with just 20 patients in 7.5 months.
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MedicalResearch.com Interview with:
Melissa Wilson, MD, PhD
Assisstant Professor
Perlmutter Cancer Center
NYU Langone Medical Center
New York, NY
Medical Research: What is the background for this study? What are the main findings?
Dr. Wilson: Metastatic cutaneous melanoma is an extremely aggressive form of skin cancer. Traditionally, it has been characterized by clinicopathologic characteristics. More recently, melanoma tumors have also been stratified by common somatic mutations for which targeted therapies have been developed or are under investigation, including BRAF, NRAS and KIT. In addition to somatic mutations, aberrant intracellular signaling pathways and cell cycle disruption contribute to melanoma pathogenesis. Indeed, recent next generation sequencing studies have identified a number of new genes involved in melanomagenesis. A comprehensive evaluation and understanding of concurrent and mutually exclusive mutations in tumors has been lacking. Therefore, we developed a comprehensive custom targeted capture of 108 genes previously implicated in melanoma pathogenesis. We used the targeted panel to perform massively parallel sequencing on 94 well-established human melanoma cell lines, 67 patient-derived xenografts (PDX), and 5 cell lines made from PDX, all untreated.
Samples were clustered based on deleterious mutations. Eighty-three percent of samples had deleterious mutations in the MAPK signaling pathway (including BRAF, RAS) and NF1. Ten percent of samples had PI3K pathway mutations which were predominantly associated with BRAF mutations. TP53 was found to be mutated in 24% of the samples and were also associated with mutations in the MAPK pathway. Mutations in chromatin remodeling genes were mutually exclusive with each other, but were associated with BRAF and NRAS mutations. Of particular interest, five of the 10 NF1mutated samples harbored likely deleterious mutations in MAP3K5 or MAP3K9, suggesting the potential involvement of JNK signal transduction pathway in a cohort of samples.
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MedicalResearch.com Interview with:
Olivier Elemento, PhD
Associate Professor
Head, Laboratory of Cancer Systems Biology
Department of Physiology and Biophysics
Institute for Computational Biomedicine
Weill Cornell Medical...
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