MedicalResearch.com Interview with: Niels de Jonge, Ph.D
Head of the Innovative Electron Microscopy group
German Cancer Research Center (DKFZ) in Heidelberg
University of Freiburg
Medical Research: What is the background for this study? What are the main findings?
Response: HER2 membrane proteins play a special role in certain types of breast cancer: amplified levels of HER2 drive unrestricted cell growth. HER2-tailored antibody-based therapeutics aim to prevent cancer cell growth. However, two-thirds of HER2 positive breast cancer patients develop resistance against HER2-targeting drugs. The reason for this is not yet understood. We now found out, that HER2 dimers appeared to be absent from a small sub-population of resting SKBR3 breast cancer cells. This small subpopulation may have self-renewing properties that are resistant to HER2-antibody therapy and thus able to seed new tumor growth.
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MedicalResearch.com Interview with:
Alpa Patel, PHD
Strategic Director, CPS-3
American Cancer Society, Inc.
Atlanta, GA 30303
Medical Research: What is the background for this study? What...
MedicalResearch.com Interview with:
Dr Yeow Tee Goh MBBS
Department of Haematology
Singapore General Hospital
Republic of Singapore
Medical Research: What is the background for this study? What are the main findings?
Dr. Goh: Relapsed or refractory peripheral T-cell lymphoma after conventional chemotherapy is associated with a very poor prognosis and there is currently no recommendation on the standard approach to helping these patients. Novel targeted treatments for relapsed or refractory peripheral T-cell lymphoma such as romidepsin, pralatrexate, belinostat, and brentuximab vedotin has been approved by the US Food and Drug Administration (FDA) based on the results of their Phase II studies. With the exception of the remarkable efficacy of brentuximab vedotin in systemic anaplastic large cell lymphoma (86% of patients responding to treatment), the efficacy of romidepsin, pralatrexate, and belinostat in relapsed or refractory peripheral T-cell lymphoma is only modest with objective response rates between 25% and 29%. To our knowledge, no other clinical study has reported on the use of novel combination of targeted agents in in relapsed or refractory peripheral T-cell lymphoma. In our study, Of 23 patients assessable for responses, 10 (43%, 95% CI 23–63) patients had an objective response, of which 5 were complete responses. The combined proteasome and histone deacetylase inhibitor treatment shows promising activity for patients with peripheral T-cell lymphoma.
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MedicalResearch.com Interview with:
Dr. Vincent L. Cryns MD
Chief of the Division of Endocrinology, Diabetes and Metabolism
Department of Medicine
University of Wisconsin Carbone Cancer Center
University of Wisconsin School of Medicine and Public Health Madison, Wisconsin
Medical Research: What is the background for this study? What are the main findings?Dr. Cryns: It’s been known for quite some time that many tumors are highly vulnerable to deficiencies in certain amino acids such as methionine, causing tumor cells to stop growing or die. What’s been missing is a molecular explanation for these effects that would allow us incorporate this approach into a rationally designed clinical trial. In our work, we have demonstrated that “starving” triple-negative breast cancer cells of methionine uncovers a “fatal flaw” by increasing the expression of a cell death receptor (TRAIL-R2) that we can activate with a therapeutic antibody to efficiently kill the tumor cells. What’s especially exciting is that we can use a specific diet to metabolically prime cancer cells to respond to a targeted cancer therapy. (more…)
MedicalResearch.com Interview with:
Haining Yang MD Ph.DAssociate ProfessorThoracic Oncology Program
University of Hawaii Cancer Center
University of Hawaii, Honolulu, HI
Medical Research: What is the background for this study?
Dr. Yang: Mesothelioma is often caused by asbestos and other carcinogenic mineral fibers. When these fibers lodge in the pleura, mesothelial cells and macrophages try to phagocytize and eliminate them. However, asbestos is very bio-persistent and cannot be eliminated, which caused cells undergoing programmed necrosis that leads to the release of HMGB1 into the extracellular space. HMGB1 is a damage-associated molecular pattern molecule (DAMP) that causes inflammation. Asbestos exposure induces HMGB1 release and chronic inflammatory process that overtime may lead to malignancy. Mesothelioma cells develop out of an environment that is rich in HMGB1 and are often dependent on HMGB1 for their own growth. In fact, most mesothelioma cells actively secrete HMGB1 extra-cellularly to promote their own tumor growth. Accordingly HMGB1 levels are high in the serum of mesothelioma patients (reviewed in Yang and Carbone, Clinical Cancer Res 2013). We tested several anti-inflammatory agents to see if we were able to reduce HMGB1-induced mesothelioma cell growth, and none of them worked except for aspirin, that led us to conduct a series of experiments in vitro and in vivo to test the hypothesis that aspirin inhibits HMGB1 activities, and that by doing so, inhibits mesothelioma growth.Medical Research: What are the main findings?
Dr. Yang: We found that aspirin inhibits the growth of human mesothelioma cells in a xenograft model, moreover in vitro experiments demonstrated that this effects was specifically mediated via inhibition of HMGB1 and not via COX2 inhibition. We propose that the so far enigmatic anticancer activity of aspirin is mediated, at least partially, via inhibition of HMGB1, and that aspirin may help delay the onset of mesothelioma and may help inhibit the growth of mesothelioma.(more…)
MedicalResearch.com Interview with:
MB. Pinkham, Clinical Oncology
Christie NHS Foundation Trust
Manchester UK
Medical Research: What is the background for this study? Response: Brain metastases are a serious complication of advanced malignancy and for most patients the objective is to maximise quality of survival. As treatment decisions become increasingly tailored to the individual, patient-focussed measures of efficacy such as neurocognitive function (NCF) are an important consideration. This is illustrated by the NCCTG N0574 randomised study reported last month at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting. 208 patients with 1-3 brain metastases each <3cm were randomised to stereotactic radiosurgery (SRS) or SRS with whole brain radiotherapy (WBRT). The addition of WBRT improved intracranial disease control but did not translate into a survival benefit and was associated with a decline in neurocognitive function at 3 months.
The objective of our study was to describe the types of changes in neurocognitive function that can occur, summarise how they are assessed and review approaches used to mitigate their effects. We wanted to provide busy physicians with a clear and comprehensive overview of the topic that could be used to inform clinical decisions.
Medical Research: What are the main findings?
Response: Using sensitive tests, most patients with brain metastases have deficits in neurocognitive function at diagnosis. Evaluating and understanding changes after treatment is complex because neurocognitive function is a dynamic process that is influenced by a long list of inter-related factors.
For patients treated using whole brain radiotherapy alone, worsening neurocognitive function is observed in about two-thirds within 2-6 months. Deficits in verbal memory and fine motor control are most common. It is unclear what proportion relates to treatment toxicity as opposed to disease progression or pre-terminal decline because both are unfortunately also common events during this interval. By contrast, in other patients, NCF improves after WBRT due to treatment response.
For patients with 1-4 brain metastases treated using SRS, the addition of WBRT improves intracranial disease control at the expense of deficits in verbal memory at 4 months but the impact of recurrence and salvage therapy on neurocognitive function later than this is uncertain. Scant data suggests that some deficits in neurocognitive function after WBRT may improve with time in long term survivors. For patients with ≥5 brain metastases, SRS and/or systemic therapies may be considered in select patients instead of upfront whole brain radiotherapy but high quality evidence is lacking.
Advanced radiotherapy technologies, such as hippocampal-sparing WBRT and post-operative cavity SRS, can limit the dose delivered to unaffected areas of the brain in the hope of reducing toxicity. Randomised studies assessing their efficacy and cost-effectiveness in various clinical situations are underway prior to routine use. Small but statistically significant improvements in certain neurocognitive domains can also be achieved using medications such as memantine and donepezil. Preclinical data suggests that some commonly available drugs (such as ramipril, lithium and indomethacin) may have neuroprotective properties following WBRT; further evaluation is warranted.
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MedicalResearch.com Interview with:
S. Yousuf Zafar, MD, MHS
Associate Professor of Medicine
Duke Cancer Institute
Duke Clinical Research Institute
Medical Research: What is the background for this study? What are the main findings?
Dr. Zafar: Multiple studies have suggested that obesity and colorectal cancer are related. For instance, obesity has been linked with an increased incidence of colon cancer. Obesity has also been associated with a greater risk of colon cancer recurrence. To date, no study has looked at the role of obesity in outcomes for patients with metastatic colorectal cancer. In our study of over 6000 patients receiving treatment for metastatic olcolorectal cancer, we found that patients with the lowest body mass index (BMI) were at greatest risk for worse survival. This does not mean that obesity is good. More likely, it means that those who are very underweight are least able to tolerate the best treatment, or being very underweight is a biologic marker of poor prognosis.
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MedicalResearch.com Interview with:
Dr. Hannah Arem Ph.D. M.H.S. Postdoctoral Fellow
Nutritional Epidemiology Branch
Division Cancer Epidemiology and Genetics
National Cancer Institute
MedicalResearch: What is the...
MedicalResearch.com Interview with: Junichi Nishimura MD, PhD
Assistant professor
Osaka University in Japan
Medical Research: What is the background for this study? What are the main findings?
Dr. Nishimura: Oxaliplatin is classified as moderately emetogenic chemotherapy and 2-drug combination antiemetic therapy is recommended for Oxaliplatin based chemotherapy including FOLFOX and XELOX in all guidelines for antiemesis. Nausea and vomiting are still frequent adverse events which decrease the patient’s QOL. However, there was no study investigating whether 3-drug combination antiemetic therapy (5HT3 receptor antagonist+dexamethasone+aprepitant) reduce chemotherapy-induced nausea and vomiting. In this study, we conducted a multicentre, randomized phase III study to evaluate the usefulness of the combined use of aprepitant in colorectal cancer patients treated with Oxaliplatin based chemotherapy. In this phase III study, 3-drug combination therapy significantly increased the inhibition rate of vomiting which was the primary endpoint of this study. Moreover, the inhibition rate of nausea, complete response (no vomiting and no rescue medication use), and complete protection (no vomiting , no rescue medication use and no moderate or worsened nausea) was significantly higher in aprepitant group in overall and delayed phase. We, next, compared the inhibition of vomiting and nausea between males and females in delayed phase. When patients were grouped by sex regardless of the assigned treatment group, females were more affected by nausea and vomiting than males. Finally, in female, aprepitant did significantly prevent nausea and vomiting as well as increased chance of complete protection.
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MedicalResearch.com Interview with:
Howard S. Hochster, MD
Associate Director, Yale Cancer Center
Professor of Medicine, Yale School of Medicine
New Haven, CT 06520
Medical Research: What is the background for this study? What are the main findings?
Dr. Hochster: TAS-102 is a novel anti-metabolite, recently combined with a metabolic inhibitor to make it orally bioavailable and active in the treatment of cancer. In pre-clinical studies, it is non-cross reactive with 5FU. What this means practically is that we have another chemotherapy agent that can be used for patients with colon cancer. This drug will be an addition to the approved chemotherapy agents 5FU, oxaliplatin and irinotecan. It may be combinable with these and with targeted agents to provide new active regimens.
The main findings of the study were published in NEJM, May 15, 2015. The study enrolled 800 patients randomized (2:1 ratio) to drug vs placebo. Patients with advanced colon cancer who had been treated with all the previously approved drugs were eligible. The drug was active in reducing time to tumor growth (Progression Free Survival) by 50% and improved overall survival for treated patients by about 25%.
The data I presented at ESMO included a further analysis on specific genomic subsets of patients within the 800 patient study. All patients were tested locally for RAS mutations and about 50% had such mutations (as expected). There was no differences in benefit or toxicity for those with RAS wild-type tumors or RAS mutated tumors. We also looked at those with BRAF mutations, but only 15% of patients were tested and this mutation occurs in about 8% of colon cancer, so we had very few patients with BRAF mutation. Given this limitation, it appeared that this did not make a difference for benefit or toxicity either.
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MedicalResearch.com Interview with:
Jennifer Mack, MD, MPH
Pediatric oncologist
Dana-Farber/Boston Children’s Cancer and Blood Disorders CenterMedical Research: What is the background for this study? What are the main findings?
Dr. Mack: This study evaluated the intensity of end-of-life care received by adolescents and young adults (AYAs) with cancer. Little was previously known about the kind of end-of-life care these young patients receive. We evaluated the care of 663 Kaiser Permanente Southern California patients who died between the ages of 15 and 39 between the years 2001 and 2010. We found that more than two-thirds of adolescents and young adults received at least one form of intensive end-of-life care before death. This includes chemotherapy in the last two weeks of life (11%), more than one emergency room visit in the last month of life (22%), intensive care unit care in the last month of life (22%), and hospitalization in the last month of life (62%).
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MedicalResearch.com Interview with:
Amol Narang MD
Radiation Oncology Resident
Johns Hopkins Medicine
Medical Research: What is the background for this study? What are the main findings?
Dr. Narang: The care provided to cancer patients at end-of-life can be intense, including frequent ER visit, hospitalizations, and ICU stays in the last month of life, administration of chemotherapy in last two weeks of life, and late referrals to hospice. Providing high-intensity treatments at end-of-life has been associated with reduced patient quality-of-life and increased caregiver bereavement. Advance care planning represents an opportunity for patients to indicate their preferences for end-of-life care to try to ensure that the care that they receive at end-of-life is consistent with their values, and has been endorsed by oncologic professional societies, such as ASCO and the NCCN. As such, we wanted to assess if oncologists’ long-standing recognition of the merits of advance care planning has translated into increased participation in advance care planning by cancer patients, and to determine which forms of advance care planning are associated with intensity of care given at end-of-life.
From 2000-12, we found that the only type of advance care planning that increased was the assignment of a power of attorney (52% in 2000 to 74% in 2012). However, having a power of attorney was not associated with receiving less aggressive end-of-life care. On the other hand, having a living wills and engaging in a discussion with a provider or loved one about preferences for end-of-life care were both associated with reduced treatment intensity. However, the frequency with which cancer patients created a living or discussed their preferences for end-of-life care did not increase over the study period; importantly, 40% of patients dying of cancer never communicated their preferences for care at end-of-life with anyone.
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MedicalResearch.com Interview with:
Mario Mandalà, MD
Department of Oncology and Haematology
Papa Giovanni XXIII Hospital
Bergamo, ItalyMedical Research: What is the background for this study?
Dr. Mandalà: In addition to their established molecular mechanism of action, growing evidence suggests that the therapeutic efficacy of BRAFi relies on additional factors that affect the tumor–host interactions, including the enhancement of melanoma antigen expression and the increase in immune response against tumor cells. Preclinical data show that oncogenic BRAF contributes to immune evasion, and that targeting this mutation may increase the melanoma immunogenicity. Data in vitro or from animal models propose PD-L1 as a potential mechanism that favors BRAFi resistance through the modulation of host immune responses. However, demonstration of this hypothesis in the clinical setting is lacking.
Medical Research: What are the main findings?Dr. Mandalà: In the present study, we have evaluated, in a homogeneous series of MMP treated with BRAFi, the association of tumoral PD-L1 IHC expression and the density of TIMC with RR, PFS and OS. Results provide the first proof-of-principle clinical evidence of the predictive and prognostic relevance of PD-L1 IHC expression and density of immune cell infiltration in BRAFV600 mutated MMP receiving BRAFi.
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MedicalResearch.com Interview with:
Aung Ko Win, MBBS MPH PhD
Research Fellow
NHMRC Early Career Clinical Research Fellow
Centre for Epidemiology and Biostatistics
Melbourne School of Population and Global Health
The University of Melbourne VIC 3010
Australia
Medical Research: What is the background for this study?
Response: At least 1 in 1,000 people in the population have a mutation in one of the mismatch repair genes that causes Lynch syndrome. These people have a very high risk of bowel cancer (colorectal cancer): if nothing is done, about half would develop the disease. The main risk reduction method for these people is to have regular colonoscopy screening every year. Almost nothing is known whether or not lifestyle factors and medications can modify the risk of bowel cancer for people with Lynch syndrome.
A study was conducted to investigate the associations between aspirin and ibuprofen intake and the risk of bowel cancer, by studying 1,858 people with Lynch syndrome who were recruited into the Colon Cancer Family Registry from Australia, New Zealand, Canada and the USA. This is the largest study to date investigating the associations between aspirin, ibuprofen and bowel cancer risk for people with Lynch syndrome. (more…)
MedicalResearch.com Interview with:
Aung Ko Win, MBBS MPH PhD
Research Fellow
NHMRC Early Career Clinical Research Fellow
Centre for Epidemiology and Biostatistics
Melbourne School of Population and Global Health
The University of Melbourne VIC 3010
Australia
Medical Research: What is the background for this study? What are the main findings?
Response: About 2-5% of uterine cancer are associated with an underlying genetic condition mainly Lynch syndrome. Lynch syndrome is caused by a mutation in one of the mismatch repair genes. At least 1 in 1000 people in the population have a mutation that causes Lynch syndrome and these people have a very high risk of cancers mainly bowel and uterine cancers. One in three women with a mutation in one of the mismatch repair genes are likely to develop a uterine cancer in their lifetime. The only way to reduce the risk of uterine cancer for these women is to remove the uterus. There is no current recommendation for screening method to detect uterine cancer early. Almost nothing is known about if and how lifestyle factors and hormonal factors can modify their risk of uterine cancer.
By studying 1128 women with a mutation that causes Lynch syndrome who were recruited from Australia, New Zealand, Canada and the USA, we found that later age at first menstrual cycle, having one or more live births, and using hormonal contraceptive use for one year or longer were associated with a lower risk of uterine cancer.
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MedicalResearch.com Interview with:
Dr. Jürg Bernhard Ph.D.
International Breast Cancer Study Group Coordinating Center and Bern University Hospital, Inselspital, Bern, Switzerland
Medical Research: What is the background for this study? What are the main findings?
Response: In the combined analysis of the SOFT and TEXT trials, the aromatase inhibitor exemestane was more effective than tamoxifen in preventing breast cancer recurrence in young women (premenopausal) who also receive ovarian function suppression (OFS) as adjuvant (post-surgery) treatment for hormone-sensitive early breast cancer, providing a new treatment option for these women. These trials were conducted by the International Breast Cancer Study Group (IBCSG) and involved more than 4700 patients of over 500 centers in 27 countries. Now we present patient-reported quality of life outcomes from these trials.
In the TEXT and SOFT trials, patients assigned exemestane+OFS reported more detrimental effects of bone or joint pain, vaginal dryness, greater loss of sexual interest and difficulties becoming aroused, while patients assigned tamoxifen+OFS were more affected by hot flushes and sweats. Global quality of life domains (mood, ability to cope and physical well-being) were similar between the randomized treatment groups. (more…)
MedicalResearch.com Interview with:
Wen-Qing Li Ph.D
Department of Dermatology Warren Alpert Medical School
Department of Epidemiology, School of Public Health,
Brown University, Providence, RI
Medical Research: What is the background for this study?
Response: Rosacea is a chronic inflammatory cutaneous disorder and may be an end-organ response in a systemic disorder. We systemically examined the association between personal history of rosacea and risk of cancer based on 75088 whites in the Nurses’ Health Study II, during a follow-up of 20 years.
Medical Research: What are the main findings?
Response: We suggest possible associations between personal history of rosacea and an increased risk of thyroid cancer and Basal Cell Cancer. Analyses did not find significant associations for other individual cancer types. (more…)
MedicalResearch.com Interview with:
Dr Ananya Choudhury
Consultant and Honorary Senior Clinical Lecturer, Clinical Oncology
The Christie NHS Foundation Trust,
Wilmslow Road
Withington, Manchester, UK
Medical Research: What is the background for this study? What are the main findings?
Response: Although more than half of newly diagnosed cancer patients are treated with radiotherapy, it is still not possible to select patients who will respond and tolerate radiotherapy compared to those who do not. There has been a lot of work done to try and isolate intrinsic biomarkers which will identify either radio-responsive or radio-resistant disease. We have undertaken a systematic view summarising the evidence for biomarkers as predictors of radiotherapy.
Despite identifying more than 500 references during a systematic literature search, we found only twelve studies which fulfilled our inclusion criteria. Important exclusion criteria included pre-clinical studies, studies with no control population and a sample size of less than 100 patients.
Only 10 biomarkers were identified as having been evaluated for their radiotherapy-specific predictive value in over 100 patients in a clinical setting, highlighting that despite a rich literature there were few high quality studies suitable for inclusion. The most extensively studied radiotherapy predictive biomarkers were the radiosensitivity index and MRE11; however, neither has been evaluated in a randomised controlled trial. (more…)
MedicalResearch.com Interview with:
Chao Cheng, Ph.D.
Assistant Professor
Department of Genetics
Institute for Quantitative Biomedical Sciences
Geisel School of Medicine at Dartmouth
Hanover NH, 03755
Medical Research: What is the background for this study?
Dr. Cheng: Bladder cancer is a common tumor type, with non-muscle-invasive bladder cancer (NMIBC) representing the majority of cases. Bacillus Calmette-Guerin (BCG) treatment is an effective immunotherapy that is commonly used to treat cancers of this subtype. However, this treatment fails to suppress tumor recurrence in up to 40% of patients. For this reason, biomarkers that predict the recurrence/progression of bladder cancer and patient response to BCG therapy are needed to tailor treatment strategies to individual patients.
Medical Research: What are the main findings?
Dr. Cheng: We had previously developed an E2F4 signature that consisted of the E2F4 transcription factor and its target genes identified by ChIP-seq and ChIP-chip experiments. Here, we found that the E2F4 signature is predictive of the progression of both non-muscle-invasive and muscle-invasive bladder cancer. Furthermore, this signature is also predictive of patient responsiveness to intravesical BCG immunotherapy. Our results suggest that patients with positive E2F4 scores (indicating high E2F4 activity) benefit significantly from BCG therapy, while the progression of patients with negative E2F4 scores (indicating low E2F4 activity) does not show significant difference from untreated patients.
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MedicalResearch.com Interview with:
Ashley S. Felix, PhD
Bethesda, MD
MedicalResearch: What is the background for this study? What are the main findings?Dr. Felix: Endometrial cancer prognosis is strongly affected by disease stage, or the extent of spread from the primary site. Endometrial cancers can spread via the lymph nodes, blood vessels, through the uterine wall, or through the fallopian tube into the peritoneal cavity. The last of these mechanisms is poorly understood, but appears to be a more common mode of spread for aggressive histologic subtypes of endometrial cancer. We hypothesized that women who previously underwent tubal ligation (TL) and later developed endometrial cancer would have lower stage disease, possibly by blocking passage of tumor cells along the fallopian tubes. Further, we hypothesized that TL would be associated with better prognosis, due to its relationship with lower stage.
We found that women in our study who previously had tubal ligation were more likely to have lower stage endometrial cancer compared with women who did not report a previous tubal ligation. Specifically, tubal ligation was inversely associated with stage III and stage IV cancer across all subtypes of the disease, including aggressive histologic subtypes. Further, in statistical models of tubal ligation, tumor stage, and mortality, we observed no independent association with improved survival, suggesting that tubal ligation impacts mortality mainly through its effects on stage.
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MedicalResearch.com Interview with:Dr. Janaiah Kota
Assistant Professor, Department of Medical and Molecular Genetics
Indiana University School of Medicine
Indianapolis, IN,
Medical Research: What is the background for this study?
Dr. Kota: Pancreatic cancer tumors are surrounded by a thick fibrotic shell known as “stroma” which protects the cancer cells from anticancer drugs such as chemotherapy. However, complete depletion of tumor stroma leads to more aggressive disease and decreases survival. The stromal abundance needs to be appropriately moderated (i.e. not too much nor too little) in pancreatic tumors. None of the current anti-stromal therapies have been effective enough to resolve this problem. Unless we understand the molecular signatures associated with tumor stroma, it will be challenging to develop an effective therapeutic strategy.
There is a desperate need to develop new therapies for pancreatic cancer as only 7 percent of people with the disease survive more than 5 years after diagnosis. According to the National Cancer Institute, there will be an estimated 48,960 new cases of pancreatic cancer and 40,560 deaths from the disease in 2015.
Medical Research: What are the main findings?Dr. Kota: We found that the loss of microRNA-29 (miR-29) is a common phenomenon of pancreatic cancer stromal cells, and that by restoring it, the viability and growth of the cancerous cells and stromal accumulation was reduced. The use of miR-29 as a therapeutic agent may be more effective in targeting reactive stroma, as a single miRNA regulates the expression of several genes associated with disease mechanisms. We expect that this novel approach has the potential to overcome the problems associated with current anti-stromal drugs and could lead to improved therapeutic strategies, enhanced drug delivery to the tumor bed, and, in the future, improved patient survival.
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MedicalResearch.com Interview with: Dr Klervi Leuraud, Epidemiologist
Institute for Radiological Protection and Nuclear Safety
Cedex, France
MedicalResearch: What is the background for this study? What are the main findings?Dr. Leuraud: INWORKS was performed to quantify the risk of cancer mortality associated to protracted low doses of ionizing radiation typical of occupational or environmental exposures, as well as of diagnostic medical exposures. While such risks are well known for acute exposures as those experienced by the Japanese survivors of the A-bombs, there is still a lack of information for exposures experienced by the workers and the public. Our study confirms the existence of an association between leukemia mortality and chronic exposure to low doses received by nuclear workers.
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MedicalResearch.com Interview with:
Dr. Mitchell Kamrava MDDepartment of Radiation Oncology
University of California Los Angeles
Los Angeles, CA
Medical Research: What is the background for this study? What are the main findings?
Dr. Kamrava: Breast conservation (lumpectomy followed by radiation) is known, based on multiple randomized trials with over 20 years of follow-up, to provided equivalent outcomes as mastectomy. The radiation component of breast conservation has standardly been delivered to the whole breast. Studies show that the majority of breast recurrences occur near the lumpectomy cavity causing some to ask whether it is necessary to treat the whole breast in order to reduce the risk of a recurrence.
Partial breast radiation delivers treatment just to the lumpectomy cavity with a small margin of 1-2 cm. It’s delivered in a shorter time of 1 week compared with about 6 weeks for standard whole breast radiation and 3-4 weeks for hypofractionated whole breast radiation.
The original method developed to deliver partial breast radiation is interstitial tube and button brachytherapy. This uses multiple small little tubes that are placed through the lumpectomy cavity to encompass the area at risk. One end of these tubes can be connected to a high dose rate brachytherapy machine that allows a motorized cable with a very small radiation source welded to the end of it to be temporarily pushed in and out of each of the tubes so that the patient can be treated from “inside out”. This helps concentrate the radiation to the area of the lumpectomy cavity while limiting exposure to normal tissues. This treatment is most commonly delivered as an out-patient two times per day for a total of 10 treatments.
The main finding from our paper is that in reviewing the outcomes on over 1,000 women treated with this technique with an average follow-up of 6.9 years that the 10 year actuarial local recurrence rate was 7.6% and in women with more than 5 years of follow-up physician reported cosmetic outcomes were excellent/good in 84% of cases.
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MedicalResearch.com Interview with: Hui Zhu, MD, ScD
Section Chief, Urology Section
Louis Stokes Cleveland Veterans Affairs Medical Center
and Staff, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation
Cleveland, Ohio
MedicalResearch: Tell me a little bit about the impetus for this study. What gap in knowledge were you trying to fill? Dr. Zhu: Prostate cancer is a very challenging disease to understand and manage. For the minority of men, prostate cancer is a lethal disease, and in fact, it is the second leading cause of cancer death in American men, behind only lung cancer. However, for the majority of men, prostate cancer poses little risk of death. In fact, about 1 man in 7 will be diagnosed with prostate cancer during his lifetime, but only 1 man in 38 will die from prostate cancer.
In an effort to avoid suffering and death from prostate cancer for those men with the lethal form, the early detection of prostate cancer (before the disease has reached a stage when it is no longer curable) through widespread prostate cancer screening was instituted in the late 1980s and early 1990s. As a result, prostate cancer diagnosis increased substantially, and most prostate cancers were detected at an early, treatable stage. Screening successfully reduced the risk of death from prostate cancer by 20%.
Unfortunately, our best available screening tests, i.e. prostate-specific antigen (PSA) testing and the digital rectal exam, do not differentiate well between lethal and nonlethal prostate cancer. Consequently, screening is associated with a high risk of overdiagnosis of nonlethal prostate cancer. As a result, about 800 men must be screened and about 30 men must be diagnosed and treated to avoid one death from the prostate cancer, according to recent results from the largest prostate cancer screening trial.
Since the natural history of newly diagnosed screen-detected prostate cancer is difficult to predict (i.e. lethal or nonlethal), most prostate cancers have been treated aggressively, leading to overtreatment of many nonlethal cancers. Aside from receiving unnecessary treatment, these men are exposed to the potential side effects and complications of treatment, including erectile dysfunction and urinary incontinence.
In response to the harms associated with screening and treatment, the US Preventative Services Task Force issued a statement in 2011 (formalized in 2012) recommending against prostate cancer screening in all men. Unfortunately, while minimizing the risks of overdiagnosis and overtreatment for men with nonlethal prostate cancer, this solution eliminates any of the potential benefits of screening for those men with the lethal form of the disease.
As urologists, our solution is different. Rather than throw the baby out with the bathwater, we prefer to preserve PSA screening and its benefits by addressing and hopefully minimizing its associated risks. To achieve this, our goal is to better distinguish between those men who have lethal vs. nonlethal prostate cancer, limiting treatment only to those men who have the lethal form of the disease at an early stage when it is still curable. The dilemma is that our currently available diagnostic tests are unable to accurately differentiate lethal from nonlethal prostate cancer with 100% certainty at the time of initial diagnosis.
The solution, or at least part of the solution, is active surveillance. In men who appear to have nonlethal (“low risk”) cancer at the time of diagnosis, it now appears to be safe to observe these cancers, at least initially. This is the concept behind active surveillance. Active surveillance entails carefully monitoring men with low-risk prostate cancer using serial testing and reserving the option of treatment for those men with prostate cancers that exhibit lethal characteristics. In this way, active surveillance preserves the benefits of screening while minimizing the harms of overdiagnosis and overtreatment.
Active surveillance was first introduced in the early 2000s, but its efficacy and safety have only been elucidated recently over the last 5 years. Given that active surveillance may be one solution to the screening dilemma, we wanted to evaluate contemporary active surveillance utilization, which is the impetus for our study. Based on the most recent data available to us, we chose the years 2010-2011, which coincide to the time immediately before and during the release of the US Preventative Services Task Force statement against PSA screening.
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MedicalResearch.com Interview with: Timothy P. Padera, PhD
Edwin L. Steele Laboratories
Department of Radiation Oncology
MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School
Boston, Massachusetts 02114
MedicalResearch: What is the background for this study? What are the main findings?Dr. Padera: Systemic therapy benefits cancer patients with lymph node metastases; however all phase III clinical trials to date of antiangiogenic therapy have failed in the adjuvant setting. We have previously reported the lack of efficacy of antiangiogenic therapies in pre-clinical models of spontaneous lymphatic metastasis, however there were no mechanistic data to explain these observations. Here, we developed a novel chronic lymph node window model to facilitate new discoveries in the mechanisms of growth and spread of lymph node metastases. Our new data provide pre-clinical evidence along with supporting clinical evidence that angiogenesis does not occur in the growth of metastatic lesions in the lymph node. These results reveal a mechanism of treatment resistance to antiangiogenic therapy in adjuvant setting, particularly those involving lymph node metastases.
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MedicalResearch.com Interview with:
Nishant Agrawal M.D.
Associate Professor of Otolaryngology
Johns Hopkins University School of Medicine
Medical Research: What is the background for this study? What are the main findings?
Dr. Agrawal: The idea of the study really arose from the specificity of genetic changes that characterize and are the hallmark of cancer cells. Only cancer cells contain these mutations so their detection in bodily fluids was a reasonable expectation. The current study builds on previous work from our group that tumor DNA can be detected in the bodily fluids of patients with many different types of solid malignancies. The main findings of the study are that tumor DNA in saliva and plasma provides a non-invasive biomarker for head and neck cancer. The take home message is that tumor DNA has potential to be used as a biomarker for screening, early detection, monitoring during treatment, and surveillance after cancer treatment is completed.
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MedicalResearch.com Interview with:
Michael B. Burns, Ph.D.
HHMI Post-Doctoral Fellow
Dept. of Genetics, Cell Biology and Development
Dept. of Ecology, Evolution, and Behavior
Masonic Cancer Center
Dept. of Biology Teaching and Learning
University of Minnesota Twin Cities
St. Paul, MN 55108
Medical Research: What is the background for this study?
Dr. Burns: Recent technological advances have made it possible to survey all the of microbes that are in, on, and around us. One of the surprising things is the sheer quantity and diversity of the bacteria in our environments and our microbiomes. Many researchers have begun the systematic characterization of the microbes that are associated with specific disease states, including cancer. With regard to colorectal cancer, there have been numerous studies that have identified specific bacteria that are linked to the presence of the disease. There have been many reports that have identified particular potentially important microbes that may be causing the cancer, driving the cancer, or some combination of the two. Among these microbes, one of the best studied so far is a group of bacteria called Fusobacterium.
Medical Research: What are the main findings?
Dr. Burns: In our work, we set out to perform another characterization of the bacteria in the gut microbiome that are specifically associated with colorectal tumors. We used samples of normal colon tissue from the same individuals as controls, which allowed us to account for much of the variability in the different bacteria we found that might have been simply the result of, for instance, diet. In our analysis, we confirmed the previous results related to Fusobacterium, and additionally discovered a new potential culprit in colorectal cancer, a group of bacteria named Providencia.
The finding of another new set of microbes that might be causing or driving cancer is not surprising. As indicated above, there are many groups who have found other potential candidate microbes that could be implicated in the disease. Our next question was to determine if there was some reason why there might be so many different bacteria that are linked with the disease and what it might be able to tell us about what these bacteria are doing. To that end, we used computational approaches to assess what these two groups of bacteria might be doing at a functional level and if there were any similarities. We found that there was a great deal in common between Fusobacterium and Providencia, including a finding that one of the common functions was related to a large group of virulence genes.
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MedicalResearch.com Interview with:
Mitchell S. Stark
Senior Research Assistant/PhD Student
Oncogenomics Group
QIMR Berghofer Medical Research Institute
Herston, Brisbane, Australia
Medical Research: What is the background for this study?
What are the main findings?
Response: Melanomas are among the most commonly occurring cancers with the number of new cases rising each year. Melanoma is currently is listed as the 4th and 6th most common cancer in Australia and the USA with >11,000 and >76,000 news diagnoses each year. The overall 5-year survival for melanoma is 91%, which is largely due to curative surgery for early stage disease. However, cure rates are <15% if distant metastasis occurs (stage IV). We now have evidence that current therapeutic options for late stage disease are more effective if the disease is treated with a lower disease burden. 2010). Hence, melanoma must be treated in earlier stages to maximize the chances of patient survival. Therefore, the ability to identify signs of melanoma progression sooner would be a valuable clinical tool.
The use of melanoma progression markers have been used for many years however it is clear from the survival rates that melanoma must be detected before disease progresses thus highlighting that the current methods of progression detection are inadequate. We have identified a seven-microRNA panel (MELmiR-7) that has the ability to detect the presence of melanoma with high sensitivity and specificity which is superior to currently used markers for melanoma progression, recurrence, and survival. This panel may enable more precise measurement of disease progression and may herald an increase in overall survival.
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MedicalResearch.com Interview with:
Dr. Ayalew Tefferi, M.D.
Department of Medicine,
Mayo Clinic
Rochester, MinnesotaMedicalResearch: What is the background for this study? What are the main findings?Dr. Tefferi: William Vainchenker discovered and reported an activating JAK2 mutation (JAK2V617F) in myelofibrosis and related myeloproliferative neoplasms in 2005 (Nature. 2005;434:1144-1148). This seminal observation led to the recognition of activated JAK-STAT as the potential disease-driving pathway in myeloproliferative neoplasms and development of several JAK inhibitors, including fedratinib, ruxolitinib and momelotinib, for treatment of myelofibrosis. In phase 2 studies, these JAK inhibitors showed similar activity in alleviating constitutional symptoms and reducing spleen size. However, none of them were able to induce complete or partial remissions or reversal of bone marrow fibrosis or significant lowering of JAK2 mutant allele burden. A subsequent phase 3 study provided the information required for FDA approval of ruxolitinib and the current phase 3 study was meant to do the same for fedratinib.
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MedicalResearch.com Interview with:
Dr.Stacy Loeb, MD, MSc
Department of Urology, Population Health,
and Laura and Isaac Perlmutter Cancer Center
New York University, New YorkMedical Research: What is the background for this study?
Dr. Loeb: A paper published last year suggested a relationship between use of (Viagra) and melanoma. That study had only 142 cases of melanoma, and of these men 14 had used sildenafil. This study got a lot of publicity leading numerous patients to express concern over whether erectile dysfunction drugs could cause melanoma.
Our goal was to look more closely at this issue in a larger population from Sweden (including 4065 melanoma cases of whom 435 used any type of erectile dysfunction drug- Viagra, as well as Levitra and Cialis). Sweden has a national health system so we were able to access prescription records for men across the entire country, which we linked to the national registries for melanoma and basal cell skin cancer. (more…)
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MedicalResearch.com Interview with:
Niels de Jonge, Ph.D
Head of the Innovative Electron Microscopy group
German Cancer Research Center (DKFZ) in Heidelberg
University of Freiburg
Medical Research: What is the background for this study? What are the main findings?
Response: HER2 membrane proteins play a special role in certain types of breast cancer: amplified levels of HER2 drive unrestricted cell growth. HER2-tailored antibody-based therapeutics aim to prevent cancer cell growth. However, two-thirds of HER2 positive breast cancer patients develop resistance against HER2-targeting drugs. The reason for this is not yet understood. We now found out, that HER2 dimers appeared to be absent from a small sub-population of resting SKBR3 breast cancer cells. This small subpopulation may have self-renewing properties that are resistant to HER2-antibody therapy and thus able to seed new tumor growth.
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