Melanoma of the foot

NewsBot · Jan 6, 2015

Press Release:
Melanoma: Scientists find new link between pigment production and mitochondrial function
New research in the FASEB Journal shows that when melanoma cells produce more melanin pigment, their mitochondria become revved up to produce more damaging reactive oxygen species

A new research report published in the January 2015 issue of the FASEB Journal helps explain what goes wrong to when someone gets skin cancer and the relationship between changing skin pigment and the cancer itself. In particular, this research shows that there is a direct link between changes in mitochondrial function and melanin production in cancerous skin cells. This link may also serve as a viable drug target for the disease.

"This study reports a novel correlation between a protein involved in the bioenergy process within the human skin (i.e., Complex II) and skin pigmentation," said Mark Birch-Machin, Ph.D., a researcher involved in the work from the Department of Dermatological Sciences at the Institute of Cellular Medicine at The Medical School of Newcastle University in Newcastle Upon Tyne, United Kingdom. "This leads to interesting possibilities of Complex II playing a central role in coupling stress sensing and cellular adaptation via ROS signalling and as this study was performed in skin cancer cells may help in the development of anti-cancer drugs."

Scientists examined three types of melanoma skin cancer cell lines that displayed low, medium, and high pigment levels as standard and analyzed their levels of Reactive Oxygen Species (ROS) or oxidative stress and mitochondrial Complex II (a component of the mitochondrial energy generating protein chain) function in a resting state. They found that the darker the cells, the higher the Complex II function. They also found that the rate of ROS generation by Complex II in darker cells was higher too. The researchers then triggered the light and medium cells to produce more melanin (a process called hyperpigmentation) by providing them with more L-tyrosine, a building block for melanin production. Both cell types gradually exhibited higher pigment levels, while simultaneously showing increased Complex II function. The amount of melanin present with gradual hyperpigmentation of medium pigment level cells was measured and compared to the amount of ROS produced the mitochondria. Study results demonstrated that immediately after treatment, the ROS level increased approximately 300%, but gradually reduced to a basal level with further hyperpigmentation.

"Melanoma may be preventable by using sunscreen," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal, "but too many people still die of the disease. This research shows a direct relationship between pigment production (as when our skin tans) and the production of Reactive Oxygen Species by mitochondria (and/or the sun). It's not a very attractive relationship since it leads to cancer progression."
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NewsBot · Feb 10, 2015

Melanoma of the lower extremities: foot site is an independent risk factor for clinical outcome
Martina Sanlorenzo et al
International Journal of Dermatology; Early View

Background
Despite the better prognosis of melanomas localized on lower extremities, some studies have suggested that melanomas on the foot are related to a poorer survival and should be considered separately.

Objective
To review our case series of cutaneous melanomas on the lower extremities and to analyze the clinicopathological association, time course, types of progression, and survival differences.

Methods
We included 1671 patients (stage 0–II) with a cutaneous melanoma on the lower extremities (subungual melanomas were excluded). Of these, 327 were localized on the foot. Multivariate analyses were performed to evaluate disease-specific survival and disease-free interval.

Results
Distribution of known prognostic factors and patterns of progression of foot and leg melanoma differ across genders. The foot site was confirmed as a negative independent prognostic factor on disease-specific survival and disease-free interval.

Conclusion
Foot melanoma could represent a particular subgroup, which could require specific management in the future.
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NewsBot · Feb 21, 2015

Acral melanoma of the hallux
S. GENTILESCHI, M. D’ETTORRE, D. TAMBASCO, R. BRACAGLIA, A. SANTORO
European Review for Medical and Pharmacological Sciences

OBJECTIVE: A case of misdiagnosed
acral melanoma of the hallux and its diagnostic
challenge are herein presented. Acral
melanoma is insidious and subtle. A methodic
approach to any suspicious lesions is mandatory.
A case of misdiagnosed acral melanoma of the
hallux is herein reported in a 66-year-old healthy
man. Suggestions concerning similar non-healing
lesions are herein presented.
MATERIALS AND METHODS: It was firstly
clinically diagnosed and treated as a micosis at
another centre. The absence of any amelioration
after three years pushed us to perform a
biopsy.
RESULTS: An acral melanoma was revealed,
treated by amputation.
CONCLUSIONS: In case of a non-healing ulcer
of the lower extremities, melanoma should
be taken into consideration. Even in absence of
any suggestive risk factors or clear signs of
melanoma, the lack of any improvement after
treatment should raise doubts about diagnosis.
In particular, biopsy is advisable as a first attempt
to guide the management.
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NewsBot · Mar 11, 2015

Closure of Melanoma Defects on the Sole of the Foot Using Glaborous Skin: The End of the Flap?
Maker AV, Iteld L.
Ann Surg Oncol. 2015 Mar 7

INTRODUCTION:
Plantar melanomas are a challenge to reconstruct after wide excision. Non-glaborous skin grafts have resulted in tissue loss, hyperkeratosis, marginal scarring, and poor functional outcomes, leading many to utilize various flaps for reconstruction that are technically demanding and associated with increased failure rates. Glaborous skin is better suited to withstand compressive and shear forces, and provides a more robust graft for plantar defects.
METHODS:
Data were collected prospectively. Wide excision to the plantar fascia and sentinel lymph node biopsies were performed as indicated. The defect was treated with negative pressure dressings until granulation tissue was flush with surrounding skin. Two 8/1000 inch grafts were harvested from the ipsilateral non-weight-bearing instep. The epidermis/papillary dermis was replaced on the donor site and the deeper glaborous dermal graft was secured to the defect. This technique is demonstrated in the multimedia file. Primary endpoints were graft take, complication rates, and functional outcomes.
RESULTS:
Consecutive plantar melanomas of the foot were prepared for glaborous grafting. Mean Breslow thickness was 3.9 mm (range 1.25-10; n = 5), and the average width of the defect was 6.2 cm. Mean follow-up was 304 days. The graft take was 100 %, and pre- and post-surgery results are displayed in the media file and Fig. 1. There were no recipient site complications, incidences of significant hypo- or hyperpigmentation, or hypertrophic scarring at either site. One patient experienced a donor site hematoma without delayed healing or hypertrophic scarring. There were no other donor or recipient site complications. Cosmesis was excellent, with minimal to no residual contour irregularity. Functional outcomes demonstrated a 100 % return to baseline activities without orthotics, including snowboarding and windsurfing.
CONCLUSION:
Glabrous dermal grafting of plantar defects after melanoma resection is extremely reliable, affords excellent cosmesis, has minimal to no donor site morbidity, and results in excellent functional outcomes. Flaps are now rarely performed for these patients at our institution. Fig. 1 Plantar melanoma defect before and after split-thickness glaborous skin grafting using the current technique.
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NewsBot · Apr 1, 2015

Acral lentiginous melanoma: A case and literature review
Kinna A Patel, DPM, and Anthony J Ferraro, DPM
The Foot and Ankle Online Journal 8 (1): 1 (full text)

Acral lentiginous melanoma (ALM) of the foot and ankle is an aggressive variant of melanoma. More prevalent in patients with darker skin, ALM is often misdiagnosed and inappropriately treated do to its frequent atypical presentation, poor clinical examination and low index of suspicion ultimately leading to a poor prognosis.
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NewsBot · Apr 2, 2015

Press Release:
Personalized Melanoma Vaccines Marshal Powerful Immune Response
Vaccines target unique mutations in each patient's tumor
Science Express, April 2, 2015

Newswise — Personalized melanoma vaccines can be used to marshal a powerful immune response against unique mutations in patients' tumors, according to early data in a first-in-people clinical trial at Washington University School of Medicine in St. Louis.
The tailor-made vaccines, given to three patients with advanced melanoma, appeared to increase the number and diversity of cancer-fighting T cells responding to the tumors. The finding is a boost to cancer immunotherapy, a treatment strategy that unleashes the immune system to seek out and destroy cancer.
The research is reported April 2 in Science Express, in a special issue devoted to cancer immunology and immunotherapy. [Editor's note: Science-AAAS will hold an embargoed telephone press conference about the paper on Thursday, April 2 at 11 am ET. For information, please contact scipak@aaas.org.]
In a new approach, the cancer vaccines were developed by first sequencing the genomes of patients' tumors and samples of the patients' healthy tissues to identify mutated proteins called neoantigens unique to the tumor cells. Then, using computer algorithms and laboratory tests, the researchers were able to predict and test which of those neoantigens would be most likely to provoke a potent immune response and would be useful to include in a vaccine.
The vaccines were given to melanoma patients who had had surgery to remove their tumors but whose cancer cells had spread to the lymph nodes, an indicator the deadly skin cancer is likely to recur. These clinical findings set the stage for a phase I vaccine trial, approved by the Food and Drug Administration as part of an investigational new drug application. The trial will enroll six patients.
Data on the immune response seen in the first three patients is reported in the paper. If additional testing in more patients indicates the vaccines are effective, they may one day be given to patients after surgery to stimulate the immune system to attack lingering cancer cells and prevent a recurrence.
"This proof-of-principle study shows that these custom-designed vaccines can elicit a very strong immune response," said senior author Gerald Linette, MD, PhD, a Washington University medical oncologist leading the clinical trial at Siteman Cancer Center and Barnes-Jewish Hospital. "The tumor antigens we inserted into the vaccines provoked a broad response among the immune system's killer T cells responsible for destroying tumors. Our results are preliminary, but we think the vaccines have therapeutic potential based on the breadth and remarkable diversity of the T-cell response."
It's too early to say whether the vaccines will be effective in the long term, the researchers cautioned. The study was designed to evaluate safety and immune response; however, none of the patients has experienced adverse side effects.
Earlier attempts at vaccines have focused on targeting normal proteins commonly expressed at high levels in particular cancers. Those same proteins also are found in healthy cells, making it difficult to stimulate a potent immune response.
The new approach investigated by the Washington University team merges cancer genomics with cancer immunotherapy.
"This is about as personalized as vaccines can get," said co-author Elaine Mardis, PhD, co-director of the McDonnell Genome Institute at Washington University, where the cancer genome sequencing, analysis and neoantigen prediction were performed. "The approach we describe is fundamentally different from conventional mutation discovery, which focuses on identifying mutated genes that drive cancer development. Instead, we're looking for a unique set of mutated proteins in a patient's tumor that would be most likely to be recognized by the immune system as foreign."
Melanomas are notorious for having high numbers of genetic mutations caused by exposure to ultraviolet light. Biopsy samples of melanomas typically carry 500 or more mutated genes. Using prediction algorithms, the researchers narrowed their search for vaccine candidates by identifying neoantigens that not only were expressed in a patient's tumor but also were likely to be seen by that patient's immune system as "non-self."
Biochemical validation of neoantigen peptide expression on the cancer cells' surfaces was performed in collaboration with William Hildebrand's group at the University of Oklahoma Health Sciences Center and provided critical assurance that the vaccine would elicit the most effective T cells to combat the melanoma.
"You can think of a neoantigen as a flag on each cancer cell," said first author Beatriz Carreno, PhD, associate professor of medicine. "Each patient's melanoma can have hundreds of different flags. As part of validating candidate vaccine neoantigens, we were able to identify the flags on the patients' cancer cells. Then we created customized vaccines to a select group of flags on each patient's tumor."
Carreno and her colleagues selected a set of seven unique neoantigens for each vaccine and used specialized immune cells called dendritic cells, derived from the patients, to carry those neoantigens to the immune system. Dendritic cells play an important role in waking up the immune system, reminding T cells to attack the cancer.
After the vaccine infusions, the patients' blood was drawn every week for about four months. By analyzing the blood samples, the researchers could see that each patient mounted an immune response to specific neoantigens in their vaccines. The vaccines also stimulated diverse clones of battle-ready T cells against neoantigens, suggesting this approach also could be used to activate a range of T cells and target them to mutations in other cancers with high mutation rates, such as lung cancer, bladder cancer and certain colorectal cancers.
"Our team has developed a new strategy for personalized cancer immunotherapy," Linette said. "Many researchers have hypothesized that it would be possible to use neoantigens to broadly activate the human immune system, but we didn't know that for sure until now. We still have much more work to do, but this is an important first step and opens the door to personalized immune-based cancer treatments."
###
The research was supported by the Barnes-Jewish Hospital Foundation, Siteman Cancer Frontier Fund, Our Mark on Melanoma Foundation, Come Out Swinging Foundation, Blackout Melanoma Foundation, the National Cancer Institute, grants R21 CA179695 and P30 CA91842, and the National Human Genome Research Institute, grant 5U54HG00307, at the National Institutes of Health (NIH).
Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J, Petti AA, Ly A, Lie W-R, Hildebrand WH, Mardis ER and Linette GP. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cell. Science Express, April 2, 2015.
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NewsBot · May 28, 2015

Press Release:
A sight for sore eyes: Visually training medical students to better identify melanomas
UAlberta researchers hope by improving training methods for health professionals, patients will enjoy better health outcomes

Each year, thousands of Canadians are given the news: they have skin cancer. It is the most common form of cancer in Canada and around the world, but if detected early, survival rates are extremely high. According to Liam Rourke, it doesn't happen nearly as often as it could.

"The difficulty is that people have a really hard time detecting skin cancer melanomas early," says Rourke, an associate professor in the Faculty of Medicine & Dentistry's Department of Medicine at the University of Alberta. "One of the reasons is that it's an exceptionally difficult task because the melanomas look exactly like freckles and moles and other common benign lesions that everybody has.

"The ability to detect these things early is pivotal and so we wanted to look at how people are trained to detect these things."

Rourke is the lead author of a new study in JAMA Dermatology that examines best practices in teaching medical students and health professionals how to detect, categorize and identify skin lesions. By conducting a meta-analysis other studies in the field, his team found that many traditional methods of teaching focus on what some would argue are the least important aspects of the job.

"The conventional sense of how this should be taught is by giving people factual knowledge about skin and its normal and abnormal development. We were surprised to see that there was very little effort to stress the visual part of this task. There was very little organized and systematic effort to train people's visual systems to discriminate between two things that look a lot alike," says Rourke.

The team of researchers concluded there's much room for improvement in how health professionals are trained. Based on the results of the study, Rourke's team is developing perceptual training modules they hope to test through further studies.

According to Rourke, an initial pilot study has already been undertaken that has shown promising early results. In it, a small group of undergraduate students with no medical knowledge, training or vocabulary were given iPads containing a module showing different types of skin lesions. Over the course of about two hours the students were presented with several examples of melanomas and non-melanomas. At first the examples were labeled as such, followed by the pictures again being shown without labelling. The students were then asked to identify the examples correctly. As the students progressed through the module, the examples became more varied and complex.

"We saw an enormous effect," says Rourke. "Within the two to three hours of training they reached a level of expertise that was close to the level of a dermatology resident."

He adds, "The training translates well to other groups because it doesn't rely on learning a lot of anatomy or physiology or biomedical knowledge about skin lesions. The task is simply to identify skin cancers and differentiate them from benign lesions."

Rourke's team hopes to expand the pilot study in coming months. With further research they are confident the training modules can become an important tool in helping train future physicians.
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NewsBot · May 30, 2015

MELANOMA OF THE HEEL A CASE SERIES OF A RARE MELANOMA SUBTYPE.
Wollina U, Tchernev G, Chokoeva AA, Lotti T
J Biol Regul Homeost Agents. 2015 Jan-Mar;29(1(S)):69-73

Melanoma of the heel is a rare subtype of the disease, which shows some variations of its incidence in different geographic areas as well as atypical clinical manifestations, resembling numerous other dermatologic conditions, which often leads to misdiagnosis at the early stages of the disease. We present a case series of four patients with malignant melanoma of the heel, with delay of diagnosis due to their atypical presentation, which is illustrated by tumor thickness, Clark level (VI and V), and tumor stage. All of the reported cases are from our own files and demonstrate the challenges with melanoma of the heel, with the aim to emphasize the necessity to biopsy all lesions with unknown significance to avoid the delay in diagnosis and prevent wrong subsequential treatments.
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NewsBot · May 30, 2015

HEEL MELANOMA: THE FINAL RESULT OF WRONG DIAGNOSTIC AND THERAPEUTIC APPROACH IN ANOTHER BULGARIAN PATIENT. FIRST DOCUMENTED CASE FROM THE BOARD OF THE ADCRSTR-ASSOCIATION FOR DERMATOHISTOPATHOLOGIC CONTROL, REEVALUATION AND SUBSEQUENT THERAPEUTIC RECOMME.
Chokoeva AA, Tchernev G, Gianfaldoni S, Patterson JW, Wollina U, Lotti T
J Biol Regul Homeost Agents. 2015 Jan-Mar;29(1(S)):111-115.

Difficulties with frequent misdiagnoses and incorrectly defined tumor thicknesses applied to the same histopathological preparation occurring among Bulgarian patients, has led to the creation of national and/or international associations or boards for control in problematic circumstances, particularly for patients with melanocytic and non melanocytic cutaneous tumors. Once again we report a problematic case of a patient with acral lentiginous melanomа, localized in the heel area of the right foot, in an otherwise healthy 69-year old woman. A pigmented lesion gradually developed in her heel area, where the patient had been previously treated several times with invasive therapeutic methods (cryosurgery, shave curettage) due to misdiagnosis as a verrucous lesion or as a viral wart in the absence of any prior histopathology report. Years later, the lesion progressed and changed in color, leading to surgical removal, followed by several histopathological evaluations that produced very different results on three separate occasions. The first result described the lesion as melanocytic nevus, and removed with tumor-free margins. The second report from the Department of Dermatology and Venereology, Military Academy in Sofia , Bulgaria, stated no data for Verrucous carcinoma. Only on the third assessment the correct diagnosis of malignant melanoma was given. A relapse of the melanoma occurred as only at the time of the last histopathologic evaluation, (following surgical resection of the lesion with adequate margins, performed in the Onkoderma- Policlinic for Dermatology, Venereology and Dermatologic Surgery, Sofia, Bulgaria) were criteria followed for appropriate pathological evaluation consistent with the recommendations of the AJCC for reporting of melanomas. Tumor thickness at that time was 1.31 mm. Removal of the draining lymph node, followed by inguinal lymphadenectomy was performed in the National Oncological Hospital in accordance with the recommendations of the AJCC. Unfortunately disease progression was observed with loco-regional lymph node involvement. Systemic therapy with interferon was planned. The incorrect therapeutic approach in this patient, as well as the several subsequent misdiagnoses that were made in the leading pathology departments of the capital, undoubtedly helped lead to the creation of a national board with international participation in order to minimize errors in the diagnostic and therapeutic approach in dermatology, surgery and histopathology. The already-created Association for Dermatohistopathologic Control, Reevaluation and Subsequent Therapeutic Recommendations-ADCRSTR, aims to take control of histopathological preparations with wrong diagnoses and subsequent therapy in patients with cutaneous tumors, as well as their documentation. Another task of the Institution is to focus on the preservation and protection of the rights and interests of affected patients.
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NewsBot · Jul 11, 2015

Melanoma manifesting as a verrucous lesion in the interdigital toe space.
Scarfì F, Galeone M, Bassi A, Arunachalam M, Massi D, Difonzo EM.
Int J Dermatol. 2014 Sep;53(9):1125-6. doi: 10.1111/ijd.12638
(no abstract)

NewsBot · Aug 18, 2015

CDKN2B loss promotes progression from benign melanocytic nevus to melanoma
Andrew S. McNeal, Kevin Liu, Vihang Nakhate, Christopher A. Natale, Elizabeth K. Duperret, Brian C. Capell, Tzvete Dentchev, Shelley L. Berger, Meenhard Herlyn, John T. Seykora, and Todd W. Ridky
Cancer Discovery CD-15-0196; Published OnlineFirst July 16, 2015

Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here we show that CDKN2B is highly upregulated in benign melanocytic nevi, contributes to maintaining nevus melanocytes in a growth-arrested premalignant state, and is commonly lost in melanoma. Using primary melanocytes isolated directly from freshly excised human nevi naturally expressing the common BRAF(V600E) activating mutation, nevi progressing to melanoma, and normal melanocytes engineered to inducibly express BRAF(V600E), we show that BRAF activation results in reversible, TGFβ-dependent, p15 induction that halts proliferation. Further, we engineer human skin grafts containing nevus-derived melanocytes to establish a new, architecturally faithful, in vivo melanoma model, and demonstrate that p15 loss promotes the transition from benign nevus to melanoma.
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NewsBot · Sep 28, 2015

Press Release:
Drug combination improves progression-free survival in melanoma patients regardless of genetic status, age and spread of disease

Patients with advanced melanoma skin cancer survive for longer without their disease progressing if they have been treated with a combination of two drugs, nivolumab and ipilimumab, than with either of these drugs alone. New results show that these patients also do better regardless of their age, stage of disease and whether or not they have a cancer-driving mutation in the BRAF gene.

Dr James Larkin, a Consultant Medical Oncologist at The Royal Marsden, London, UK, told the 2015 European Cancer Congress [1], that results from the CheckMate 067 phase III clinical trial had already shown that the combination of the two drugs, which target two different pathways that regulate the immune system, improved the progression-free survival in patients with melanoma who had not received any other treatment. However, until now it was not known whether this remained the case when the results were analysed according to genetic status, age and how advanced was their disease.

Nivolumab is an inhibitor of the programmed cell death protein 1 (known as PD-1), which functions as an immune checkpoint, playing an important role in the immune system. Ipilimumab inhibits the CTLA-4 checkpoint, which also plays a role in the immune system [2].

Dr Larkin said: “Results from our large analysis of pre-defined sub-groups of patients with advanced melanoma provide evidence that suggests the combination of the two drugs consistently improves progression-free survival across a range of sub-groups, including patients with poor prognostic factors, when compared with either nivolumab or ipilimumab alone.”

Out of a total of 945 patients in 20 different countries [3] who were randomised to receive the combination therapy or one of the drugs alone, those on the combination therapy survived for an average of 11.5 months without their disease progressing, compared, to 6.9 months for patients on nivolumab alone and 2.9 months for those on ipilimumab alone.

When the researchers looked at progression-free survival times among patients with and without the V600 type of mutation of the BRAF gene, the average for patients taking both drugs without the mutation was 11.2 months, and it was 11.7 months for those with the mutation. This compared with 7.9 months and 5.6 months respectively for patients on nivolumab alone and 2.8 months and four months respectively for those on ipilimumab alone.

“These results provide evidence that the efficacy of the combination therapy is similar whether or not the tumours harbour BRAF mutations. This has important practical implications for clinicians treating patients with melanoma,” said Dr Larkin.

The same pattern was seen when the researchers looked at groups of patients according to the extent of the spread of the disease to other parts of the body (metastases), and whether the patients were aged less that 65, between 65 and 75, and 75 and older (older patients can often be less able to cope with the side effects of treatments).

Among patients with metastatic melanomas with the worst prognosis (stage M1c), the average progression-free survival times were 8.5 months for the combination treatment, 5.4 months for nivolumab alone and 2.8 months for ipilimumab alone.

Patients younger than 65 years, had average progression-free survival times of 11.7 months (combination), 5.5 months (nivolumab) and 2.8 months (ipilimumab), while the 262 patients aged between 65 and 75 had average progression-free survival times of 11.1 months, 12.7 months and 2.9 months respectively. For those aged 75 and over (118 patients), the average progression-free survival time for those on the combination treatment could not be calculated as the patients’ disease had not progressed yet; it was 5.3 months for those on nivolumab alone and four months for those on ipilimumab alone.

Dr Larkin said: “The sub-groups included in these analyses are those of particular interest to melanoma clinicians, such as patients aged 75 and over. We believe that the data will give confidence to patients and their healthcare providers that the combination of nivolumab and ipilimumab will be effective regardless of advanced age, the presence of a BRAF mutation, or poor prognostic factors.”

Overall, significant (grade 3-4) side effects related to treatment occurred in 55%, 16% and 27% of patients in the combination, nivolumab and ipilimumab groups respectively. A similar pattern was seen in the sub-groups of patients; for instance, in patients aged 75 and over, significant side effects occurred in 48%, 21% and 36% respectively, and in patients with stage M1c disease, they occurred in 54%, 14% and 25% respectively.

The most common side effects were those that related to the way the drugs affect the functioning of the immune system, such as diarrhoea, colitis (inflammation of the lining of the colon) and raised levels of alanine aminotransferase (an enzyme, raised levels of which can indicate liver damage).

The CheckMate 067 trial started in May 2013, recruitment of patients ceased in 2014, and the next significant milestone will be when the researchers report results on overall survival.

Professor Peter Naredi, the ECCO scientific co-chair of the Congress, who was not involved in the research, commented: “Although the CheckMate 067 study has already reported that a combination of two checkpoint inhibitors, nivolumab and ipilimumab, is superior to either drug alone, the results presented here in Vienna have important clinical implications. These drugs come with a substantial frequency of adverse effects for the patients and it is important to spare patients who will not benefit from the treatment. What Dr Larkin and co-authors show is that bad prognostic indicators, such as BRAF mutations, metastatic pattern or increased age, do not negatively influence progression-free survival. Therefore, more patients can be considered for treatment, and tolerance to the treatment becomes a more important factor.”

[1] The European Cancer Congress is the 18th congress of the European CanCer Organisation (ECCO) and the 40th congress of the European Society for Medical Oncology (ESMO).

[2] CTLA-4 stands for cytotoxic T-lymphocyte antigen 4.

[3] The study was conducted at 137 centres in 20 countries in Australia, Europe, Israel, New Zealand, and North America. The authors of the current study represent nine of these countries: Australia, Canada, Europe (Belgium, France, Germany, Italy, and the UK), Israel, and the United States.

[4] Bristol-Myers Squibb funded the CheckMate 067 trial and these analyses.
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NewsBot · Oct 29, 2015

Ramifications of poor medical education and screening in minority populations: an extensive acral melanoma.
Jackson CR, Fernelius C, Arora N.
BMJ Case Rep. 2015 Jan 30;2015. pii: bcr2014207139. doi: 10.1136/bcr-2014-207139.

After 2 years of holistic self-treatment on his home island, an elderly Samoan man presented with a painful, hyperpigmented mass on his left heel. Physical examination revealed a black, friable tumour with necrotic tissue and superficial ulcerations with no other associated symptoms. Further investigation revealed that the mass was invasive. The tumour was treated with resection and a final diagnosis of acral lentiginous melanoma, stage T4b was made. Poor access to care and screening services are large barriers to care for minorities and patients with low socioeconomic status. Once access is obtained, however, patient compliance is not guaranteed. Healthcare practices often clash with societal beliefs, and so patient education regarding their disease and its possible progression, along with treatment options, is important. Furthermore, a lack of ethnically diverse physicians contributes to low cultural competency during interaction with patients from minorities, resulting in poor communication and low patient satisfaction.
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NewsBot · Nov 12, 2015

Press Release:
Melanoma?s Genetic Trajectories Are Charted in New Study
Study Confirms ?Intermediate? Disease Stage Between Benign Moles and Malignancy

An international team of scientists led by UC San Francisco researchers has mapped out the genetic trajectories taken by melanoma as it evolves from early skin lesions, known as precursors, to malignant skin cancer, which can be lethal when it invades other tissues in the body.

By tracing the genetic changes that take place over time in the development of the disease, the research reaffirms the role of sun exposure in the emergence of precursor lesions, such as the common moles known as nevi, but also suggests that continued ultraviolet radiation (UV) damage to benign precursor lesions may push them on a path toward malignancy.

More significantly, the study provides new evidence that genetic and cellular characteristics of skin lesions that are neither clearly benign moles nor malignant melanoma place them in a distinctive intermediate category, the existence of which has been hotly debated among dermatologists and pathologists.

?What happens to patients now is totally unstandardized,? said Boris Bastian, MD, PhD, the Gerson and Barbara Bass Bakar Distinguished Professor of Cancer Research at the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC), and senior author of the new study. ?Some doctors consider these ?intermediate? types of lesions to be entirely benign, or shave off only part of the lesion and leave some behind. But others treat it as an early melanoma. This work should open the door to understanding how risky these lesions are and when they should be completely removed.?

When a melanoma is diagnosed, its precursor lesion is sometimes still present on the skin adjacent to the cancer. As reported in the November 12 issue of The New England Journal of Medicine, the research team took advantage of this unique feature of the disease to identify the genetic differences between precursors and melanoma.

Led by A. Hunter Shain, PhD, a postdoctoral fellow in the Bastian laboratory and HDFCCC member, the scientists gathered skin samples containing both precursor lesions and melanoma that had been obtained from 37 patients, and they then sequenced 293 cancer-causing genes in 150 distinct areas micro-dissected from those samples.

In a clever study design, to determine how genetic analysis would align with standard techniques used in melanoma diagnosis, each of these 150 areas was independently examined through microscopes by eight pathologists specializing in skin disease. The pathologists assigned each area to four main categories ranging from ?benign? to ?invasive melanoma? based on their judgments of how far the cells in each area had progressed toward malignancy.

Intriguingly, in all of the 13 areas that were unanimously assessed as benign by the pathologists, the researchers found only a single pathogenic mutation, one called BRAF V600E, which has long been associated with melanoma. Based on these data, this single alteration in the BRAF gene appears to be sufficient for the formation of a nevus, the term for a common mole that can sometimes progress to melanoma.

Likewise, there was quite good agreement among the pathologists regarding invasive melanomas, which on genetic analysis were found to contain a large number of point mutations?alterations of a single genetic ?letter??affecting many genes, as well as a significant number of copy-number alterations, in which sizeable segments of the genome containing genes are either deleted or duplicated.

As expected, most disagreement among the pathologists was seen in their assessments of non-invasive melanomas (known as ?in situ? melanomas) and so-called intermediate lesions, which were sub-classified as ?probably benign? or ?probably malignant.?

But the genetics of these lesions presented a clearer picture: in most cases, BRAF mutations, most often the V600E mutation seen in the benign lesions, were accompanied by additional pathogenic mutations, but not the full set observed in invasive melanoma. In particular, many BRAF mutations in the intermediate lesions were accompanied by mutations in a gene known as TERT. The TERT gene helps to set the limits of cell division, and the gene has been implicated in a number of types of cancer.

Moreover, while the researchers found more point mutations in intermediate lesions than in benign moles, there were far fewer point mutations in intermediate lesions than in invasive melanomas, and copy-number alterations were rare.

?There?s good agreement between the pathologists? assessments at the extremes of the spectrum, but less so with intermediate lesions,? said Shain. ?On a genetic level, however, this work clearly shows that there are intermediate lesions. These things really exist?it?s not a binary situation.?

Mutations caused by UV damage have a distinctive genetic ?signature,? and in another significant finding, the researchers observed this signature in cancer-causing genes at every stage of melanoma progression.

?A lot of melanomas have been sequenced at this point, and while it?s clear they carry UV-induced mutations, no one knew when they occurred,? Bastian said. ?This study shows that they occur in benign moles, in the melanoma that arises from these moles, and in intermediate lesions. UV both initiates and causes the progression of melanoma, so exposing even benign moles to the sun is dangerous.?

According to Shain, the new study?s findings on UV-induced mutations provides additional grounding to well-documented aspects of melanoma epidemiology.

?Kids who are in the sunlight more tend to have a greater number of benign moles, and if they continue to stay in the sunlight, those moles are more likely to progress to melanoma,? Shain said. ?This study shows that UV-radiation-induced mutations start to accumulate before a benign mole forms, and that UV-radiation-induced mutations continue to drive the progression of some benign and intermediate lesions towards melanoma. So exposing even benign moles to UV is not without risk.?

In addition to Bastian and Shain, UCSF researchers participating in the study included Iwei Yeh, MD, PhD, assistant professor of dermatology; Eric Talevich, PhD, programmer and analyst in the department of pathology; Alexander Gagnon, BA, a former research assistant in the Department of Pathology and Department of Dermatology, now at Genia Technologies in Oakland, Calif.; Jeffrey North, MD, assistant professor of dermatology and pathology; Laura Pincus, MD, assistant professor of dermatology and pathology; and Beth Ruben, MD, professor of clinical dermatology and pathology. They were joined by colleagues from the Cleveland Clinic, in Ohio; Orlando Health, in Florida; University Hospital of Zurich, in Switzerland; Dorset County Hospital, in Dorchester, England; and St. John?s Institute of Dermatology, in London, England.

The work was supported by grants from the National Institutes of Health and the Gerson and Barbara Bass Bakar Distinguished Professorship in Cancer Research.
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NewsBot · Dec 5, 2015

Melanoma of the Right Foot Simulating Kaposi's Disease.
Kouassi KA et al
Case Rep Dermatol Med. 2015;2015:750491

Melanoma is a malignant tumor rarely being described in sub-Saharan Africa. We reported an unusual and atypical clinical presentation. It was a 59-year-old patient who was hospitalized for a monomelic black tumor evolving for 10 years. Histopathological examination confirmed the melanocytic origin of this tumor. Paraclinical assessment did not find any visceral metastasis. A partial resection of the tumor was performed. The patient left the hospital against medical consent due to lack of technical facilities. The delay in the consultation and the lack of knowledge of melanoma by doctors and patients might contribute to the severity and the difficulties of its management.
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NewsBot · Jan 7, 2016

PUBLIC RELEASE: 7-JAN-2016
Blocking melanoma's escape: Avatars break theraping resistance in relapsed cancers
Scientists at The Wistar Institute are using revolutionary mouse 'avatar' models to discover effective combination treatments that may prolong responses and survival rates

PHILADELPHIA--(Jan. 7, 2016) -- Melanoma patients who receive treatment with targeted therapies experience an initial response that feels like a cure, but that early excitement is quickly dampened when patients relapse as their cancers find alternative pathways in our cells to grow and spread. With melanoma so good at escaping targeted treatments, there's a dire need to halt these cancers in their tracks to prolong good responses and promote longer, healthier lives.

Now, by utilizing a revolutionary method that allows mice to serve as "avatars" for patients, scientists at The Wistar Institute have shown that a previously ineffective targeted drug for melanoma may actually be quite potent in halting the progression of disease in certain patients.

The findings were published by the journal Clinical Cancer Research.

Personalized medicine holds enormous promise for melanoma patients. Melanoma accounts for only about five percent of all skin cancer cases, yet the disease is responsible for about 75 percent of all skin cancer deaths. Since specific mutations are responsible for melanoma growth and proliferation, drugs that target mutated skin cancer cells are an attractive treatment option. For example, the gene BRAF is mutated in about half of all melanomas, leading to aberrant activation of an important growth pathway. Drugs that inhibit activated BRAF can extend the lives of patients.

However, almost every patient who receives drugs eventually relapses and no longer responds to initial treatments. That's because the melanoma cells become aware of the blockade and find an alternative survival mechanism. Researchers are now studying these melanoma "escape routes" in the hope of cornering cancerous cells with combination treatments that don't allow them to survive.

"There are about fifteen routes of escape that we've identified in melanoma patients, and it is never easy to predict which one will be used in any given patient," said Meenhard Herlyn, D.V.M., D.Sc., director of the Melanoma Research Center and Caspar Wistar Professor in Melanoma Research at The Wistar Institute, and lead author of this study. "These melanoma cells will do anything to get reactivated."

To identify escape routes and test therapeutic treatments that block the spread of the disease, researchers at Wistar are using a revolutionary method called patient-derived xenograft (PDX) mouse models. Researchers implant tumor samples from patients into mice, thereby creating avatars for individual patients. One tumor can be studied in a pool of mouse avatars. This allows researchers to study different drugs and combinations of drugs to see how one type of tumor will respond.

In this latest study, the team at Wistar used PDX models to test tumors from patients who had received a BRAF inhibitor and then relapsed after treatment. In addition, observing mutations in genes such as NRAS and MAP2K1 - which are known escape route genes for previously treated BRAF-mutated melanomas - the scientists also observed amplification of MET, which suggested a possible new mechanism of resistance.

Wistar's team used this information to test a combination of targeted therapies as a means of halting disease progression. A MET inhibitor called capmatinib, currently in clinical trials, showed significant tumor regression when used by itself to treat melanoma, but the results were only temporary, meaning that an amplification of MET was not the sole driver of tumor growth. However, when capmatinib was given in combination with encorafenib (a BRAF inhibitor) and binimetinib (a MEK inhibitor hitting the BRAF pathway), the researchers observed complete and sustained tumor regression in all animals who received this combination.

"Historically, MET inhibitors have not shown much activity in melanoma patients," said Clemens Krepler, M.D., research assistant professor in the Herlyn Lab at The Wistar Institute and first author of the study. "While our findings need to be validated in more robust trials, this study provides evidence than MET inhibitors given either after or at the same time as BRAF inhibitors appear to successfully halt the progression of the disease and may considerably lengthen response and overall survival in melanoma patients."
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NewsBot · Jan 16, 2016

The Prognosis of Nail Apparatus Melanoma: 20 Years of Experience from a Single Institute.
Dika E et al
Dermatology. 2016 Jan 16

INTRODUCTION AND OBJECTIVES:
Nail apparatus melanoma (NAM) is an uncommon tumor, especially in Caucasians. The prognosis of patients affected by NAM was analyzed and correlated with the histopathological criteria and the surgical management of the tumors.
MATERIALS AND METHODS:
We collected data regarding NAM referred to the Skin Cancer Unit of the Dermatology Department of the University of Bologna, from 1992 to January 2012.
RESULTS:
Out of 1,327 melanoma cases diagnosed between 1992 and 2012, 42 patients were affected by NAM (2.93%). All the patients were Caucasian. Two deceased patients with insufficient medical records and 1 woman with a personal history of breast cancer were excluded. Thirty-nine cases entered this study: 24 were women (67%) and 15 men (33%). The mean age at diagnosis of NAM was 57.3 years (range 29-88 years). Statistical analyses showed that prognosis was significantly correlated with the Breslow thickness (≥/<2 mm; p = 0.02), regression (p < 0.0001) and ulceration (p = 0.04). Regarding surgical management, Kaplan-Meier's test pointed out that performing functional surgery compared to disarticulation did not correlate with a better prognosis of patients (p = 0.08).
CONCLUSIONS:
In our experience, the surgical management (disarticulation with respect to functional surgical excision) did not influence the prognosis of NAM patients. The latter was affected by the histopathological characteristics (Breslow thickness, regression and mitoses) and location (fingers vs. foot).
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NewsBot · Feb 6, 2016

Characteristics and Treatment of Cutaneous Melanoma of the Foot.
Nam KW et al
Arch Plast Surg. 2016 Jan;43(1):59-65.

BACKGROUND:
In East Asia, the foot is the most common site of cutaneous melanoma. The purpose of this study was to investigate the differences between cutaneous melanoma of the foot and melanomas of other sites.
METHODS:
We studied 52 patients who underwent surgical treatment for cutaneous melanoma of the foot from September 2000 to January 2015. Through a retrospective review of their medical records, we collected data relating to their sex, age, histopathological subtype, Clark level, tumor thickness, lymph node involvement, stage, and survival rate, and we compared these parameters to those of 61 patients treated for melanoma of other sites. Moreover, we analyzed the surgical procedures, complications, and mortality rates associated with cutaneous melanoma on various parts of the foot.
RESULTS:
Melanoma of the foot differed from other melanomas only in the histopathological subtype. Other clinical features, including survival rate, did not differ significantly between the two groups heel was the most common site of melanoma of the foot (22 cases, 42.3%). The method of reconstruction varied depending on the region involved.
CONCLUSIONS:
A comparison of melanoma of the foot to other melanomas showed that melanoma of the foot was associated with a significantly different distribution of histological subtypes. Consistent with previous findings, we found that the acral lentiginous subtype was the most common among melanomas of the foot. Furthermore, in contrast with previous studies, we did not find a worse prognosis or lower survival rate for melanoma of the foot in comparison with other melanomas.
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NewsBot · Feb 19, 2016

Tumor-to-bone distance of invasive subungual melanoma: an analysis of 30 cases.
Nakamura Y1, Fujisawa Y, Teramoto Y, Sato S, Yamada K, Sekine K, Fujimoto M, Otsuka F, Yamamoto A.
J Dermatol. 2014 Oct;41(10):872-7

Subungual melanoma (SUM) is rare and represents approximately 2-3% and 20% of all cutaneous melanomas in Caucasians and Asians, respectively. Amputation has usually been performed for invasive SUM; however, not all invasive SUMs invade or attach to the distal phalanx. To investigate the possibility of non-amputative surgery for patients with invasive SUM, the distances between the deepest base of the melanoma cells and the bony surface in the surgical specimens of invasive SUM were measured. Thirty surgical specimens of invasive SUM were retrospectively reviewed. The contents of the specimens were as follows: 14 first toes, 10 thumbs, three second fingers, two third fingers, and one fifth finger. Four specimens showed bone invasion, and the tumor was attached to the bone in four specimens. The tumor-to-bone distance exceeded 0.9 mm in all the specimens with thicknesses <4 mm. In the non-ulcerated SUMs (nine specimens), only one SUM specimen showed bone attachment. There was a higher likelihood of bone attachment or invasion when tumor thickness (TT) exceeded 4 mm (Pearson chi-square test, P = 0.009; Fisher exact test, P = 0.004; student t test, 0.033). Univariate and multivariate analysis also revealed that thick TT had a statistically significant affect (odds ratio 1.807 and 1.865, 95% CI 1.11-3.01 and 1.11-3.13, P = 0.023 and 0.018). Non-amputative surgery may be possible for SUM tumors that are of intermediate-thickness. However, there has been little evidence demonstrating survival with non-amputative surgery for invasive SUM. A large, randomized, prospective clinical study is required to address this issue.
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NewsBot · Mar 1, 2016

PUBLIC RELEASE: 1-MAR-2016
New biomarker identifies uveal melanoma patients at high risk for metastasis

MIAMI, March 1, 2016-- A study by J. William Harbour, M.D., associate director for Basic Research and leader of the Eye Cancer Site Disease Group at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, and colleagues published today in Clinical Cancer Research details the discovery of a biomarker that puts patients at a higher risk for metastasis of uveal melanoma. Among uveal melanomas categorized as class 1, those with high levels of the biomarker PRAME mRNA were more likely to metastasize than those with low levels of PRAME mRNA, indicating that patients with this biomarker be monitored more closely for metastatic disease.

The estimated five-year rate of metastasis was 0 percent for PRAME mRNA-low class 1 uveal melanomas and 38 percent for PRAME mRNA-high class 1 uveal melanomas. This research builds upon Harbour's identification of class 1 and 2 uveal melanomas in 2004.

There are about 2,000 to 3,000 cases of uveal melanoma diagnosed each year in the United States, according to Harbour, who is also a professor and vice chairman for Translational Research, the Mark J. Daily Endowed Chair, and director of the Ocular Oncology Service at Bascom Palmer Eye Institute, part of UHealth - the University of Miami Health System. He explained that uveal melanomas are categorized into class 1 and class 2 tumors by gene expression profiling and that class 1 tumors have a much lower chance of metastasizing than class 2 tumors.

"However, about 10 percent of patients with class 1 uveal melanoma do develop metastasis," said Harbour. "The main purpose of this study was to identify a clinically useful biomarker for this subgroup of class 1 uveal melanomas, which in turn might help in the development of precision medicines for melanoma patients.

"We were surprised to find that one biomarker alone--PRAME--was sufficient to identify the subgroup of class 1 tumors with increased metastatic risk," continued Harbour. "These findings could have immediate clinical impact. The data imply that patients with class 1 uveal melanomas with increased PRAME expression should be managed differently than patients with class 1 uveal melanomas without PRAME expression. They should be monitored more closely for metastatic disease and they should be considered for clinical trials of adjuvant therapy."

Harbour and colleagues performed genome-wide analysis of mRNA isolated from five class 1 uveal melanomas that metastasized and eight class 1 tumors that did not metastasize. The most highly overexpressed mRNA in the tumors that metastasized was PRAME. Further analysis of PRAME mRNA levels showed that seven of seven class 1 tumors that metastasized had high levels of PRAME mRNA and that 16 of 19 class 1 tumors that did not metastasize had minimal levels of PRAME mRNA.

Among 64 class 1 uveal melanoma samples, 39 (61 percent) had low levels of PRAME mRNA (PRAME negative) and 25 (39 percent) had high levels of PRAME mRNA (PRAME positive). None of the patients with PRAME-negative tumors developed metastasis while seven of the patients with PRAME-positive tumors did.

To validate the association between high levels of PRAME mRNA and metastasis for class 1 uveal melanomas, the researchers analyzed two additional datasets. The first was a combination of two independently published datasets and the second was a dataset from Leiden University in the Netherlands. In both these datasets, PRAME-positive tumors had a significantly increased risk for metastasis compared with PRAME-negative tumors.

Harbour noted that because this is a retrospective study, meaning that the researchers identified PRAME by looking back at patients who had been treated in the past, they are planning a prospective, multicenter study to validate the findings. He explained that the class 1/class 2 gene expression profile test remains the only prognostic assay for uveal melanoma that has ever been prospectively validated in a multicenter study and that they will hold PRAME to this same high standard of prospective validation.

###

The study was supported by the National Institutes of Health, the National Cancer Institute, Research to Prevent Blindness, the Melanoma Research Alliance, the Melanoma Research Foundation, the 2015 AACR-Ocular Melanoma Foundation Fellowship, and the Department of Defense.
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NewsBot · Mar 25, 2016

Is the prognosis and course of acral melanoma related to site-specific clinicopathological features?
Paolino G, Bekkenk MW, Didona D, Eibenschutz L, Richetta AG, Cantisani C, Viti G, Carbone A, Buccini P, De Simone P, Ferrari A, Scali E, Calvieri S, Silipo V, Cigna E, Viti GP, Bottoni U.
Eur Rev Med Pharmacol Sci. 2016 Mar;20(5):842-848.

OBJECTIVE:
Acral melanoma is an uncommon type of melanoma in Caucasian patients. However, acral melanoma is the most common type of melanoma in African and Asian patients. Comparison analyses between hand-acral melanoma and foot-acral melanoma have been rarely reported in the literature. Acral melanoma is an uncommon melanocytic tumor characterized by an intrinsic aggressiveness, with specific histological and clinicopathological features. Acral melanoma involves the palms, soles and sub-ungueal sites.
PATIENTS AND METHODS:
A total of 244 patients with acral melanoma were included in our analysis. The current study was performed in three different medical centers: Sapienza University of Rome, San Gallicano Institute of Rome and University of Magna Graecia (Italy). The Kaplan-Meier product was used to estimate survival curves for disease-free survival and overall survival. The log-rank test was used to evaluate differences between the survival curves. Assuming that the effects of the predictor variables are constant over time, the independent predictive factors were assessed by Spearman's test and subsequently data were analyzed performing Cox proportional-hazard regression.
RESULTS:
In both univariate and multivariate analyses Breslow thickness (p < 0.0001) and ulceration (p = 0.003) remained the main predictors. General BRAF mutation was detected in 13.8% of cases. We found that median Breslow value and the percentage of recurrences were similar in hand-acral melanoma and foot-acral melanoma, as well as there were no differences in both short and long-term.
CONCLUSIONS:
The absence of differences in survival between hand-acral melanoma and foot-acral melanoma shows that the aggressiveness of the disease is related to distinct mutational rate, as well as to anatomical site-specific features, rather than to the visibility of the primary lesion.
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NewsBot · Apr 4, 2016

Press Release:
Aging Impacts Therapeutic Response of Melanoma Cells
APRIL 4, 2016

PHILADELPHIA—(April 4, 2016)—Cancer risk increases with one’s age as accumulated damage to our cells and chronic inflammation occur over time. Now, an international team of scientists led by The Wistar Institute have shown that aged tumor cells in melanoma behave differently than younger tumor cells, according to study results published in the journal Nature.

Changes in the microenvironment make these older tumor cells more metastatic and more resistant to treatment with targeted therapies. In light of these findings, the scientists demonstrated how antioxidants could serve as a better treatment strategy for older patients with melanoma.

“It’s fascinating to see that the microenvironment can have such a profound effect on both metastasis, and response to a therapy that is specifically targeted to a mutation in a gene. This tells us that no tumor is an island, and even therapies targeted against these driver mutations are affected by the way the tumor cell communicates with its microenvironment,” said lead author Ashani Weeraratna, Ph.D., associate professor in the Tumor Microenvironment and Metastasis Program at Wistar.

Melanoma is the deadliest form of skin cancer, and patients with advanced cases of the disease only have a 20 percent chance of surviving five years after their diagnosis. Multiple targeted therapies for melanoma have been approved in the last few years, but patients who receive these drugs eventually relapse and become resistant to these treatment options.

While multiple factors may contribute to the age-related increases in cancer, for the first time, the Weeraratna Lab has pinpointed age-related changes that occur in the microenvironment of tumor cells. Cells found in the skin called dermal fibroblasts help the skin recover from injuries, and can contribute to the growth and invasion of melanoma cells. The researchers used dermal fibroblasts from healthy donors 25-35 years of age or from donors 55-65 years of age to understand what factors contribute to the difference in melanoma progression in aging cell populations.

Weeraratna and colleagues determined that a secreted factor sFRP2 was present in aging cells. SFRP2 regulates another protein called β-catenin that normally blocks the invasion of melanoma cells. In addition, b-catenin loss has been shown to promote oxidative stress in some cell types. The researchers showed that in an aged microenvironment, there are fewer scavengers of free oxygen radicals, leading to more activity of reactive oxygen species (ROS). At the same time, the age-induced loss of beta-catenin renders melanoma cells less capable of dealing with ROS, resulting in a genetically unstable tumor.

Treatment resistance experienced by older melanoma patients was found with increased activity of ROS and decreased levels of β-catenin all contribute to increased resistance to treatment with drugs that inhibit a gene, BRAF, mutated in approximately half of all cases of melanoma. Wistar scientists also showed how antioxidants might be a more effective strategy for treating older melanoma patients. An antioxidant called N-acetylcysteine (NAC) killed melanoma cells in aged dermal fibroblasts.

“Our findings highlight how vital it is to treat that melanoma in an age-appropriate manner,” said Amanpreet Kaur, a graduate student in the Weeraratna lab and first author of the study. “With other studies confirming the effectiveness of anti-oxidants in treating BRAF-mutated cancers, we have more evidence of how an older population may benefit from new therapeutic strategies.”

Wistar's business development team is actively seeking meaningful collaborations with biotechnology and pharmaceutical partners to comprehensively interrogate the tumor microenvironment's response to targeted therapies.

This work was supported by the National Institutes of Health grants P01CA114046-06, T32CA9171-36, R01CA174746-01, the National Institute on Aging, The Melanoma Research Foundation, The Harry J. Lloyd Foundation, and an American Cancer Society Institutional Research Grant award. Core facilities support was provided by the CCSG grant P30CA010815.

Co-authors of this study from The Wistar Institute include: Marie Webster, Katie Marchbank, Reeti Behera, Abibatou Ndoye, Curtis Kugel III, Vanessa Dang, Jessica Appleton, Michal O’Connell, Alexander Valiga, Andrew Kossenkov, Hsin-Yao Tang, Xiangfan Yin, Katherine Aird, Rugang Zhang, Qin Liu, and David Speicher. Other co-authors of this study include: Phil Cheng from the University of Zurich in Switzerland; Nazli McDonnell, Luigi Ferrucci, William Wood III, Elin Lehrmann, and Kevin Becker from the National Institute on Aging (NIH); Katrina Meeth and Marcus Bosenberg from Yale University; Keith Flaherty and Dennie Frederick from Massachusetts General Hospital Cancer Center; Jennifer Wargo, Zachary Cooper, Michael Tetzlaff, and Courtney Hudgens from M.D. Anderson Cancer Center; Xiaowei Xu and Giorgos Karakousis from Abramson Cancer Center at the University of Pennsylvania; Zeynep Eroglu from City of Hope Medical Center; Roger Lo and Antoni Ribas from the University of California Los Angeles; Matthew Chan from Crown Princess Mary Cancer Centre in Australia; Alexander Manzies and Georgina Long from the Melanoma Institute Australia and The University of Sydney; Douglas Johnson and Jeffrey Sosman from Vanderbilt University Medical Center; and Bastian Schilling and Dirk Schadendorf from West German Cancer Center at the University Duesburg-Essen.
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NewsBot · Apr 14, 2016

Melanoma of the Foot
Ivan Bristow, PhD, FFPM, RCPS(Glasg), Chris Bower, MB ChB, FRCP
Clins Pod Med Surg; Article in Press

Melanoma is a rare form of skin cancer that is responsible for most skin cancer deaths globally. Tumors arising on the foot continue to be a particular challenge. Patients present later and lesions are frequently misdiagnosed, leading to more advanced disease with an overall poorer prognosis then melanoma elsewhere. In order to improve early recognition, this article reviews the clinical features of the disease along with published algorithms. Emerging assessment techniques such as dermoscopy are also discussed as tools to improve clinical decision making. Contemporary drug therapies in the treatment of advanced disease are also discussed.
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NewsBot · May 1, 2016

From Podiatry Today:
Acral Lentiginous Melanoma: What Sets It Apart?

NewsBot · Jun 9, 2016

Distance from Primary Tumor Is the Strongest Predictor for Early Onset of Brain Metastases in Melanoma.
Gorka E et al
Anticancer Res. 2016 Jun;36(6):3065-3069.

BACKGROUND/AIM:
The frequency of brain metastasis (BM) is up to 45-50% in patients with advanced melanoma. Our aim was to identify the risk factors for the early occurrence of BM.
PATIENTS AND METHODS:
A total of 333 patients with BM were identified from our database of 2,972 patients with melanoma between 2003-2015.
RESULTS:
The median elapsed time to BM (TTBM) was significantly associated with Breslow thickness, ulceration, location, and patient age. Head and neck location was the strongest predictor for early BM development [hazard ratio (HR)=1.81, 95% confidence interval (CI)=1.05-3.12; p=0.031) followed by Breslow thickness >2 mm (HR=1.53, 95% CI=1.04-2.23; p=0.027). Body part-specific median TTBM was 51.5, 43, 38.5, 32, 35, 36.5, 35.5 and 19 months in leg-foot, thigh, abdomen-pelvic, chest-back, lower arm-hand, upper arm-shoulder, face-neck and scalp regions, respectively.
CONCLUSION:
We suggest brain magnetic resonance imaging follow-up in the high-risk patient group of patients with melanoma in the head and neck region, especially for those with primary melanoma over Breslow 2 mm located in the scalp.
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Admin2 · Jun 16, 2016

Melanomas and Mechanical Stress Points on the Plantar Surface of the Foot.
Minagawa A, Omodaka T, Okuyama R.
N Engl J Med. 2016 Jun 16;374(24):2404-2406.

To the Editor: Sun exposure is widely recognized as the main causative factor in cutaneous melanoma. However, melanomas also emerge in areas of the skin (such as palmoplantar surfaces) that are not exposed to the sun. Genetic analyses indicate that melanomas in sun-exposed skin are frequently associated with oncogenic BRAF mutations that are largely absent from palmoplantar lesions.1 These findings suggest that different pathogenic processes may be at work.2 Here we report on a series of patients with melanomas that developed in areas of plantar surfaces that had the most mechanical stress. We retrospectively collected data on 123 patients (54 . . .
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NewsBot · Jul 2, 2016

Melanoma diagnosed in lesions previously treated by laser therapy
Sarah Delker, Elisabeth Livingstone, Tobias Schimming, Dirk Schadendorf andKlaus G. Griewank
The Journal of Dermatology; Early View

Laser therapy has become a routine procedure in dermatological practice and is frequently also used for pigmented lesions. Few reports exist of melanomas diagnosed in lesions previously treated by laser therapy. Between 2007 and 2014, we identified 11 patients who presented to our department with a melanoma diagnosed in a region previously treated by laser therapy. The course of events until the diagnosis of melanoma was assessed as well as patient outcome including treatment for disease progression. No histological assessment had been performed prior to laser therapy in nine of 11 (82%) cases. Benign melanocytic lesions had been diagnosed by biopsy prior to laser therapy in the other two cases. Time from laser therapy to diagnosis of melanoma ranged from less than 1 to 10 years. Stage of disease at diagnosis varied from stage IA to IIIC. Four patients progressed to stage IV disease, of whom at least one died of melanoma. We conclude that laser treatment of pigmented lesions can complicate the diagnosis of melanoma and lead to diagnosis delay with potentially fatal consequences. Considering this risk, we believe laser therapy for pigmented lesions should either be avoided entirely or at a minimum performed only after prior histological assessment.
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NewsBot · Jul 13, 2016

PUBLIC RELEASE: 13-JUL-2016
Detecting melanoma early, without a biopsy
Colorado State University researcher Jesse Wilson's goal is to build a microscope that will make early detection of melanoma faster, cheaper and less invasive than a biopsy

FORT COLLINS, COLO. - Melanoma is a form of skin cancer that becomes dangerous when it spreads, but is treatable in its early stages. Doctors diagnose melanoma by cutting away a piece of a suspicious skin lesion -- a procedure known as a biopsy -- and testing it for malignant cells.

It's an imperfect, invasive method that Colorado State University researcher Jesse Wilson wants to improve. His goal is to make early detection of melanoma faster, cheaper and less invasive than a biopsy.

An assistant professor in the Department of Electrical and Computer Engineering and in the School of Biomedical Engineering, Wilson's expertise is in pushing the boundaries of biomedical optics. He has received a one-year, $30,000 grant from the Colorado Clinical and Translational Sciences Institute to develop a new microscope that can distinguish between benign and malignant pigmented skin lesions, without the need for biopsy.

If his idea works, it could lead to low-cost, in-vivo imaging of melanin, the skin pigment that's made by cells called melanocytes, which can become cancerous and lead to melanoma.

The grant is through the CCTSI's CO-Pilot program, which provides start-up funds for early-career researchers embarking on multidisciplinary new ideas. Wilson, who did his undergraduate, master's and Ph.D. work at CSU, has returned to campus as a faculty member to continue applying cutting-edge biomedical optics to early cancer detection.

The CO-Pilot is funding Wilson's development of an experimental microscope that uses a technology called pump-probe, which can provide contrast between normal tissue and melanoma without stains or dyes.

Pump-probe is a type of multiphoton microscopy, an established technique used for deep imaging of living tissue. In standard multiphoton microscopy, an extremely short laser pulse is used to excite fluorescent molecules in the sample, which can then be detected when they light up.

In pump-probe, excited molecules are detected not through fluorescence, but through their interactions with a second laser pulse. This allows pump-probe to distinguish molecules based on their absorption properties, which provide strong contrast between different types of melanin.

Pump-probe microscopes that can detect melanoma were developed in the lab of Warren Warren at Duke University, where Wilson completed his postdoctoral training. However, these microscopes require a short-pulse laser source that costs upwards of $300,000 - a major barrier to commercializing the technology for widespread use.

That's the problem Wilson will tackle with the CO-Pilot grant. He is designing a pump-probe microscope that can distinguish between benign and malignant melanoma in vivo, but built around a simpler laser source that's already widely used in telecommunications applications to encrypt voice communications. That laser only costs about $5,000, and would make the pump-probe technology more realistic for melanoma applications.

Wilson will work with Ali Pezeshki, associate professor in ECE and mathematics, on the signal processing that will be central to constructing images with the new microscope. He also plans to collaborate with Dan Gustafson, director of research at the Flint Animal Cancer Center.

Wilson's lab is also pursuing other pump-probe applications, including imaging cytochromes, molecules involved in metabolic activities that can't be imaged with conventional techniques.
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NewsBot · Jul 20, 2016

This from 1989, but turned up today!

Clinical Features and Distribution of Malignant Melanoma and Pigmented Nevi on the Soles of the Feet in Japan
Journal of Investigative Dermatology; Volume 92, Issue 5, Supplement, May 1989, Pages S210?S213
Atsushi Kukita, M.D., Kazuyuki Ishihara, M.D.

This Study, based on 842 cases of malignant melanoma from 108 medical schools and medical centers in Japan (from 1983 to 1985), presents information regarding the incidence, sex and age distribution, anatomical location, and clinical features of malignant melanoma in Japan and compares it with data from the United States. In the white population, the epidemiologic evidence indicates that exposure to sunlight may be an important causal factor of the disease. On the other hand, in more heavily pigmented races, such as Negroids and Orientals, many of the malignant melanomas occur on the skin of the unexposed soles of the foot. In our survey, 241 out of 833 cases of melanoma (28.9%) in Japanese patients involved the skin of the soles. Whites tend to have a wide distribution of cutaneous melanoma over the whole body surface, showing the greatest aggregation of lesions on the head, neck, and trunk, with small number on the soles of the feet. This comparative study revealed that the anatomical distribution and clinical types of malignant melanoma in the United States and Japan were different. The racial difference ? the highest frequency or proportion of melanoma on the skin of the soles in the pigmented races, and the lowest ratio of this anatomical area in the least-pigmented races? remains to be investigated
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NewsBot · Jul 23, 2016

Initial misdiagnosis of melanoma located on the foot is associated with poorer prognosis.
Sondermann W et al
Medicine (Baltimore). 2016 Jul;95(29):e4332.

Acral melanoma has been reported to be associated with poorer outcomes than melanoma occurring on other cutaneous sites. It has been suggested that part of this disparity in outcomes may be related to delay in diagnosis. Therefore, we have analyzed the rate of misdiagnoses in patients with melanoma located on the foot and have characterized the influence on the clinical course and survival of the patients. A prospective, computerized melanoma database at the Skin Cancer Center of the University Hospital Essen, Germany was used to identify patients with histologically confirmed melanoma located on the foot between 2002 and July 2013 for subsequent analysis. A cohort of 151 patients diagnosed with primary melanoma located on the foot was identified. One hundred seven patients qualified for subsequent analysis. Forty-two patients were male (39.3%) and 65 (60.7%) were female; the mean age at first diagnosis was 61.6 years (median 66 years). The youngest patient was 19 years, the oldest 88 years old.Of the 107 patients analyzed, 32 (30%) were initially misdiagnosed. Misdiagnoses included chronic wounds, nevi, hematoma, fungal infections, warts, and paronychia. Misdiagnosis caused a median delay in diagnosis of 9 months. The 5-year disease-free survival rate (47.8% vs 72.7%) and the 5-year overall survival rate (63.5% vs 88.4%) were statistically significant lower in the misdiagnosis cohort.The awareness of potentially overlooked melanoma located on the foot has to increase among physicians.To improve early detection and, thus, the prognosis of patients with melanoma located on the foot, taking a biopsy from any suspicious lesion should be taken into consideration as soon as possible.
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NewsBot · Jul 23, 2016

Pediatric melanomas often mimic benign skin lesions: A retrospective study
Mario Mitkov et al
Journal of the American Academy of Dermatology; 16 July 2016

Background
Childhood melanoma can be misdiagnosed because of its rarity and atypical presentation.

Objective
We sought to correlate the clinical appearance of pediatric melanomas with Breslow depth and clinical behavior, and to identify diagnostic errors made by dermatologists and nondermatologist physicians.

Methods
This was a retrospective review of Mayo Clinic records of children and young adults 21 years of age or younger with a diagnosis of primary cutaneous melanoma between January 2000 and January 2015.

Results
Pediatric melanomas that mimicked benign skin lesions were more often deeper (>1 mm; odds ratio 5.48; P = .002) and had a higher T stage (odds ratio [T2, T3, or T4] 6.28; P = .001) than melanomas with a clinically malignant appearance. Of pediatric melanomas, 66% originally diagnosed as benign melanocytic lesions exhibited changes in size, shape, and color.

Limitations
Sample size and retrospective design are limitations.

Conclusions
Benign-appearing pediatric skin lesions with a history of evolution, bleeding, or ulceration should raise suspicion for melanoma. Melanomas demonstrating these features are associated with a higher Breslow depth and T stage. Although biopsy of all lesions that exhibit change in children is not practical, safe, or desired, close monitoring is recommended.
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NewsBot · Sep 21, 2016

The Advantages of Dermoscopy in the Diagnosis of Acral Melanoma from Other Podiatric Lesions: A Literature Review
Mansi Patel, HyunJi Boo, Suganthi Kandasamy, Dhagash Patel, and Anthony Iorio
Journal of the American Podiatric Medical Association: September 2016, Vol. 106, No. sp1, pp. 2-2.

INTRODUCTION AND OBJECTIVES: Melanoma is one of the most common primary malignant tumors arising in the lower extremity. It is crucial to diagnose melanoma as quickly and as efficiently as possible for a better prognosis. The use of dermoscopy is helpful in diagnosing such conditions. Dermoscopy is a non-invasive, in-vivo technique primarily used in the examination of pigmented skin lesions. This procedure allows the visualization of subsurface skin structures in the epidermis, dermoepidermal junction, and upper dermis - structures not visible to the naked eye. This poster presents the advantages of dermoscopy in the field of podiatry by assessing the dermoscopic criteria with positive predictive values for distinguishing acral melanoma from acral nevus. Additionally it analyzes cases of melanomas misdiagnosed as a plantar-pigmented wart and a diabetic ulcer.

METHODS: The authors used PubMed to perform an English language literature search. The exclusion criteria included articles older than 10 years. Inclusion criteria consisted of research done on humans and the terms dermoscopy and foot lesions or melanoma. After retrieving a total of 140 articles, 14 articles were found to meet both the inclusion and exclusion criteria.

RESULTS: Qualitative analysis of relevant articles demonstrates that the detection of malignant dermoscopic patterns enhances quick and correct diagnosis.

CONCLUSIONS: The use of dermoscopy is slowly evolving in podiatry. It aims to minimize the amount of biopsies taken, thereby decreasing the risk of creating an ulcer and reducing the patients exposure to anesthesia. While controversy remains over sensitivity and specificity of using a dermatoscope alone to diagnose pedal lesions, particular attention should be paid to the accuracy of diagnosing a lesion when dermoscopy is used in conjunction with a biopsy. With the continued usage of a dermatoscope along with experience and expertise in the field, the need for a biopsy could eventually be eliminated.
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NewsBot · Sep 21, 2016

Cutaneous Complications of Targeted Melanoma Therapy.
de Golian E et al
Curr Treat Options Oncol. 2016 Nov;17(11):57.

The landscape of advanced and metastatic melanoma therapy has shifted dramatically in recent years. Since 2011, eight drugs (ipilimumab, vemurafenib, dabrafenib, trametinib, cometinib, pembrolizumab, nivolumab, and talimogene laherparepvec) have received FDA approval for the treatment of advanced or metastatic melanoma, including combination regimens of both small molecule kinase and immune checkpoint inhibitors. These therapies have revolutionized the management of unresectable regional nodal and distant melanoma, providing hope of extended survival to patients. As the use of novel agents has increased, so have the cutaneous toxicities associated with these medications. While most skin reactions are low-grade and can be managed conservatively with topical therapies, malignant lesions and more serious or life-threatening drug reactions can arise during therapy, requiring prompt dermatologic recognition and treatment in order to improve patient outcome. Given the survival benefit attributed to these new agents, treating skin toxicity and maintaining patient quality of life is of paramount importance. Oncologists should be aware of the common cutaneous toxicities associated with these medications and should be encouraged to involve dermatologists in the collaborative care of advanced melanoma patients. Close communication between oncologists and dermatologists can help to avoid unnecessary dose reduction or treatment discontinuation and identify situations when treatment cessation is truly warranted.
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NewsBot · Nov 21, 2016

Clinical Characteristics of Malignant Melanoma in Southwest China: A Single-Center Series of 82 Consecutive Cases and a Meta-Analysis of 958 Reported Cases.
Yu J et al
PLoS One. 2016 Nov 18;11(11):e0165591. doi: 10.1371/journal.pone.0165591. eCollection 2016.

Melanoma was located in the foot in 79% of patients
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NewsBot · Nov 23, 2016

Press Release:
Expression of Specific Gene Differentiates Moles from Melanoma
Penn Study Paves Way for Simple Test for Borderline Cases

PHILADELPHIA - Most melanomas are driven by mutations that spur out-of-control cell replication, while nevi (moles composed of non-cancerous cells at the skin surface) harboring the same mutations do not grow wildly. However, changes in the level of gene expression can cause nevi to become melanomas. Dermatologists surmise that 30 to 40 percent of melanomas (approximately 30,000 cases per year) may arise in association with a nevus. However, clinicians would like to be able to better distinguish between the two, especially in borderline cases when they examine skin tissue after a patient biopsy.

Senior author John T. Seykora, MD, PhD, a professor of Dermatology in the Perelman School of Medicine at the University of Pennsylvania, led a study that found that decreased levels of the gene p15 represents a way to determine if a nevus is transitioning to a melanoma. The protein p15 functions to inhibit nevus cell proliferation. They published their findings in the most recent issue of the American Journal of Pathology.

“We showed that p15 expression is a robust biomarker for distinguishing nevus from melanoma,” said Seykora. “Making this distinction has been a long-standing issue for dermatologists. We hope that this new finding will help doctors determine if a nevus has transformed to melanoma. This could help doctors and patients in difficult cases. Current research will hopefully move this into the realm of standard practice in about one to two years.”

Decreased expression in the related protein p16 has also been associated with melanoma, but p15 appears to be a primary driver of oncogene-induced cell senescence in nevus cells. When p15 levels drop, then nevus cells begin to grow.

The team stained human nevus and melanoma tissue samples with p15 and p16 antibodies. Staining was evaluated and graded for percentage and intensity to determine an “H score,” which correlates with the level of protein in the cells. This approach could also form the basis of a clinical determination, taking the form of an antibody test for p15 from a patient’s biopsy specimen. “If the staining level is high then that would be most consistent with a benign nevus,” Seykora said. “If the staining level is low then that would be consistent with a melanoma.”

RNA was also extracted from 14 nevus and melanoma tissue samples to determine levels of p15 mRNA. The expression of p15 mRNA was significantly increased in melanocytic nevi compared with melanomas as determined by real-time quantitative RT-PCR analysis.

Other Penn authors are Laura A. Taylor, Conor O’Day, Tzvete Dentchev, Kyle Hood, Emily Y. Chu, and Todd W. Ridky.

This work was supported by the Dermatology Foundation Career Development Award and the National Institutes of Health (RO1 CA-163566, RO1 CA-165836).
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NewsBot · Dec 6, 2016

PUBLIC RELEASE: 6-DEC-2016
Research providing promising new treatments for melanoma

New Orleans, LA - In a paper published online November 30, 2016, in Melanoma Management, Adam Riker, MD, Professor of Surgery and Chief of Surgical Oncology at LSU Health New Orleans School of Medicine, reviews approaches to manage melanoma, including one tested at LSU Health New Orleans that provoked a complete response in a patient with a long history of the disease.

The editorial provides an overview, including progress made over the last few decades in treating this potentially fatal skin cancer. More recent studies have shown the promise of vaccines and immunotherapy. Combinatorial immunotherapy represents the newest advance. Riker and colleagues recently reported results of a novel combinatorial immunotherapy Phase II clinical trial at LSU Health New Orleans. Twenty-five patients were given a combination of an interferon and a melanoma vaccine genetically altered to trigger a potent immune response. The researchers found that the approach clearly activated the immune system in a select few, including the astounding complete response in a patient who had melanoma for eight years at the time of the study.

"I saw this happy patient back in my office just a few months ago, still without evidence of disease," Riker reports.

Riker and co-author Erika Bisgaard, now an MD and an alumna of LSU Health New Orleans School of Medicine, also discuss a first-of-its-kind therapy for inoperable melanoma in the skin and lymph nodes. The FDA recently approved talimogene laherparepvec (IMLYGIC®, T-VEC). It uses herpes simplex virus-type 1 designed to selectively replicate within tumors and produce GM-CSF, a white blood cell growth factor that enhances systemic anti-tumor immune responses. This combination has shown a complete response rate of 10.8%. Ongoing trials are studying its possible use in melanomas that are operable as well.

"We still have much work ahead in our continuing efforts to identify effective treatment options that will stimulate and activate the immune system to destroy melanoma wherever it may grow," notes Riker. "Current research is very promising, though," he adds. "We have entered a truly exciting era in our ability to successfully treat patients with melanoma."

Melanoma is a form of skin cancer in which cancer cells form in melanocytes (cells that make melanin, a pigment giving skin its color). Melanoma can occur anywhere on the skin. It is more likely than other skin cancers to metastasize or spread to other parts of the body, and the number of new cases has been increasing over the past 40 years. The death rate varies by age - fewer people younger than 50 have been dying from melanoma since the mid-1980s, with the death rate on the rise in people age 50 and older.
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NewsBot · Dec 25, 2016

Rare nodular malignant melanoma of the heel in the Caribbean: A case report.
Warner WA et al
Int J Surg Case Rep. 2016 Nov 27;30:172-176. doi: 10.1016/j.ijscr.2016.11.047

INTRODUCTION:
Malignant melanoma of the heel is a rare melanoma subtype with incidence rates that reflect the complex relationship between sun exposure at certain geographic locations, individual melanin levels and overall melanoma risk. It is oftentimes characterized by poor prognosis because of delays in presentation resulting in longitudinal tumor invasion, lymph node involvement and metastasis.
PRESENTATION OF CASE:
A 59-year-old woman was admitted to the Eric Williams Medical Sciences Complex, Trinidad and Tobago with a 5mm pruritic lesion on her left heel. At presentation, the lesion was asymmetric with border irregularities, color heterogeneity, with dynamics in elevation and overall size. She was subsequently diagnosed with malignant melanoma with left inguinal lymphadenopathy. A single stage wide local excision (WLE) of the left heel lesion with a split-thickness skin graft (STSG) and a left inguinal lymphadenectomy were performed. Dacarbazine (Bayer) was administered post operatively.
DISCUSSION:
Globally, the incidence of malignant melanoma is rapidly increasing, particularly, in countries like Trinidad and Tobago with a significant population of non-fair skinned individuals. There is need for strategic initiatives to increase patient adherence in these populations.
CONCLUSION:
The rarity of malignant heel melanomas heightens the need for increased patient awareness and greater clinical surveillance to ensure early diagnosis and treatment.
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NewsBot · Dec 28, 2016

PUBLIC RELEASE: 28-DEC-2016
State, regional differences in melanoma rates 2003 vs 2013

A new research letter published online by JAMA Dermatology compares melanoma death and incidence by states and in four geographic regions.

Melanoma death and incidence rates vary among states, partly because of demographic differences.

Robert P. Dellavalle, M.D., Ph.D., M.S.P.H., of the Denver Veterans Affairs Medical Center and the University of Colorado School of Medicine, Aurora, and coauthors used a publicly available database to analyze melanoma death and incidence rates by state and geographic region. Researchers report:

* 23 of 48 states (with data for 2003 and 2013) had a decrease in melanoma death rates; four states had no change and 21 states saw an increase.
* 11 of the 49 states with reported melanoma incidence rates saw a decrease and 38 states had an increase.

"Promoting greater awareness of skin cancer through public health programs has been associated with increased documentation and incidence rates. Lower death rates may further indicate that better treatment may be prolonging the life of patients with melanoma. Further research into the prevalence of melanoma in these four geographic regions is needed," the article concludes.
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NewsBot · Feb 7, 2017

PUBLIC RELEASE: 7-FEB-2017
Melanoma research breakthrough gives hope to treatment
A QUT-driven project has identified the way in which melanoma cells spread, opening up new pathways to treatment via drugs to 'turn off' the invasive gene

Led by Dr Aaron Smith from QUT's School of Biomedical Sciences within the Institute of Health and Biomedical Innovation at the Translational Research Centre, the project results have just been published in international journal EBiomedicine and could offer a new avenue for cancer treatment.

"Cancer is characterised by uncontrolled growth of cells but if uncontrolled growth was the only problem then cancer cells would be easily treated with surgery in most cases," said Dr Smith who collaborated with colleagues from UQ, QIMR and Oxford University.

"What makes cancer deadly is its tendency to invade tissue and migrate to other regions of the body, a process we call metastasis. Metastatic melanoma is one of the most aggressive and difficult to treat of all cancer types.

"By examining melanoma tumour samples we know that some cells are primarily proliferative and some are more invasive and migratory. We also know some cells can switch between those two behaviours; in other words a cell capable of establishing a new tumour at the same site can change to be more invasive and facilitate the spread the cancer to other parts of the body.

"What we did not know though was the reason why this happened. Our research project has discovered the mechanism by which those melanoma cells switch behaviours.

"This is an important breakthrough as we have identified a 'druggable' target as part of this process. Preventing this switch to invasive behaviour will enable us to prevent metastatic spread of melanoma and potentially other cancer types as well."

Dr Smith explained the two types of behaviours were marked by the expression of two different regulatory factors MITF (proliferating cells) and BRN2 (invasive).

"BRN2 function reduces MITF expression to slow down proliferation and put the cells into invasive mode," he said.

"Our project has identified a pathway that allows BRN2 to do this, firstly by increasing the expression of another regulatory factor called NFIB that further controls an invasive program in these cells.

"An important target of NFIB is an enzyme called EZH2 which then produces global (wide ranging) changes to the cells activity. EZH2 favours the expression of invasive genes and also turns "off" MITF to prevent proliferation, further re-enforcing the invasive capability of the tumour cells.

"Once cells migrate away from the tumour we believe they no longer receive the signal that triggered the switch so the system re-sets to the MITF driven proliferation state which will then allow a new tumour to form at the new site.

"We have evidence the NFIB-EZH2 pathway may also underpin metastasis of other cancer types as well such as lung cancer. The good news is there are drugs to chemically inhibit EZH2 which are already in pre-clinical trials and which could be used to block the invasion. "
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NewsBot · Feb 8, 2017

PUBLIC RELEASE: 8-FEB-2017
NIH study reveals how melanoma spreads
Insights provide possible new targets for personalized treatments

Cancerous tumors are voracious. Once they have consumed all the oxygen and nutrients in the original tumor site, the cancer cells travel to other parts of the body (metastasize) to find more nourishment.

Searching for clues about how the body signals the lack of oxygen in melanoma skin cancer, National Institutes of Health (NIH) researchers focused on HIF1α (hypoxia inducible factor 1 alpha), a protein that acts as a sensor for oxygen and nutrients in many types of cancer. They discovered 40 new genes that are either turned on or off by HIF1α, and 10 genes that were associated with the amount of time it took the melanoma to move from the original tumor to the rest of the body. They published their findings February 6, 2017, in Pigment Cell and Melanoma Research.

"These newly identified genes and genetic pathways in primary melanoma could give researchers new targets for developing personalized treatments for melanoma, and potentially other cancers," said Stacie Loftus, Ph.D., lead author and staff scientist in the Genetic Disease Research Branch at the National Human Genome Research Institute, a part of NIH. "In addition, changes in how the genes are expressed (turned on or off) could be used in the future to predict how and when the cancer cells will spread to other parts of the body and how fast they will grow."

The lifetime risk of an individual being diagnosed with melanoma is 2 percent. With more than 10,130 deaths (and 76,380 new diagnoses) in 2016, melanoma is one of the leading causes of skin cancer-related deaths, according to the National Cancer Institute at NIH. Melanoma occurs when melanocytes -- cells that make pigment in skin and hair -- undergo a malignant transformation. Ultraviolet (UV) rays from the sun and from tanning beds can damage the DNA in skin cells, causing melanoma.

If melanoma is caught early, before cancer cells leave the skin and move to lymph nodes and the rest of the body, patients have a 91.5 percent 5-year survival rate. If the cancer is caught at later stages, the prognosis is much less favorable, with a 30 to 60 percent 5-year survival rate.

When tumor cells are present in an environment that lacks oxygen and nutrients, they receive a signal that it is time for the cells to move to a different part of the body. Identifying which genes define this critical tumor state provides researchers and clinicians biomarkers of this critical stage of disease progression. Biomarkers are molecules found in the blood, other body fluids or tissues that signal a normal or abnormal process. In melanoma, they can be used to determine tumor stage, diagnosis, therapy selection and when to monitor for disease recurrence.

"In many ways, melanoma is a poster child for precision medicine," Dr. Loftus said. "Current therapies in clinical trials are focused on targeting genetic changes in tumors and helping to boost one's immune system to fight the cancer cells. Identifying how cells respond to their surrounding environment is important information that can be used to help guide treatment decisions for patients."

In the next phase of her work, Dr. Loftus and her team will analyze the roles that HIF1α and other transcription factors play in turning genes on and off in melanocytes and melanomas. They will also delve into the newly discovered genes regulated by low oxygen levels that are distinct from HIF1α to better understand the role they have in tumor progression.
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Melanoma of the foot

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