Progression of Mutations From Moles To Melanoma Identified

Boris C. Bastian, MD, PhD Professor of Dermatology and Pathology Gerson and Barbara Bass Bakar Distinguished Professor in Cancer Research University of California, San Francisco

Dr. Bastian

MedicalResearch.com Interview with:
Boris C. Bastian, MD, PhD
Professor of Dermatology and Pathology
Gerson and Barbara Bass Bakar Distinguished Professor in Cancer Research
University of California, San Francisco

Medical Research: What is the background for this study? What are the main findings?

Dr. Bastian:  The cost of DNA sequencing has dropped substantially since the initial sequencing of the human genome in 2001. As a result, the most common cancer subtypes have now been sequenced, revealing the pathogenic mutations that drive them. A typical cancer is driven by 5-10 mutations, but we still do not understand the order in which these mutations occur for most cancers.

Determining the order in which mutations occur is challenging for cancers that are detected at a late stage. Melanomas, however, lend themselves to this type of analysis because they are pigmented and found on the surface of the skin, allowing them to be identified early. Sometimes, melanomas are even found adjacent to their remnant precursor neoplasms, such as benign nevi (also known as common moles). We performed detailed genetic analyses of 37 cases of melanomas that were adjacent to their intact precursor neoplasms. We microdissected and sequenced the surrounding uninvolved normal tissue, the precursor neoplasm, and the descendent neoplasm. By comparing the genetic abnormalities in each of the microdissected areas, we were able to decipher the order of genetic alterations for each case.

Our work reveals the stereotypic pattern of mutations as they occur in melanoma. Mutations in the MAPK pathway, usually affecting BRAF or NRAS, occur earliest, followed by TERT promoter mutations, then CDKN2Aalterations, and finally TP53 and PTEN alterations. Benign nevi typically harbor a single pathogenic alteration, whereas fully evolved melanomas harbor three or more pathogenic alterations. We also identified an intermediate stage of neoplasia with some but not all of the pathogenic mutations required for fully evolved melanoma. There has been a longstanding debate whether morphologically intermediate lesions, such as dysplastic nevi, truly constitute biological intermediates or whether they simply represent a gray zone of histopathological assessment. Our data indicates that these neoplasms are genuine biological entities. Finally, we observe evidence of UV-radiation-induced DNA damage at all stages of pathogenesis, implicating UV radiation in both the initiation and progression of melanoma.

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Influence of Pregnancy on Melanoma May Vary By Stage

Pedram Gerami, MD Department of Dermatology Northwestern University Chicago, IL

Dr. Gerami

MedicalResearch.com Interview with:
Pedram Gerami, MD
Department of Dermatology
Northwestern University
Chicago, IL

Medical Research: What is the background for this study? What are the main findings?
 

Dr. Gerami: The influence of pregnancy on the prognosis of melanoma has been debated for decades. Even in the last ten years, population-based and cohort studies have given us mixed results, with some suggesting no adverse influence of pregnancy, and others reporting poorer outcomes and increased cause-specific mortality. The conflicting data leave many clinicians uncertain of how to advise patients to proceed with family planning after a diagnosis of melanoma. Since one-third of all new cases of melanoma diagnosed in women will occur during childbearing age, this represents a fairly common clinical dilemma for physicians and their patients.

We suspected that the different results from different investigators maybe related to the melanoma stage of the patients being studied. We investigated the impact of pregnancy on tumor proliferation in women with primarily early stage melanoma. In comparing melanomas from a group of women with pregnancy-associated melanoma (PAM) and a non-PAM group, we found that women with pregnancy-associated melanoma  actually had a significantly greater proportion of in situ disease, and for cases of invasive melanoma there was no significant difference in proliferative activity, as assessed by mitotic count or two immunohistochemical markers of cell proliferation. In a comparison of additional prognostic features such as Breslow depth and ulceration, we found no significant differences between groups to suggest more aggressive tumor behavior in association with pregnancy.

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More Moles On Right Arm May Mean Higher Melanoma Risk

Simone Ribero, M.D., Ph.D. University of Turin Department of Medical Sciences Italy &King’s College London Department of Twin Research and Genetic Epidemiology St Thomas’ campus London, UK

Dr. Simon Ribero

MedicalResearch.com Interview with:
Simone Ribero,  M.D., Ph.D. 
University of Turin
Department of Medical Sciences
Italy & King’s College London
Department of Twin Research and Genetic Epidemiology
St Thomas’ campus
London, UK

Medical Research: What is the background for this study? What are the main findings?

Dr. Ribero: The total body naevus count is the principal risk factor for melanoma. having more than 100 moles increases  6 times the risk of developping a melanoma.

In our study we described a model to predict the total number naevus count with the count of one arm.

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Internet Can Deliver Valuable Information To Melanoma Patients

Ashley K. Day, Ph.D., M. Psych (Hlth) Post-Doctoral Associate Rutgers Cancer Institute of New JerseyMedicalResearch.com Interview with:
Ashley K. Day, Ph.D., M. Psych (Hlth)
Post-Doctoral Associate
Rutgers Cancer Institute of New Jersey

Medical Research: What is the background for this study? What are the main findings?

Dr. Day: Skin cancer is one of the most common cancers in the US, and it is estimated that more than 9,000 Americans will die of melanoma this year. Melanoma patients have a 9-times greater risk for a diagnosis of another melanoma compared to the general population. Because of this, it is important that melanoma patients practice regular sun protection and skin self-examination behaviors. There is potential opportunity to use the Internet to deliver information and interventions to help melanoma patients engage in these behaviors. However, it is important to understand patients’ preferences. Our research explored factors associated with the receptivity of patients with melanoma to such Internet-delivered behavioral interventions.

We found that, in a sample of 176 melanoma patients, the vast majority (84.1%) had Internet access and had previously sought melanoma information online (77.7%). More than two-thirds of patients (68.4%) reported being at least moderately interested in participating in an Internet-based intervention to promote engagement in sun protection and skin self-examination behaviors. Receptivity to such an intervention was higher among patients who were younger, had greater knowledge of the ABCDE signs of melanoma (looking at the asymmetry, border irregularity, color, diameter, and evolution of the mole or affected area), and were more comfortable using the Internet.

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Antioxidants May Encourage Lung Cancer and Melanoma to Spread

Prof. Martin O. Bergo Sahlgrenska Cancer Center Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg, Sweden

Prof. Martin O. Bergo

MedicalResearch.com Interview with:
Prof. Martin O. Bergo
Sahlgrenska Cancer Center
Department of Molecular and Clinical Medicine
Institute of Medicine
University of Gothenburg
Gothenburg, Sweden

Medical Research: What is the background for this study? What are the main findings?

Prof. Bergo: Dietary antioxidants and antioxidant supplements can protect cells and people from harmful effects of free radicals. The free radicals have the potential, over time, to cause cancer. But why is this research field so enormously fraught with controversy, and why have clinical trials with antioxidants not established this potential anti-cancer effects? We believe it is because the question of “whether antioxidants protect against cancer” should be divided into two separate questions:

1. Do antioxidants protect a healthy cell or a tumor-free person from cancer in the future.?and

2. What is the impact of antioxidant supplementation on an already established tumor?

Focusing specifically on the second question, we showed previously that the antioxidants N-acetylcysteine and vitamin E markedly increase lung cancer progression in mice and cause human lung cancer cells to proliferate faster. The mechanism for this effect was directly linked to the ability of the antioxidants to scavenge free-radicals, which is why it is likely that other antioxidants, synthetic or natural, could have a similar effect. In the current study, we argued that it would be important to test this in malignant melanoma for three reasons.

First, melanoma cancer cells are known to be sensitive to changes in free radicals. Second, melanoma is the cancer that increases most in incidence and lethality in the western world.
And third, primary melanomas may be exposed to antioxidants from both the diet and from skin lotions and sun creams.

We found that supplementing the diet of mice with acetylcysteine has no impact on the primary tumors on the skin but doubles the rate of metastasis – i.e. the ability of the tumor cells to spread in the body. We found similar results with human malignant melanoma cells in culture: antioxidants (acetylcysteine and vitamin E) increased their ability to migrate and invade surrounding tissue. Thus, all in all, we have found that antioxidants can worsen cancer in two different ways, one in the lung, and another in the skin.    

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Factors Associated With Aggressive Conjunctival Melanoma Outlined

Ann-Cathrine Larsen MD, PhD-student University of Copenhagen Faculty of Health Sciences Department of Neuroscience and Pharmacology, Eye Pathology Section CopenhagenMedicalResearch.com Interview with:
Ann-Cathrine Larsen MD, PhD-student
University of Copenhagen
Faculty of Health Sciences
Department of Neuroscience and Pharmacology, Eye Pathology Section
Copenhagen

Medical Research: What is the background for this study?

Dr. Larsen: Conjunctival melanoma is an uncommon malignancy with a high mortality. Population-based studies evaluating prognostic features and treatment are rare. The clinicopathological and prognostic features associated with BRAF-mutations in conjunctival melanoma are unclear.

Medical Research: What are the main findings?

Dr. Larsen: Extrabulbar tumor location and invasion of adjacent tissue structures were poor prognostic features. Incisional biopsy and excision without adjuvant therapy were associated with metastatic disease. Younger age at diagnosis, bulbar or caruncular tumor location, T1 stage tumor, lack of clinical melanosis and mixed or non-pigmented tumor color were features associated with BRAF-mutated conjunctival melanoma. Furthermore, Patients with BRAF mutated tumors seem to have an increased risk of distant metastatic disease.

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Vaccinating New Melanoma Patients With Immune Booster Reduced Tumor Recurrences

Tanja D de Gruijl PhD Professor Translational Tumor Immunology Head Immunotherapy Lab Department of Medical Oncology VU University medical center-Cancer Center Amsterdam Amsterdam, The NetherlandsMedicalResearch.com Interview with:
Tanja D de Gruijl PhD
Professor Translational Tumor Immunology
Head Immunotherapy Lab
Department of Medical Oncology
VU University medical center-Cancer Center Amsterdam
Amsterdam, The Netherlands

Medical Research: What is the background for this study? What are the main findings?

Dr. de Gruijl: Patients that have just been diagnosed with melanoma after heaving a suspect mole removed, at this moment in time don’t have any treatment options to eliminate any sub-clinical micrometastases that (sometimes years later) can grow into distant tumors. These patients, even at these early stages of melanoma, nevertheless run a risk of this happening (between 10 and 30%, depending on local tumor penetration and spread) and all they can do is wait and it see if the surgical removal of the tumor came in time. We reasoned that if we could boost immune cells directed against the tumor in the first-line melanoma-draining (i.e. sentinel) lymph node that remained after removal of the primary tumor we could achieve a systemic immune response against the tumor that would provide a body-wide protection against outgrowth of metastases at a later time. We indeed found (and described in publications) that we were able to boost anti-tumor immunity in this way, by locally injecting the immune stimulatory compound CpG-B into the scar at the site where the primary melanoma was surgically removed, in the week leading up to the surgical removal of the sentinel lymph node. CpG-B resembles bacterial DNA and alerts the immune system to a possibly dangerous infection, thus effectively inducing immune activation. We performed two randomized clinical trials and found T cells recognizing protein fragments associated with melanoma tumors to indeed be expanded and activated in the tumor-draining sentinel lymph node but, importantly, also in the blood of the treated patients. In patients who were administered a placebo control these effects were not observed. We are now seven to eleven years on from when we carried out these trials and have performed clinical follow-up on these patients. We are excited to conclude that patients treated with the CpG-B compound have indeed experienced fewer tumor recurrences during that time (only two out of 30) than patients from the control group who show the (expected) higher rate of tumor recurrences (nine out of 22).  Continue reading

PET/CT May Yield False Positive Findings in Early Stage Melanoma

MedicalResearch.com Interview with:
Benjamin Y. Scheier, MD
Division of Hematology/Oncology
Department of Internal Medicine
University of Michigan, Ann Arbor

Medical Research: What is the background for this study? What are the main findings?

Dr. Scheier: Existing data suggests that PET/CT has use in the detection of metastases from multiple primary tumor types. However, PET/CT lacks data supporting its use in staging asymptomatic patients with early-stage melanoma, may inconsistently impact treatment decisions, and carries a false-positive finding risk that may detract from its use. To evaluate an evolving practice, this study aims to assess the use of PET/CT in detecting occult metastases in SLN-positive melanoma prior to resection. In this retrospective evaluation of patients with melanoma and clinically silent regional lymph nodes treated at the University of Michigan, only 7% had PET/CT findings that ultimately identified metastatic melanoma and precluded LND. Of the 46 patients who underwent a preoperative PET/CT, 15 (33%) had intense uptake distant from the primary tumor and local lymph node basin. Nine of those 15 patients (60%) had abnormalities biopsied prior to LND. Three of the 9 biopsies yielded metastatic melanoma, a false-positive rate of 67% for PET/CT in identifying distant metastases in asymptomatic patients.

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Cell Death Biomarker May Help Predict Melanoma PD-1 Responders

Dr. Roxana S. Dronca, M.D Assistant Professor of Oncology Assistant Program Director of Hematology-Oncology Fellowship Mayo Clinic College of Medicine Rochester, Minnesota MedicalResearch.com Interview with:
Dr. Roxana SDronca, M.D
Assistant Professor of Oncology
Assistant Program Director of Hematology-Oncology Fellowship
Mayo Clinic College of Medicine
Rochester, Minnesota 

Medical Research: What is the background for this study? What are the main findings?

Dr. Dronca: We previously showed that Bim (BCL-2-interacting mediator of cell death ) is a downstream signaling molecule of PD-1 pathway reflecting the degree of PD-1 interaction with its ligand PD-L1 (unpublished data).

In the current study we found that patients who experienced clinical benefit (CR/PR/SD) after 4 cycles of anti-PD1 therapy had higher frequency of Bim+ PD-1+ T-killer cells in the peripheral blood at baseline compared to patients with radiographic progression, likely reflecting an abundant PD-1 interaction with its tumor-associated ligand PD-L1 (B7-H1). In addition, the frequencies of Bim+ PD-1+ CD8 T cells decreased significantly after the first 3 months of treatment in responders compared to nonresponders, indicating tumor regression and therefore less PD-1 engagement with tumor-associated PD-L1.

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Gene Mutation May Be Key to Melanoma Chemotherapy Sensitivity

Rutao Cui M. D., Ph. D.  Vice Chair, Professor,  Department of Pharmacology and Experimental Therapeutic Associate Professor of Pharmacology and Dermatology, and Member The Cancer Center Director The Laboratory of Skin Cancer Therapeutics (LSCT) Boston UniversityMedicalResearch.com Interview with:
Rutao Cui M. D., Ph. D. 
Vice Chair, Professor
Department of Pharmacology and Experimental Therapeutic
Associate Professor of Pharmacology and Dermatology, and Member The Cancer Center
Director The Laboratory of Skin Cancer Therapeutics (LSCT)
Boston University

Medical Research: What is the background for this study? What are the main findings?

Dr. Cui: Recent studies have revealed that the APC/CCdh1 E3 ubiquitin ligase may function as a tumor suppressor. However, the tumor suppressor role of APC/CCdh1 in melanoma remains largely unclear. Here, we report sporadic mutations occurring in APC components, including Cdh1 in human melanoma samples and that loss of APC/CCdh1 may predispose human melanomagenesis.

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Microscopic Regression in Thin Melanoma May Be Good Prognostic Sign

Simone Ribero,  M.D., Ph.D.  University of Turin Department of Medical Sciences Turin Italy and King’s College London Department of Twin Research and Genetic Epidemiology St Thomas’ campus London, UKMedicalResearch.com Interview with:
Simone Ribero,  M.D., Ph.D. 
University of Turin
Department of Medical Sciences
Turin Italy and
King’s College London
Department of Twin Research and Genetic Epidemiology
St Thomas’ campus London, UK

Medical Research: What is the background for this study? What are the main findings?

Response: The histologic regression is a discussed feature and its prognostic role is debated in literature. Our group has previously described a favorable prognostic role of histological regression in stage I-II melanoma patients. Some clinicians still perform Sentinel Lymph Node biopsy on the basis of regression in thin melanoma considering this feature as able to underestimate Breslow Thickness.

In this study we described in a metanalyses with more then 10000 melanoma patients that histological regression is inversely associated with Sentinel Lymph Node positivity.

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Immunosuppressed Melanoma Patients Have More Aggressive Disease

MedicalResearch.com Interview with:
Christina Y. Lee BA
Department of Dermatology
Pedram Gerami, MD
Robert H. Lurie Cancer Center
Feinberg School of Medicine
Northwestern University
Chicago, Illinois

Medical Research: What is the background for this study? What are the main findings?

Response: Melanoma is responsible for the majority of skin cancer-related mortality. While AJCC staging of melanoma provides highly valuable information that helps predict the behavior of cutaneous melanoma, there are likely a number of other variables not included that may help predict which melanomas may result in metastasis. Some of these data points are not be easily assessed or available in large databases. In this study, we sought to assess a broad range of specific clinical factors directly obtained from clinic notes that may help predict melanoma behavior. The study consisted of a large cohort of patients with clinical follow up from our melanoma center at Northwestern University. Some examples of evaluated characteristics include a documented history of tanning bed use, blistering sunburns, or outdoor activity. In our study, patients who were older or immunosuppressed at the time of diagnosis were associated with aggressive tumor behavior in multivariate statistical analysis, when controlled for traditional AJCC factors such as  tumor depth, ulceration, and mitotic figures.

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Melanoma: Lymph Node Radiation After Lymphadenectomy Did Not Improve Survival

MedicalResearch.com Interview with:
Michael A Henderson
MBBS BMedSc MD FRACS
Professor of Surgery, University of Melbourne
Deputy Director Division of Cancer Surgery
Head Skin and Melanoma Service
Division of Cancer Surgery
Peter MacCallum Cancer Centre
East Melbourne Victoria  Australia

Medical Research: What is the background for this study? What are the main findings?

Dr. Henderson:  A number of retrospective reviews of adjuvant radiotherapy after lymphadenectomy for patients at high risk of further lymph node field relapse had all suggested that the risk of lymph node field relapse was reduced but there was controversy about whether there was any impact on survival. In addition many clinicians were concerned about the side effects of radiotherapy and in the absence of a proven survival benefit were reluctant to recommend it. Previously a phase 2 trial of adjuvant radiotherapy conducted by one of our co-authors Prof Bryan Burmiester confirmed that the morbidity of lymph node field radiotherapy was limited and the risks of recurrence was reduced. On that basis the current ANZMTG TROG randomised multicentre trial was initiated.

In summary this final report updates information on overall survival, lymph node field relapse etc and provides information for the first time on long term toxicity of treatment, quality of life and lymphedema. Adjuvant lymph node field radiotherapy for patients at high risk of further lymph node field relapse reduces the risk of further lymph node field relapse by 50% but it has no effect on survival. Although radiotherapy toxicity was common (3 in 4 patients), mostly involving skin and subcutaneous tissue it was mild-to-moderate in severity and had little impact upon the patient’s quality of life as measured by the FACT-G quality of life tool. Specific regional symptoms were more common in the radiated group. Limb volume measurements confirmed a significant but modest increase for patients receiving inguinal radiation (15%) but not for axillary radiation.

In the design of this trial, a decision was made to allow patients in the observation arm who developed an isolated lymph node field relapse to be salvaged by surgery and or radiotherapy. There were only two patients in the radiotherapy arm who developed an isolated lymph node field relapse and both died of metastatic disease. In the observation arm 26 patients developed an isolated lymph node field relapse and the majority (23) achieved lymph node field control with a combination of surgery and or radiotherapy. The five-year survival FROM development of a lymph node field relapse in this group was 34% which is comparable to the overall survival of the entire cohort (42% five-year overall survival). This information whilst a subset analysis suggests that if it would be reasonable in some patients to consider a policy of observation only, reserving further surgery and or radiotherapy for a second relapse.

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PD-L1 and TILS Predict Resistance in BRAF-Treated Melanoma Patients

MedicalResearch.com Interview with:
Mario Mandalà, MD
Department of Oncology and Haematology
Papa Giovanni XXIII Hospital
Bergamo, Italy

Medical Research: What is the background for this study?

Dr. Mandalà: In addition to their established molecular mechanism of action, growing evidence suggests that the therapeutic efficacy of BRAFi relies on additional factors that affect the tumor–host interactions, including the enhancement of melanoma antigen expression and the increase in immune response against tumor cells.  Preclinical data show that oncogenic BRAF contributes to immune evasion, and that targeting this mutation may increase the melanoma immunogenicity. Data in vitro or from animal models propose PD-L1 as a potential mechanism that favors BRAFi resistance through the modulation of host immune responses. However, demonstration of this hypothesis in the clinical setting is lacking.

Medical Research: What are the main findings?

Dr. Mandalà: In the present study, we have evaluated, in a homogeneous series of MMP treated with BRAFi, the association of tumoral PD-L1 IHC expression and the density of TIMC with RR, PFS and OS. Results provide the first proof-of-principle clinical evidence of the predictive and prognostic relevance of PD-L1 IHC expression and density of immune cell infiltration in BRAFV600 mutated MMP receiving BRAFi.

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New Blood Biomarker Panel May Detect Melanoma Micro-Metastases

Mitchell S. Stark Senior Research Assistant/PhD Student Oncogenomics Group QIMR Berghofer Medical Research Institute Herston, Brisbane, AustraliaMedicalResearch.com Interview with:
Mitchell S. Stark
Senior Research Assistant/PhD Student
Oncogenomics Group
QIMR Berghofer Medical Research Institute
Herston, Brisbane, Australia

Medical Research: What is the background for this study?
What are the main findings?

Response: Melanomas are among the most commonly occurring cancers with the number of new cases rising each year. Melanoma is currently is listed as the 4th and 6th most common cancer in Australia and the USA with >11,000 and >76,000 news diagnoses each year.  The overall 5-year survival for melanoma is 91%, which is largely due to curative surgery for early stage disease. However, cure rates are <15% if distant metastasis occurs (stage IV). We now have evidence that current therapeutic options for late stage disease are more effective if the disease is treated with a lower disease burden.  2010). Hence, melanoma must be treated in earlier stages to maximize the chances of patient survival. Therefore, the ability to identify signs of melanoma progression sooner would be a valuable clinical tool.

The use of melanoma progression markers have been used for many years however it is clear from the survival rates that melanoma must be detected before disease progresses thus highlighting that the current methods of progression detection are inadequate. We have identified a seven-microRNA panel (MELmiR-7) that has the ability to detect the presence of melanoma with high sensitivity and specificity which is superior to currently used markers for melanoma progression, recurrence, and survival. This panel may enable more precise measurement of disease progression and may herald an increase in overall survival.

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Larger Study Finds No Link Between Melanoma and Viagra

Dr. Stacy Loeb, MD, MScDepartment of Urology, Population Health, and Laura and Isaac Perlmutter Cancer CenterNew York University, New York 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 York

Medical Research: What is the background for this study?

Dr. Loeb: A paper published last year suggested a relationship between use of sildenafil (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.   Continue reading

Some Melanoma Cells Hide From BRAF Inhibitor Therapy

MedicalResearch.com Interview with:
Keiran Smalley, PhD.
Scientific Director
The Comprehensive Melanoma Research Center
Associate Professor
The Moffitt Cancer Center & Research Institute,
Tampa, FL

Medical Research: What is the background for this study? What are the main findings?

Dr. Smalley: The major finding of this study is that some melanomas (those which are BRAF mutant and PTEN null) can evade BRAF inhibitor therapy by remodeling their environment. Essentially the cells make a protective niche that allows them to escape from the drug. By attaching to this newly synthesized extracellular matrix the melanoma cells generate their own survival signals.

Medical Research: What should clinicians and patients take away from your report?

Dr. Smalley: This work has uncovered another mechanism by which melanoma cells can “hide” from therapy. Developing strategies that target these adaptations will prove critical if we ever want to achieve cures for cancer. This is particularly important for an aggressive cancers like melanoma where as little as one cell can repopulate the tumor.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Smalley: New strategies need to be developed that target both the tumor and its mechanisms of adaptation to therapy.

Citation:

I V Fedorenko, E V Abel, J M Koomen, B Fang, E R Wood, Y A Chen, K J Fisher, S Iyengar, K B Dahlman, J A Wargo, K T Flaherty, J A Sosman, V K Sondak, J L Messina, G T Gibney, K S M Smalley. Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells. Oncogene, 2015; DOI: 10.1038/onc.2015.188

Neutrophil-to-Lymphocyte Ratio May Identify Melanoma Patients Likely To Benefit From Ipilimumab

MedicalResearch.com Interview with:
Chiara Martinoli, PhD
Medical Oncology of Melanoma
European Institute of Oncology
Milan, Italy

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Martinoli: The recent advent of new immunomodulatory drugs and targeted therapies is changing the therapeutic algorithm for metastatic melanoma patients. Immunomodulation with the anti-CTLA-4 antibody ipilimumab improves survival but is not devoid of potential risks. There is an urgent need for biomarkers to identify patients best suited to receive this therapy, in order to maximize treatment benefit and spare toxicities.

In this study, by analyzing pre-therapy hematological parameters of a large group of metastatic melanoma patients treated with ipilimumab, we showed that neutrophil-to-lymphocyte ratio is strongly and independently associated to patient outcome. Patients with a low baseline neutrophil-to-lymphocyte ratio had a double-reduced risk of disease progression and a two-to-four-fold reduced risk of death, regardless of age, sex and LDH.

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JAK1 Inhibitors May Be New Option To Treat Resistant Melanoma

Prof. Ze'ev Ronai Ph.D Scientific Director Sanford-Burnham's La JollaMedicalResearch.com Interview with:
Prof. Ze’ev Ronai Ph.D
Scientific Director
Sanford-Burnham’s La Jolla

Medical Research: What is the background for this study? What are the main findings?

Prof. Ronai: There is an urgent need to find new approaches to treat melanoma in patients that are resistant to current therapeutic regimes—and this represents a significant percent of melanoma patients.  We used  samples from patients with drug resistant tumors  to study the molecular basis of resistance and screened for genes involved in the process.

We have identified a new player in melanoma resistance to therapy—a molecular target, which provides the basis for clinical trials with drugs currently available to these targets. We found that JAK1 kinase is one target that  is upregulated in the resistant tumors. Inhibiting JAK1 kinase can effectively overcome such resistance.  Continue reading

Melanoma Survival Improved By Cancer-Killing Virus

Howard L. Kaufman, MD, FACS Rutgers Cancer Institute of New Jersey New Brunswick, NJMedicalResearch.com Interview with:
Howard L. Kaufman, MD, FACS
Rutgers Cancer Institute of New Jersey
New Brunswick, NJ

Medical Research: What is the background for this study? What are the main findings?

Response: The study clearly demonstrated that advanced melanoma patients achieved a significant improvement in both response rate and durable response rate with Talimogene laherparepvec, or T-VEC. T-VEC is the first oncolytic virus to show a clinical benefit in a randomized phase 3 clinical trial for the treatment of cancer. Patients who received T-VEC also had an improved progress-free and overall survival with nearly 11% obtaining a complete response. T-VEC is an oncolytic virus that mediates anti-tumor activity by directly killing injected tumor cells and by initiating a systemic immune response. Treatment was also associated with few side effects, which were mostly low grade fever, fatigue, chills, nausea and pain at the injection site.

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Gene Expression Profile Improves Melanoma Risk Assessment

Pedram Gerami, M.D.Associate Professor of Dermatology Director, Melanoma Research Northwestern Skin Cancer Institute Northwestern UniversityMedicalResearch.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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Targeted Melanoma Panel Identifies Genetic Subsets of Melanoma

Melissa Wilson, MD, PhD Assisstant Professor Perlmutter Cancer Center NYU Langone Medical Center New York, NYMedicalResearch.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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PIM Kinase Inhibitors May Offer New Melanoma Therapeutic Target

Adina Vultur, Ph.D. Staff Scientist Meenhard Herlyn Laboratory Melanoma Research Center The Wistar Institute, PhiladelphiaMedicalResearch.com Interview with:
Adina Vultur, Ph.D.
Staff Scientist
Meenhard Herlyn Laboratory
Melanoma Research Center
The Wistar Institute, Philadelphia

Medical Research: What is the background for this study? What are the main findings?

Dr. Vulture: Our goal was to identify new drugs with anti-melanoma activity but with minor effects on normal cells. We screened structurally distinct kinase inhibitors first, against multiple cell lines and normal cells, and identified the organometallic compound SM200 as being the most effective and selective molecule, capable of halting melanoma cell growth and invasion. Further characterization of SM200 indicated that PIM kinases are highly inhibited by this compound compared to other targets. We then confirmed the contribution of PIM kinases to melanoma pathobiology by knockdown studies and by using a clinically available PIM-inhibitor. Encouraging results with PIM kinase inhibition in multiple melanoma models including xenografts suggests that this could be a useful strategy against melanoma.

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Melanoma: BRAF or NRAS Mutations Associated With Worse Survival

Nancy E. Thomas, MD, PhD Department of Dermatology University of North CarolinaMedicalResearch.com Interview with:
Nancy E. Thomas, MD, PhD

Department of Dermatology
University of North Carolina

MedicalResearch: What is the background for this study?

Dr. Thomas: BRAF and NRAS mutations found in melanomas are important for tumor initiation and maintenance. There are drugs that target BRAF mutations or the pathway that are approved for BRAF-mutant metastatic melanoma and help improve survival. However, it remains unknown whether these mutations in primary melanoma are markers for melanomas with a worse prognosis.

MedicalResearch: What are the main findings?

Dr. Thomas:

  • In a large international population-based study, we found that of primary melanomas, 30% harbor BRAF mutations, 13% have NRAS mutations and the other 57% do not have these mutations (wildtype).
  • In higher primary tumor stage melanomas, BRAF or NRAS mutations were associated with an approximately 3-fold increased rate of death from melanoma compared to wildtype melanoma adjusted for other prognostic factors.
  • Primary melanomas with NRAS mutations were less likely to have tumor infiltrating lymphocytes (TILs) in the tumor microenvironment. Continue reading

Melanoma: Study Examines Metastases in Nonhottest Sentinel Nodes

MedicalResearch.com Interview with:
Lyn McDivitt Duncan, MD
Professor of Pathology, Harvard Medical School
Chief, Dermatopathology Unit and
Su Luo, MD Dermatology Resident
Massachusetts General Hospital
Boston, MA 02114

Medical Research: What is the background for this study? What are the main findings?

Response: We studied 475 patients with cutaneous melanoma diagnosed at the Massachusetts General Hospital (MGH) who also had a sentinel lymph node biopsy procedure performed.  There is a practice gap in the sentinel lymph node biopsy procedure ranging from removal of one “sentinel” lymph node to removing the hottest lymph node and any lymph nodes with radioactive tracer of 10% or more of the hottest lymph node’s counts (with an average of three lymph nodes removed).  At the MGH we use this latter method.  We examined the sentinel lymph nodes in each case to determine whether the positive cases with microscopic melanoma metastases had metastases only in the most radioactive, or “hottest”, node or whether tumor was also present in the less hot nodes. We found that in 19% of positive cases there were metastases present only in the less hot nodes. We also performed survival analysis and showed that the less hot nodal positive cases are of equivalent prognostic significance.  We found that removal of only the hottest lymph node would have led to under-staging of 19% of patients with melanoma.

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Imiquimod Cream May Be Effective In Primary And Adjuvant Treatment Of Lentigo Maligna

Susan Swetter, MD Professor of Dermatology and Director, Pigmented Lesion and Melanoma Program Stanford University Medical Center and Cancer Institute.MedicalResearch.com Interview with:
Susan Swetter, MD

Professor of Dermatology and Director, Pigmented Lesion and Melanoma Program
Stanford University Medical Center and Cancer Institute.

 

Medical Research: What is the background for this study?

Dr. Swetter: This retrospective cohort study sought to explore the role of the topical immunomodular – imiquimod 5% cream – as both primary and adjuvant therapy (following optimal surgery) for patients with the lentigo maligna subtype of melanoma in situ. Assessment of alternative treatments to surgery for this melanoma in situ subtype are warranted given the increasing incidence of lentigo maligna in older, fair-complexioned individuals in the United States. Surgical management of lentigo maligna is complicated by its location on cosmetically sensitive areas such as the face, histologic differentiation between lentigo maligna and actinic melanocytic hyperplasia in chronically sun-damaged skin, and potential surgical complications in the elderly who may have medical co-morbid conditions.

Medical Research: What are the main findings?

Dr. Swetter: We conducted a retrospective review of 63 cases of lentigo maligna in 61 patients (mean age 71.1 years) who used topical 5% imiquimod cream instead of surgery (22 of 63 cases, 34.9%) or as an adjuvant therapy following attempted complete excision (63 cases, 65.1%), in which no clinical residual tumor was present but the histologic margins were transected or deemed narrowly excised. Our study showed overall clinical clearance of 86.2% in the 58 patients analyzed for local recurrence at a mean of 42.1 months of follow-up (standard deviation 27.4 months), with primarily treated cases demonstrating 72.7% clearance at a mean of 39.7 months (standard deviation 23.9 months), and adjuvant cases showing 94.4% clearance at a mean of 39.7 months (standard deviation 23.9 months).  We found a statistically significant association between imiquimod-induced inflammation and clinical or histologic clearance in primary but not adjuvant cases, although this latter finding may be explained by a lack of residual atypical melanocytes or true LM in the adjuvant setting, in which wide local excision had already been performed.

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Melanoma: Targeting Macrophages Increases BRAF Inhibitors’ Effectiveness

Russel E. Kaufman, MD President Emeritus Professor, Molecular and Cellular Oncogenesis Program Molecular and Cellular Oncogenesis Program The Wistar InstituteMedicalResearch.com Interview with:
Russel E. Kaufman, MD President Emeritus
Professor, Molecular and Cellular Oncogenesis Program
Molecular and Cellular Oncogenesis Program
The Wistar Institute

Medical Research: What is the background for this study? What are the main findings?

Response: Targeted therapies in cancer were hailed as a “magic bullet” because of their ability to act upon the mutations responsible for cancer while leaving nearby healthy cells alone. Using an approach like this, it would make sense that therapies designed to target mutations of BRAFV600E/K could be effective for melanoma, since that gene is mutated in about half of all cases of the disease.

However, we’ve learned over time that these targeted therapies simply aren’t as effective as we had hoped they would be. In the case of these BRAF inhibitors, while patients do live slightly longer, they eventually relapse within months of treatment. We wanted to know why this was happening.

We decided to look at macrophages, which are the most abundant inflammatory cells in melanoma. The more macrophages present in a patient with melanoma, the worse his or her outcome will be. They’ve been linked to cancer progression, but before this study, no one had really looked at the role they may play in the resistance to treatment with BRAF inhibitors.

We found that BRAF inhibitors activate the mitogen-activated protein kinase (MAPK) pathway in macrophages. When this pathway is activated, it leads to the production of vascular endothelial growth factor (VEGF), a signaling protein closely associated with angiogenesis. The VEGF produced in the macrophages is able to activate the MAPK pathway in melanoma cells, thereby stimulating the growth of cancer cells.

Taking these findings one step further, we discovered that when we blocked the MAPK pathway or VEGF signaling, we appeared to reverse macrophage-mediated resistance. When we targeted macrophages, we were able to increase the antitumor activity of BRAF inhibitors in mouse and human models.

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Gene Signature May Predict Risk of Metastases and Death From Melanoma

Pedram Gerami MD Associate Professor of Dermatology and Pathology Northwestern UniversityMedicalResearch.com Interview with:
Pedram Gerami MD
Associate Professor of Dermatology and Pathology
Northwestern University

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Gerami: The outcomes for patients with cutaneous melanoma are highly variable and there are limitations to the conventional staging system for melanoma. For example while the status of the sentinel lymph node biopsy is considered the strongest prognosticator, approximately 2/3 of cutaneous melanoma patients that ultimately die from their melanoma will have a negative sentinel lymph node biopsy result. In this study we showed that using a technique known as mRNA expression profiling to determine which genes are highly active and which are not that a molecular prognostic assay with accuracy could be developed. This assay can accurately classify patients based on their gene signature as having a high or low risk for metastasis and death from their melanoma. In an independent validation cohort, patients with a class I or low risk signature had a 5 year disease free survival rate of 97% while those with a class II or high risk signature had a 5 year disease free survival rate of only 31%.

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Genetic Study Confirms Most Pediatric Melanoma Linked To Sun Exposure

Dr. Pappo and Dr. Bahrami by Peter Barta

Dr. Pappo and Dr. Bahrami

MedicalResearch.com Interview with:
Alberto Pappo, M.D.
Member, Oncology; Director, Solid Tumor Division
St. Jude Children’s Research Hospital

Medical Research: What is the background for this study? What are the main findings?

Dr. Pappo: Researchers have identified three distinct subtypes of childhood and adolescent tumors of pigment-producing skin cells called melanocytes. The subtypes have different genetic alterations and often different outcomes for patients. The findings should aid efforts to improve diagnosis and treatment of melanoma, which is the most common skin cancer in children and adolescents.

The study provides the most comprehensive analysis yet of the genetic alteration underlying pediatric melanoma, including the first genetic evidence that sun damage causes melanoma in children and adolescents as well as adults. Researchers used whole genome sequencing and other techniques to study the normal and cancer genomes of 23 young patients with a variety of melanocytic tumors, including conventional melanoma. Patients ranged in age from 9 months to 19 years old.

The melanoma subtypes in this study included conventional melanoma, which scientists showed was the same disease in children, adolescents and adults. More than 90 percent of pediatric conventional melanoma had DNA changes linked to sun damage.

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Melanoma: Assaying Multiple Proteins Helps Identify BRAF-Inhibitor Resistance

Linda Chin, MD Department Chair, Department of Genomic Medicine, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TXMedicalResearch.com Interview with:
Linda Chin, MD

Department Chair, Department of Genomic Medicine, Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

Medical Research: What is the background for this study? What are the main findings?

Dr. Chin: BRAF inhibitors have worked very well against melanoma in the clinic, but when the tumors relapse on treatment, it is not always clear what causes it. Without this information, it can be difficult for doctors to identify specific second-line therapies likely to overcome the drug resistance. In this study, we used both mouse and patient melanoma samples to identify patterns of selected protein levels that can categorize modes of drug resistance when other assays such as DNA sequencing are uninformative. We hope that this information can provide missing clues for clinicians. Continue reading

Sentinel Lymph Node Biopsy Should Be Considered For All Thick Melanomas

Maki Yamamoto MD Health Sciences Clinical Assistant Professor UC Irvine Health University of California, Irvine Orange, CA 92868MedicalResearch.com Interview with:
Maki Yamamoto MD
Health Sciences Clinical Assistant Professor
UC Irvine Health
University of California, Irvine
Orange, CA 92868

Medical Research: What is the background for this study? What are the main findings?

Dr. Yamamoto: The Multicenter Selective Lymphadenectomy Trial-I (MSLT-I), a large, prospective randomized trial, evaluated patients with clinically lymph node-negative melanoma who were undergoing sentinel lymph node biopsy (SLNB) or observation of their lymph node basins. The MSLT-I helped to form the basis for the recent recommendation in the ASCO-SSO joint guideline that SLNB is indicated for patients with intermediate-thickness melanoma (measuring 1-4mm). However, controversy remains regarding the use of SLNB in both patients with thin (measuring <1 mm) and thick (measuring>4mm) melanoma.

Medical Research: What should clinicians and patients take away from your report?

Dr. Yamamoto: Our study retrospectively studied 571 patients with thick cutaneous melanoma (>/=4mm) and their associated outcomes.  We found that we had an acceptably low false negative rate with SLNB in this group of patients and a negative sentinel node biopsy had a significantly prolonged overall, disease-specific and recurrence-free survival when compared to those with a positive biopsy.  Therefore, SLNB should be considered as indicated for patients with thick, clinically lymph node-negative melanoma.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Yamamoto: One of the next steps in future research could be to refine techniques to decrease the false negative rate for SLNB in melanoma or to elucidate why some patients may recur distally despite a negative SLNB.

Citation:

Sentinel lymph node biopsy is indicated for patients with thick clinically lymph node-negative melanoma

Yamamoto M1, Fisher KJ, Wong JY, Koscso JM, Konstantinovic MA, Govsyeyev N, Messina JL, Sarnaik AA, Cruse CW, Gonzalez RJ, Sondak VK, Zager JS.
Cancer. 2015 Feb 11. doi: 10.1002/cncr.29239. [Epub ahead of print]

 

MedicalResearch.com Interview with: Maki Yamamoto MD (2015). Sentinel Lymph Node Biopsy Should Be Considered For All Thick Melanomas 

Molecular Biomarkers May Help Determine Which Melanomas Will Spread

Iman Osman, MD Professor, Departments of Dermatology, Medicine and Urology Associate Director, NYU Cancer Institute  Director, Interdisciplinary Melanoma Program  New York University Langone Medical Center New York, NY 10016MedicalResearch.com Interview with:
Iman Osman, MD

Professor, Departments of Dermatology, Medicine and Urology
Associate Director
The Laura and Isaac Perlmutter Cancer Center
Director, Interdisciplinary Melanoma Program
New York University Langone Medical Center
New York, NY 10016

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Osman: We were interested in exploring molecules that could be biomarkers or functional regulators of metastasis in melanoma in early-stage tumor lesions on the skin. Though these tumors are treated largely the same (by surgical removal ), patients with these tumors have vastly different outcomes (apparent cure vs. metastatic spread of the disease). The reasons for these disparities are unclear and we have little ability to identify or predict the patients that will be cured and those that won’t. We also don’t have much data to know even if these tumors have differences at the molecular level. Our findings indicate that there are molecular differences in these tumors and that some of these differences contribute to tumor spread.  Continue reading

Skin Damaged by Sunlight Even When Out of the Sun

Douglas E. Brash, PhD Professor of Therapeutic Radiology and Dermatology Yale School of Medicine New Haven, CTMedicalResearch.com Interview with:
Douglas E. Brash, PhD

Professor of Therapeutic Radiology and Dermatology
Yale School of Medicine New Haven, CT

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Brash: We wanted to know whether the origin of melanoma differed from other cancers because of the melanin. It has long been known that blondes and redheads are sensitive to sunlight, but the prevailing view was that this was because their skin is light. But there are light-skinned, dark-haired people in countries near the equator and they don’t have the high skin cancer incidence seen in Australia. Several labs, including ours, had irradiated cells or mice with UV and found more cell death in cells containing melanin than cells lacking melanin. In the last couple of years, two papers have focused attention on the issue; one study found that irradiating mice with UVA only gave melanomas if the skin contained melanin and the other study found that mice genetically predisposed to UV-induced melanoma developed melanomas even without UV if they also had red melanin.

The most important findings are:

First, our skin continues to be damaged by sunlight even when we’re out of the sun.

Second, the melanin pigment in your skin is bad for you as well as good: it may be carcinogenic as well as protective.

Third, the chemistry underlying these events, chemical excitation of electrons, has not been seen in mammals before. Continue reading

How Much Does Specialized Melanoma Screening Cost?

MedicalResearch.com Interview with:
Caroline Watts| PhD Candidate
Cancer Epidemiology and Services Research | Sydney School of Public Health
The University of Sydney

MedicalResearch: What is the background for this study? What are the main findings?

Response: A clinic for people at high risk of melanoma was established at the Royal Prince Alfred Hospital, Sydney in 2006 to look at the impact of surveillance regime which included regular full body skin examination supported by dermoscopy and total body photography at 6 monthly intervals. If a suspicious lesion was identified, the lesion was either removed or sequential digital dermoscopy was performed and the patient returned in 3 months for review. This study aimed to estimate the costs associated with surveillance in this type of specilaised clinic.

The mean number of clinic visits per year was 2.7 (95% CI, 2.5-2.8) for surveillance and 3.8 (95% CI, 3.4-4.1) for patients requiring surgical excisions. The mean annual cost per patient to the health system was A $882 (95% CI, A $783-$982) (US $599 [95% CI, US $532-$665]) and mean annual societal cost per patient (excluding health system costs) was A $972 (95% CI, A $899-$1045) (US $660 [95% CI, US $611-$710). Diagnosis of melanoma or non-melanoma skin cancer and frequent excisions for benign lesions in a relatively small number of patients was responsible for skewed health system costs.

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Epigenetic Control Protein Allows Melanoma Cells To Metatasize

MedicalResearch.com Interview with:
Prof Lukas Sommer. Ph.D.
Cell and Developmental Biology
University of Zurich Institute of Anatomy
Zurich Switzerland

MedicalResearch: What is the background for this study? What are the main findings?

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

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Coffee May Lower Melanoma Risk

MedicalResearch.com Interview with:
Erikka Loftfield
Doctoral student at the Yale School of Public Health
Fellow at the National Cancer Institute

Medical Research: What is the background for this study? What are the main findings?

Response: Previous studies have reported conflicting results on the association between coffee drinking and melanoma. We sought to clarify this relationship using data from the large NIH-AARP Diet and Health Study. We followed over 400,000 retirees aged 50 to 71 years at study entry for an average of 10 years. Participants were asked to report typical coffee intake. During the course of follow-up nearly 3,000 cases of malignant melanoma occurred. In our study, we observed that individuals who reported the highest total coffee intake (4 cups/day) had about 20% lower risk of malignant melanoma compared with those who did not consume coffee.

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Melanoma: BRAF Inhibition May Switch Cancer Cells To Become More Metastatic

Keiran Smalley, PhD. Scientific Director, The Comprehensive Melanoma Research Center Associate Professor The Moffitt Cancer Center & Research Institute, Tampa, FLMedicalResearch.com Interview with:
Keiran Smalley, PhD.

Scientific Director, The Comprehensive Melanoma Research Center
Associate Professor The Moffitt Cancer Center & Research Institute, Tampa, FL

 

Medical Research: What is the background for this study? What are the main findings?

Dr. Smalley: Although many patients with BRAF mutant melanoma respond very well to BRAF inhibitors and the BRAF/MEK inhibitor combination, resistance is commonplace and the majority of those treated ultimately fail therapy. Most studies to date have focused upon the genetic changes that are associated with acquired BRAF and BRAF/MEK inhibitor resistance. We decided to take a different approach and to use proteomics to comprehensively map all of the signaling changes associated with resistance. Our study showed that melanoma cells with resistance to BRAF and BRAF/MEK inhibition were highly invasive and aggressive. This aggressive phenotype was driven through a cell surface receptor called EphA2, and this became upregulated in both melanoma cell cultures and in patient tumors following BRAF inhibitor treatment. As this suggested that the resistant cells would be more metastatic, we then performed animal experiments and analyzed tumors from melanoma patients receiving BRAF inhibitor. These studies showed an increase in EphA2 expression in the metastatic tumors that was lacking in the primary tumors. When we looked at cohorts of melanoma patients who received either a BRAF inhibitor or an older chemotherapy drug, we found that more of the BRAF inhibitor treated patients seemed to develop disease at new sites. Together this suggested that BRAF inhibition may switch the cancer cells to being more metastatic.

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Melanoma: Study Support 6mm Criteria in ABCD Rule

MedicalResearch.com Interview with:
Razieh Soltani-Arabshahi, MD, MSci

Department of Dermatology,
University of Utah, Salt Lake City, Utah

MedicalResearch.com: What is the background for this study?

Dr. Soltani-Arabshahi: The incidence of melanoma is rapidly rising. Dermatologists are the leading specialty group to diagnose melanoma. While ABCD cirteria for diagnosis of melanoma have been used by many dermatologists, there are few studies of it’s predictive value.

MedicalResearch.com: What are the main findings?

Dr. Soltani-Arabshahi: We showed that at an academic dermatology center, nearly 16 clinically suspicious lesions need to be biopsied to find one case of melanoma. Biopsies of lesions larger than 6 mm in diameter on older male patients had the highest yield.
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Even Thin Melanomas Can Be Fatal

Prof. David Whiteman Group leader, Cancer Control Group QIMR Berghofer Herston, QueenslandMedicalResearch.com Interview with:
Prof. David Whiteman
Group leader, Cancer Control Group
QIMR Berghofer
Herston, Queensland

 

Medical Research: What are the main findings of the study?

Dr. Whiteman: Mortality from melanoma has continued to rise in Queensland, Australia, the jurisdiction with the world’s highest incidence of this disease. We analysed more than 4000 deaths from melanoma over the last 2 decades, and calculated mortality rates according the thickness of the primary lesion.
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Dendritic Cell Vaccination May Help Uveal Melanoma

MedicalResearch.com Interview with:
Prof I. Jolanda M. de Vries
Professor, Dept of Tumor Immunology
Radboud University Nijmegen

Medical Research: What are the main findings of the study?

Prof. de Vries: Dendritic cells are antigen-presenting cells with the unique capacity to activate naive antigen-specific T cells, and by this means are very suitable to induce immunologic antitumor responses. Dendritic cells cultured from monocytes can be matured and loaded with tumor antigen ex vivo and administered back into the patient. Within the lymph node, dendritic cells present antigens to T cells to initiate an immune response.

Metastatic uveal melanoma patients were vaccinated with autologous DCs loaded with tumor antigens (gp100 and tyrosinase), obtained by leukapheresis, according to a schedule of 3 biweekly vaccinations. One to 2 weeks after the last vaccination, a skin test was performed to analyse the induction of immunologic responses.

We can conclude that dendritic cell vaccination is feasible and safe in metastatic uveal melanoma. Dendritic cell-based immunotherapy is potent to enhance the host’s antitumor immunity against uveal melanoma in approximately one third of patients.
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Melanoma: Combination BRAF and MEK Inhibitors Has Better Safety Profile

Martina Sanlorenzo, MD Department of Dermatology Mt. Zion Cancer Research Bldg. San Francisco, CA 94143-0808MedicalResearch.com Interview with:
Martina Sanlorenzo, MD
Department of Dermatology
Mt. Zion Cancer Research Bldg.
San Francisco, CA 94143-0808


Medical Research:
What are the main findings of the study?

Dr. Sanlorenzo: In the treatment of BRAF mutant melanoma, the combination of BRAF inhibitor and MEK inhibitor has a better cutaneous safety profile compared with BRAF inhibitor monotherapy. Combination regimen shows fewer cutaneous adverse events and longer cutaneous adverse event-free interval. In particular, the development of squamous cell carcinoma or keratoacanthoma was significantly less frequent.
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Melanoma Cells Make Steering Signals To Enter Bloodstream

Professor Robert Insall CR-UK Beatson Institute for Cancer Research Glasgow UKMedicalResearch.com Interview with:
Professor Robert Insall
CR-UK Beatson Institute for Cancer Research
Glasgow UK

Medical Research: What are the main findings of the study?

Prof. Insall: The principal message is that melanoma cells make their own steering signals, and thus drive themselves out of the tumour and into the bloodstream.  This comes in two parts:

(a) The principal steering signal when we assay melanoma spread in vitro is lysophosphatidic acid, LPA.  LPA steers cells with really remarkable accuracy; blocking LPA receptors stops them from spreading without hurting their health or ability to move.

(b) Where does the LPA gradient come from?  They make it themselves.  There seems to be lots of LPA around; they break down the LPA near them, leading to a gradient that’s low near the cells and high further away.  This is the gradient that steers the tumour cells.
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As Tanning Became More Fashionable, Melanoma Became More Common

David Polsky, MD, PhD Alfred W. Kopf, MD, professor of Dermatologic Oncology Ronald O. Perelman Department of Dermatology NYU Langone Medical CenterMedicalResearch.com Interview with:
David Polsky, MD, PhD
Alfred W. Kopf, MD, professor of Dermatologic Oncology
Ronald O. Perelman Department of Dermatology
NYU Langone Medical Center


Medical Research: What are the main findings of the study?

Dr. Polsky: We utilized a multi-disciplinary approach including an analysis of socioeconomic factors to elucidate the evolution of attitudes and behaviors maximizing personal ultraviolet light exposure during the 20th century in the United States.  We then compared melanoma incidence rates from national cancer registries to estimated skin exposure and found that they rose in parallel. Though causation cannot be made in an analysis such as this one, this paper describes a historical context for the changing attitudes promoting increased UV exposure, and the rising incidence of melanoma throughout the past century.  It also provides a framework in which to consider public health and education measures that may ultimately help reverse melanoma incidence trends.
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Melanoma: Combination BRAF and MEK Inhibition Improved Outcomes

Georgina Long BSc PhD MBBS FRACP Associate Professor of Melanoma Biology and Translational Research Melanoma Institute Australia and the University of Sydney MedicalResearch.com Interview with:
Georgina Long BSc PhD MBBS FRACP
Associate Professor of Melanoma Biology and Translational Research
Melanoma Institute Australia and the University of Sydney

Medical Research: Could you provide some background on this project? Why did you decide to do this research project? What prior work led up to this latest paper?

Dr. Long: Pre-clinically, we had data that showed that the combination of BRAF inhibitor + MEK inhibitor

  • Decreased skin proliferative toxicity seen with BRAF inhibitors alone (seen as hyperproliferative lesions in rats)
  • and delayed the emergence of resistance I.e. The tumours in the mice reduced in size more, and stayed reduced for longer.We then confirmed this concept in a randomised phase 2 study, although it was not powered for a definitive progression free survival (PFS_ difference like a phase 3 trial is, we saw a strong difference in response rate and in PFS, yet there were only 54 patients per arm.

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Melanoma: PD-L1 As Negative Prognostic Marker

Mario Mandalà, MD Unit of Clinical Research Department of Oncology and Haematology Papa Giovanni XXIII Hospital Piazza OMS 1, 24100, Bergamo, ItalyMedicalResearch.com Interview with:
Mario Mandalà, MD
Unit of Clinical Research
Department of Oncology and Haematology
Papa Giovanni XXIII Hospital
Piazza OMS 1, 24100, Bergamo, Italy

Medical Research: What are the main findings of the study?

Dr. Mandalà: We evaluated PD-L1 expression by IHC in 81 consecutive metastatic melanoma patients, with well-defined demographic and clinical characteristics. Protein expression levels were correlated with clinical outcome. PD-L1+ and PD-L1- subsets of the A375 cell line were stabilized in vitro and compared using gene expression profiling and functional assays. Results were confirmed using xenograft models. In our study PD-L1 membrane positivity was an independent negative prognostic marker. Furthermore PD-L1 expression defined a subset of the BRAF-mutated A375 cell line characterized by a highly invasive phenotype and by enhanced ability to grow in xenograft models. If confirmed, our clinical and experimental data suggest that PD-L1+ melanomas should be considered a disease subset with distinct genetic and morpho-phenotypic features, leading to enhanced aggressiveness and invasiveness.
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Melanoma Cells Alter Their Environment To Promote Progession

Dr. Constance Brinckerhoff Professor of Medicine Professor of Biochemistry Geisel School of Medicine at DartmouthMedicalResearch.com Interview with:
Dr. Constance Brinckerhoff
Professor of Medicine
Professor of Biochemistry
Geisel School of Medicine at Dartmouth


Medical Research: What are the main findings of the study?

Dr. Brinckerhoff: The genetic mutation BRAFV600E , frequently found in metastatic melanoma, not only secretes a protein that promotes the growth of melanoma tumor cells, but can also modify the network of normal cells around the tumor to support the disease’s progression. Targeting this mutation with Vemurafenib reduces this interaction, and suggests possible new treatment options for melanoma therapy.
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How Closely Is Melanoma Survival Linked To Sun Exposure?

Marianne Berwick, PhD, MPH for the GEM Study Team Professor, Division of Epidemiology University of New Mexico, Department of Internal Medicine New Mexico Cancer Research Facility University of New Mexico, Albuquerque, NM 87131MedicalResearch.com Interview with:
Marianne Berwick, PhD, MPH for the GEM Study Team
Professor, Division of Epidemiology
University of New Mexico, Department of Internal Medicine
New Mexico Cancer Research Facility
University of New Mexico, Albuquerque, NM 87131

Medical Research: What are the main findings of this study?

Dr. Berwick: In our study of Sun Exposure and Melanoma Survival: A GEM Study we found that there is little strong evidence that sun exposure at any time in life influences melanoma-specific survival. This study took place in Australia, Italy, Canada and the United States among 3,578 individuals newly diagnosed with melanoma, who we followed for a mean of 7.4 years.

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Do Dermatologists Find Thinner Melanomas?

MedicalResearch.com Interview with:
Estee L. Williams, MD
SUNY Downstate Medical Center, Brooklyn, New York
Madfes Integrated Dermatology, New York, New York
williams.estee@gmail.com

Medical Research: What are the main findings of the study?

Dr. Williams: In our retrospective review of all melanomas diagnosed at the Veterans’ Affairs Hospital in Brooklyn since 2000, we discovered that although a majority of the melanomas (63%) were found by the dermatologist during a yearly “full body” screening examination (versus detection by the patient), melanomas found by the dermatologist were not necessarily thinner (hence, earlier, more curable) than those found by the patient.
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Study Probes Hormonal Pathway in Skin That Influences Melanoma Risk

John D'Orazio, M.D., Ph.D. Drury Pediatric Research Endowed Chair Associate Professor, Univ. KY College of Medicine Pediatric Hematology-Oncology The Markey Cancer Center Lexington, KY 40536-0096MedicalResearch.com Interview with:
John D’Orazio, M.D., Ph.D.
Drury Pediatric Research Endowed Chair
Associate Professor, Univ. KY College of Medicine
Pediatric Hematology-Oncology
The Markey Cancer Center
Lexington, KY 40536-0096

Medical Research: What is the background for this study?

Dr. D’Orazio: Malignant melanoma is the deadliest of skin cancers, and it’s incidence has increased enormously over the last several decades.  In the 1930’s only one in every fifteen hundred Americans would get melanoma in his/her lifetime.  Now it’s one in fifty or sixty.  Plus, it often affects young adults in the prime of their lives.  Altogether, nearly 10,000 Americans die of melanoma every year.  However, risk is not equally shared.  Fair-skinned people who tend to burn rather than tan from sun exposure have a much higher risk than dark skinned people.  On the surface, it would appear that the amount of melanin in the skin would be the only determinant of melanoma risk but the truth is more complex.  Our lab has been interested in a particular hormonal pathway in the skin that directly influences melanoma risk.  When UV radiation (sunlight) hits the skin, it causes damage to the cells of the skin.  Cells respond to this damage to protect themselves against further injury.  One way in which they do this is by turning on a hormone called melanocyte stimulating hormone, abbreviated “MSH”.  Made by keratinocytes, the most abundant cells in the epidermis, MSH is directly responsible for ramping up melanin production by melanocytes, the cells that make the pigment in the skin that gives us a tan.  This pigment called melanin acts as natural sunscreen and blocks UV radiation from penetrating into the skin.  This is very important because people who can tan are in a much safer state the next time they get sun exposure.  Because they have more melanin in the skin, the UV won’t cause as much damage.  The key is to realize that UV causes mutations in melanocytes, and with enough damage to the DNA, melanocytes can turn cancerous and become melanomas.   People who have the melanoma-prone, “can’t tan” skin type often have problems in this MSH hormonal pathway.  Specifically, they have inherited problems with the receptor on melanocytes that binds to MSH and makes the cells make more pigment.  This protein, called the melanocortin 1 receptor (or “MC1R”), is the way that melanocytes sense that the skin has been injured and needs more melanin.  If the MC1R won’t signal, then melanocytes just sit there and can’t be induced to make more melanin pigment.  Surely this is a major reason why people with MC1R signaling defects are at high risk of melanomas.
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Animal Model Demonstrates Pediatric Use of Sunscreen Prevents Melanoma

John L. VandeBerg PhD Southwest National Primate Research Center Texas Biomedical Research Institute San Antonio, TX 78245-0549MedicalResearch.com Interview with:
John L. VandeBerg PhD
Southwest National Primate Research Center
Texas Biomedical Research Institute
San Antonio, TX 78245-0549

MedicalResearch: What are the main findings of this study?

Dr. VandeBerg: Despite the increasing use of sunscreen in recent decades, the incidence of melanoma continues to rise by 3% annually, leading to concerns that sunscreen may not be effective in preventing melanoma despite its efficacy in preventing sunburn.  Our results established in the laboratory opossum, which is the only natural mammalian model of UVB-induced melanoma, that SPF 15 sunscreen applied to infants prior to low dose UVB radiation leads later in life to a 10-fold reduction in pre-melanotic lesions, which are known to progress to malignant melanoma.

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