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Skin Cancer

Skin cancer is the most common type of cancer and accounts for half of all new cancers in Western populations. It occurs more often in people with light coloured skin who have had a high exposure to sunlight. The two most frequent types of skin cancer are Basal Cell Carcinomas and Squamous Cell Carcinoma (often grouped under "non-melanoma skin cancer"). The third most frequent skin cancer is Melanoma, this is a malignancy of the cells which give the skin it's colour (melanocytes). In addition there are a number of other, less common cancers starting in the skin including Merkel cell tumours, cutaneous lymphomas, and sarcomas (see the pages on sarcoma and lymphoma in this guide).

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Prevention of Skin Cancer
Non Melanoma Skin Cancer
-- Basal Cell Carcinoma
-- Squamous Cell Carcinoma
Cutaneous T-cell Lymphoma
Dermatofibrosarcoma Protuberans
Merkel Cell Cancer

Information Patients and the Public (10 links)

Information for Health Professionals / Researchers (6 links)

  • PubMed search for publications about Skin Cancer - Limit search to: [Reviews]

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    MeSH term: Skin Neoplasms
    International US National Library of Medicine
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Loeb S, Folkvaljon Y, Lambe M, et al.
Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma.
JAMA. 2015 Jun 23-30; 313(24):2449-55 [PubMed] Related Publications
IMPORTANCE: The target for the oral erectile dysfunction drugs, phosphodiesterase type 5 (PDE5) inhibitors, is part of a pathway implicated in the development of malignant melanoma. An increased risk of melanoma in sildenafil users was recently reported.
OBJECTIVE: To examine the association between use of PDE5 inhibitors and melanoma risk, including data on specific PDE5 inhibitors, number of prescriptions, and melanoma stage.
DESIGN, SETTING, AND PARTICIPANTS: Nationwide, population-based, nested case-control study in the Swedish Prescribed Drug Register, the Swedish Melanoma Register, and other health care registers and demographic databases in Sweden, including 4065 melanoma cases diagnosed from 2006 through 2012 and 5 randomly selected controls per case with matching year of birth.
EXPOSURES: Number of filled prescriptions for the PDE5 inhibitors sildenafil and vardenafil or tadalafil.
MAIN OUTCOMES AND MEASURES: Risk of melanoma; overall and by stage and risk of basal cell carcinoma in multivariable logistic regression analyses.
RESULTS: Of 4065 melanoma cases, 435 men (11%) had filled prescriptions for PDE5 inhibitors, as did 1713 men of 20,325 controls (8%). In multivariable analysis, there was an increased risk of melanoma in men taking PDE5 inhibitors (OR, 1.21 [95% CI, 1.08-1.36]). The most pronounced increase in risk was observed in men who had filled a single prescription (OR, 1.32 [95% CI, 1.10-1.59]; exposure rate, 4% for cases vs 3% for controls), but was not significant among men with multiple filled prescriptions (for 2-5 prescriptions: OR, 1.14 [95% CI, 0.95-1.37], 4% for cases and 3% for controls; for ≥6 prescriptions: OR, 1.17 [95% CI, 0.95-1.44], 3% for cases vs 2% for controls). PDE5 inhibitors were significantly associated with melanoma stage 0 (OR, 1.49 [95% CI, 1.22-1.83], 13% for cases vs 8% for controls) and stage I (OR, 1.21 [95% CI, 1.02-1.43], 12% for cases vs 10% for controls), but not stage II through IV (OR, 0.83 [95% CI, 0.63-1.09], 6% for cases vs 7% for controls). The risk estimates were similar for sildenafil and vardenafil or tadalafil. PDE5 inhibitor use was also associated with an increased risk of basal cell carcinoma (OR, 1.19 [95% CI, 1.14-1.25], 9% for cases vs 8% for controls). Men taking PDE5 inhibitors had a higher educational level and annual income, factors that were also significantly associated with melanoma risk.
CONCLUSIONS AND RELEVANCE: In a Swedish cohort of men, the use of PDE5 inhibitors was associated with a modest but statistically significant increased risk of malignant melanoma. However, the pattern of association (eg, the lack of association with multiple filled prescriptions) raises questions about whether this association is causal.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al.
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
N Engl J Med. 2015; 373(1):23-34 [PubMed] Related Publications
BACKGROUND: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma.
METHODS: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here.
RESULTS: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group.
CONCLUSIONS: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

Holm RP
Skin cancer prevention and screening.
S D Med. 2015; Spec No:75-7, 79-81 [PubMed] Related Publications
Skin cancer is the most common and recognizable of all cancers. The human dermis can turn malignant due to excessive solar exposure and chronic injury, with the influence of genetic risk and inherited pigmentation. Basal cell carcinoma, the most common skin cancer in lighter pigmented individuals, spreads locally, and usually appears pearly and often ulcerative. Squamous cell carcinoma, the most common skin cancer in darker pigmented people, metastasizes to lymph nodes 2-5 percent of the time, appears often scaly, smooth, nodular, ulcerative, or even pigmented. Malignant melanoma accounts for 2 percent of skin cancers, but for the vast majority of skin cancer deaths. All three can mimic each other. Solar or ultraviolet (UV) light exposure is the most common carcinogen; however, any chronic irritant can increase the risk, and efforts to avoid such exposure is apropos. Though not yet absolutely proven, skin cancer research strongly supports the following statements: sunscreen is protective, tanning devices are causative, and the routine screening of high-risk individuals is preventative. Authorities strongly recommend avoiding excess sun and UV light, using sunscreen, and keeping a watchful eye for unusual skin lesions.

Vemurafenib (Zelboraf) with longer follow-up. Metastatic melanoma: a few extra months of life, but many adverse effects.
Prescrire Int. 2015; 24(159):89-90 [PubMed] Related Publications
Further analysis of the unblinded trial described in the initial clinical evaluation suggests that vemurafenib prolongs survival by a median of about 4 months compared with dacarbazine. The adverse effects of vemurafenib are frequent and sometimes serious. More data are needed on renal and pancreatic toxicity and the risk of extracutaneous cancers.

Rogers-Vizena CR, Lalonde DH, Menick FJ, Bentz ML
Surgical treatment and reconstruction of nonmelanoma facial skin cancers.
Plast Reconstr Surg. 2015; 135(5):895e-908e [PubMed] Related Publications
LEARNING OBJECTIVES: After reading this article, the participant should be able to: (1) Identify the appropriate resection margins for common types of nonmelanoma skin cancer. (2) Discuss indications for secondary intention healing, skin grafting, and local flaps for reconstruction of facial skin cancer defects. (3) Describe at least one local flap for reconstruction of scalp, forehead, temple/cheek, periocular, nose, and lips.
SUMMARY: Current evidence for diagnosis and surgical treatment of nonmelanoma facial skin cancers is reviewed. In addition, reconstructive options for facial defects are discussed by anatomic location.

Robert C, Schachter J, Long GV, et al.
Pembrolizumab versus Ipilimumab in Advanced Melanoma.
N Engl J Med. 2015; 372(26):2521-32 [PubMed] Related Publications
BACKGROUND: The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma.
METHODS: In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival.
RESULTS: The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%).
CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).

Surace L, Lysenko V, Fontana AO, et al.
Complement is a central mediator of radiotherapy-induced tumor-specific immunity and clinical response.
Immunity. 2015; 42(4):767-77 [PubMed] Related Publications
Radiotherapy induces DNA damage and cell death, but recent data suggest that concomitant immune stimulation is an integral part of the therapeutic action of ionizing radiation. It is poorly understood how radiotherapy supports tumor-specific immunity. Here we report that radiotherapy induced tumor cell death and transiently activated complement both in murine and human tumors. The local production of pro-inflammatory anaphylatoxins C3a and C5a was crucial to the tumor response to radiotherapy and concomitant stimulation of tumor-specific immunity. Dexamethasone, a drug frequently given during radiotherapy, limited complement activation and the anti-tumor effects of the immune system. Overall, our findings indicate that anaphylatoxins are key players in radiotherapy-induced tumor-specific immunity and the ensuing clinical responses.

Liu X, He Y, Li F, et al.
Caspase-3 promotes genetic instability and carcinogenesis.
Mol Cell. 2015; 58(2):284-96 [PubMed] Article available free on PMC after 16/04/2016 Related Publications
Apoptosis is typically considered an anti-oncogenic process since caspase activation can promote the elimination of genetically unstable or damaged cells. We report that a central effector of apoptosis, caspase-3, facilitates rather than suppresses chemical- and radiation-induced genetic instability and carcinogenesis. We found that a significant fraction of mammalian cells treated with ionizing radiation can survive despite caspase-3 activation. Moreover, this sublethal activation of caspase-3 promoted persistent DNA damage and oncogenic transformation. In addition, chemically induced skin carcinogenesis was significantly reduced in mice genetically deficient in caspase-3. Furthermore, attenuation of EndoG activity significantly reduced radiation-induced DNA damage and oncogenic transformation, identifying EndoG as a downstream effector of caspase-3 in this pathway. Our findings suggest that rather than acting as a broad inhibitor of carcinogenesis, caspase-3 activation may contribute to genome instability and play a pivotal role in tumor formation following damage.

Arena V, Pennacchia I, Guerriero G, Mancuso C
The heme oxygenase/biliverdin reductase system in skin cancers.
J Biol Regul Homeost Agents. 2015 Jan-Mar; 29(1):259-64 [PubMed] Related Publications
The heme oxygenase/biliverdin reductase (HO/BVR) pathway enhances cell stress response by degrading excess heme or producing antioxidant and cytoprotective molecules. Recently, members of the HO/BVR system have been proposed as biomarkers for the early diagnosis of free radical-related diseases. In this study, the presence of both the inducible and constitutive HO isoforms (HO-1 and HO-2, respectively) and BVR was evaluated by immunohistochemistry in human skin cancer samples. Moderate/strong immunoreactivities against HO-1, HO-2 and BVR were detected in 100% of the nodular malignant melanoma samples, whereas in basal cell carcinoma specimens these figures were 62%, 88% and 60%, respectively, with a faint/moderate degree of expression. Faint/moderate HO-1, HO-2 and BVR immunoreactivities were detected in 33%, 66% and 100% of melanocytic nevi samples, respectively. In conclusion, HO-1 and HO-2 and BVR were expressed in the cytosols of skin cancer cells, whereas perilesional normal epidermis showed only faint staining, thus leading to the hypothesis that the HO/BVR system is activated in skin cancers.

Kamstrup MR, Gniadecki R, Iversen L, et al.
Low-dose (10-Gy) total skin electron beam therapy for cutaneous T-cell lymphoma: an open clinical study and pooled data analysis.
Int J Radiat Oncol Biol Phys. 2015; 92(1):138-43 [PubMed] Related Publications
PURPOSE: Cutaneous T-cell lymphomas (CTCLs) are dominated by mycosis fungoides (MF) and Sézary syndrome (SS), and durable disease control is a therapeutic challenge. Standard total skin electron beam therapy (TSEBT) is an effective skin-directed therapy, but the possibility of retreatments is limited to 2 to 3 courses in a lifetime due to skin toxicity. This study aimed to determine the clinical effect of low-dose TSEBT in patients with MF and SS.
METHODS AND MATERIALS: In an open clinical study, 21 patients with MF/SS stages IB to IV were treated with low-dose TSEBT over <2.5 weeks, receiving a total dose of 10 Gy in 10 fractions. Data from 10 of these patients were published previously but were included in the current pooled data analysis. Outcome measures were response rate, duration of response, and toxicity.
RESULTS: The overall response rate was 95% with a complete cutaneous response or a very good partial response rate (<1% skin involvement with patches or plaques) documented in 57% of the patients. Median duration of overall cutaneous response was 174 days (5.8 months; range: 60-675 days). TSEBT-related acute adverse events (grade 1 or 2) were observed in 60% of patients.
CONCLUSIONS: Low-dose (10-Gy) TSEBT offers a high overall response rate and is relatively safe. With this approach, reirradiation at times of relapse or progression is likely to be less toxic than standard dose TSEBT. It remains to be established whether adjuvant and combination treatments can prolong the beneficial effects of low-dose TSEBT.

Specht L, Dabaja B, Illidge T, et al.
Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group.
Int J Radiat Oncol Biol Phys. 2015; 92(1):32-9 [PubMed] Related Publications
Primary cutaneous lymphomas are a heterogeneous group of diseases. They often remain localized, and they generally have a more indolent course and a better prognosis than lymphomas in other locations. They are highly radiosensitive, and radiation therapy is an important part of the treatment, either as the sole treatment or as part of a multimodality approach. Radiation therapy of primary cutaneous lymphomas requires the use of special techniques that form the focus of these guidelines. The International Lymphoma Radiation Oncology Group has developed these guidelines after multinational meetings and analysis of available evidence. The guidelines represent an agreed consensus view of the International Lymphoma Radiation Oncology Group steering committee on the use of radiation therapy in primary cutaneous lymphomas in the modern era.

Mann MB, Black MA, Jones DJ, et al.
Transposon mutagenesis identifies genetic drivers of Braf(V600E) melanoma.
Nat Genet. 2015; 47(5):486-95 [PubMed] Related Publications
Although nearly half of human melanomas harbor oncogenic BRAF(V600E) mutations, the genetic events that cooperate with these mutations to drive melanogenesis are still largely unknown. Here we show that Sleeping Beauty (SB) transposon-mediated mutagenesis drives melanoma progression in Braf(V600E) mutant mice and identify 1,232 recurrently mutated candidate cancer genes (CCGs) from 70 SB-driven melanomas. CCGs are enriched in Wnt, PI3K, MAPK and netrin signaling pathway components and are more highly connected to one another than predicted by chance, indicating that SB targets cooperative genetic networks in melanoma. Human orthologs of >500 CCGs are enriched for mutations in human melanoma or showed statistically significant clinical associations between RNA abundance and survival of patients with metastatic melanoma. We also functionally validate CEP350 as a new tumor-suppressor gene in human melanoma. SB mutagenesis has thus helped to catalog the cooperative molecular mechanisms driving BRAF(V600E) melanoma and discover new genes with potential clinical importance in human melanoma.

Gilani S, Al-Khafaji B
Dermatofibrosarcoma protuberans of the vulva: a mesenchymal tumour with a broad differential diagnosis and review of literature.
Pathologica. 2014; 106(4):338-41 [PubMed] Related Publications
Dermatofibrosarcoma protuberans (DFSP) is a malignant cutaneous soft tissue tumour, which rarely presents in the vulva. We report an unusual case of this tumour involving the vulva. A 61-year-old female presented with a mass in the left mons pubis. Subsequent excisional biopsy of the mass was performed. Histologic evaluation of the specimen showed a spindle cell lesion consisting of fibroblast-like cells arranged in a storiform pattern. On average, there were 2 to 3 mitotic figures per 10 high power field (hpf). The neoplastic cells showed extension into the surrounding fibroadipose tissue. A panel of immunohistochemical stains including CD34, S-100, melan-A, HMB-45, vimentin and smooth muscle actin (SMA) were tested. The neoplastic cells showed diffuse staining with CD34 and vimentin, while the rest were negative. Based on the morphologic and immunohistochemical staining pattern, a diagnosis of DFSP was rendered. The patient underwent two subsequent resections before she had clear resection margins. The postoperative course was unremarkable. The patient is disease free without recurrence after a follow-up of 12 months. DFSP infrequently involves the vulva and should be considered in the differential diagnosis of other spindle cell lesions presenting in this unusual site. The role of immunohistochemical staining with CD34 is imperative in establishing the diagnosis. The rate of local reoccurrence is high, but it rarely shows metastasis. Treatment of choice is wide local surgical excision with close follow-up to detect reoccur- rence.

Filotico M, Damuri A, Filotico R
A peculiar fibroma-like lesion of superficial soft tissue: morphologic and immunophenotypic evaluation.
Pathologica. 2014; 106(4):327-9 [PubMed] Related Publications
Apeculiar lesion of superficial soft tissue characterised by fibroma-like morphology and an immunohistochemical profile consisting of CK+, VIM+, CD34+, CD31+/-, FLI1+ and INI-1 retained is described. The lesion entered into differential diagnosis with the so-called fibroma-like variant of epithelioid sarcoma, with the entities defined as ES-like/pseudomyogenic haemangioendothelioma and the recently identified entity defined as superficial CD34+ fibroblastic tumour. All of these entities share a common morphological structure, but differ in their immunophenotypic profile.

Samimi M, Gardair C, Nicol JT, et al.
Merkel cell polyomavirus in merkel cell carcinoma: clinical and therapeutic perspectives.
Semin Oncol. 2015; 42(2):347-58 [PubMed] Related Publications
Merkel cell carcinoma (MCC) is a rare and often aggressive cutaneous cancer with a poor prognosis. The incidence of this cancer increases with age, immunodeficiency and sun exposure. Merkel cell polyomavirus (MCPyV), a new human polyomavirus identified in 2008, is detected in the majority of the MCCs and there is a growing body of evidence that healthy human skin harbors resident or transient MCPyV. A causal link between MCPyV and MCC has been evidenced and this is the first polyomavirus to be clearly implicated as a causal agent underlying a human cancer, and MCPyV was recently classified as a 2A carcinogen. MCC is thus a rare tumor caused by a very common viral skin infection. The aim of this review is to provide a basic overview of the epidemiological, clinical, and pathological characteristics of MCC, to present the current knowledge on MCPyV polyomavirus and its causal association with MCC development, and to describe the therapeutic implications of this causal link.

McLaughlin-Drubin ME
Human papillomaviruses and non-melanoma skin cancer.
Semin Oncol. 2015; 42(2):284-90 [PubMed] Related Publications
Human papillomaviruses (HPVs) infect the squamous epithelium and can induce benign and malignant lesions. To date, more than 200 different HPV types have been identified and classified into five genera, α, β, γ, μ, and ν. While high-risk α mucosal HPVs have a well-established role in cervical carcinoma and a significant percentage of other anogenital tract and oral carcinomas, the biology of the cutaneous β HPVs and their contribution to non-melanoma skin cancer (NMSC) has been less studied. Although the association of β HPV infection with NMSC in patients with a rare, genetically determined condition, epidermodysplasia verruciformis has been well established, the role of β HPV infection with NMSC in the normal population remains controversial. In stark contrast to α HPV-associated cancers, the presence of the β HPV genome does not appear to be mandatory for the maintenance of the malignant phenotype. Moreover, the mechanism of action of the β HPV E6 and E7 oncoproteins differs from the β HPV oncoproteins.

Carreno BM, Magrini V, Becker-Hapak M, et al.
Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells.
Science. 2015; 348(6236):803-8 [PubMed] Related Publications
T cell immunity directed against tumor-encoded amino acid substitutions occurs in some melanoma patients. This implicates missense mutations as a source of patient-specific neoantigens. However, a systematic evaluation of these putative neoantigens as targets of antitumor immunity is lacking. Moreover, it remains unknown whether vaccination can augment such responses. We found that a dendritic cell vaccine led to an increase in naturally occurring neoantigen-specific immunity and revealed previously undetected human leukocyte antigen (HLA) class I-restricted neoantigens in patients with advanced melanoma. The presentation of neoantigens by HLA-A*02:01 in human melanoma was confirmed by mass spectrometry. Vaccination promoted a diverse neoantigen-specific T cell receptor (TCR) repertoire in terms of both TCR-β usage and clonal composition. Our results demonstrate that vaccination directed at tumor-encoded amino acid substitutions broadens the antigenic breadth and clonal diversity of antitumor immunity.

Kim JT, Ho SY, Kim YH
An improved perforator-based island flap: the heart balloon flap.
Plast Reconstr Surg. 2015; 135(5):1472-5 [PubMed] Related Publications
BACKGROUND: Reconstructive surgery has entered a "perforator flap era" with more surgeons performing successful perforator flap procedures. The perforator-based island flap is an extension of this perforator concept and one of the most successful. In perforator-rich or -reliable areas, this allows for primary closure of the donor site and the construction of highly customized flaps with little tissue waste.
METHODS: The authors present a design modification of the perforator-based island flap used in 73 patients who underwent heart balloon perforator-based island flap reconstruction between 2008 and 2012.
RESULTS: There were no reported cases of total flap necrosis. Marginal necrosis of the flap was noted in three cases, which resolved with simple dressings. The donor sites were closed primarily in all cases.
CONCLUSIONS: The heart balloon perforator-based island flap enables tension-free closure of the donor site, reduces donor-site complications, and minimizes tissue waste. The resulting shape resembles a heart and gives rise to the flap's name. Key principles for success are perforators close to the defect, a flap axis that allows for primary donor-site closure, flap border adjacent to the defect that is smaller than the postresection defect, flap harvest until an adequate arc of rotation is obtained, primary closure of the donor site before flap inset, and preservation of a triangular area between the proximal apex of the flap and the defect.

Zhang RZ, Zhu WY, Zhou L
Centrally located acquired bilateral nevus of ota-like macules: a bizarre pattern.
Skinmed. 2014 Nov-Dec; 12(6):385-7 [PubMed] Related Publications
A 22-year-old woman was referred to our hospital for pigmented lesions located on her face. These had gradually increased during the past 4 years. Computed tomography (CT) of her head revealed no significant parenchymal abnormalities of temporal, maxillary and sphenoid bones or of either parietal bone. Further screening, including neurologic, ophthalmologic, orthopedic, and visceral investigations, did not reveal any abnormalities. There was no family history of abnormal cutaneous pigmentation.

Agar NJ, Kirton C, Patel RS, et al.
Predicting lymph node metastases in cutaneous squamous cell carcinoma: use of a morphological scoring system.
N Z Med J. 2015; 128(1411):59-67 [PubMed] Related Publications
BACKGROUND: Predicting which patients will develop nodal metastasis from cutaneous squamous cell carcinoma (cSCC) remains difficult. This study evaluates a recently described histological risk model validated for mucosal head and neck SCC (HNSCC) when applied to cutaneous tumours. In this model, morphologic variables including worst pattern of invasion, lymphocytic host response and perineural invasion were shown to predict disease recurrence, loco regional recurrence and overall survival in mucosal HNSCC.
METHODS: Patients with cSCC and known metastatic spread were identified from the author's database over a 5-year period between July 2007 and July 2012. Histology specimens from the original primary tumour were separately analysed by 2 histopathologists. Scores were compared against T-Stage matched control specimens without metastatic spread.
RESULTS: 27 patients with metastatic cSCC were identified. Scores for worst pattern of invasion (WPOI) were significantly higher in individuals with lymph node metastases (p=0.02).
CONCLUSIONS: Adverse pattern of invasion, defined as presence of small tumour islands or tumour satellites may be an independent risk factor for developing nodal metastases in cSCC. These tumours are difficult to investigate histopathologically as it is difficult to be confident the correct primary is chosen for study.

Audrain H, Bray A, De Berker D
Full-thickness skin grafts for lower leg defects: an effective repair option.
Dermatol Surg. 2015; 41(4):493-8 [PubMed] Related Publications
BACKGROUND: Repair of lower leg defects after excision of skin lesions that are not amenable to primary closure can be challenging.
OBJECTIVE: To evaluate the outcome of full-thickness skin grafts (FTSG) to repair lower leg defects after excision of cutaneous lesions. To assess graft take at Days 7 and 30 and the number of visits to secondary care after procedure.
MATERIALS AND METHODS: Retrospective review of 50 consecutive patients who underwent FTSG to cover defects below the knee between January 2009 and February 2014. Graft take was defined as good (90% healing and pink/purple), moderate (50% healing and pink/purple and >50% graft take), or poor (>50% graft failure).
RESULTS: Mean age was 75 years (range, 49-96 years). The mean area of the defect was 52.4 cm. The mean maximum and minimum diameters of the defect were 2.8 and 2.3 cm. Graft take was good in 44 patients (88%), moderate in 5 patients (10%), and poor in 1 patient (2%) at Day 30. Complications were infrequent and included infection and ulceration. There was no significant association between the graft size and graft take.
CONCLUSION: Full-thickness skin graft is an effective method of repairing defects on the lower leg after removal of cutaneous lesions. The aftercare of FTSG was acceptable with 86% of patients requiring 5 or fewer visits to secondary care.

Johnson AS, Crandall H, Dahlman K, Kelley MC
Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma.
J Am Coll Surg. 2015; 220(4):581-93.e1 [PubMed] Related Publications
BACKGROUND: We conducted a prospective trial of BRAF and mitogen-activated protein kinase kinase (MEK) targeted therapy in advanced, operable BRAF mutation-positive melanoma to determine feasibility, tumor response rates, and biomarkers of response and resistance.
STUDY DESIGN: Thirteen patients with locally or regionally advanced BRAF mutation-positive melanoma received dabrafenib 150 mg po bid for 14 days, followed by dabrafenib plus trametinib 2 mg po daily for 14 days before operation. Biopsies and tumor measurements were obtained at baseline and days 14 and 28. Formalin-fixed paraffin embedded specimens were analyzed with hematoxylin and eosin, Ki-67, cleaved caspase-3, CD8, phosphorylated extracellular signal-regulated kinase (ERK), and phosphorylated MEK immunostains.
RESULTS: Therapy was tolerated well, with toxicity ≥ grade 3 in 2 of 13 (15%) patients. All 12 patients receiving >14 days of therapy had substantial reduction in tumor volume (65% at day 14 and 78% at day 28) and underwent resection. After 14 days of dabrafenib therapy, there was a marked reduction in viable melanoma cells and a CD8 T-cell--rich infiltrate. Proliferation of the residual melanoma cells was reduced and apoptosis was increased. The cells continued to express phosphorylated ERK and phosphorylated MEK consistent with incomplete mitogen-activated protein kinase pathway inhibition.
CONCLUSIONS: Preoperative targeted therapy of advanced BRAF-mutant melanoma is feasible, well tolerated, induces brisk tumor responses, and facilitates correlative science. A CD8 T-cell-rich infiltrate indicates a potential immune-mediated mechanism of action. Both proliferation and apoptosis were inhibited, but the mitogen-activated protein kinase pathway remained activated, suggesting intrinsic resistance in a subset of tumor cells. Additional investigation of the anti-tumor immune response during targeted therapy and the mechanisms of intrinsic resistance can yield novel therapeutic strategies.

Finger EC, Castellini L, Rankin EB, et al.
Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells.
Proc Natl Acad Sci U S A. 2015; 112(14):4441-6 [PubMed] Article available free on PMC after 07/10/2015 Related Publications
Scaffold proteins are critical hubs within cells that have the ability to modulate upstream signaling molecules and their downstream effectors to fine-tune biological responses. Although they can serve as focal points for association of signaling molecules and downstream pathways that regulate tumorigenesis, little is known about how the tumor microenvironment affects the expression and activity of scaffold proteins. This study demonstrates that hypoxia, a common element of solid tumors harboring low oxygen levels, regulates expression of a specific variant of the scaffold protein AKAP12 (A-kinase anchor protein 12), AKAP12v2, in metastatic melanoma. In turn, through a kinome-wide phosphoproteomic and MS study, we demonstrate that this scaffolding protein regulates a shift in protein kinase A (PKA)-mediated phosphorylation events under hypoxia, causing alterations in tumor cell invasion and migration in vitro, as well as metastasis in an in vivo orthotopic model of melanoma. Mechanistically, the shift in AKAP12-dependent PKA-mediated phosphorylations under hypoxia is due to changes in AKAP12 localization vs. structural differences between its two variants. Importantly, our work defines a mechanism through which a scaffold protein can be regulated by the tumor microenvironment and further explains how a tumor cell can coordinate many critical signaling pathways that are essential for tumor growth through one individual scaffolding protein.

Geller AC, Swetter SM, Weinstock MA
Focus on early detection to reduce melanoma deaths.
J Invest Dermatol. 2015; 135(4):947-9 [PubMed] Related Publications
Thin fatal melanomas are a relatively new clinical and public health concern, representing an estimated 20% of melanoma deaths. Understanding this phenomenon will require a multi-pronged approach, including in-depth investigation of its behavioral and biological underpinnings. As we proceed with relevant studies, the benefits in lives saved will grow via early detection.

Katiyar SK
Hsp90 inhibitor can inhibit UV carcinogenesis.
J Invest Dermatol. 2015; 135(4):945-7 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Extensive exposure to solar UVR is a well-recognized etiologic factor for cutaneous non-melanoma skin cancer. In this issue of the Journal, Singh et al. show that topical treatment of the skin with 17-[allylamino]-17-demethoxygeldanamycin (17AAG), a heat-shock protein 90 (Hsp90) inhibitor, prevents UVR-induced squamous cell carcinomas (SCCs) in mice. The inhibitory effect of 17AAG on SCC was associated with the inhibition of the UVR-induced (i) hyperplastic response, (ii) Hsp90β-PKCɛ interaction, and (iii) pStat3 and pAkt expression in mouse skin.

Huang HP, Tsai MC, Hong KT, et al.
Outcome of microscopic excision of a subungual glomus tumor: a 12-year evaluation.
Dermatol Surg. 2015; 41(4):487-92 [PubMed] Related Publications
BACKGROUND: Glomus tumors are rare benign neurovascular tumors, up to 75% of which occur in the hand, mainly the subungual area. Local recurrence and nail deformity are commonly seen if tumor excision is not performed completely or properly.
OBJECTIVE: This study was designed to assess the long-term efficacy of microscopic excision of subungual glomus tumors.
MATERIALS AND METHODS: This retrospective analysis reviewed a total of 22 patients diagnosed with glomus tumors who underwent microscopic surgical excision at a single medical center over a 12-year period (2002-2014). Outcomes were analyzed based on symptom relief, recurrence rate, finger function, nail esthetics, and patient satisfaction.
RESULTS: With a mean follow-up period of 48.4 months, neither recurrence nor postexcision nail deformity developed in any patient. Patient satisfaction was rated as "good" in 86.3% of patients (19/22).
CONCLUSION: Microscopic surgical excision enables the surgeon to completely remove a glomus tumor while minimizing damage to the nail unit, thereby resulting in significantly decreased recurrence and nail deformity. In this study, an incision made according to the anatomic location provided an easy approach and the best visualization. Patients' finger function was successfully restored, nail esthetic outcome was good, and patient satisfaction was high.

Porcel Chacón R, del Boz González J, Navarro Morón J
Delayed-onset of multiple cutaneous infantile hemangiomas due to propranolol: a case report.
Pediatrics. 2015; 135(4):e1064-6 [PubMed] Related Publications
Infantile hemangiomas are the most common vascular tumors in childhood. In view of its proven effectiveness in such cases, propranolol is the drug of choice. We present the case of a male infant who started treatment with propranolol shortly after birth due to heart disease. After 7 months, when the patient had suffered various respiratory exacerbations, this treatment was suspended. One week later, multiple skin lesions (ie, multifocal infantile hemangiomas) began to appear, with no extracutaneous involvement. It was decided to resume treatment with propranolol, although at lower doses than before, and the skin lesions improved rapidly, with some disappearing completely. Treatment was definitively withdrawn at age 16 months, with only slight recurrence of the lesions. The case described is of multifocal infantile hemangiomas without extracutaneous involvement appearing beyond the neonatal period after treatment with propranolol beginning in the first days of life. The details of the case support the hypothesis that this drug is not only therapeutic but also plays a prophylactic role against infantile hemangiomas. In turn, this supports the recent proposal that this drug may be useful in preventing the growth and spread of tumors with high angiogenic potential. It is postulated that the inhibition of β-adrenergic receptors is associated with multiple intracellular processes related to the progression and metastasis of different tumors.

Burke MT, Morais C, Oliver KA, et al.
Expression of Bcl-xL and Mcl-1 in the nonmelanoma skin cancers of renal transplant recipients.
Am J Clin Pathol. 2015; 143(4):514-26 [PubMed] Related Publications
OBJECTIVES: This study aims to investigate how immunosuppression influences the protein expression of antiapoptotic members of the Bcl-2 family-namely, Bcl-xL and Mcl-1-in nonmelanoma skin cancer (NMSC) and the peritumoral epidermis of renal transplant recipients.
METHODS: NMSC and peritumoral epidermis protein expression of Bcl-xL and Mcl-1 were assessed by immunohistochemistry in renal transplant recipients receiving tacrolimus or sirolimus and the general population not receiving immunosuppression.
RESULTS: NMSC from renal transplant recipients compared with patients not receiving immunosuppressant medications had a reduced Bcl-xL expression intensity (P = .042). Mcl-1 expression intensity in NMSC was decreased in tacrolimus-treated patients compared with sirolimus-treated patients and the nonimmunosuppressed population (P = .024). Bcl-xL expression intensity was increased in peritumoral epidermis compared with NMSC (P = .002).
CONCLUSIONS: It was shown for the first time that Bcl-xL and Mcl-1 expression are widespread in the peritumoral epidermis and NMSC of renal transplant recipients. Importantly in NMSC, Bcl-xL expression was reduced with immunosuppression exposure, and Mcl-1 expression was reduced in tacrolimus-treated compared with sirolimus-treated patients.

Karamanou M, Stratigos AJ, Saridaki Z, et al.
René-Théophile-Hyacinthe Laennec (1781-1826) and the description of metastatic pulmonary melanoma.
J BUON. 2015 Jan-Feb; 20(1):354-6 [PubMed] Related Publications
In 19th century, the anatomo-clinical school of Paris linked clinical signs with anatomical lesions establishing clinical medicine. One of the most enlightened promoters of this method was the French physician René-Théophile-Hyacinthe Laennec, known as the inventor of stethoscope. In our article, we reveal his work on pulmonary melanoma.

Lee YH, Gyu Song G
Vitamin D receptor FokI, BsmI, TaqI, ApaI, and EcoRV polymorphisms and susceptibility to melanoma: a meta-analysis.
J BUON. 2015 Jan-Feb; 20(1):235-43 [PubMed] Related Publications
PURPOSE: The purpose of this study was to examine whether vitamin D receptor (lVDR) polymorphisms are associated with susceptibility to melanoma.
METHODS: A meta-analysis was carried out to investigate the association between the VDR FokI, BsmI, TaqI, ApaI, and EcoRV polymorphisms and susceptibility to melanoma.
RESULTS: A total of 11 studies were evaluated, which included 4,413 patients and 4,072 controls (all European). The meta-analysis revealed no association between melanoma and the BsmI B allele (odds ratio/OR=0.901, 95% confidence interval/CI=0.783-1.036, p=0.144). However, an association was shown between melanoma and the Bb+bb genotype (OR=0.868, 95% CI=0.767-0.982, p=0.025). No association was noticed between melanoma and FokI polymorphism (OR for the F allele=1.016, 95% CI=0.869-1.189, p=0.839). Moreover, melanoma risk was not associated with the TaqI, ApaI, and EcoRV polymorphisms (OR for the T allele=0.986, 95% CI=0.842-1.156, p=0.864; OR for the A allele=0.949, 95% CI=0.842-1.069, p=0.388; OR for the E allele=0.993, 95% CI=0.875-1.126, p=0.911, respectively).
CONCLUSIONS: This meta-analysis demonstrated that the VDR BsmI polymorphism is associated with susceptibility to melanoma in Europeans, suggesting that carrying the VDR BsmI B allele may be a protective factor against melanoma development.

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