Author Interviews, JAMA, Melanoma / 27.01.2016

[caption id="attachment_20934" align="alignleft" width="133"]DeAnn Lazovich, Ph.D. Associate Professor Division of Epidemiology and Community Health University of Minnesota Minneapolis, MN 55454 Dr. Lazovich[/caption] MedicalResearch.com Interview with: DeAnn Lazovich, Ph.D. Associate Professor Division of Epidemiology and Community Health University of Minnesota Minneapolis, MN 55454 Medical Research: What is the background for this study? What are the main findings? Dr. Lazovich: In Minnesota, as well as nationally, melanoma rates have been increasing more steeply in women than men younger than age 50 years since about the mid-1990s.  Some have speculated that this could be due to women's indoor tanning use, as women use indoor tanning much more than men do.  We had data on indoor tanning for men and women according to their age from a case-control study on indoor tanning and melanoma that was published in 2010.  In that 2010 report, we examined the association for individuals regardless of sex, all ages combined.  In this analysis, we restricted the study to individuals under age 50 years, and looked at the association between indoor tanning and melanoma according to three age groups (less than 30 years, 30-39 years and 40-49 years) for men and women separately.
AACR, Author Interviews, Melanoma, NYU/NYMC, Personalized Medicine / 25.01.2016

[caption id="attachment_20908" align="alignleft" width="166"]Tomas Kirchhoff, PhD Assistant Professor, Departments of Population Health and Environmental Medicine NYU Langone Medical Center Member, Laura and Isaac Perlmutter Cancer Center NYU Langone Dr. Thomas Kirchhoff[/caption] MedicalResearch.com Interview with: Tomas Kirchhoff, PhD Assistant Professor, Departments of Population Health and Environmental Medicine NYU Langone Medical Center Member, Laura and Isaac Perlmutter Cancer Center NYU Langone  Medical Research: What is the background for this study? Dr. Kirchhoff: Melanoma is the deadliest form of skin cancer, and the cause of approximately 80% of all skin cancer patients annually. One factor that can help reverse this negative trend is efficient prediction of which patients at early melanoma stage will likely progress to more advanced metastatic disease. Current clinical predictors of patient survival, based on tumor characteristics, are important, but are relatively non-specific to inform melanoma prognosis to an individual patient level. It is critical to identify other factors that can serve as more personalized markers of predicting the course of melanoma. Medical Research: What are the main findings? Dr. Kirchhoff: In our study, we found that inherited genetic markers that impact activity of certain immune genes correlate with melanoma survival. More specifically, our findings show that patients with more frequent forms of these genetic markers (genotypes) have, on average, a five-year shorter survival than patients with less common genotypes. We suggest that these genetic markers are independent of the current tumor surrogates and, as such, can serve as novel personalized markers of melanoma prognosis.
Author Interviews, Melanoma, Race/Ethnic Diversity / 21.01.2016

[caption id="attachment_20046" align="alignleft" width="149"]Dr. Jennifer A. Stein MD PhD Associate Professor Department of Ronald O. Perelman Department of Dermatology NYU Langone Medical Center Dr. Jennifer Stein[/caption] More on Dermatology on MedicalResearch.com MedicalResearch.com Interview with: Dr. Jennifer A. Stein MD PhD Associate Professor Department of Ronald O. Perelman Department of Dermatology NYU Langone Medical Center Medical Research: What is the background for this study? What are the main findings? Dr. Stein: Although acral melanoma is not a common cancer, it is the most common form of melanoma in African Americans. There is low awareness about acral melanoma, and it tends to get detected later and is more often fatal than other types of melanoma. Our study looked at awareness of and the prevalence of pigmented lesions on the hands and feet. People with darker skin were more likely to have a pigmented lesion on their soles or palms than people with lighter skin. We found that more than half of the people in the study were not aware that they had a pigmented lesion on their feet. Our study found that most pigmented lesions on the hands and feet are benign, and that an imaging technique called dermsocopy can be used to distinguish benign from malignant acral lesions.
Author Interviews, Dermatology, JAMA, Melanoma, Technology / 08.01.2016

MedicalResearch.com Interview with: Marc Haspeslagh, MD Dermpat, Ardooie, Belgium Department of Dermatology University Hospital, Ghent, Belgium Medical Research: What is the background for this study? Dr. Haspeslagh: In daily practice, most pathology laboratories process skin biopsy specimens without access to the clinical and /or dermoscopic images. In pigmented skin tumors, this information can be crucial to process and diagnose the lesion correctly. With increasingly smaller diameter lesions undergoing biopsy, these focal changes are only visible with dermoscopy; therefore, communication of this dermoscopic information to the pathologist is important. In many dermatopathology laboratories, this communication is often insufficient or totally absent, and one can presume that these suspicious areas are often missed with the standard random sectioning technique that examines less than 2% of the tissue. To overcome this diagnostic limitation we developed in 2013 a new method for processing skin biopsies, were we routinely take an ex vivo dermoscopic image of most tumoral skin lesions. In combination with marking specific and suspected areas seen on the ex vivo dermoscopy (EVD) with nail varnish, EVD with derm dotting is a simple and easy method that brings this crucial information to the pathologist and in the slides to be examined (Am J Dermatopathol 2013; 35(8),867-869).
Author Interviews, Dermatology, Melanoma, Surgical Research / 05.01.2016

[caption id="attachment_20428" align="alignleft" width="120"]Jason B. Lee MD Professor , Clinical Vice Chair Department of Dermatology and Cutaneous Biology Director, Jefferson Dermatopathology Center Thomas Jefferson University Philadelphia, Pennsylvania Dr. Jason Lee[/caption] MedicalResearch.com Interview with: Jason B. Lee MD Professor , Clinical Vice Chair Department of Dermatology and Cutaneous Biology Director, Jefferson Dermatopathology Center Thomas Jefferson University Philadelphia, Pennsylvania  Medical Research: What is the background for this study? What are the main findings? Dr. Lee: When initially described, Clark et al. suggested that dysplastic nevi were intermediate lesions that lie biologically on a spectrum between benign and malignant. As such, they were to be histologically graded as mild, moderate, and severe (or a combination thereof), with mild presumably closer to benign and severe closer to malignant. In this paradigm, adopted by most dermatologists, these nevi are routinely excised based on histologic grading and margin status. Recent outcomes of follow-up and excision studies of dysplastic nevi suggest that they are over treated as there have been very low rates of melanoma on re-excision. An alternative approach considers dysplastic or eponymously Clark nevi as common acquired nevi, typically in fair skin individuals, and rejects the entire notion that they are intermediate lesions as there exists no formal proof of their intermediate status. This approach omits grading and margin status entirely, providing the clinician an explicit recommendation for excision only for those cases of diagnostic uncertainty. In this study, excision recommendation rate of dysplastic/Clark nevi was determined along with analysis of excision outcomes in a laboratory where non-grading histologic diagnostic approach to these nevi has been adopted. The excision recommendation rate, representing the diagnostic uncertainty rate, was 11.1%. Out of 80% of the cases returned for excision, only 2.0% of the cases were interpreted as melanoma on excision; all were in situ or thin melanomas. This excision rate is much lower than in prior reports, which vary from 22-52%, while still capturing melanomas within this subset of lesions.
Author Interviews, Dermatology, Genetic Research, JAMA, Melanoma / 10.12.2015

[caption id="attachment_19964" align="alignleft" width="168"]Susana Puig MD PhD Chief Dermatology Service Research Director "Melanoma: Imaging, genetics and immunology" at IDIBAPS Consultant & Assistant Professor Melanoma Unit, Dermatology Department Hospital Clinic, University of Barcelona Barcelona Spain Dr. Susana Puig[/caption] MedicalResearch.com Interview with: Susana Puig MD PhD Chief Dermatology Service Research Director "Melanoma: Imaging, genetics and immunology" at IDIBAPS Consultant & Assistant Professor Melanoma Unit, Dermatology Department Hospital Clinic, University of Barcelona Barcelona Spain  Medical Research: What is the background for this study? What are the main findings? Dr. Puig: CDKN2A is the main high-penetrance melanoma susceptibility gene. A rare functional variant in MITF, p.E318K (rs149617956), has been identified as a moderate risk allele in melanoma susceptibility and also predisposes to renal cell carcinoma. In this study MITF p.E318K was associated with an increased melanoma risk (OR=3.3, p<0.01), especially in patients with multiple primary melanoma (OR=4.5, p<0.01) and high nevi count (>200 nevi) (OR=8.4, p<0.01). Interestingly, two fast growing melanomas were detected among two MITF p.E318K carriers during dermatologic digital follow-up. Furthermore, we have detected a similar prevalence of MITF p.E318K in CDKN2A wild-type and mutated individuals.
Author Interviews, Melanoma, Pharmacology / 07.12.2015

MedicalResearch.com Interview with: Jeff Legos Senior Vice President Global Program Head Novartis Oncology Medical Research: What is the background for this study? What are the main findings? Response: Melanoma is the most serious form of skin cancer, and in recent years, research has discovered that melanoma is a diverse disease. In metastatic melanoma, approximately half of all patients have a mutation in the BRAF gene, and genetic testing can identify whether BRAF mutations are present in a tumor. Identifying a mutation can help doctors determine the appropriate treatment to treat BRAF-positive melanoma. Since January 2014, the combination of Tafinlar + Mekinist has been approved for use in the US in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma as detected by an FDA-approved test. The combination was initially approved based on Phase II data through the FDA’s Accelerated Approval program and reviewed under a priority review designation. The approval was contingent on the results of the Phase III COMBI-d study, which was designed to evaluate the clinical benefit of the combination in patients with unresectable or metastatic melanoma with a BRAF V600E/K mutation. The regular approval is based on survival data from two Phase III studies: COMBI-d and COMBI-v. These studies showed that Tafinlar + Mekinist demonstrated statistically significant overall survival (OS) and progression-free survival (PFS) compared with dabrafenib or vemurafenib, in patients with BRAF V600E/K mutation-positive unresectable or metastatic melanoma. In addition, combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the EU, Australia, Canada and additional countries.
Author Interviews, Cancer Research, Melanoma / 30.11.2015

MedicalResearch.com Interview with: Ze'ev Ronai, PhD Sanford Burnham Prebys Medical Discovery Institute Medical Research: What is the background for this study? What are the main findings? Dr. Ronai: We have been studying the parent compound for some time and have performed a series of complementing assays to identify mechanisms underlying the activity of this compound as well as to determine the primary target for this small molecule. These included gene expression changes, mutations in tumor cells that became resistant to the drug and also direct association with cellular proteins.

The main finding is that sbi-756 is a potent compound which can be used to overcome couple of the utmost clinical unmet needs today, namely, resistance of melanoma to currently used inhibitors in the clinic (i.e. vemurafenieb) and use in tumors that are braf negative (to which we lack specific therapies today)

The use of drugs that can tamper with the translation initiation complex to the degree sufficient to affect tumors but not normal cells, as reflected in the lack of toxicity seen with sbi-756 offers important advance in our quest for novel therapeutic modalities that address unmet clinical needs.
Author Interviews, Dermatology, Melanoma, NEJM, UCSF / 13.11.2015

[caption id="attachment_19293" align="alignleft" width="105"]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[/caption] 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.
Author Interviews, Melanoma, OBGYNE / 06.11.2015

[caption id="attachment_19139" align="alignleft" width="128"]Pedram Gerami, MD Department of Dermatology Northwestern University Chicago, IL Dr. Gerami[/caption] 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.
Author Interviews, Dermatology, Melanoma, Primary Care / 24.10.2015

[caption id="attachment_18697" align="alignleft" width="112"]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[/caption] 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.
Author Interviews, JAMA, Melanoma, Technology / 15.10.2015

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.
Author Interviews, Lung Cancer, Melanoma / 12.10.2015

[caption id="attachment_18318" align="alignleft" width="207"]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[/caption] 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.    
Author Interviews, JAMA, Melanoma, Ophthalmology / 01.10.2015

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.
Author Interviews, Melanoma / 01.10.2015

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). 
Author Interviews, Cancer Research, CT Scanning, JAMA, Melanoma, Radiology, University of Michigan / 25.09.2015

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.
Author Interviews, Biomarkers, Mayo Clinic, Melanoma / 17.09.2015

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 S. Dronca, 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.
Author Interviews, Chemotherapy, Genetic Research, Melanoma / 04.09.2015

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.
Author Interviews, Dermatology, JAMA, Melanoma / 03.09.2015

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.
Author Interviews, Dermatology, Melanoma / 28.07.2015

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.
Author Interviews, Lancet, Melanoma, Radiation Therapy / 23.07.2015

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.
Author Interviews, Biomarkers, Melanoma / 09.07.2015

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.
Author Interviews, Biomarkers, Melanoma / 25.06.2015

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.
Author Interviews, Erectile Dysfunction, JAMA, Melanoma, NYU/NYMC, Pharmacology / 24.06.2015

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 (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.  
Author Interviews, Immunotherapy, Melanoma, Nature / 19.06.2015

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.
Author Interviews, Immunotherapy, Melanoma / 02.06.2015

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. 
ASCO, Author Interviews, Journal Clinical Oncology, Melanoma / 02.06.2015

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.
Author Interviews, Dermatology, Genetic Research, Melanoma / 23.04.2015

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.
AACR, Author Interviews, Genetic Research, Melanoma, NYU/NYMC, Personalized Medicine, Wistar / 21.04.2015

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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